AU2012247053B2 - Anti-viral compounds - Google Patents

Abstract

Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") are described This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

Description

S&F Ref: 990100D2 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Abbott Laboratories, of 100 Abbott Park Road, D-377 of Applicant: AP6A-1, Abbott Park, Illinois, 60064, United States of America Actual Inventor(s): David A. Degoey Warren M. Kati Charles W. Hutchins Pamela L. Donner Allan C. Krueger John T. Randolph Christopher E. Motter Lissa T. Nelson Sachin V. Patel Mark A. Matulenko Ryan G. Keddy Tammie K. Jinkerson Douglas K. Hutchinson Charles A. Flentge Rolf Wagner Clarence J. Maring Michael D. Tufano David A. Betebenner Todd W. Rockway Dachun Liu John K. Pratt Kathy Sarris Kevin R. Woller Seble H. Wagaw Jean C. Califano Wenke Li Daniel D. Caspi Mary E. Bellizzi Yi Gao 5845c(6855393_1) Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Anti-viral compounds The following statement is a full description of this invention, including the best method of performing it known to me/us: 5RP~RV _q na ?PP iCzr C' 1N R ~PrcP-i I5zrfl 1 ANTI-VIRAL COMPOUNDS The present application claims the benefit from and incorporates by reference the entire content of U.S Provisional Application Serial No. 611186,291, filed June 11,2009, U.S. Provisional Application Serial No. 611242,836, filed September 16,2009, and 5 U.S. Provisional Application Serial No. 61/243,596, filed September 18, 2009. FIELD The present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV"). The present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection. 10 BACKGROUND HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome encoding alllaown virus-specific proteins in a single, uninterrpted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large 15 polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon 20 alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection. SUMMARY A first aspect of the invention provides a compound of Formula IB, or a 25 pharmaceutically acceptable salt thereof, D R La3R R12

R

5 2 N

A-L-X-L

2 -B /NT-R' RR-T

IB

la wherein: X is , wherein X 3 is N and is directly linked to -L 3 -D;

L

1 , L 2 and L 3 are bond; N A is H and is unsubstituted or is substituted with one or more 5 halogen; N B is H and is unsubstituted or is substituted with one or more halogen; J RN RN RN RN D is ,and each RN is independently selected from hydrogen or halogen, and J is C 3

-C

6 carbocycle or 3- to 6-membered heterocycle and is unsubstituted 10 or substituted with another C 3

-C

6 carbocycle or 3- to 6-membered heterocycle which is unsubstituted or substituted with one or more halogen; Rc' is hydrogen;

R

2 and R 5 , taken together with the atoms to which they are attached, form ; and 15 R 9 and R 1 2 , taken together with the atoms to which they are attached, form -T-RD' is each independently-C(O)-Ly'-N(RB)C(O)O-RD', and wherein Ly' is each independently C 1

-C

6 alkylene which is unsubstituted or substituted with -0-C 1 C 6 alkyl; 20 RD' is each independently C1-C 6 alkyl; RB is hydrogen. A second aspect of the invention provides a pharmaceutical composition comprising the compound of the first aspect of the invention or a pharmaceutically acceptable salt thereof.

lb A third aspect of the invention provides a pharmaceutical composition comprising (1) dimethyl (2S,2'S)- 1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- 1-(4-tert butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3 -methyl-1 H3" Hf1~ H N N -- N O -oN os., N - - ,O 0 Na 5 oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV protease inhibitor. A fourth aspect of the invention provides a pharmaceutical composition comprising (1) dimethyl (2S,2'S)- 1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- 1-(4-tert butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 10 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3 -methyl-1 H3, H H N N -oo o 0 ,O 00 0 a oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV polymerase inhibitor. A fifth aspect of the invention provides a pharmaceutical composition comprising (1) a pharmaceutically acceptable salt of dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2' 15 (4,4'-((2S,5S)- 1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3 -methyl-1 Hl H H N N -oo o oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV protease inhibitor. A sixth aspect of the invention provides a pharmaceutical composition 20 comprising (1) a pharmaceutically acceptable salt of dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2' (4,4'-((2S,5S)- 1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3 -methyl-1 H3, H H N N -oo os 0 ,O 00 0 a oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV polymerase inhibitor.

lc The present invention features compounds of Formulae I, IA, IB, Ic and ID, and pharmaceutically acceptable salts thereof. These compounds and salts can inhibit the replication of HCV and therefore are useful for treating HCV infection. The present invention also features compositions comprising the compounds or 5 salts of the present invention. The compositions can also include additional therapeutic agents, such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors. The present invention further features methods of using the compounds or salts 10 of the present invention to inhibit HCV replication. The methods comprise contacting cells infected with HCV virus with a compound or salt of the present invention, thereby inhibiting the replication of HCV virus in the cells. In addition, the present invention features methods of using the compounds or salts of the present invention, or compositions comprising the same, to treat HCV infection. The methods 5 comprise administering a compound or salt of the present invention, or a pharmaceutical composition comprising the same, to a patient in need thereof, thereby reducing the blood or tissue level of HCV virus in the patient. 'lie present invention also features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection. 10 Furthermore, the present invention features processes of making the compounds or salts of the invention. Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating preferred embodiments of the invention, are given by way of illustration only, not 15 limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION The present invention features compounds having Formula I, and pharmaceutically acceptable 20 salts thereof, D

L

3

Y-A-L

1

-X-L

2 -B-Z wherein: X is C 3 -Cl 2 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with 25 one or more RA; L, and L 2 are each independently selected from bond; or Ci-Calkylcne, C 2

-C

6 alkcnylene or

C

2

-C

6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL;

L

3 is bond or -Ls-K-Ls'-, wherein K is selected front bond, -0-, -S-, -N(RB)-, -C(O)-, 30 S(0)2-, -S(O)-, -OS(O)-, -OS(O)2-, -S(0)20-, -S(0)0-, -C(O)O-, -OC(O)-, OC(0)0-, -C(O)N(R,)-, -N(R,)C(0)-, -N(R,)C(O)O)-, -OC(O)N(R,)-, -N(Rjj)S(O)-, -N(RH)S(C)2-, -S(O)N(RH)-, -S(O) 2 N(Rs)-, -C(O)N(R i)C(O)-, -N(RH)C(O)N(Rs')-, N(RB)SO 2 N(RB')-, or -N(RB)S(O)N(RB')-; 2 A and B are each independently C 3

-C

12 carbocycle or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more RA; D is CrC 12 carbocycle or 3- to 12-iembered heterocycle, and is optionally substituted with one or more RA; or D is hydrogen or RA; 5 Y is selected from -T'-C(RR 2 )N(Rs)-T-RD, -T'-C(R 3

R)C(R

6

R

7 )-T-RD, -LK-T-RD. or LK-E; Ri and R 2 are each independently Re, and R 5 is RH; or R, is Re, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA; 10 R 3 , R 4 , R 6 , and R 7 are cach independendy Rc; or R 3 and R 6 are each independcntly Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 3- to 12 membered carbocycle or heterocycle which is optionally substituted with one or more RA; Z is selected from -T'-C(RsR 9 )N(R 12 )-T-RD, -T'-C(R ioR)C(R 3 R])-T-RD, -LK-T-RD. or -LK-E; 15 R 8 and R 9 are each independently Rc, and R 2 is RB; or R 8 is Rc, and R 9 and Ra 2 , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA; Rio, Rij, R 13 , and R 1 4 are each independently Rc; or Rio and R 13 are each independently Rc, and R 11 and R 14 , taken together with the atoms to which they are attached, form a 3- to 20 12-memnbered carbocycle or heterocycle which is optionally substituted with one or more RA; T and T' are each independently selected at each occurrence from bond, -Ls-, -Ls-M-Ls'-, or -L.-M-Ls'-M'-L 5 "-, wherein M and M' are each independently selected at each occurrence from bond, -0-, -S-, -N(RH)-, -C(O)-, -S(0)2-, -S(O)-, -OS(O)-, 25 OS(O)2-, -S(O)20-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R 8 )-, N(RB)C(O)-, -N(RB)C(O)0-, -OC(O)N(RB)-, -N(RB)S(O)-, -N(R3)S(0) 2 -, S(O)N(RB)-, -S(0)2N(RB)-, -C(O)N(RB)C(O)-, -N(RB)C(O)N(RB')-, N(R3)S0 2 N(RB')-, -N(R3)S(O)N(RB')-, CrCl 2 carbocycle or 3- to 12-membered heterocycle, and wherein said C 3 -Ci 2 carbocycle and 3- to 12-membered heterocycle are 30 each independently optionally substituted at each occurrence with one or more RA; IK is independently selected at each occurrence from bond, -LS-N(RH)C(O)-l..s'- or -Ls C(O)N(R)-Ls'-; or CI-C 6 alkylene, C 2

-C

6 alkenylene or C 2

-C

6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL; or C 3 C 12 carbocycle or 3- to 12-mnembered heterocycle, each of which is independently 35 optionally substituted at each occurrence with one or more RA; 3 F is independently selected at each occurrence from C-Cl 2 carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more RA; RD is each independently selected at each occurrence from hydrogen or RA 5 R, is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-RE, wherein two adjacent RA, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle; RB and RB' are each independently selected at each occurrence from hydrogen; or CI-C' 6 alkyl, 10 C 2 -C(alkenyl or C-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapio, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6 membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-mnembered carbocycle or heterocycle in RB or RB' is independently 15 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formoyl, cyano, C,-Cralkyl, C 2 -Coalkenyl, C 2 -Calkynyl, CI-C6haloalkyl, C 2 C 6 haloalkenyl or C 2

-C

6 haloalkynyl; Rc is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, 20 amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Cr

C

6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formal, cyano or 3- to 6-membered carhocycle or heterocycle; or 3- to 6-membered carbocycle or 25 heterocycle; wherein each 3- to 6-miembered carbocycle or heterocycle in Rc is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl, C-C 6 alkenyl, C 2

-C

6 alkynyl, C

C

6 haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl; 30 RF is independently selected at each occurrence from -O-RS, -S-R, -C(O)R, -OC(O)Rs, C(O)OR,, -N(RRs'), -S(0)R,, -SO 2 R,, -C(O)N(RR,'), -N(R,)C(O)Rs', N(Rs)C(O)N(Rs'Rs"), -N(Rs)S0 2 Rs', -SO 2 N(RsRs'), -N(Rs)SO2N(Rs'Rs"), N(Rs)S(O)N(Rs'Rs"), -OS(O)-Rs, -OS(O) 2 -Rs, -S(O)20Rs, -S(O)ORs, -OC(O)ORs, N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(O)-Rs', -S(O)N(RsRs') or 35 C(O)N(Rs)C(O)-Rs'; or CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents 4 selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C-C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapio, amino, carboxy, 5 nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl, C 2 -COalkenyl,

C

2

-C

6 alkynyl, C 1

-C

6 haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl; RI. is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -S-R, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RsRs'), S(O)Rs, -S0 2 Rs, -C(O)N(RsRs') or -N(Rs)C(O)Rs'; or C 3

-C

6 carbocycle 3- to 6 10 membered heterocycle, each of which is indcpendcnIly optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, niercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl,

C

2

-C

6 alkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C 2 -C6haloalkynyl; wherein two adjacent RI, taken together with the atoms to which they are attached and 15 any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle; 1.,, Ls' and ,s" are each independently selected at each occurrence from hond; or C 1 .

C

6 alkylene, C 2

-C

6 alkenylene or C 2

-C

6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL; and 20 Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; C 1 C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, foryl, cyano or 3- to 6-niembered carbocycle or heterocycle; or 3- to 6-membered carbocycle or 25 heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs , Rs' or Rs' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cl-C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C 1 C 6 haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl. 30 A and B preferably are independently selected from Cs-Cecarbocycle (e.g., phenyl), 5- to 6 membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such as Z W'W Z "W Ww3 , weor 6 , where Zi is independently selected at each occurrence from 0, S, NH or CH- 2 , Z2 is independently selected at each occurrence from N or CH, Z 3 is independently selected at each occurrence from N or CH, Z 4 is 5 independently selected at each occurrence from 0, S, NH or CH 2 , and W 1 , W 2 , WI, W 4 , Wj and W 6 are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more RA. More preferably, A is selected from Cs-C 6 carbocycle, 5- to 6-membered heterocycle, 5 z or *, and is optionally substituted with one or more RA; B is wz selected from C 5

-C

6 carbocycle, 5- to 6-membered heterocycle, w 3 or W, ' , and is optionally substituted with one or more RA; where ZI, Z 2 , Z 3 , Z 4 , W 1 , W 2 ,

W

3 , W 4 , WS, W 6 are as defined above. Preferably, Z 3 is N and Z4 is NI-I. For instance, A can be selected from phenyl (e.g., pyridinyl (e.g., - ), thiazolyl (e.g., H 2 N 10 s (e.g., ), or (e.g., /7 N N NN H or H ), and is optionally substituted with one or more RA; and B can be selected from phenyl (e.g., pyridinyl (e.g., ), thiazolyl (e.g., ), N ( N 1S rfeaN bgN or Aa Baepn (e.g., NN N4r N H or H ),and is optionally substituted with one or more RA. H-ighly 15 preferably, both A and B are phenyl (e.g., both A and B are /_ Also highly preferably, A Is and 1 is N orAis N an d is or Ais H H N. N N N nd Bis 7 N ;or A s Na ad13 is - or A 6 N is and B is N wherein each A and B is independently optionally substituted with one or more RA. D preferably is selected from C 5

-C

6 carbocycle, 5- to 6-mcmbered heterocycle, or 6- to 12 membered bicycles, and is optionally substituted with one or more RA. D can also be preferably 5 selected from Cl-C 6 alkyl, C 2

-C

6 alkenyl or C-C 6 alkynyi, and is optionally substituted with one or more substituents selected from RL. More preferably, D is C 5

-C

6 carbocycle (e.g., phenyl), 5- to 6 membered heterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to 12-membered bicycles (e.g., indanyl, 4,5,6,7-tetrahydrobenzo[dJthiazolyl, henzoldjthiazolyl, indazolyl, benzo[d][,3Jdioxol-5-yl), and is substituted with one or more Rm, where Rm is halogen, nitro, oxo, phosphonoxy, phosphono, 10 ihioxo, cyano, or -Ls-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more RM, wherein Rm is as defined RM R, RN RN RN RN above. Highly preferably, D is or , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. 15 D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or RM RM RN N N 'N RN RN RN -RN more RM. Highly preferably, ) is -^^~ , , or , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7 20 tetrahydrobenzo[dtlhiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d]I 1,3]dioxol-5-yl, and is substituted with one or more Rm. Highly preferably, D Q S N- -0 H 0 N S N, S isr~ , ~~ , , , , or ~ and is optionally substituted with one or more Rm. 7 Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1 -Cealkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, fornyl or 5 cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

1 alkyl, C 2 -Calkenyl, C 2

-C

1 alkynyl, C 1

-C

6 1haloalkyl, C 2 -Cohaloalkenyl or C 2 -C(haloalkynyl. More preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C 2 10 C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapio, amino or carboxy. Highly preferably, Rm is

CI-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Also preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 15 phosphono, thioxo, or cyano; or RM is -Ls-RE, wherein Ls is a bond or C 1

-C

6 alkylene, and RE is N(RR.'), -0-Rs, -C(O)Rs, -C(O)OR, -C(O)N(RRs'), -N(Rs)C(O)Rs'. -N(Rs)C(0)ORs', N(Rs)SO 2 Rs', -SO 2 Rs, -SRs, or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) C-C 6 alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -0-C-C 6 alkyl or 3- to 6-meinbered 20 heterocycle; or Rm is CI-C 6 alkyl, C-C 6 alkenyl or C,-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, iercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Rm iS C 3 -Ccarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, 25 mercapio, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cl-C 6 alkyl,

C

2

-C

6 alkenyl, C 2

-C

6 alkynyl, Cl-C 6 haloalkyl, C 2

-C

6 haloalkenyl, C 2

-C

6 ialoalkynyl, -C(O)ORs, or N(RsRs'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or C 1

-C

6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents 30 selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example Rm is CF 3 , C(CF 3 )r-OH, -C(CH 3

)

2 --CN, -C(CH 3

)

2

-CH

2 OH, or -C(CH 3

)

2

-CH

2 NH2. Also preferably Rm is -Ls RE where L.s is a bond and RE is -N(RsRs.), -0-Rs, -N(Rs)C(O)ORs', -N(Rs)SO 2 Rs', -S0 2 RS, or SRs. For example where Ls is a bond, RE is -N(CI-C 6 alkyl) 2 (e.g., -NMc 2 ); -N(C 1

-C

6 alkylenc- i-C 1 C 6 alkyl) 2 (e.g. -N(CIH1 2 CH20Me)2); -N(C -C 6 Lalkyl)(C-C 6 alkylene-0-C-C 6 alkyl) (e.g. 35 N(CI1 3

)(CI

2 CHI20Me));--OCl-C 6 alkyl (e.g., -O-Me, -0-Et, -0-isopropyl, -0-tert-butyl, -0-n hexyl); -0-C-C 6 haloalkyl (e.g., - OCF 3 , -OCII 2

CF

3 ); -0-C-C 6 alkylene-piperidine (e.g., -0 8

CH

2 C-l 2 -I-piperidyl); -N(C -Ctalkyl)C(0)OC-C 6 alkyl (e.g., -N(CH 3 )C(O)O-CHlI 2

CH(CH

3 )2), N(CI-Calkyl)SO 2 CI-Ctalkyl (e.g., -N(CH 3

)SO

2

CH

3 ); -SO 2 C -C 6 alkyl (e.g., -SO 2 Me); -SO 2 C,

C

6 haloalkyl (e.g., -SO 2

CF

3 ); or -S-Cl-Chaloalkyl (e.g., SCF 3 ). Also preferably Rm is -Ls-RE where Ls is Ci-C 6 alkylene (e.g., -CH 2 -, -C(CH 3 )2, -C(CH 3

)

2

-CH

2 -) and RE is -O-Rs, -C(O)ORs, 5 N(Rs)C(O)ORs', or -P(O)(ORs) 2 . For example Rm is -- Ci-C 6 alkylene-O-Rs (e.g., -C(CH 3

)

2

-CH

2 OMe); -C -C 6 alkylene-C(O)ORs (e.g., -C(Cl3),-C(0)OMe); -Cj-C 6 alkylene-N(Rs)C(O)ORs' (e.g., -C(CH3) 2

-CH

2 -NHC(O)OCHI); or -C-Ccalkylene-P(O)(ORs)2 (e.g., -CH 2 -P(O)(OEt2). Also more preferably Rm is C 3 -C(,carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 10 hydroxy, niercapto, anino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci

C

6 alkyl, C,-C 6 alkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2 -Cdhaloalkenyl, C 2 -Cjhaloalkynyl, C(O)ORs, or -N(RsRs'). For example Rm is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-I methylcycloprop- I -yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-nethoxycarbonylpiperazin-1-yl, pyrrolidin-l 15 yl, piperidin-l-yl, 4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-I-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(diimethylamino)pyridiin-3-yl). Highly preferably, Rm is C 1

-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ). X preferably is CS-C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered 20 bicycles, and is optionally substituted with one or more RA. X can also be C 5

-C

6 carbocycle or 5- to 6 membered heterocycle which is optionally substituted with one or more RA, wherein two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6 <x membered carbocycle or heterocycle. Also preferably, X is X , wherein X 3 is C(H) or preferably N and is directly appended to -1 3 -D; X 4 is C-C 4 alkylene, C-C 4 alkenylene or C 2 25 C 4 alkynylene, each of which optionally contains one or two heteroatoms selected from 0, S or N; and X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are attached, can optionally form a 5- to 6-membered carbocycle or x x heterocycle. In addition, X can be 4 or X , wherein X 3 is C and is directly linked to -L 3 -D, X 4 is C 2

-C

4 alkylene, C 2

-C

4 alkenylene or Cr-C 4 alkynylene each of which 30 optionally contains one or two heteroatoms selected from 0, S or N, and X is optionally substituted 9 with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. X3 X 3 3 For instance, X can he XcX 1 , X 2

=X

2

X--X

2 , X2-X X XX X3X XcX, XX2, XX 2 X2=X 2 or XI-X , wherein X, is 5 independently selected at each occurrence from ClH 2 , 0, S or NiH, X 2 is independently selected at each occurrence from CH or N, X 3 is N and is directly linked to -L 3 -D, and X 3 ' is C and is directly linked to -L 3 -D; and X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered XAX X X" X, X1 ePX2 X, ,1 X2 carbocycle or heterocycle. For another example, X is X , 2 , X X X 3X3 X3 X X3 X"' ,X 2 XZ, IA2 X, I~X' X"' IX 2 X IX 2 XNI I.,X, 10 ~X2 X1 ix X2 X2y X 101 XJI X X 13 ^2 12 Xj" IX1 lXI2 X, ' X, 2 , , 2 or 2 , wherein X, is independently selected at each occurrence from CH 2 , 0, S or NH, X 2 is independently selected at each occurrence from CH or N, X 3 is N and is directly linked to -L.-D, and X.' is C and is directly linked to -3-); and wherein X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the 15 ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. X3 X- X3 Highly preferably, X is , or , wherein X 3 is C(H) or N and is directly linked to -1.3-D, X 3 ' is C and is directly linked to -L 3 -D, and wherein X is optionally substituted with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. 20 More preferably, X 3 is N. Non-limiting examples of X include: 10 , "N 4-N 4, 4, , -_N NH N-NH N N-N HN-NH 0 sHN-NH HN NH 0 NH S N N- N-NH N-0 \N INK5.A 1N N N N A N HN~~~ NN N~S \/ H NN 'I NA j N 0 N NHN NN 0 K Ks N : NJI H *'kN wherein "-*" indicates the covalent attachment to -1 3 -D. Each X can be optionally substituted with one or more RA, and two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. Non-limiting examples of preferred X include the following pyrrolidine rings, each of which 5 is optionally substituted with one or more RA: tO N N I / N N 0 0~0 0\ 0 O 'O- 0 O As shown, the relative stereochemistry at the 2- and 5-positions of the above pyrrolidine ring may be either cis or trans. The stereochemnistries of optional substituents RA at the 3- or 4-positions of the pyrrolidine may vary relative to any substituent at any other position on the pyrrolidine ring. 10 Depending on the particular substituents attached to the pyrrolidine, the stereochemistry at any carbon may be either (R) or (S). Non-limiting examples of preferred X also include the following pyrrole, triazole or thiomnorpholine rings, each of which is optionally substituted with one or more RA: N// N N N " / "/ " /N-N Br Br Br Br S"o, S S)" 15 O As shown, the relative stercochemistry at the 3- and 5-positions of the thiomorpholine ring may be either cis or trans. Depending on the particular substituents attached to the thiomorpholine, the stereochemistry at any carbon may be either (R) or (S). L, and L 2 are preferably independently bond or CI-C 6 alkylene, L 3 is preferably selected from 20 bond, C-C 6 alkylene or -C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RL. More preferably, LI, L, and L 3 are each independently bond or C 1

-C

6 alkylene (e.g., 12

CH

2 - or -CH 2 CH1 2 -), and are each independently optionally substituted with one or more R 1 . Highly preferably, L,, L2 and L., are bond. Y is preferably selected from -Ls-C(RIR 2 )N(Rs)-T-RD, -Ls-C(R 3

R

4

)C(R

6 R,)-T-RD, -G C(R, R 2

)N(R)-T-R

0

-G-C(R

3 R4)C(R 6 R7)-T-RD, -N(RB)C(O)C(R IR 2 )N(Rs)-T-RD, 5 N(R3)C(O)C(R3R 4

)C(R

6 R,)-T-RD, -C(O)N(R,)C(RR,)N(Rs)-T-R 0

-C(O)N(R,)C(R

3

R

4

)C(RR

7

)

T-Ro, -N(RO)C(O)-Ls-E, or -C(O)N(R,)-Ls-E. G is C 5

-C

6 carbocycle or 5- to 6-membered H H i--, N HN'N HN heterocycle, such as N , N', or and is optionally substituted with one or more RA (e.g., one or more chloro or bromo). F preferably is a 7- to 12

V

N O membered bicycle (such as Z 20 - U , wherein UJ is independently selected at each occurrence from 10 -(CH 2 )- or -(NH)-; V and Z 2 () are each independently selected from C-C 4 alkylene, C 2

-C

4 alkenylene or

C

2

-C

4 alkynylene, in which at least one carbon atom can be independently optionally replaced with 0, S or N), and is optionally substituted with one or more RA. More preferably, R, is Rc, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6 to 12-membered bicycle (e.g., or ; or H N S 15 ~ or j , or which is optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C 1 -Coalkyl (e.g., methyl), or C 2 -Calkenyt (e.g., allyl)); and R3 and R6 are each independently Rc, and R 4 and R7, taken together with the atoms to which they are attached, fonn a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., or ) which is 20 optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C

C

6 alkyl (e.g., methyl), or C 2

-C

6 alkenyl (e.g., allyl)). Y can also be selected from -M-C(RR 2 )N(R)-C(O)-Ly'-M'-RD, -M-C(RIR 2

)N(R

5 )-Ly'

M'-R

0 , -Ls-C(RIR 2 )N(Rs)-C(O)-Ly'-M'-RD, -LS--C(RIR 2 )N(R)-Ly'-M'-RD, -M 13 C(R3R4)C(R6R7)-(0)-Ly'"-M'-Rl), -M-C(R3R'4)C(RfR-I)-Ly'N-M'-R,,, -L-s--C(R.IR4)C(R6R7)-C(0) Ly'-M'-R 0 , or -L 5

-C(R

3

R

4

)C(R

6

R

7 )-L.y'-M'-R,, wherein M preferably is bond, -C(O)N(Rj)- or N(R)C(O)-, M' preferably is bond, -C(O)N(RB)-, -N(RB)C(O)-, -N(RB)C(0)O-, N(RB)C(O)N(Ra')-, -N(RB)S(O)- or -N(RB)S(0)2-, and Ly' preferably is Cl-C 6 alkylene which is 5 optionally substituted with one or more RL. Ly', for example, is a C-C 6 alkylene such as, but not limited to, , , , or ; and the optional RL is a substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group Ly' can be either (R) or (S). More preferably, R, is Rc, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12 1N mN 0 memnbered bicycle (e.g., or ) which is optionally substituted with one or more RA (e.g., one or more hydroxy); and R 3 and R( are each independently Rc, and R 4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more RA. 15 Also preferably, Y is selected front -N(RB)CO-C(RIR2)N(Rs)-C(O)-Ly'-N(RB)C(O)O-RD, N(Rs3)CO-C(RR2)N(Rs)-C(O)-Ly'-N(Rs3)C(0)-RD, -N(R,3)CO-C(R IR2)N(R5)-C(O)-Ly' N(RB)S(0)2-RD, -N(RB)CO-C(R R 2 )N(R,)-C(O)-Ly'-N(RR,')-RD, -N(RB)CO-C(RIR 2 )N(Rs) C(O)-Ly'-O-RD, -N(R,)CO-C(RR2)N(Rs)-C(O)-Ly'-RD, -N(Rs3)CO-C(RIR2)N(Rs)-RD, ~~LS~ C(RiR 2

)N(R

5 )-C(O)-Ly'-N(RB)C(O)O-RD, -Ls-C(RiR 2 )N(R)-C(O)-Ly'-N(RB)C(O)-RD, -LS 20 C(R R2)N(R,)-C(O)-Ly'-N(R,)S(O) 2 -R), -L,-C(R R2)N(Rs)-C(O)-Ly'-N(RR,')-R,,, -Ls C(RI R 2 )N(Rs)-C(O)-L..y'-O-R,), -L.,-C(RIR 2

)N(R

9 )-C(O)-l.,y'-R), -Ls-C(RR 2 )N(Rs)-RI), N(R 5

)CO-C(R

3

R

4

)C(R

6

R

7 )-C()-Ly'-N(Rs)C(O)O-RD, -N(RB)CO-C(R 3

R

4

)C(R

6

R

7 )-C(O)-Ly' N(RB)C(0)-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(0)-Ly'-N(RB)S(O)2-Ro, -N(RB)CO

C(R

3 R4)C(R 6

R

7 )-C(O)-Ly'-N(RRB' )-RD, -N(RB)CO-C(R 3 R4)C(RR 7 )-C(O)-Ly'-O-RD, 25 N(RB)CO-C(R 3

R

4

)C(R

6

R

7 )-C(O)-Ly'-RD, -N(R,)CO-C(R 3

R

4

)C(R

6

R

7 )-RD, -Ls-C(R 3

R

4

)C(R

6

R

7

)

C(O)-Ly'-N(Rs)C(O)O-RD, -Ls-C(R 3

R

4

)C(R

6

R

7 )-C(O)-Ly'-N(RB)C(O)-RD, -LS~

C(R

3

R)C(R(,R

7 )-C(O)-Ly'-N(Rd)S(O)2-R,), -L,-C(R 3

R

4

)C(R(,R

7 )-C(O)-Ly'-N(RR')-R), -Ls C(R R 4

)C(R(,R

7 )-C(O)-Ly'-O-R), -Ls-C(R3R 4 )C(RsR 7 )-C(O)-Ly'-R), or -Ls-C(RIR 4

)C(R

6

R

7

)

RD, wherein Ly' preferably is Ci-C 6 alkylene which is optionally substituted with one or more RL. R, 14 may be R,, and R 2 and Rs, taken together with the atoms to which they are attached, may form a 5- to Nq_ 6-membered heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more RA; and R 3 and R6 may be each independently Rc, and R., and

R

7 , taken together with the atoms to which they are attached, may Form a 5- to 6-membered 5 carhocycle/hetcrocyclc or 6- to 12-membcred bicycle (e.g., or) which is optionally substituted with one or more RA. Highly preferably, Y is selected from -N(RB")CO-C(RIR2)N(Rs)-C(O)-Ly-N(RB")C(0) Ls-RE or -C(RIR 2 )N(Rs)-C(O)-Ly-N(RB")C(O)-Ls-RE, or Y is -G-C(RR 2

)N(R

5 )-C(O)-Ly N(RB")C(O)-Ls-RE, wherein Ly is CI-C 6 alkylene optionally substituted with one or more RL, and 10 RB" is each independently RB. RB" and R, are each preferably hydrogen or C-C 6 alkyl, and R 2 and

R

5 , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered _N_ heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C 1 -Csalkyl (e.g., methyl), or C 2

-C

6 alkenyl (e.g., allyl)). Preferably, Ly is CI-C 6 alkylene substituted with one or 15 more RI, such as a C1-Crcarbocycle 3- to 6-membered heterocycle which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C-C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, Cj

C

6 haloalkyl, C 2 -Chaloalkenyl or C 2 -Cjhaloalkynyl. Highly preferably, Ly is a CI-C 6 alkylene such as, but not limited to, , , , , or (stereochenistry at a 20 carbon within the group Ly can be either (R) or (S)), Ly is optionally substituted with one or more RL H N (e.g., one or more phenyl or methoxy), G preferably is N , RB" is hydrogen; -C(RiR 2

)N(R

5

)

is ;Ls is a bond; and RE is metoXy. 15 N N'CN | HN I HN Non-limiting examples of preferred Y include: RE T H N Br N N N N N I HN HN | HN R -- T R __T R -T R 0 _T HO HO ,H C O NO CN__O C O C O I HN- I HN .j I HN-.. I HN-.... HN.j RD -_T RD-'--T RD - RD---T RD OO FF O F O O. NN N N I HNsj HN-1 I HN.. I HN-..j | HN.j RD'-D R -T R T R T O O O H 4 I HNj I HN- I HN- HN HN 5 RD.--T RD---T R- ,T RD---T or RD wherein T and RD are as defined herein. T, for example, can be -Ls-M-Ls'-M'-Ls"- where Ls is a bond; M is C(O); Ls' is Cj-Ctalkylene such as, but not limited to, or , where Ls' is optionally substituted with one or more RL; RL is a substitueni such as, but not limited to phenyl or methoxy; M' is -NI-IC(O)- or -NMeC(O)-; and Ls" is a bond. 10 Any stereochemistry at a carbon within the group Ls' can be either (R) or (S). RD, for example is H H O N 0 O N 00 methoxy. T-Ro includes, but is not limited to: O ~ H H 1 1 N N 10Y N 0 H H N O 0 N o 'O N N SMe O , or O 16 T-R) may also include certain stereochemical configurations; thus T-RI) includes, but is not limited H H H H O N O OO N N ON 0 0 H0H0 t O H H SMe to: H O N O and O H Non-limting examples of preferred Y also include: OHN O N O N HN 7 0 0 H O N N H N HN O H HN H H H HN O N_ O N O O HN OH O j H OH H 0 ,or Z is preferably selected from -Ls-C(Rs)N(R 1 2 )-T-RD, -- LS-C(R 0

R

11

)C(R

1 3

R

14 )-T-RD, 10 G-C( R 8

R

9 )N(R )-T-RD, - -(R1 0 R ) 1 4 )-- , -N(R 8

)C()C(RR

9 )N(R0)-T-RD,

N(R

1 )C(O)C(RioR )C(R oRj 4 )-T1-Ro), -. C(O)N(RiI)C(RxRs))N(Rj 2 )-T-RI), C(0)N(R 1 1 )C(R i i )C(R 1

R

14 )-Tl-R 1 ), -N(R 11 )C(0)-Ls-E, or -.C(O)N(R 8

)-L.

5 -B. G is Cs 17 H H N N NH

C

6 carbocyclc or 5- to 6-mnembered heterocycle, such as N , or HN'N , and is optionally substituted with one or more RA (e.g., one or more chloro or bromo). N o E preferably is a 8- to 12-membered bicycle (such as Z2-U , wherein U is independently selected at each occurrence from -(CH 2 )- or -(NH)-; and V and Z 20 are each independently selected 5 from Ci-C 4 alkylene, C-C 4 alkenylene or C 2

-C

4 alkynylene, in which at least one carbon atom is independently optionally replaced with 0, S or N), and is optionally substituted with one or more RA. More preferably, R, is R:, and R 9 and R 1 2 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., or or ;or N NL . 0 S 10 , , or ) ) which is optionally substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), CI-C 6 alkyl (e.g., methyl), or C 2

-C

6 alkenyl (e.g., allyl)); and Rio and R 13 are each independently Rc, and RI, and R, 4 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12 membered bicycle (e.g., or) which is optionally substituted with one or 15 more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), CI-C 6 alkyl (e.g., methyl), or C 2 C 6 alkenyl (e.g., allyl)). Z can also be selected from -M-C(RsR)N(R )-C(O)-Ly'-M'-RD, -M-C(RsR 9 )N(R,)-Ly' M'-RD, -LS-C(R 8

R

9 )N(R )-C(O)-Ly'-M'-RD, -Ls-(RsR 9

)N(R

2 )--Ly'-M'-RD, -M C(RioRI)C(Rl3R,)-C(O)-Ly,'-M'-RD, -M-C(RioRI)C(Rl3R,4)-Ly'-M'-RD, -LS 20 C(RoR ,)C(Rl 3

RI

4 )-C(O)-Ly'-M'-RD, or -LS-C(RoRI )C(R 13 R 4 )-Ly'-M'-RD, wherein M 18 preferably is bond, -C(O)N(R)- or -N(RH)C(O)-, M' preferably is bond, -C(O)N(R)-, N(R,)C(O)-, -N(RH)C(0)O-, N(k)C(O)N(R,')-, -N(Rs)S(0)- or -N(R 8 )S(0)2-, and Ly' preferably is CI-C(alkylene which is optionally substituted with one or more RL. Ly', for example, is a C 1

-C

6 alkylcne such as, but not limited to, r , , , , or 5 and the optional RL is a substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group Ly' can be either (R) or (S). More preferably, R 8 is Re, and R 9 and R1 2 , taken together with the atoms to which they are attached, form a 5- to 6 N4 membered heterocycle or 6- to 12-ieibered bicycle (e.g., or ' ) which is optionally substituted with one or more RA (e.g., one or more hydroxy); and RIO and RB are each 10 independently Rc, and RII and R 14 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., or which is optionally substituted with one or more RA. Also preferably, Z is selected from -N(RB)CO-C(R 8

R

9 )N(R l)-C(O)-Ly'-N(RB)C(O)O-RD, -N(RB)CO-C(RsR,)N(R 1)-C(O)-Ly'-N(RB)C(0)-RD, -N(Rs)CO-C(RsR9)N(R 1)-C(O)-Ly' 15 N(RH)S(O) 2 -R), -N(RH)CC--C(RsR,))N(R ,)-C(O)-Ly'-N(RRR')-RI), -N(Rs)CO-C(RR,)N(R 2

)

C(O)-Ly'-O-RD, -N(Rs)CO-C(RsR9)N(R, 2 )-C(O)-Ly'-RD, -N(R,)CO-C(RR9)N(R 2 )-RD, -Ls C(RsRq)N(R ,)-C(O)-Ly'-N(RB)C(O)O-RD, -L--C(RsR 5 )N(R )-C(O)-Ly'-N(RB)C(O)-RD, -Ls C(RsR 9

)N(R,

2 )-C(O)-Ly'-N(RB)S(0) 2 -RD, -LS-C(R 8

R

9 )N(R 1 )-C(O)-Ly'-N(RBR')-RD, -LS C(RsRq)N(R 2 )-C()-Ly'-O-RD, -LS-C(R 8

R

9 )N(R )-C()-Ly'-RD, -Ls-C(RsR 9 )N(R,2)-RD, 20 N(RB)CO-C(RioR 1

)C(R,

3

R

4 )-C(O)-Ly'-N(RB)C(O)O-RD, -N(RB)CO-C(RoR,,)C(R 13

R

1

)-C(O)

Ly'-N(RB)C(O)-RD, -N(RB)CO-C(RioR )C(Rl 3 R)-C(O)-Ly'-N(RS)S(0)2-RD, -N(RB)CO C(R IR I)C(R 1R 4 )-C(O)-Ly'-N(RRII')-R), -N(RR)CO-C(R 1 1

R

1

)C(R

3

R

4 )-C(O)-Ly'-O-RI), N(R)CO-C(R 0 oR n)C(R 3 R 4 )-C(O)- .y'-Ro), -N(R)CO-C(R mR n)C(R 3 R )-RI), -Ls C(R oR, )C(R 3 R 1 )-C(O)-Ly'-N(RB)C(O)O-RD, -LS-C( R 1 0 R )C(R 3 R )-C(O)-Ly'-N(RB)C(O) 25 RD, -LS-C(RioRI)C(RlR4)-C(O)-Ly'-N(RB)S(O)2-RD, -LS-C(RioR,)C(RlR)-C(O)-Ly' 19 N(RKjRH')-R), -L.,s-C(RIORI I)C(R 13

R

1 )-C(O)-l.y'-O-RI), --. s-C(R(lRI I)C(R3R 1 4 )-C(O)-L.y'-Rl), or -Ls-C(RiouR)C(RnR1 4 )-RI, wherein Ly' preferably is CI-Coalkylene which is optionally substituted with one or more RL. R 8 may be Rc, and RO and R 12 , taken together with the atoms to which they are attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., N 5 or N ) which is optionally substituted with one or more RA; and Rim and R 1 3 may be each independently R(, and RI, and R 1 4 , taken together with the atoms to which they are attached, may form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., or which is optionally substituted with one or more R,. Highly preferably, Z is selected from -N(R 8

")CO-C(R

8

R

9

)N(RI

2 )-C(O)-Ly-N(R'")C(O) 10 Ls-RE or -C(RSR9)N(R 2 )-C(O)-Ly-N(RB")C(O)-Ls-RE, or Z is -G-C(R 8

R

9

)N(R[

2 )-C(O)-Lr N(RB")C(O)-Ls-RE, wherein Ly is C-Cealkylene optionally substituted with one or more RL, and RB" is each independently RB. RB" and R 8 are each preferably hydrogen or C-C 6 alkyl, and R 9 and

R

12 , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered N N heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally 15 substituted with one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), C-C 6 alkyl (e.g., methyl), or C-C 6 alkenyl (e.g., allyl)). Preferably, Ly is C 1 -Coalkylene substituted with one or more RL such as a C 3

-C

6 carbocycle 3- to 6-membered heterocycle which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, Cr 20 C 6 1laloalkyl, C 2 -Cohaloalkenyl or C 2

-C

6 haloalkynyl. Highly preferably, Ly is a C-C 6 alkylene such as, but not limited to, , , , , or (stereochemistry at a carbon within the group Ly can be either (R) or (S)); Ly is optionally substituted with one or more RL 20 H (e.g., one or more phenyl or ielhoxy); G preferably is N RB" is hydrogen; N

C(R

8

R

9

)N(R[

2 )- is ; Ls is a bond; and RE is methoxy. N C N \ N \ N NH I NH I Non-limiting examples of preferred Z include: R T-- R T-RD H ,~ Br N N N NN N H | | NH | NH I T Ro T- RD 2 T- 'R T Ro OOH OH HO o0".0 o .) 0~ 0~Q 0~7 .- NH I -NH I -H I NH I .N.-NH | 5 T R-- R T T R RD OOO F F 0F 'F ..- H -NH | ...- NH | ..- NH | -N | 0 R 0 0 TCR I NN NNI6 N .- NH | .- NH |-NH I .- NH ...- NH I T RD T-R T T D D wherein T and RD are as defined herein. T, for example, can be -Ls-M-Ls'-M'--Ls"- where L 5 is a bond; M is C(O); Ls' is Cr-Coalkylene such as, but not limited to, ,,2, 10 , or , where Ls' is optionally substituted with one or more RL; the optional RL is a substituent such as, hut not limited to phenyl or methoxy; M' is -NHC(O)- or -NMeC(O)-; and Ls"' is a hond. Any stereochemistry at a carbon within the group L*s' can he either (R) or (S). RD, for 21 H H 1 0 N 0 example is inethoxy. T-RD includes, but is not limited to: 0 HH H .10 N 0 .0 yN _O 1-1 y 0 H H 0O OON N/0 NNO 0 0 0 11 0 0I 10 .0 y SMe 0 , or O T-RD may also include certain stereochemical configurations; thus 'T-RD includes, but is not limited H to: HO H A SMe H N O' H H H NH H 0 N O Non-limiting examples of preferred Z also include: 0 N N N" ' NH HNH HYNH H 0 H 5 NH H OjN N O 0 N 2 0 0 N [*1H0 y . H H0 T N22 . N NH H .- NH H S ON OH N O1 H 0 0 H , H H OH 0 H H .--NH H N O N O1 --NHN O HiI N 0 N 00 or T can be, without limitation, independently selected at each occurrence from -C(O)-Ls'-, C(0)O-Ls'-, -C(O)-Ls'-N(RB)C(O)-Ls"-, -C(O)-Ls'-N(RB)C(O)O-Ls"-, -N(RB)C(O)-Ls' 5 N(RB)C(O)-Ls"-, -N(RB)C(O)-Ls'-N(R)C(O)O-Ls"-, or -N(RB)C()-Ls'-N(RB)-Ls"-. Preferably, T is independently selected at each occurrence from -C(O)-Ls'-M'-Ls"- or N(R)C()-Ls'-M'-Ls"-. More preferably, T is independently selected at each occurrence from C(O)-Ls'-N(Rs)C(O)-Ls"- or -C(O)-Ls'-N(RB)C(O)O-Ls"-. T can also be, for example, -Ls-M-Ls'-M'-Ls"- where Ls is a bond; M is C(O); Ls' is C 10 C 6 alkylene (e.g., ), where Ls' is optionally substituted with RT; the optional RT is a substituent selected from -C,-C 6 alkyl, -C 2

-C

6 alkenyl, -C-COalkyl-Ol, -C,-C 6 alkyl-O-C,-C 6 alkyl, 3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C 3

-C

6 carbocyclyl (e.g., phenyl, cyclohexyl); M' is -NHC(O)-, -N(Et)C(O)- or -N(Me)C(O)-; and Ls" is a bond. RD preferably is hydrogen, -Cl-C 6 alkyl (e.g., methyl), -O-Cl-Coalkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or 15 -N(C-Coalkyl) 2 (e.g., -NMe 2 ). H H H N 0 N O O N O 0 T-RD can be, without limitation, O O H H H H H O N O O N 0 70 N O O N O O N O O 0 0 0 0 H H H O O N O O N O 0 H 0 No Y 0 Y 0 HO~ 0 O O O O N 0~ OH 23 H~r N II 0 0O '-O N 10' 0 0N H ~ O N H 0 H O OH OH 0 O H "Ol N 0N O O 0 -1 0 ,or , wherein the stereochemistry at a carbon within the group T RD can be either (R) or (S). T can also be, without limitation, -L.-M-L.'- where Ls is a bond; M is C(O); Ls' is C 1 5 C 6 alkylene (e.g., where Ls' is optionally substituted with RT; the optional RT is a substituent selected from -C-Csalkyl, -C--C 6 alkyl-OH, -C-C 6 alkyl-O-Cj-C 6 alkyl, or a Cr

C

6 carbocyclyl (e.g., phenyl, cyclohexyl). RD, for example is -OH; -OC(O)Me; -NH(C-C 6 alkyl) (e.g., -NI-IMe, -NlEt); -N(C-C 6 alkyl) 2 (e.g., -NMe 2 , -NEt 2 ); a 3- to 10-inembered heterocyclyl (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl) optionally 10 substituted with one or more halogen, oxo; C-Cocarbocycle (e.g., cyclopentyl) optionally substituted with -OH; -C 1

-C

6 alkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -01-; or NHRT where R is a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrinidinyl). T-RD includes, but is not limited to: N N H 0 HN N O N O O 0 F N' HN N 04 N 0 N N F S^OH NN U ** 0 0 H H O N N N N N S 15 24 0 H " 0 0 00 0 0 | | or , wherein the stereochemistry at a carbon within the group T-RD can be either (R) or (S). For each compound of Formula I, LK can also be independently selected at each occurrence from a bond; -Ls'-N(R)C(O)-L..s-; -L'-C(O)N(Rj)-l..s-; or C,-C 6 alkylene, C 2 -C(,alkenylene, C 2 5 Calkynylene, C 3 -Cocarbocycle or 3- to 10-niembered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT O-Rs, -S-Rs, -N(RsRs'), -OC(O)Rs, -C(O)ORs, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, wherein Ls and Ls' are as defined above. For Formula I as well as Formulae 1A, lB, Ic and ID described below, including each and every 10 embodiment described thereunder, RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CI-C 6 alkyl, C 2

-C

6 alkenyl or Cz-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

-C

6 carbocycle or 3- to 6-menibered heterocycle, cach of 15 which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C-COalkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C-C 6 haloalkyl, C 2

-C

6 haloalkenyl or

C

2 -Cohaloalkynyl; or -LA-O-Rs, -LA-S-Rs, -LA-C(O)RS, -LA-OC(O)Rs, -LA-C(O)ORs, -LA N(RsRs'), -L.A-S(0)Rs, -LrA-SO2Rs, -L.eAC(O)N(RsRs'), -LrAN(Rs)C(O)Rs'. -LeA 20 N(R)C(O)N(Rs'Rs"), -LA-N(Rs)SORs', -l--A-SO 2 N(RsRs'), -l A-N(Rs)SO 2 N(Rs'Rs"), -LA N(Rs,)S(O)N(Rs,'Rs"), -LrAOS(O)-Rs, -LrAOS(O)2-Rs, -Lr-S(0)2ORs, -Lr-S(O)ORs, -LeA OC(O)ORs, -LA-N(Rs)C(O)ORS', -LA-OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or -LA-C(O)N(Rs)C(O)-Rs', wherein LA is bond, C-COalkylene, C-COalkenylene or C 2

-C

6 alkynylene. More preferably, RA is halogen, hydroxy, nercapto, amino, carboxy, nitro, oxo, 25 phosphonoxy, phosphono, thioxo, cyano; or C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

-C

6 carbocycle or 3- to 6-memobered heterocycle, cach of which is independently optionally substituted at each occurrence with one or more substimuents selected from halogen, 30 hydroxy, mercapio, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2

-C

6 alkenyl, C-C 6 alkynyl, C,-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl. Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C,-Csalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which 25 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or 5 CI-C 6 alkylene, C 2 -C5alkenylene or C 2 -Coalkynylene. A and B can be the same or different. Likewise, L, and L 2 , or Y and Z, or Y-A- and Z-B-, or -A-L 1 - and -B-L 2 -, can be the same or different. In some instances, Y-A-L 1 - is identical to Z B-l.,-. In some other instances, Y-A-L- is different from Z-R-L2-. In one embodiment, A and B are each independently 5- or 6-membered carbocycle or 10 heterocycle (e.g., phenyl such as - ), and are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle X3 - X3 . (e.g., or , wherein X 3 is N and is directly linked to -L 3 -D) and is optionally substituted with one or more RA. Specific examples of X are described hereitiabove. D is

C

5

-C

6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with RM RM RN RN I I RN RN 15 one or more RA. Preferably, D is or . , wherein Rm and RN are as defined above. L, and L2 are each independently bond or C-C 6 alkylene, and L 3 is bond, CI-C 6 alkylene or C(O)-, and LI, L2, and L 3 are each independently optionally substituted with one or more RI.. Preferably, Li, L 2 , and L 3 are bond. Y is -N(RII)C(O)C(RIR 2 )N(Ri)-'-RI), or N(RB)C(O)C(R 3

R

4

)C(ROR

7 )-'-RD, and Z is -N(RB)C(O)C(RR)N(RI 2 )-'-RD, or 20 N(RB)C(O)C(RoR 1

)C(R

3

R,

4 )-''-RD. R, is Rc, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-tmembered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; R 3 and R 6 are each independently Rc, and R 4 and R 7 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. R 8 is Rc, 25 and Rq and R 12 , taken together with the atoms to which they are attached, form a 5- to 6-iembered 26 heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; and RIO and

R

1 1 are each independently Re,, and R 11 and R 1 4 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. T is preferably independently selected at each occurrence 5 from -C(0)-Ly'-N(RB)C(O)-Ls"- or -C(O)-Ly'-N(Rs)C(O)O-Ls"-. Ly' is each independently Ls' and, preferably, is each independently C 1

-C

6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(O) Ly'-Ls"-, -C(O)-Ly'-0-Ls-, -C(O)-Ly'-N(Ra)-Ls"-, or -C(O)-Ly'-N(RB)S(0)-Ls"'-. In N Ly o some cases, at least one of Y and Z is, or both Y and Z are independently, 10 wherein non-limiting examples of Rj) include (1) -O-C-C 6 alkyl, -(-C 2 -Ccalkenyl, -O-C 2 C 6 alkynyl, CI-C 6 alkyl, C 2 -Calkenyl or C 2 -Coalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 Cocarbocycle or 3- to 6-membered heterocycle; or (2) C 3

-C

6 carbocycle or 3- to 6-membered 15 heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-Coalkyl, C 2 -Coalkenyl, C 2 -Coalkynyl, C-Cohaloalkyl, C Cshaloalkenyl or C-C(,haloalkynyl; and non-limiting examples of Ly' include C 1 -Calkylene optionally substituted with halogen, hydroxy, mtercapto, amino, carboxy, phosphonoxy, -0-C. 20 Calkyl, -0-C 2

-C

6 alkenyl, -O-C 2

-C

6 alkynyl, or 3- to 6-membered carhocycle or heterocycle, said 3 to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C -C 6 alkyl, C 2 -Calkenyl, C 2

-C

6 alkynyl, C,-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C-C,haloalkynyl. 25 In another embodiment, A is N or H, and is optionally ".zi ('C Z substituted with one or more RA; B is N or H , and is optionally substituted with one or more RA. ZI is independently selected at each occurrence from 0, S, NH or 27

CH

2 ; and Z2 is independently selected at each occurrence from N or CH. X is 5- or 6-membered X . carbocycle or heterocycle or 6- to 12-membered bicycle (e.g., or , wherein X 3 is N and is directly linked to -Lr.-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is CS-C 6 carbocycle or 5- to 6-meibered 5 heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is RM R, RN RN I I RN RN or , wherein Rm and RN are as defined above. L, and L 2 are each independently bond or C 1

-C

6 alkylene, and L3 is bond, Ci-C 6 alkylene or -C(O)-, and L 1 , L 2 , and L3 are each independently optionally substituted with one or more RI. Preferably, LI, L 2 , and L 3 are bond. Y is -Ls-C(RIR 2

)N(R

5 )-T-RD or -Ls-C(R 3

R

4

)C(R

6

R

7 )-T-RD, and Z is -Ls-C(RgR)N(R[ 2 )-T-RD Or 10 -Ls-C(RjoR 1

)C(R

13

R

4 )-T-RD. R, is Rc, and R, and R5, taken together with the atoms to which they are attached, form a 5- to 6-iembered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; R 3 and R 6 are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. R8 is Rc, and R 9 and R1 2 , 15 taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; and Rio and R 1 3 are each independently R(, and R 1 and R 4 , taken together with the atoms to which they are attached, form a 5- to 6-inembered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. r is preferably independently selected at each occurrence from -C(O)-Ly' 20 N(Rs)C(O)-Ls"- or -C(O)-Ly'-N(RB)C(O)O-Ls"-. Ly' is each independently Ls' and, preferably, is independently CI-COalkylene (e.g., -Cl-I 2 -) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-Ly'-O Ls"-, -C(0)-Ly'-N(RB)-Ls"-, or -C(O)-Ly'-N(RB)S(0) 2 -Ls"-. In some cases, at least one of Y 28 0 H :N 'rRD and Z is, or both Y and Z are independently, , wherein non-limiting examples of RD include (1) - F-C 1

-C

6 alkyl, -O-C 2

-C

6 alkenyl, -O-C 2

-C

6 alkynyl, Cl-C 6 akyI, C C 6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, 5 phosphonoxy, phosphono, thioxo, formyl, cyano, C 3

-C

6 carbocycle or 3- to 6-membered heterocycle; or (2) C 3

-C

6 carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C,-C 6 alkyl,

C

2

-C

6 alkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C -Cshaloalkynyl; and non-limiting 10 examples of Ly' include Cl-C 6 alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-C -C 6 alkyl, -0-C 2 -Calkenyl, -0-C 2

-C

6 alkynyl, or 3- to 6 membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CrCoalkyl, C 2 15 Calkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C-Cohaloalkynyl. In still yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as - ), and are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle X, X3. or heterocycle or 6- to 12-memnbered bicycle (e.g., or , wherein X 3 is N 20 and is directly linked to -L 3 -D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D can be, for example, CS-C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is AM AM RN RN or . , wherein Rm and RN are as defined above. L, and L 2 are each independently bond or CrCoalkylene, and L 3 is bond, C-C 6 alkylene or -C(0)-, and LI, L 2 , and L 3 are 25 each independently optionally substituted with one or more RL. Preferably, LI, L 2 , and L 3 are bond. Y is .-G-C(R 1

R

2

)N(R

5 )-T-RD or -G-C(R 3

R

4

)C(R

6

R

7 )-T-RD, and Z is -G-C(R 8

R

9

)N(RI

2 )-T-RD or G-C(RoRI)C(Rj3Rj 4 )-T-R). G is independently CS-C 6 carbocycle or 5- to 6-membered heterocycle, 29 H H N N such as K or N , and is independently optionally substituted with one or more RA. R, is Rc, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6 membered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA;

R

3 and R6 are each independently Rc, and R 4 and R 7 , taken together with the atoms to which they are 5 attached, form a 5- to 6-mnembered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. R 8 is Rc, and R 9 and RI., taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; and Rio and R 13 are each independently Rc, and R 11 and

R,

4 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or 10 heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(O)-Ly'-N(R8)C(O)-Ls"- or -C(O) Ly'-N(RB)C(O)O-Ls"-. Ly' is each independently Ls' and, preferably, is each independently C

C

6 alkylene (e.g., -Cl-I 2 -) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-Ly'-O-Ls"-, -C(O)-Ly' 15 N(RB)-Ls"-, or -C(O)-Ly'-N(RB)S(O)-Ls"-. In some cases, at least one of Y and Z is, or both Y NH N O HNH N RD HNR, N Y O N LY o and Z are independently, or , wherein non-limiting examples of RD include (1) -O--CI-COalkyl, -O-C 2

-C

6 alkenyl, -O-C 2

-C

6 alkynyl, C

C

6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, 20 nitro, oxo, phosphonoxy, phosphono, thioxo, fornyl, cyano, C 3

-C

6 carbocycle or 3- to 6-membered heterocycle; or (2) C 3

-C

6 carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cl 30

C

6 alkyl, C-C)alkenyl, C 2 -Ctalkynyl, CI-Chaloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl; and non limiting examples of Ly' include CI-Calkylene optionally substituted with halogen, hydroxy, mercapto, amnino, carboxy, phosphonoxy, -O-C-C 6 alkyl, -O-C 2

-C

6 alkenyl, -O-C 2

-C

6 alkynyl, or 3 to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being 5 optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl, C 2 C 6 alkenyl, C 2

-C

6 alkynyl, CI -Chaloalkyl, C 2 -C(,haloalkenyl or C 2 -Cohaloalkynyl. In yet another embodiment, A and B are each independently 5- or 6-menbered carhocycle or heterocycle (e.g., A and B are each independently phenyl, such as and are each 10 independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle or X, Xa heterocycle or 6- to 12-membered bicycle (e.g., or , wherein X 3 is N and is directly linked to -L 3 -D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D can be, for example, C 5

-C

6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D is Rm Rm RN RN I I RN RN 15 or , wherein R.\ and RN are as defined above. L 1 and L 2 are each independently bond or C-C 6 alkylene, and L 3 is bond, C 1

.C

6 alkylene or -C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RI.. Preferably, L 1 , L 2 , and L 3 are bond. Y is -N(Rfi)C(O)C(RIR 2 )N(RS)--'-R) or -N(RB)C(O)C(R 3

R

4 )C(R(,R7)-'-RI), and Z is -G C(RR,)N(R,)-T-RD or -( 1- 0 (R,,R)C(RR D)-'l-RD; or Y is -G-C(RiR 2 )N(RS)-T-RD or -G 20 C(R 3

R

4 )C(RR,)-T-R,, and Z is -N(R)C(O)C(RSRN)N(R 12 )-T-RD or N(RB)C(O)C(RioR 1 )C(RoR1 4 )-T-Ro). R, is Re, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-inembered heterocyclic ring (e.g., ' ) which is optionally substituted with one or more RA; R 3 and R 6 are each independently Rc, and R 4 and R 7 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or 25 heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. R 8 is Rc, and R 9 and R 12 , taken together with the atoms to which they are attached, form a 5- to 6-menibered 31 heterocyclic ring (e.g., ) which is optionally substituted with one or more RA; and RIO and

R

1 . are each independently Re,, and R 1 1 and R 14 , taken together with the atoms to which they are attached, forn a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. G is independently C 5

-C

6 carbocycle or 5- to 6-membered H H N N 5 heterocycle, such as N or , and is independently optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -(O)-Ly'-N(RB)C(O) Ls"- or -C(O)-Ly'-N(R3)C(0)O-Ls"-. Ly' is each independently Ls' and, preferably, is each independently Ci-C 6 alkylene (e.g., -(1-12-) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-Ly'-O 10 Ls"--, -C(0)-L.y'-N(R3)-L..s"-, or -(O)-..y'-N(RB)S(Oh-Ls'"-. In some cases, Y is NH "IN "I-RD A~ T RD N L o N Y O as described above, and Z is or N O H S H H N - R N Y o as described above. In some other cases, Y is S NH ON " N TRD HN Ro N Y O N L' O or as described above , and Z is H0 N LY O as described above. 15 In still another embodiment, A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl Z Z such as ) and B a d is N or H (e.g., 32 N\ or ); or A is N or NN N N H (e.g., N H ,or H ),and B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as ). A and B are each independently optionally substituted with one or more RA. ZI is independently selected at each 5 occurrence from 0, S, N-I or CH; and Z 2 is independently selected at each occurrence from N or CH. -1 X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-memnbered bicycle (e.g., X3. or , wherein X 3 is N and is directly linked to -L 3 -D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is C 5

-C

6 carbocycle or 5- to 6 membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, D RM R RN RN N N RN RN 10 is or , wherein Rm and RN are as defined above. L, and L 2 are each independently bond or C,-C 6 alkylene, and L 3 is bond, CI-COalkylene or -C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RL- Preferably, LI, L 2 , and L 3 are bond. When A is 5- or 6-nembered carbocycle or heterocycle (e.g., phenyl such as - ), Y is N(R )C(O)C(RR,)N(Rs)-'-R), -N(R)C(O)C(RR 4 )C(R(R)-'-RI), -G-C(RjR 2 )N(RW)-T-R) or 15 G-C(R 3 R4)C(R6R)-T-RD, and Z is -Ls-C(R 8

R

9

)N(R

12 )-T-RD or -Ls-C(RIoR 1

)C(R

3

R

1 4 )-T-Ro. When B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as ), Y is -Ls C(RLR2)N(Rs)-T-RD or -LS-C(R 3 R4)C(RSR)-T-RD, and Z is -N(RB)C(O)C(RsR)N(RI 2 )-T-RD, N(R)C(O)C(RioR )C(R 3 RI4)-T-RI), -G-C(RR,)N(R 2 )-l-Rj) or -G-C(RioR a)C(R 3 Ri 4 )-'-R). R, is Rc, and R 2 and R5, taken together with the atoms to which they are attached, form a 5- to 6 20 membered heterocyclic ring (e.g., ) which is optionally substituted with one or more RA;

R

3 and R 6 are each independently Rc, and R4 and R 7 , taken together with the atoms to which they are 33 attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. R 8 is Rc, and R 9 and R1 2 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., N which is optionally substituted with one or more RA; and RI() and R 13 are each independently R(:, and R 1 and 5 R 14 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more RA. O is H H N N independently Cs-C 6 carbocycle or 5- to 6-membered heterocycle, such as N or and is independently optionally substituted with one or more RA. ' is preferably independently selected at each occurrence from -C(O)-Ly'-N(RB)C(O)-Ls"-- or -C(O)-Ly'-N(R3)C(O)O-Ls"-. 10 Ly' is each independently L.s' and, preferably, is each independently CI-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RI,. T can also be, without limitation, selected from -C(O)-Ly'-Ls"-, -C(O)-Ly'-O-Ls"--, -C(O)-Ly'-N(RB)-Ls"-, or C(O)-Ly'-N(Rn)S(0)-Ls"-. In some cases when A is 5- or 6-niembered carbocycle or heterocycle NH N Ly N o N Ly Ro (e.g., phenyl such as Y is 0 N O H D HN N Ly N O 15 or as described above, and Z is as described above. In some other cases when B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such O H L- N IrRD as ), Y is as described above, and Z is 34 NH N N H H N N R_ N-RD HN N r N Ly 0 N Y O N Ly 0 or as described above. In another aspect, the present invention features compounds of Formula IA and pharmaceutically acceptable salts thereof. 5 D Ij5 29 12 N , A-L 1

-X-L

2 -Bs -Ns RD'-T N N T-RD IC I RC' RC' RNB RNB C IA wherein: RNn is each independently selected from RB; 10 Re' is each independently selected front Rc; Rj)' is each independently selected from RI;

R

2 and R 5 , taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA;

R

9 and R 12 , taken together with the atoms to which they are attached, form a 3- to 12 15 membered heterocycle which is optionally substituted with one or more RA; A, B, D, X, L 1 , L 2 , L 3 , T, RA, RB, Rc, and RD are as described above in Formula 1. In this aspect, A and B preferably are independently selected from C 5 -Cscarbocycle or 5- to 6 membered heterocycle, and are each independently optionally substituted with one or more RA. More preferably, at least one of A and 13 is phenyl (e.g., - ), and is optionally substituted with 20 one or more RA. Highly preferably, both A and B are each independently phenyl (e.g., - ) and are each independently optionally substituted with one or more RA. D preferably is selected from CS-Cecarbocycle, 5- to 6-membered heterocycle, or 8- to 12 membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, and is optionally substituted with one or 25 more RL. More preferably, D is C 5

-C

6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12 membered bicycles, and is substituted with one or more RM, where Rm is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-RE. Also preferably, D is phenyl, and is optionally 35 substituted with one or more RA. More preferably, ) is phenyl, and is substituted with one or more RM Rm R RN RN RN Rm, wherein R\ is as defined above. Highly preferably, D is or , wherein RA is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. 5 D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or RM RM RN N"N N NN N N RN RN RN RN RN more RM. Highly preferably, ) is , , or , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. ) is also preferably indanyl, 4,5,6,7 10 tetrahydrobenzo[dJthiazolyl, benzo[d]thiazolyl, or indarnolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more Rm. Highly preferably, D S N /-0 N H0 N S N S is ~ , , , , , or , and is optionally substituted with one or more Rm. 15 Preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently 20 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formnyl, cyano, C 1 C 6 alkyl, C2-C 6 alkenyl, C 2

-C

6 alkynyl, CI-Cohaloalkyl, C 2 -Chaloalkenyl or C 2 -Cohaloalkynyl. More preferably, R, is halogen, hydroxy, mercapto, amino, carboxy; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C 2 C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more 25 substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RM is

C-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. 36 Also preferably, RM is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RM is -L-R 1 , wherein Ls is a bond or C 1

-C

6 alkylene, and RI is N(RsRs'), -0-Rs, -C(O)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(O)Rs'. -N(Rs)C(O)ORs', N(Rs)SO2Rs', -SO 2 Rs, -SRs, or -P(O)(ORs) 2 , wherein Rs and Rs' can be, for example, each 5 independently selected at each occurrence from (1) hydrogen or (2) C-C 6 alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -0-C-Cealkyl or 3- to 6-inembered heterocycle; or RM is Cr-Calkyl, C 2 -Calkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or 10 Rm is C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C-COalkyl,

C

2

-C

6 alkenyl, C-C 6 alkynyl, Cl-Cjialoalkyl, C 2

C

6 haloalkenyl, C 2

-C

6 haloalkynyl, -C(O)ORs, or N(RsRs'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, 15 amino, carboxy, or C 1

-C

6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2

-C

6 alkenyl or C 2 Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RM is CF 3 , C(CF 3 )2-OH, -C(Cl-l 3 )-CN, -C(CH 3

)

2

-CH

2 OH, or -C(CH 3

)

2

-CH

2

NH

2 . Also preferably Rm is -Ls RE where Ls is a bond and RE is -N(RsRs-), -0-Rs, -N(Rs)C(O)ORs', -N(Rs)S0 2 Rs', -SO 2 Rs, or 20 SRs. For example where Ls is a bond, RE is -N(C-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(C,-C 6 alkylene-O-Cr

C

6 alkyl) 2 (e.g. -N(CH 2

CH

2 OMe) 2 ); -N(C-C 6 alkyl)(C-C 6 alkylene-O-C-C 6 alkyl) (e.g. N(CH 3

)(CH

2

CH

2 OMe));-0O-C-C 6 alkyl (e.g., -0-Me, -0-Et, -0-isopropyl, -0-tert-butyl, -0-n hexyl); -0-C-C,,haloalkyl (e.g., - OCF 3 , -OCI-1 2

CF

3 ); -0-C,-C 1 ,alkylene-piperidine (e.g., -0

C

2

C

2 - I-piperidyl); -N(C,-C(,alkyl)C(0)OCI-C,alkyl (e.g., -N(CH3)C(0)O-CH 2

CH(CH

3

)

2 ), 25 N(C,-C 6 alkyl)SO2Cj-C 6 alkyl (e.g., -N(CH 3

)SO

2

CH

3 ); -S0 2

CI-C

6 alkyl (e.g., -SO 2 MC); -SO2CI

C

6 haloalkyl (e.g., -SO 2

CF

3 ); or -S-CI-C 6 haloalkyl (e.g., SCF 3 ). Also preferably Rm is -Ls-RE where Ls is C-C 6 alkylene (e.g., -CH 2 -, -C(CH-1 3 )2-, -C(CH 3

)

2 -CI-1 2 -) and RE is -0-Rs, -C(O)ORs, N(Rs)C(O)ORs', or -P(O)(ORs) 2 . For example Rm is -C-Coalkylene-O-Rs (e.g., -C(CI13)2-CI12 OMe); -C -Csalkylene-C(O)ORs (e.g., -C(CH 3 )2-C(0)OMe); -C 1

-C

6 alkylene-N(Rs)C(O)ORs' (e.g., 30 -C(CHI 3

)

2 -CH-1 2 -NllC(0)OCH 3 ); or -CrCoalkylene-P(O)(ORS) 2 (e.g., -Clrl 2 -P(O)(OE)2). Also more preferably km is CrC 1 ,carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, CrC6 1 -haloalkyl, C 2

-C

6 haloalkenyl, C-C 6 haloalkynyl, 35 C(O)ORs, or -N(RsRs'). For example Rm is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-t methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 37 dioxidothionorpholin-4-yl, 4-methylpiperazin-l-yl, 4-inethoxycarbonylpiperazin- i-yl, pyrrolidin-1 yl, piperidin-l-yl, 4-niethylpiperidin-1-yl, 3,5-dimethylpiperidin-I-yl, 4,4-difluoropiperidin- I -yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(diimeihylamino)pyridin-3-yl). Highly preferably, Rm is CI-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, 5 hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ). X preferably is Cs-C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered X3

X

3 bicycles (e.g., or, wherein X 3 is N and is directly linked to -L 3 -D), and is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove. L, and L 2 are preferably independently bond or CI-C,alkylene, L, is preferably selected from 10 bond, Ci-Coalkylene or -C(O)-, and L,, l.a, and LA are each independently optionally substituted with one or more RL. More preferably, LI, L 2 and L 3 are each independently bond or CI-C 6 alkylene (e.g., CH 2 - or -CH 2

CH

2 -), and are each independently optionally substituted with one or more RL. -lighly preferably, LI, L 2 and L- are bond.

R

2 and R 5 , taken together with the atoms to which they are attached, preferably form a 5- to 6 qN N 15 membered heterocycle or 6- to 12-nimnbered bicycle (e.g., or which is optionally substituted with one or more RA.

R

9 and RI,, taken together with the atoms to which they are attached, preferably form a 5- to q 1 .N 6-membered heterocycle or 6- to 12-mnembered bicycle (e.g., or which is optionally substituted with one or more RA. 20 -T-RD' can be, without limitation, independently selected at each occurrence from -C(O) Ly'-, -C(O)O-Ly'-Ro', -C(O)-Ly'-N(R3)C(O)-Ls"-RD', -C(O)-Ly'-N(RB)C(O)O-Ls"-RD', N(RB)C()-Ly'-N(RB)C(O)-Ls"-RD', -N(RB)C()-Ly'-N(RB)C(O)O-Ls"-RD', or -N(RB)C(O) Ly'-N(R)-Ls"-R)', wherein Ly' is each independently Ls' and, preferably, is each independently CI-C,alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituentis selected from RI,. 25 Preferably, -'-R 2 ' is independently selected at each occurrence from -C(O)-Ly'-M'-L..s"-R 2 ' or N(RB)C(O)-Ly'-M'-Ls"-RD'. More preferably, -T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(RB)C(O)-Ls"-RD' or -C(O)-Ly'-N(RB)C(O)O-Ls"-RD'. Highly preferably, 'T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(RB)C(O)-Ro' or -C(0)-Ly' 38 N(RH)C(O)O-RI)', wherein Ly' preferably is each independently C 1

-C

6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R. RNB and Rc' are preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from C 5 COalkyl, C 2 -Calkenyl or C-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C-Cecarbocycle or 3- to 6-membered heterocycle; or C 1 -Ccarhocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 10 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 1 C 6 alkyl, C 2 -COalkenyl, C-COalkynyl, C-C 6 fhaloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl. RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 15 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C-C 1 ,carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr

C

6 alkyl, C-C 6 alkenyl, C-C 6 alkynyl, C 1 -Cshaloalkyl, C 2

-C

6 haloalkenyl or Cz-Cshaloalkynyl; or -LA 20 O-R,, -L,-S-Rs, -L,-C(O)Rs, -LA-OC(O)Rs, -L,-C(O)ORs, -L,-N(RsRs'), -L,-S(O)Rs, -LA S0 2 Rs, -LA-C(O)N(RsRs'), -LAN(Rs)C(O)Rs', -LAN(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO 2 Rs', LA-SO 2 N(RsRs'), -L,-N(Rs)SO 2 N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA OS(O)2-Rs, -LA-S(O) 2 0Rs, -LN-S(O)ORs, -L-OC(O)OR,, -LA-N(R,)C(O)OR,', -LA OC(Oi))N(RsRs'), -L A-N(Rs)S(O)-Rs', -l.A-S(O)N(RsR,') or -L AC(O)N(Rs)C(O)-Rs', wherein LA 25 is bond, C 1

-C

6 alkylene, C 2

-C

6 alkcnylcnc or C 2

-C

6 alkynylene. More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CrCoalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or 30 cyano; or C'-C(,carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formnyl, cyano, C

C

6 alkyl, C,-C 6 alkcnyl, C 2

-C

6 alkynyl, C 1

-C

6 haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl. highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, 35 phosphonoxy, phosphono, thioxo, cyano; or C-C 6 alkyl, C 2

-C

6 alkenyl or C-COalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 39 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or C -C 6 alkylene, C 2

-C

6 alkenylene or C-COalkynylene. 5 A and B can be the same or different. Likewise, L, and L 2 can be the same or different. In one embodiment of this aspect, A, B, and D are each independently phenyl, and are each R N RN RN RN )RN, independently optionally substituted with one or more RA. Preferably, D is or Ru wherein Rm and RN are as defined above. L, and L 2 are each independently bond or C 1 C 6 alkylene, and L 3 is bond, C 1

-C

6 alkylene or -C(O)-, and Li, L 2 , and L 3 are each independently 10 optionally substituted with one or more RL. Preferably, L 1 , L2, and L 3 are bond. -T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(Rj)C(O)-Ls"-RD' or -C(0)-Ly' N(RB)C(O)O-LS"-RD', wherein Ly' is CI-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RI., and L," preferably is bond. -T-R)' can also be, without limitation, selected from -C(O)-Ly'-Ls"-RD', -C(O)-Ly'-O-Ls"--RD', -C(O)-Ly'-N(RB)-Ls" 15 RD', or -C(O)-Ly'-N(RB)S(0) 2 -Ls"-RD' In still another aspect, the present invention features compounds of Formula IB and pharmaceutically acceptable salts thereof: 0

L

3 R12 | R 2 I S A-L 1

-X-L

2 -B NsT-RD Rc. Rc' RC'B 20 wherein: Rc' is each independently selected from Rc; RD' is each independently selected from RD; R2 and RS, taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA; 40

R

9 and R12, taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA; A, B, D, X, LI, L,, L 3 , T, RA, Rc, and RD are as described above in Formula I. In this aspect, A and B preferably are independently selected from 8- to 12-membered Z3 Z 5 bicycles such as , 3 , or W4 4 w6 ,where Z, is independently selected at each occurrence from 0, S, NH or C-I 2 ,

Z

2 is independently selected at each occurrence from N or CH, Z 3 is independently selected at each occurrence from N or CH, Z 4 is independently selected at each occurrence from 0, S, NI-I or CH 2 , and WI, W 2 , W3, W 4 , W 5 and W 6 are each independently selected at each occurrence from CH or N. A 10 and B are each independently optionally substituted with one or more RA. KX 'W2 XW5~ More preferably, A is selected from a w or we , and is W.w, z

W

2 -C optionally substituted with one or more RA; B is selected from Wa a or w 4 W W 4 , and is optionally substituted with one or more RA, where Z , Z 2 , Z 3 , Z 4 , W,, W 2 ,

W

3 , W 4 , W 5 , W 6 arc as defined above. Preferably, Z 3 is N and Z 4 is NH. For instance, A can be N 15 selected from N (e.g., N or H(e.g., or H), and is optionally substituted with one or more RA; and B can be selected from N (e.g., N ) or H (e.g., H or H ), and is optionally substituted with one or more RA. 41 N N Also preferably, A is H (e.g., H ), and B is (e.g., ), wherein A' and B' are independently selected from

C

5 -Ce,carbocycle or 5- to 6-membered heterocycle, and A and B are independently optionally substituted with one or more RA. 5 D preferably is selected from C 5

-C

6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12 membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, and is optionally substituted with one or more substituents selected from RL. More preferably, D is CS-C 6 carbocycle, 5- to 6-mnembered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more Rm, where Rm is 10 halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more RM, wherein Rm is as defined above. Highly preferably, D is R, RN RN RN - RN or . , wherein Rm is as defined above, and each RN is independently selected from RI) and preferably is hydrogen. One or more RN can also preferably be halo such as F. 15 D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or Rm Rm R, N NN N N N RN RN RN RN o RN more Rm. Highly preferably, D is , , or , wherein RM is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7 20 tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[dthiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more Rm. Highly preferably, D 42 ~SiN---. -O 2N HN O N S N S is ~' , , ~ or ,and is optionally substituted with one or more Rm. Preferably, R.m is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CI-Coalkyl, C 2 -Calkenyl or C 2 Calkynyl, each of which is 5 independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, anno, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or eyano; or C 3

-C

6 carbocycle or 3- to 6-memnbered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj 10 C 6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C 2 -Cjhaloalkynyl. More preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy; or C 1

-C

6 alkyl, C-C 6 alkenyl or C 2 Ccalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, Rm is

C

1

-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, 15 hydroxy, mercapto, amino or carboxy. Also preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RM is -Ls-RE, wherein Ls is a bond or C 1 -C(alkylene, and RE is N(RsRs'), -O-Rs, -C(O)Rs, C(O)ORs, -C(O)N(RR,'), -N(Rs)C(O)Rs'. -N(Rs)C(O)ORs',

N(R,)SO

2 R,', -S0 2 Rs, -SRs, or -P'(O)(ORS)2, wherein Rs and Rs' can be, for example, each 20 independently selected at each occurrence from (1) hydrogen or (2) CI-C 6 alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Cl-C 6 alkyl or 3- to 6-membered heterocycle; or Rm is CI-C 6 alkyl, C-C 6 alkenyl or C-COalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected front halogen, hydroxy, nercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or 25 Rm is C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-Calkyl,

C

2 -Calkenyl, C 2

-C

1 ,alkynyl, CI-C6,haloalkyl, C 2 -C(,haloalkenyl, C 2 -C(,haloalkynyl, -C(0)ORs, or N(RsRs'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, 30 amino, carboxy, or Ci-Csalkyl (e.g., methyl, isopropyl, tert-butyl), C 2

-C

6 alkenyl or C 2 -CoaLkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example Rm is CF 3 , C(CF 3 )2-OH, -C(CH 3 )2-CN, -C(CH 3 )2-CH 2 OH, or -C(CH 3

)

2

-CH

2

NH

2 . Also preferably Rm is -Ls 43 RF where Ls is a bond and RF. is -N(R.,Rs-), -O-Rs, -N(Rs)C(0)ORs', -N(RS)S0 2 Rs', -S0 2 R, or S Rs. For example where Ls is a bond, R. is -N(C.C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-O-Cr

C

6 alkyl) 2 (e.g. -N(CH 2

CH

2 OMe) 2 ); -N(CI-C 6 alkyl)(C 1

-C

6 alkylene-O-C.C 6 alkyl) (e.g. N(CH 3

)(CH

2

CH

2 OMe));--O-C-C 6 alkyl (e.g., -0--Me, -0-Et, -0--isopropyl, -0-tert-butyl, -0-n 5 hexyl); -0-C-C 6 haloalkyl (e.g., - OCF 3 , -OCH 2

CF

3 ); -0-C.C 6 alkylene-piperidine (e.g., -O CH1 2

CH

2 - I-piperidyl); -N(C-C 6 alkyl)C(O)OC .C 6 alkyl (e.g., -N(CI1 3

)C(O)O-CH

2 CH(C1 3

)

2 ), N(Cj-C(,alkyl)SO 2

C

1 -C(alkyl (e.g., -N(CH 3

)SO

2

CH

3 ); -SO 2 Cj-C 6 alkyl (e.g., -SO 2 Me); -SO 2

C

Chaloalkyl (e.g., -SO 2

CF

3 ); or -S-C-Cohaloalkyl (e.g., SCF-). Also preferably Rm is -Ls-RE where L's is C 1

-C

6 alkylene (e.g., -CH 2 -, -C(CH 3

)

2 -, -C(CH 3

)

2

-CH

2 -) and RE is -- O-Rs, -C(O)ORs, 10 N(Rs)C(O)ORs', or -P(O)(ORs)2. For example Rm is -Cl-C 6 alkylene-O-Rs (e.g., -C(CH 3 )2-CFI 2 OMe); -CI-Calkylene-C(O)ORs (e.g., -C(CH 3

)

2 -C(O)OMe); -C 1

-C

6 alkylene-N(Rs)C(O)ORs' (e.g.,

-C(CII

3 )2-CIH 2

-NIIC(O)OCIH

3 ); or -C 1

-C

6 alkylene-P(O)(ORs) 2 (e.g., -CIH 2 -P(0)(OEt)2). Also more preferably R.m is C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 15 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C C(,alkyl, C 2 -Coalkenyl, C 2 -Coalkynyl, Cl-C 6 1haloalkyl, C 2 -Cjhaloalkenyl, C 2

-C

6 haloalkynyl, C(O)ORs, or -N(RsRs'). For example Rm is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-l 20 yl, piperidin-1-yl, 4-methylpiperidin-I-yl, 3,5-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-I-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, Rm is C 1

-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ). X preferably is C.,-Ccarbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered X.3 X3 25 bicycles (e.g., or , wherein X 3 is N and is directly linked to -L 3 -D), and is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove. L, and L 2 are preferably independently bond or C-COalkylene, L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RL. More preferably, L 1 , L2 and L 3 are each independently bond or C 1

-C

6 alkylene (e.g., 30 CH 2 - or -CH 2

CH

2 -), and are each independently optionally substituted with one or more RL. Highly preferably, L 1 , L 2 and L 3 are bond. 44

R

2 and Rs, taken together with the atoms to which they are attached, preferably form a 5- to 6 membered heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more RA. R 9 and R 12 , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., N N. 5 or ) which is optionally substituted with one or more RA. -T-RD' can be, without limitation, independently selected at each occurrence from -C(O) Ly'-RD', -C(O)O-Ly'-RD. -(O)-Ly'-N(R3)C(O)-Ls"-RD', -C(O)-Ly'-N(RB)C(O)O-Ls"--RD', N(R)C(O)-Ly'-N(RB)C(O)-Ls"--RD', -N(RB)C(O)-Ly'-N(R,)C(O)O-Ls"-RD', or -N(R 8

)C(O)

[..y'-N(Rs)-Ls"--RD', wherein Ly' is each independently Ls' and, preferably, is each independently 10 C-C 6 alkylene (e.g., -Cl 2 -) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(O)-Ly'-M'-Ls"-RD' or N(Rs)C()-Ly'-M'-Ls"-RD'. More preferably, -T-RD' is independently selected at each occurrence from -C(O)-LY'-N(RB)C(O)-Ls"-RD' or -C(O)-Ly'-N(RB)C(O)O-Ls"-RD'. Highly preferably, T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(R3)C(O)-RD' or - -Ly' 15 N(RB)C(O)O-RD', wherein Ly' preferably is each independently Cl-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from Rl,. Re' is preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Cl-C 6 alkyl, C Csalkenyl or C 2 -COalkynyl, each of which is independently optionally substituted at each occurrence 20 with one or more substituents selected from halogen, hydroxy, mercupto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3

-C

6 carbocycle or 3- to 6-membered heterocycle; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cl-C 6 alkyl, 25 C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C 1

-C

6 haloalkyl, C 2 -Cjhaloalkenyl or C 2

-C

6 haloalkynyl. RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1

-C

6 alkyl, C 2 -Calkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or 30 cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 45 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2

-C

6 alkenyl, C 2 -C(alkynyl, C-Clhaloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl; or -LA O-R,, -LA-S-Rs, -LA-C(O)Rs, -LA-OC(O)Rs, -LA-C(O)ORs, -LA-N(RsRs'), -LA-S(O)Rs, -LA S0 2 Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs'. -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO 2 Rs', 5 LA-SO 2 N(RsRs'), -LA-N(Rs)SO2N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA OS(O)2-Rs, -LA-S(O) 2 ORs, -LA,-S(O)ORs, -LA-OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA OC(O)N(RsRs'), -LA-N(Rs)S(O)-Rs', -LA-S(O)N(RsRs') or -LA-C(O)N(Rs)C(O)-Rs', wherein LA is bond, CI-C 6 alkylene, C-Coalkenylene or C 2 -Calkynylene. More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, 10 phosphonoxy, phosphono, Ihioxo, cyano; or C,-C 6 alkyl, C 2

C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituenis selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, fornyl or cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 15 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj Calkyl, C 2 -Calkenyl, C 2

-C

6 alkynyl, C-C 6 haloalkyl, C 2 -Cfhaloalkenyl or C 2 -Chaloalkynyl. Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, ihioxo, cyano; or C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 20 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or

C

1 -Calkylene, C 2 -Calkenylene or C-C(alkynylene. A and B can be the same or different. Likewise, L, and L2 can be the same or different. 25 In one embodiment of this aspect, A is N or , and is Z' Z N optionally substituted with one or more RA; B is N or H ,and is optionally substituted with one or more RA; and D is C-C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, ) is RM R RN RN I I RN RN . or , wherein RM and RN are as defined above. Zi is independently selected at 30 each occurrence from 0, S, NI-I or Cl-2; and Z 2 is independently selected at each occurrence from N 46 or CH. L, and L2 are each independently bond or Ci-Ctalkylene, and L,. is bond, C 1

-C

6 alkylene or C(O)-, and 1,, L2, and L, are each independently optionally substituted with one or more R*. Preferably, Li, L 2 , and L. are bond. -T-R 0 ' is independently selected at each occurrence from -C(O) Ly'-N(RB)C(O)-Ls"-RI)' or -C(O)-Ly'-N(RB)C(O)O-Ls"-RD', wherein Ly' is CI-Calkylene (e.g., 5 -CH,-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(O)-Ly'-Ls"-RD', -C(O)-Ly'-O Ls"-R)', -C(O)-Ly'-N(RH)-Ls"-R,)', or -C(O)-Ly'-N(Rs)S(O)2-Ls "-R)'. In yet another aspect, the present invention further features compounds of Formula 1 c: and pharmaceutically acceptable salts thereof. D R O

L

3 R12 I R2 R I RD'-T IN

NA-L-X-L

2 -B N'T- R 10 Rc' RNB Rc' Ic wherein: RNB is RB; Re' is each independently selected from Rc:; 15 RD' is each independently selected from RD; R, and R 5 , taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA;

R

9 and R 12 , taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA; 20 A, B, D, X, LI, L 2 , L 3 , T, RA, RB, Rc, and RD are as described above in Formula I. In this aspect, A preferably is C 5

-C

1 ,carbocycle or 5- to 6-membered heterocycle, and is optionally substituted with one or more RA; and B preferably is 8- to 12-membered bicycle (such as W ZW Z4 W3 3 or W 6 ), and is optionally substituted with one or more R,. Z, is 0, S, NH or CH2; Z2 is N or CH; Z is N or CH; Z 4 is 0, S, NH or CH 2 ; and W, W 2 , W 3 , 25 W 4 , W5 and W(, are each independently selected from CH or N. More preferably, A is phenyl (e.g., ), and is optionally substituted with one or w z -W4 z more RA; and B is W3 3 or We , and is optionally substituted with one 47 or more RA, where ZI, Z 2 , Z., 74, WI, W 2 , W 3 , W 4 , W 5 , W 6 are as defined above. Preferably, Z 3 is N H ZIN and Z 4 is NH. For instance, B can be N (e.g., N ) or N N H (e.g., H or H ), and is optionally substituted with one or more RA. 5 Also preferably, A is C5-Ccarbocycle (e.g., phenyl such as - ) or 5- to 6 membered heterocycle; and B is (e.g., ), wherein B' is selected from C 5 -Cecarbocycle or 5- to 6-membered heterocycle. A and B are independently optionally substituted with one or more RA. - D preferably is selected from Cs-C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12 10 membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from CI-C 6 alkyl, C 2

-C

6 alkenyl or C-C 6 alkynyl, and is optionally substituted with one or more substituents selected from RL. More preferably, 1) is C 5

-C

6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more Rm, where Rm is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L 5 -Rs. Also preferably, D is 15 phenyl, and is optionally substituted with one or more RA. More preferably, ) is phenyl, and is substituted with one or more Rm, wherein Rm is as defined above. Highly preferably, ) is N N I |] RN RN or . , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or 20 more R, More preferably D is pyridinyl, pyrimiclinyl, or thiazolyl, and is substituted with one or Rm RM RN A-. RM N N N N N RN RN RN RN S RN more Rm. Highly preferably, ) is , , or , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably he halo such as F. ) is also preferably indanyl, 4,5,6,7 tetrahydrobenzo[dJthiazolyl, benzo[dJthiazolyl, or indazolyl, and is optionally substituted with one or 48 more R. More preferably ) is indanyl, 4,5,6,7-tetrahydrobenzo[dJthiazolyl, benzo[dJthiazolyl, indazolyl, or benzo[dj[1,3jdioxol-5-yl, and is substituted with one or more Rm. Highly preferably, ) / \ S ,N- /-O QN HN O N S N, S is , , , , , or , and is optionally substituted with one or more Rm. 5 Preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently 10 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 1 C 6 alkyl, CrC 1 alkenyl, C-Ccalkynyl, CrC-(haloalkyl, C 2 -Chaloalkenyl or C 2 -C(,haloalkynyl. More preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy; or C-Calkyl, C 2

-C

6 alkenyl or C 2

C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more 15 substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, Rm is

C-C

6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Also preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or Rm is -L-R, wherein Ls is a bond or C-C 6 alkylene, and RF is 20 N(RR,'), -O-R,, -C(O)Rs, -C(0)OR,, -C(O)N(RR,'), -N(Rs)C(O)R,' -N(R,)C(O)ORs', N(Rs)SO2Rs', -S0 2 Rs, -SRs. or -P(O)(ORs)2, wherein Rs and Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) C-C 6 alkyl optionally substituted at each occurrence wifh one or more halogen, hydroxy, -O-C 6 alkyl or 3- to 6-membered heterocycle; or Rm is C-C 6 alkyl, C 2

-C

6 alkenyl or C 2 -Coalkynyl, each of which is independently 25 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Rm is C 3

-C

6 carbocycle or 3- to 6-meinbered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formnyl, cyano, C -C 6 alkyl, 30 C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C 1

-C

6 haloalkyl, Cr 2 -haloalkenyl, C 2

-C

6 haloalkynyl, -C(O)ORs, or N(RsRs'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or C-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents 49 selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example Rm is CF 3 , C(CF)2-0l-l, -C(CH 3

)

2 -CN, -C(CH,) 2

-CH

2 OH, or -C(CH 3

)

2 rCH 2

NH

2 . Also preferably Rm is -E.s RE where Ls is a bond and RE is -N(RsRs.), -0-Rs, -N(Rs)C(O)ORs', -N(Rs)SO 2 Rs', -S0 2 Rs, or SRs. For example where Ls is a bond, RE is -N(C-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(C-Coalkylene-O-Ce 5 C 6 alkyl) 2 (e.g. -N(CHz2Cl 2 OMe) 2 ); -N(C 1

-C

6 alkyl)(C-C 6 alkylene-O-C.C 6 alkyl) (e.g. N(Ci 3

)(CI

2

CH

2 OMe));-0-C-C 6 alkyl (e.g., -0-Me, -0-Et, -0-isopropyl, -0-tert-butyl, -0-n hexyl); -O-C-Cjhaloalkyl (e.g., - OCF 3 , -OCH 2

CF

3 ); -0-C,-C,alkylene-piperidine (e.g., -0 Cl- 2 Crl 2 -- piperidyl); -N(C-C(,alkyl)C(O)OCI-C 6 alkyl (e.g., -N(CH 3

)C(O)O-CH

2 CH(CH3)2), N(CI-(C 6 alkyl)SO 2

C-C

6 alkyl (e.g., -N(CH 3

)SO

2

CH

3 ); -S0 2 C-COalkyl (e.g., -SO 2 Me); -SO 2 CI 10 C 6 haloalkyl (e.g., -SO 2

CF

3 ); or -S--CChaloalkyl (e.g., SCF 3 ). Also preferably Rm is -Ls-RE where Ls is C-C 6 alkylene (e.g., -CH 2 -, -C(CH-1 3 )2-, -C(CI-13)2-CH 2 -) and RE is -0-Rs, -C(O)ORs, N(Rs)C(O)ORs', or -P(O)(ORs) 2 . For example Rm is -C 1

-C

6 alkylene-O-Rs (e.g., -C(CH 3

)

2

-CI

2 OMe); -CI-C 6 alkylene-C(0)ORs (e.g., -C(CI 3

)

2 -C(0)OMe); -C 1

-C

6 alkylene-N(Rs)C(0)ORs' (e.g., -C(CH1) 2 -Cl 2 -NHlC(O)OC1 3 ); or -C -Calkylene-P(O)(ORS) 2 (e.g., -CH1 2 -P(O)(OEt) 2 ). Also more 15 preferably Rm is C 3 -Cecarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2 -COalkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl, C 2 -Cohaloalkynyl, C(O)ORs, or -N(RsRs'). For example Rm is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-1 20 methylcycloprop-I-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1 yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-I-yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yI). Highly preferably, Rm is C-Cr,alkyl which is optionally substituted with one or more substituents selected from halogen, 25 hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ). X preferably is Cs-C 6 carbocycle, 5- to 6-memnbered heterocycle, or 6- to 12-membered X3 . X 3 bicycles (e.g., or , wherein X 3 is N and is directly linked to -L 3 -D), and is optionally substituted with one or more RA. Non-limiting examples of X are described hereinabove. Li and L 2 are preferably independently bond or C-C 6 alkylene, L 3 is preferably selected from 30 bond, C 1

-C

6 alkylene or -C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RL. More preferably, LI, L 2 and L 3 are each independently bond or C-Coalkylene (e.g., CH 2 - or -CI-1 2 C-1 2 -), and are each independently optionally substituted with one or more RI.. Highly preferably, Li, L2 and 1.3 are bond. L, and L2 can be the same or different. 50

R

2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6 membered heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more RA. R 9 and R 12 , taken together with the atoms to which they are attached, preferably forn a 5- to 6-membered heterocycle or 6- to 12-niembered bicycle (e.g., 5 or ) which is optionally substituted with one or more RA. -T-RD' can be, without limitation, independently selected at each occurrence from -C(O) Ly'-RD', -C(O)O-Ly'-RD', -C(O)-Ly'-N(R,)C(O)-Ls"-RD', -C()-LY'-N(R)C(O)O-Ls"-RD', N(RB)C(O)-Ly'-N(RB)C(O)-Ls"-RD', -N(Rs)C(O)-Ly'-N(RB)C(O)O-Ls"-RD', or -N(RB)C(O) Ly'-N(R)-.S"-RD', wherein Ly' is each independently Ls' and, preferably, is each independently 10 CI-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(O)-Ly'-M'-Ls"-RD' or N(RB)C(0)-Ly'-M'-Ls"-RD'. More preferably, -T-RD' is independently selected at each occurrence from -C(0)-Ly'-N(RB)C(0)-Ls"-RD' or -C(O)-Ly'-N(R)C()O-L s"-RD'. Highly preferably, T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(RB)C(0)-RD' or -C(0)-Ly' 15 N(RB)C(O)O-RD', wherein Ly' preferably is each independently C 1

-C

6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RI.. RNS and Rc' are preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Cr

C

6 alkyl, C-C 6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each 20 occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, forinyl, cyano, C 3

-C

6 carbocycle or 3- to 6-membered heterocycle; or C 3

-C

6 carbocycle or 3- to 6-menbered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj 25 C 6 alkyl, C 2 -COalkenyl, C 2

-C

6 alkynyl, C-C 6 haloalkyl, C 2 -Cjhaloalkenyl or C 2 -Cjhaloalkynyl. RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or 30 cyano; or C 3 -Cecarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 51 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2 -COalkenyl, C 2

-C

6 alkynyl, C,-Cehaloalkyl, C 2 -Cohaloalkenyl or C 2

-C

6 haloalkynyl; or -LA O-Rs, -LA-S-Rs, -LA-C(O)Rs, -LA-OC(O)Rs, -LA-C(O)ORs, -LA-N(RsRs'), -LA-S(O)Rs, -LA

SO

2 Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs'. -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(RS)SO 2 Rs', 5 LA-SON(RSRS'), -LA-N(Rs)SO 2 N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-RS, -L, OS(Oh-Rs, -LA-S(0)2ORs, -LA-S(O)ORs, -LA-OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA OC(O))N(RR,'), -LA-N(RS)S(O)-Rs', -LA-S(O)N(RSRs') or -LA-C(O)N(Rs)C(O)-Rs', wherein LA is bond, C -C 6 alkylene, C 2 -Calkenylene or C-Cralkynylene. More preferably, RA is halogen, hydroxy, niercapto, amino, carboxy, nitro, oxo, 10 phosphonoxy, phosphono, thioxo, cyano; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formal or cyano; or C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 15 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 1 Cealkyl, C 2 -Calkenyl, CZ-C 6 alkynyl, C 1 -C61haloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 haloalkynyl. Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 20 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or C, -C,alkylene, C 2 -Calkenylene or C-Coalkynylene. In one embodiment of this aspect, A is phenyl, and is optionally substituted with one or more 25 RA; and B is N or H , and is optionally substituted with one or more RA, wherein Z, is 0, S, NH or CH; and Z 2 is N or CH. D is C-C 6 carbocycle or 5- to 6 membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA. Preferably, I) RM AM RN RN I I RN AN is or , wherein Rm and RN are as defined above. L, and L 2 are each independently bond or C-C 6 alkylene, and 1,3 is bond, C 1

-C

6 alkylene or -C(O)-, and LI, 12, and L.3 are 30 each independently optionally substituted with one or more R 1 . Preferably, L 1 , L,2, and L3 are bond. T-RD' is independently selected a Cach occurrence from -C(O)-Ly'-N(RB)C(O)-Ls"-RD' or -C(0) 52 l..y'-N(R)C(0)O-l..s"-R)', wherein Ly' is CrCfalkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RI, and I.s" preferably is bond. -'-R)' can also be, without limitation, selected front -(O)-Ly'-Ls"--RD', -C(O)-Ly'-O-Ls"-RD', -C(O)-Ly'-N(RB) Ls"-RD', or -C(O)-Ly'-N(R3)S(0) 2 -Ls"--RD'. 5 In yet another aspect, the present invention features compounds of Formula ID and pharmaceutically acceptable salts thereof. D

R

5 L 3 R12 I R2 IR 1 N A-L-X-L2-BG NTR Rc' Rc' 10 wherein: G, and G 2 are each independently selected from C 5

-C

6 carbocycle or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more RA; Rc' is each independently selected from Rc; RD' is each independently selected from RD; 15 R2 and Rs, taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA;

R

9 and R 1 2 , taken together with the atoms to which they are attached, form a 3- to 12 membered heterocycle which is optionally substituted with one or more RA; A, B, D, X, L 1 , L 2 , L 3 , T, RA, Rc, and RD are as described above in Formula I. 20 In this aspect, A and B preferably are independently selected from Cs-C 6 carbocycle or 5- to 6 membered heterocycle, and are each independently optionally substituted with one or more RA. More preferably, at least one of A and B is phenyl (e.g., - ), and is optionally substituted with one or more RA. Highly preferably, both A and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more RA. 25 D preferably is selected from Cs-Cecarbocycle, 5- to 6-membered heterocycle, or 8- to 12 membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from CI-Cealkyl, C 2 -Cfalkenyl or C 2

-C

6 alkynyl, and is optionally substituted with one or more RL. More preferably, D is Cs-C 6 carbocycle, 5- to 6-metmbered heterocycle, or 6- to 12 membered bicycles, and is substituted with one or more RM, where Rm is halogen, nitro, oxo, 30 phosphonoxy, phosphono, thioxo, cyano, or -Ls-RE. Also preferably, D is phenyl, and is optionally 53 substituted with one or more RA. More preferably, ) is phenyl, and is substituted with one or more RU II RN RN Rm, wherein RM is as defined above. Highly preferably, D is , or Rm R RN , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. 5 D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or inore RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or RM RM RN RM N N N "N N RN RN RN RN S RN more R.. Highly preferably, D is , , or ~ , wherein Rm is as defined above, and each RN is independently selected from RD and preferably is hydrogen. One or more RN can also preferably be halo such as F. 1) is also preferably indanyl, 4,5,6,7 10 tetrahydrobenzo[d]ihiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d] hiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][ 1,3]dioxol-5-yl, and is substituted with one or more Rm. Highly preferably, D / S ,N /-o NlS I I I is I , ~ , ~~ , , , or , and is optionally substituted with one or more Rm. 15 Preferably, Rm is halogen, hydroxy, nercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

C

6 carbocycle or 3- to 6-mnembered heterocycle, each of which is independently 20 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cr

C

6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C2-Cshaloalkynyl. More preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy; or CI-C 6 alkyl, C 2

-C

6 alkenyl or C 2 C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more 54 substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, Rm is

C

1 -Coalkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Also preferably, Rm is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 5 phosphono, thioxo, or cyano; or Rm is -Ls-RE, wherein Ls is a bond or C-C 6 alkylene, and RE is N(RsRs'), -O--Rs, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), -N(Rs)C(O)Rs'. -N(Rs)C(O)ORs', N(R,)SO 2 R,', -SO2R,, -SR,, or -P(O)(ORs)2, wherein R; and Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) C 1 -Calkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-C-C 6 alkyl or 3- to 6-membered 10 heterocycle; or Rm is C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Rm is C 3

-C

6 carbocycle or 3- to 6-memnbered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, 15 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl,

C

2 -Coalkenyl, C 2 -Calkynyl, C-C 6 1haloalkyl, C 2 -Qhaloalkenyl, C 2 -Chaloalkynyl, -C(O)ORs, or N(R,,R'). More preferably, RM is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or CI-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2

-C

6 alkenyl or C 2 -COalkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents 20 selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example Rm is CF 3 , C(CF 3

)

2 -OH, -C(CH 3

)

2 -CN, -C(CH 3

)

2

-CH

2 OH, or -C(CH 3

)

2

-CH

2

NH

2 . Also preferably Rm is -Ls RE where Ls is a bond and RE is -N(RsRs'), -O-Rs, -N(Rs)C(O)ORs', -N(Rs)SO 2 Rs', -SO 2 Rs, or SRs. For example where Ls is a bond, Rh is -N(C-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(CI-C 6 alkylene-O-Cr

C

6 alkyl)2 (e.g. -N(CH 2 CH2OMe)2); -N(CI-Cealkyl)(Cr-C 6 alkylene-O-CrC -alkyl) (e.g. 25 N(CH 3

)(CH

2 CI2OMe));--OC-C 6 alkyl (e.g., -O-Me, .-O-Et, -)-isopropyl, -0-tert-buiyl, -0-n hexyl); -0-C-C(haloalkyl (e.g., - OCF 3 , -OCH 2

CF

3 ); -O-C-C 6 alkylene-piperidine (e.g., -0 C1 2 CHl 2 -- piperidyl); -N(C-C 6 alkyl)C(O)OCj-C 6 alkyl (e.g., -N(CH 3

)C(O)O-CH

2

CH(CH

3

)

2 ), N(C -C 6 alkyl)SO 2

C-C

6 alkyl (e.g., -N(CI1 3

)SO

2 CI1 3 ); -SO 2

C-C

6 alkyl (e.g., -SO 2 Me); -SO 2 Ce

C

6 haloalkyl (e.g., -SO 2

CF

3 ); or -S-Cl-C 6 haloalkyl (e.g., SCF 3 ). Also preferably Rm is -Ls-RE where 30 Ls is C 1 -Calkylene (e.g., -CH 2 -, -C(CH 3 )-, -C(CI-1 3

)-CH

2 -) and Rh is -0-R,, -C(O)ORs, N(Rs)C(O)ORs', or -P(0)(ORs)2. For example Rm is -C,-C alkylene-O-Rs (e.g., -C(Cll 3

-)CH

2 OMe); -C-Cealkylene-C(O)ORs (e.g., -C(CH 3

)

2 -C(O)OMe); -C-C 6 alkylene-N(Rs)C(O)ORs' (e.g.,

-C(CH

3 )2--CH 2 -NHC(O)OCH3); or -Cj-C 6 alkylenc-P(O)(ORs)2 (e.g., -CH2-P(O)(OEt) 2 ). Also more preferably RM is C 3

-C

6 carbocycle or 3- to 6-membered heterocycle, each of which is independently 35 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 55

C

6 alkyl, C 2 -Coalkenyl, ( 2

-C

6 alkynyl, C -C6haloalkyl, C 2

-C

6 haloalkenyl, C 2 -Chaloalkynyl, C(O)OR,, or -N(RsRs'). For example Rm is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l miethylcycloprop-I-yl, cyclohexyl), phenyl, heterocyclyl (e.g., 'morpholin-4-yl, 1,1 dioxidothioiorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1 5 yl, piperidin-1-yl, 4-iiiethylpiperidin-1-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yi, pyridinyl, pyridin-3-yl, 6-(diimethylamiino)pyridin-3-yl). Highly preferably, RM is CI-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-hutyl, CF 3 ). X preferably is CS-C 6 ecarbocycle, 5- to 6-inembered heterocycle, or 6- to 12-membered X3 X3 10 bicycles (e.g., or , wherein X3 is N and is directly linked to -L.;-D), and is optionally substituted with one or more RA. Non-limiting examples of X arc described hereinabove. L, and L 2 are preferably independently bond or CI-C 6 alkylene, L 3 is preferably selected from bond, CI-COalkylene or -C(O)-, and Lj, L 2 , and L 3 are each independently optionally substituted with one or more RL. More preferably, Li, L 2 and L 3 are each independently bond or C-C 6 alkylene (e.g., 15 CH 2 - or -CH 2

CH

2 -), and are each independently optionally substituted with one or more RL. Highly preferably, LI, L 2 and L 3 are bond. R2 and R 5 , taken together with the atoms to which they are attached, preferably form a 5- to 6 membered heterocycle or 6- to 12-membered bicycle (e.g., or ), which is optionally substituted with one or more RA. 20 R, and Rl,, taken together with the atoms to which they are attached, preferably form a 5- to N 6-membered heterocycle or 6- to 12-membered bicycle (e.g., or which is optionally substituted with one or more RA H H N N G, and G2 preferably are each independently selected from / NN HN-N HN-\ or , and are each independently optionally substituted with one or more 56 H N RA (e-g., one or more chloro or broino). More preferably, G, is N (including any tautomer thereof), and G2 is N (including any tautomer thereof), and each G, and G 2 is independently optionally substituted with one or more RA (e.g., one or more chloro or bromo). -T-RD' can be, without limitation, independently selected at each occurrence from -C(O) 5 L,'-, -C(O)O-Ly'-R)', -C(O)-Ly'-N(R)C()-Ls"-R)', -C(O)-Ly'-N(R)C(O)O-Ls"-R)', N(RB)C(O)-l..y'-N(RB)C(O)-Ls"-RD', -N(RB)C(O)-.y'-N(RB)C(O)O-L.,s"-RD', or -N(RB)C(O) Ly'--N(RB)-Ls"-RD', wherein Ly' is each independently Ls' and, preferably, is each independently

CI-C

6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(O)-Ly'-M'-Ls"-RD' or 10 N(R,)C(O)-Ly'-M'-Ls"-RD'. More preferably, -T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(RB)C(O)-Ls"-RD' or -C(O)-Ly'-N(RB)C(0)O-Ls"-RD'- Highly preferably, T-RD' is independently selected at each occurrence from -C(O)-Ly'-N(RB)C(0)-Ro' or -C(O)-Ly' N(R)C(O)O-RI)', wherein Ly' preferably is each independently C 1 -CXalkylene (e.g., -CH,-) and optionally substituted with one or more substituents selected from R 1 . 15 Re' is preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from C-C 6 alkyl, C 2 C 6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3

-C

6 carbocycle or 3- to 6-memnbered heterocycle; 20 or C-Ccarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapio, anno, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formnyl, cyano, CI-Coalkyl,

C

2

-C

6 alkcnyl, C 2

-C

6 alkynyl, C-C 6 haloalkyl, C 2 -Cjhaloalkenyl or C 2

-C

6 lhaloalkyny L. RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 25 phosphono, thioxo, cyano; or CI-C 6 alkyl, C-C 6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or (? 3 -C(,carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 30 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj

C

6 alkyl, C 2 -Calkenyl, C-C 6 ulkynyl, Cl-Crhaloalkyl, C 2

-C

6 haloalkenyl or C 2

-C

6 hloalkynyl; or -LA O-Rs, -LA-S-Rs, -LA-C(O)Rs, -L,-OC(O)Rs, -LA-C(O)ORs, -LA-N(RsRs'), -LA-S(O)Rs, -LA

SO

2 Rs, -LA-C(O)N(RsRs'), -LA-N(Rs)C(O)Rs'. -LA-N(Rs)C(O)N(Rs'Rs"), -LA-N(Rs)SO 2 Rs', LA-SO 2 N(RsRs'), -L,-N(Rs)SO 2 N(Rs'Rs"), -LA-N(Rs)S(O)N(Rs'Rs"), -LA-OS(O)-Rs, -LA 57 OS(Oh-RS, -LA-S(O) 2 0Rs, -L,S(O)ORs, -- LA-OC(O)ORs, -LA-N(Rs)C(O)ORs', -LA OC(O)N(RsRs'), -l A-N(Rs)S(O)-Rs', --LA-S(O)N(RsRs') or -L.A-C(O)N(Rs)C(O)-Rs', wherein LA is bond, C-C 6 alkylene, C-C 6 alkenylene or C-C 6 alkynylene. More preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, 5 phosphonoxy, phosphono, thioxo, cyano; or CI-COalkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, forinyl or cyano; or Cr-Cocarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 10 hydroxy, nercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, forinyl, cyano, C 1 C 6 alkyl, C 2

-C

6 alkenyl, C-C 6 alkynyl, Cl-Chaloalkyl, C 2 -Cdhaloalkenyl or C 2 -Cdhaloalkynyl. Highly preferably, RA is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C 1

-C

6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 15 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. 1, Ls' and L.," preferably are each independently selected at each occurrence from bond; or

C

1

-C

6 alkylene, C-C 6 alkenylene or C 2 -COalkynylene. A and B can be the same or different. Likewise, L, and L 2 can be the same or different. 20 In one embodiment of this aspect, A, B, and D are each independently phenyl, and are each H NH N independently optionally substituted with one or more RA; and G, is , G2 is and each G, and G2 is independently optionally substituted with one or more RA (e.g., one or more R m AM RN RN RN )~ RN chloro or bromo). Preferably, D is or , wherein RM and RN are as defined above. L and L 2 are each independently bond or C-C 6 alkylene, and L 3 is bond, C 1

-C

6 alkylene or 25 C(O)-, and LI, L 2 , and L 3 are each independently optionally substituted with one or more RL Preferably, LI, L 2 , and L 3 are bond. -T-RD' is independently selected at each occurrence from -C(O) Ly'-N(R3)C(O)-Ls"-RD' or -C(O)-Ly'-N(RB)C(O)O-Ls"-RD', wherein Ly' is C 1

-C

6 alkylene (e.g., -CI1 2 -) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(O)-Ly'-Ls"-RD', -C(O)-Ly'-O 30 Ls"-RD', -C(O)-Ly'-N(RB)-Ls"-RD', or -C(O)-Ly'-N(RB)S(O) 2 -Ls"-RD 58 lie present invention also features the compounds of Formulae 1, IA, Ii, lc and 1 1 as described herein (including each embodiment described herein) or salts thereof, except that ) is Cr

C

12 carbocycle or 3- to 12-menibered heterocycle which is substituted with J and optionally substituted with one or more RA, where J is C 3 -C,2carbocycle or 3- to 12-meibered heterocycle and is optionally 5 substituted with one or more RA, or J is -SF 5 . Preferably, D is C-C 6 carbocycle, 5- to 6-miembered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and J is

C

3 -Ccarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA. More preferably, ) is C 5 -Ccarbocycle or 5- to 6-membered heterocycle and is optionally substituted with one or more RA, and J is C-C 6 carbocycle or 3- to 6-membered heterocycle and is optionally 10 substituted with one or more RA. Highly preferably, D is phenyl substituted with J and optionally substituted with one or more RA, where J is C 3

-C

6 carbocycle or 3- to 6-menbered heterocycle and is optionally substituted with one or more RA. Preferred RAs are as described above. In one J RN N RN RN embodiment, D is , wherein each RN is independently selected from RD and preferably is hydrogen, and J is as defined above and preferably is C 3

-C

6 carbocycle or 3- to 6-membered J 15 heterocycle optionally substituted with one or more RA. In another embodiment, D is , and J is

C

3

-C

6 carbocycle or 3- to 6-mnembered heterocycle and is optionally substituted with one or more RA. Moreover, the present invention features the compounds of Formulae 1, 1A, IH, Ica and I[ as described herein (including each embodiment described herein, as well as where ) is Cr C1 2 carbocycle or 3- to 12-memnbered heterocycle substituted with J and optionally substituted with 20 one or more RA as described hereinabove) or salts thereof, except that X is optionally substituted with . X3 one or more RA'. Specific examples of X are as described above, such as or X3 . wherein X 3 is N and is directly linked to -L 3 -D. Each RA' is independently RA; or C CloaLkyl, C 2 -Cioalkenyl or C 2 -Cloalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from 0, S or N and is optionally substituted with one or more RL. RA is as defined above. In 25 one embodiment, each RA' is independently RA; or CI-Cm(alkyl, C 2

-C

1 oalkenyl or C 2 -Cl)alkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from 0, S or N and is optionally substituted 59 with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. In another embodiments, each RA' is independently selected from RA; or C,-Cloalkyl, C 2 -Cjoalkenyl or C 2 -Cloalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 0 and is optionally substituted with one or more RL. In a further 5 embodiment, each RA' is independently selected front CI-CIoalkyl, C-C 1 oalkenyl or C 2 -Cloulkynyl, each of which contains 0, 1, 2 or 3 0 and is optionally substituted with one or more substituents selected front halogen, hydroxy, mnercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. In another aspect of the invention, each RA' is independently RA or -(Rx-Ry)N-(Rx-Ry'), 10 wherein N is 0, 1, 2, 3, 4; each Rx is independently 0, S or N(RB); each Ry is independently Cr

C

6 alkylene, C 2

-C

6 alkenylene or C 2

-C

6 alkynylene each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and Ry' is independently C 1

-C

6 alkyl, C 2 C 6 alkenyl or C 2

-C

6 alkynyl each of which is optionally substituted with one or more substituents 15 selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. RA and RH are as defined above. In one embodiment, each Rx is 0. For example, each R,' is selected from -(O-C-Calkylene)N-(O-C-C 6 alkyl), wherein N preferably is 0, 1, 2 or 3. In addition, the present invention features the compounds of Formulae I, lA' lB, IC and ID as 20 described herein (including each embodiment described herein, as well as where D is C 3 Cucarbocycle or 3- to 12-membered heterocycle substituted with J and optionally substituted with one or more RA as described hereinabove, or where X is optionally substituted with one or more RA' as described herein above), wherein: RE is independently selected at each occurrence from -O-Rs, -S-R 5 , -C(0)Rs, -OC(O)Rs, 25 C(O)ORs, -N(RsRs'), -S(O)Rs, -S0 2 Rs, -C(O)N(RsRs'), -N(Rs)C(O)Rs'. N(Rs)C(0)N(Rs'Rs"), -N(RS)S0 2 Rs', -SO 2 N(RsRs'), -N(Rs)SO 2 N(Rs'Rs"), N(Rs)S(O)N(Rs'Rs"), -OS(0)-Rs, -OS(0) 2 -Rs, -S(0)20Rs, -S(0)ORs, -OC(O)ORs, N(Rs)C(O)ORs', -OC(O)N(RsRs'), -N(Rs)S(0)-Rs', -S(0)N(RsRs'), -P(O)(ORs)2, or C(O)N(Rs)C(O)-Rs'; or C-C 6 alkyl, C 2

-C

6 alkenyl or C 2

-C

6 alkyiyl, each of which is 30 independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3

-C

6 carhocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at cache occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, 35 nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CI-C 6 alkyl, C 2

-C

6 alkenyl, 60

C

2 -Calkynyl, C-C 6 1haloalkyl, C-Cshaloalkenyl, C2-Chaloalkynyl, C(O)ORs, or N(RsRs'); and Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; Cj Calkyl, C2-C 6 alkenyl or C 2

-C

6 alkynyl, each of which is independently optionally 5 substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -0-C-C(,alkyl, -0--C -C 6 alkylene-O-C -C 1 alkyl, or 3- to 6-nembered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs , Rs' or Rs' is independently optionally 10 substituted at each occurrence with one or more substituents selected from halogen, hydroxy, nercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 1 -Cealkyl, C 2 -Calkenyl, C 2

-C

6 alkynyl, CI-C 6 haloalkyl, C 2

-C

6 haloalkenyl or C 2 C 6 haloalkynyl. The compounds of the present invention can be used in the form of salts. Depending on the 15 particular compound, a salt of a compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability under certain conditions or desired solubility in water or oil. In some instances, a salt of a compound may be useful for the isolation or purification of the compound. Where a salt is intended to be administered to a patient, the salt preferably is pharmaceutically 20 acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base addition salts, and alkali metal salts. Pharmaceutically acceptable acid addition salts may be prepared frotn inorganic or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Examples of suitable 25 organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamnate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, 30 phenylacetate, mandelate, embonate (panoate), nethanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentancpropionatc, dodecylsulfac, glycoheptanoatc, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, 35 palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate. 61 Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts and organic salts. Non-limiting examples of suitable metallic salts include alkali metal (group [a) salts, alkaline earth metal (group Ila) salts, and other pharmaceutically acceptable metal salts. Such salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, 5 sodium, or zinc. Non-limiting examples of suitable organic salts can be made from tertiary amnines and quatenhary amine, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides), dialkyl 10 sulfates (e.g., dimethyl, diethyl, dibuyll, and diatmyl sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. The compounds or salts of the present invention may exist in the form of solvates, such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate). 15 The compounds or salts of the present invention may also be used in the form of prodrugs. Some prodrugs are aliphatic or aromatic esters derived from acidic groups ont the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs. The compounds of the invention may comprise asymmetrically substituted carbon atoms 20 known as chiral centers. These compounds may exist, without limitation, as single stereoisomers (e.g., single etantioners or single diastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomers or diastereomers), or racemic mixtures. Compounds identified herein as single stereoisoners are meant to describe compounds that are present in a form that is substantially free from other stereoisomers (e.g., substantially free from other enantiomers or diastereomers). By 25 "substantially free," it means that at least 80% of the compound in a composition is the described stereoisomner; preferably, at least 90% of the compound in a composition is the described stereoisoner; and more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the described stereoisomer. Where the stereochemistry of a chiral carbon is not specified in the chemical structure of a compound, the chemical structure is intended to encompass 30 compounds containing either stereoisoner of the chiral center. Individual stereoisomers of the compounds of this invention can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastercomers, chromatographic resolution of enantiomners, conversion of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically 35 separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution. 62 Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral centers. Mixtures of stercoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for 5 example, by chromatographic techniques as appreciated by those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography resins, many of which are commercially available. In a non-limiting example, racemate is placed in solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be separated by H PLC. 10 Resolution of enantioners can also be accomplished by converting enantiomers in a mixture to diastereoiners by reaction with chiral auxiliaries. The resulting diastereomners can be separated by column chromatography or crystallization/re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will forn a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include 15 chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers are separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again. Enzymes, such as esterases, phosphatases or lipases, can be useful for the resolution of derivatives of enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl 20 group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester. Alternatively, salts of enantiolers in a mixture can be prepared using any suitable method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as 25 alkaloids or phenethylainine, followed by precipitation or crystallizalion/re-crystallization of the enantioierically pure salts. Methods suitable for the resolution/separation of a mixture of stereoisoners, including racemic mixtures, can be found in ENANTIOMERs, RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons, New York, NY). A compound of this invention may possess one or more unsaturated carbon-carbon double 30 bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are intended to be encompassed within the scope of a recited compound unless otherwise specified. In addition, where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tauloneric forms. Certain compounds of the invention may exist in different stable conformational forms which 35 may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond, 63 for example because of steric hindrance or ring strain, may permit separation of different conformers. The invention encompasses each conlormational isomer of these compounds and mixtures thereof. Certain compounds of the invention may also exist in zwilterionic form and the invention encompasses each zwitterionic form of these compounds and mixtures thereof. 5 The compounds of the present invention are generally described herein using standard nomenclature. For a recited compound having asymmetric center(s), it should be understood that all of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms, 10 the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., A, B, D, X, LI, L 2 , L 3 , Y, Z, T, RA or RB,). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. If moieties are described as being "independently" selected from a group, each 15 moiety is selected independently from the other. Each moiety therefore can be identical to or different from the other moiety or moieties. The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "C,-Cy," where x is the minimum and y is the maximum number of carbon atoms in the moiety. Thus, for example, "C-C 6 alkyl" refers to an alkyl substituent containing from I to 6 carbon atoms. Illustrating 20 further, C 3

-C

6 cycloalkyl tmcans a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms. A prefix attached to a multiple-component substituent only applies to the first component that immediately follows the prefix. To illustrate, the term "carbocyclylalkyl" contains two components: carbocyclyl and alkyl. Thus, for example, C-CccarbocyclylCr.Calkyl refers to a C 3 -Ccarbocyclyl appended to the parent molecular moiety through a C-Cralkyl group. 25 Unless otherwise specified, when a linking element links two other elements in a depicted chemical structure, the leftmost-described component of the linking element is bound to the left element in the depicted structure, and the rightmnost-described component of the linking element is bound to the right element in the depicted structure. To illustrate, if the chemical structure is -Ls-M Ls'- and M is -N(RB)S(O)-, then the chemical structure is -Ls-N(RB)S(O)-Ls' 30 If a linking element in a depicted structure is a bond, then the element left to the linking element is joined directly to the element right to the linking element via a covalent bond. For example, if a chemical structure is depicted as -L.,s-M-Ls'- and M is selected as bond, then the chemical structure will be -Ls-Ls'-. If two or more adjacent linking elements in a depicted structure are bonds, then the element left to these linking elements is joined directly to the element right to 35 these linking elements via a covalent bond. For instance, if a chemical structure is depicted as -Ls M-Ls'-M'-Ls"-, and M and Ls' are selected as bonds, then the chetnical structure will be -Ls-M' 64 Ls"--. Likewise, if a chemical structure is depicted as -L.-M-Ls'-M'-Ls"-, and M, Ls' and M' are bonds, then the chemical structure will be -Ls-L. When a chemical formula is used to describe a moiety, the dash(s) indicates the portion of the moiety that has the free valence(s). 5 If a moiety is described as being "optionally substituted", the moiety may be either substituted or unsubstituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a 10 heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with less than three substitutable positions will be optionally substituted by up to only as many non hydrogen radicals as the heterocycle has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to two 15 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only one non-hydrogen radical. The term "alkenyl" means a straight or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the 20 alkenyl moiety, relative to groups substituted on the double bond carbons. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl. The term "alkenylene" refers to a divalent unsaturated hydrocarbyl chain which may be linear or branched and which has at least one carbon-carbon double bond. Non-limiting examples of 25 alkenylene groups include -C(H)=C(H)-, -C(H)=C(H)-CH 2 -, -C(H)=C(H)-CH 2

-CH

2 -,

-CH

2

-C(H)-C(H)-CH

2 -, -C(H)=C(H)--CH(CHll 3 )-, and -CH 2 -C(l)=C(H)-CI(CH 2

CI

3

)

The term "alkyl" means a straight or branched saturated hydrocarbyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t butyl, pentyl, iso-amyl, and hexyl. 30 The term "alkylene" denotes a divalent saturated hydrocarbyl chain which may be linear or branched. Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2

CH

2 -, CH 2 CH Cl-Ir-, -CH 2

CH

2

CH

2

CH

2 -, and -CH 2

CH(CH

3 )CHr. The term "alkynyl" means a straight or branched hydrocarbyl chain containing one or more triple bonds. Non-limiting examples of alkynyl include ethynyl, I -propynyl, 2-propynyl, 3-propynyl, 35 decynyl, I -butynyl, 2-butynyl, and 3-butynyl. 65 'he term "alkynylene" refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bonds. Representative alkynylene groups include, by way of example, -C=C-, -C C-CH 2 -, -C=C-Cl 2

-CH

2 -, -Cl 2

-CEC-CH

2 -, --CC-CH(CH 3 )-, and -Cl 2

-C-C-CH(CH

2

CH

3 )-. 5 The term "carbocycle" or "carbocyclic" or "carbocyclyl" refers to a saturated (e.g., "cycloalkyl"), partially saturated (e.g., "cycloalkenyl" or "cycloalkynyl") or completely unsaturated (e.g., "aryl") ring system containing zero heteroatom ring atom. "Ring atoms" or "ring members" are the atoms bound together to form the ring or rings. A carbocyclyl may be, without limitation, a single ring, two fused rings, or bridged or spiro rings. A substituted carbocyclyl may have either cis or trans 10 geometry. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl. adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, and norpinanyl. A carbocycle group can be attached to the parent molecular moiety through any 15 substitutable carbon ring atom. Where a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as A in Formula I), the carbocycle group can be attached to the two other elements through any two substitutable ring atoms. Likewise, where a carbocycle group is a trivalent moiety linking three other elements in a depicted chemical structure (such as X in Formula I), the carbocycle group can be attached to the three other elements through any 20 three substitutable ring atoms, respectively. The term "carbocyclylalkyl" refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group. For instance, C 3

-C

6 carbocyclylCi-C 6 alkyl refers to a C3 Crcarbocyclyl group appended to the parent molecular moiety through Ci-Calkylene. The term "cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclyl moiety 25 having zero heteroaomi ring member. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and ociahydronaphthalenyl. The term "cycloalkyl" refers to a saturated carbocyclyl group containing zero heteroaomn ring member. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl. 30 The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, "C 1

-C

6 haloalkyl" means a

C

1

-C

6 alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals. Non-limiting examples of CI-C 6 haloalkyl include chloromethyl, 1-bromoeihyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if 35 a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated). 66 The term "heterocycle" or "heterocyclo" or "heterocyclyl" refers to a saturated (e.g., "heterocycloalkyl"), partially unsaturated (e.g., "heterocycloalkenyl" or "heterocycloalkynyl") or completely unsaturated (e.g., "heteroaryl") ring system where at least one of the ring atoms is a heteroaton (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently 5 selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocycle may be, without limitation, a single ring, two fused rings, or bridged or spiro rings. A heterocycle group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group. Where a heterocycle group is a divalent moiety that links two other elements in a depicted chemical structure (such as A in Formula I), the heterocycle group can be attached to the two other elements 10 through any two substitutable ring atoms. Likewise, where a heterocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I), the heterocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively. A heterocyclyl may be, without limitation, a monocycle which contains a single ring. Non 15 limiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrol idinyl, imidar.olyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triaz7olyl, tetrazolyl, dithiolyl, oxathiolyl, oxar.olyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, ihiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl"), 20 1,2,5-oxadiazolyl (also known as "furazanyl"), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4 oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2 dioxazolyl, and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "l,3-diazinyl"), and pyrazinyl (also known as "l,4-dia.inyl")), 25 piperazinyl, Iriazinyl (including s-triazinyl (also known as "l,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 30 1,3,5,2-oxadiazinyl), tnorpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl, and diazepinyl. A heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,61 naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimnidinyl, pyridopyrimidinyl, pyrazolopyriiiidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 411-quinolizinyl, purinyl, pyridopyridinyl (including 35 pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Other non-limi ting examples of fused-ring heterocycles include benzo-fused 67 heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl" or indazolyl), benzazinyl (including quinolinyl (also known as "I benzazinyl") and isoquinolinyl (also known as "2-benzazinyl")), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as "l,2-benzodiazinyl") and 5 quinazolinyl (also known as "1,3-benzodiazinyl")), benzopyranyl (including "chronenyl" and "isochromenyl"), benzothiopyranyl (also known as "thiochromenyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzoluranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thionaphthenyl", and "benzothiofuranyl"), isobenzothienyl (also known as 10 "isobenzoihiophenyl", "isothionaphihenyl", and "isobenzothiofuranyl"), benzothiazolyl, 4,5,6,7 tetrahydrobenzo[d]Ihiazolyl, benzothiadiazolyl, benzimnidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl), and tetrahydroisoquinolinyl. A heterocyclyl may also be, without limitation, a spiro ring system, such as, for example, 1,4 15 dioxa-8-azaspiro(4.51decanyl. A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or S02. The nitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the nitrogen heteroatom(s) may or may not be N-protected. 20 == in a chemical formula refers to a single or double bond. The term "pharmaceutically acceptable" is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product. The term "therapeutically effective amount" refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load. 25 The term "prodrug" refers to derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the conipoundls of the invention which are pharmaceutically active in vivo. A prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group). Prodrugs often offer advantages of 30 solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H., DESIGN OF PRoDRtiS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or aides prepared by reaction of the parent acid compound with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formnate, benzoate or 35 other acylated derivatives of alcohol or amnine functional groups within the compounds of the invention. 68 The term "solvate" refers to the physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" 5 encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and iethanolates. The term "N-protecting group" or "N-protected" refers to those groups capable of protecting an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS rN CHEMICAL SYNTiEsis (3d ed., John Wiley & Sons, NY 10 (1999). Non-limiting examples of N-proiecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bronoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p 15 methylphenyl-S(O)-) or t-butylsulfinyl (t-Bu-S(O)-); carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4 dimethoxybenzyloxycarbonyl, 3,5-di methoxybenzyloxycarbonyl, 2,4-diimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 20 trimethoxybenzyloxycarbonyl, I -(p-biphenylyl)- I -methylethoxycarbonyl, dimethyl-3,5 di methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl; 25 alkyl groups such as bcnzyl, p-mnethoxybenzyl, triphenylnethyl, or benzyloxymethyl; p mnethoxyphenyl; and silyl groups such as trimnethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, 1-butylacelyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The compounds of the present invention can be prepared using a variety of methods. As a 30 non-limiting example, the compounds of the present invention can be prepared according to Scheme I starting from compounds of Formula i (e.g., n = 0 to 8), Formula V (X 4 can be, for example, 0 or NRA, where R, is as described hereinabove and is preferably 1-1 or RE as defined above such as Cl C6alkyl, 3- to 12-mnembered carbocycle or heterocycle, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs'), SO 2 N(RsRs'), -S(O)2ORs, -S(0)ORs, -S(O)N(RsRs'), or a suitable protecting group such as Boc or 35 Fmoc), or Ponnula VIll (E can be, for example, 3- to 7-membered carbocycle or heterocycle and is optionally substituted with one or more RA), wherein A, B, D, Y, Z and RA are as described above. 69 The 1,4-diketones 11, V, and VIll can he reduced to the 1,4-diols using the methods described below, and the resultant racemic, enantiomerically enriched, or meso 1,4-diols may be converted to the dimesylates III, VI, or LX, or alternatively to ditriflates, ditosylates, or dihalides by the methods described below. The dimesylates LII, VI, and IX, ditriflates, ditosylates, or dihalides may be reacted 5 with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4 fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl ainines, substituted benzylatnines, or allylamine, under the conditions described below to give the compounds of the invention. l. and l 2 can he readily introduced to Formulae II, V and Vill, as appreciated by those skilled in the art in light of the present invention. Likewise, )-L.3 10 NI-I 2 can be used instead of D-NI-1 2 , as appreciated by those skilled in the art. Q Y Z y ~ ~ Q ~Y A B Z nn rV x 4 x OMs ON! Q1 13 Y A Q B VIII Ix x Scheme I As another non-limiting example, the compounds of the present invention can be prepared 15 starting from compounds of Formula II and Formula III as shown in Scheme II. The 1,4-diketones such as Formula IV may be prepared using known methods (see Nevar, et al., Synthesis:1259-1262 (2000), such as the reaction of a-bromoketones such as Formula 1l with methyl ketones such as Fonnula III in the presence of a suitable Lewis acid such as ZnC 2 or Ti(0iPr) 4 . The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of NaB- 4 , LiAlH 4 , or DIBAL. Alternatively, 20 enantioselective reduction of I,4-diketones such as Fonnula IV can be accomplished by analogy with reported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418 (1995), Li, et al., Tetrahedron 63:8046-8053 (2007), Aldous, et al., Tetrahedron: Asymmetry 11:2455-2462 (2000), 70 Masui, et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal. 347:1193-1197 (2005), Sato, et al., Synthesis:1434-1438 (2004)), such as reduction with (-) or (+)-diisopinocamheylchloroborane (D[P-cliloricle), with borane and an oxazaborolidine catalyst, or with asymumetric hydrogenation in the presence of a suitable Ruthenium (11) catalyst, such as [RuCl2((R)-BINAP){(R,R)-DPEN] 5 (BINAP=2,2'-bis(diarylphosphino)-1,1'-binaphthyl; DPEN=I,2-diphenylethylenediamine). The resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be reacted with methanesulfonyl chloride to provide the dimesylate Formula VI. Alternatively Formula V may be converted to a ditriflate or ditosylate by the action of p-toluenesulfonyl chloride or triflic anhydride, or to a dihalide such as a dibromide or dichloride by the action of PPh 3 in the presence of CC4 or 10 CBr 4 , or by the action of SOCl 2 , POC1 3 , or PBr 3 . The dimesylaie, ditriflate, ditosylate, or dihalide may be reacted with an amine, such as 4-fluoroaniline (as shown for illustration in Scheme II), with or without a co-solvent such as DMF at room temperature to 100 *C, to give the pyrrolidines such as Formula VII. In addition to 4-fluoroaniline, alternative aimines may be reacted with the dimesylate Formula VI, including but not limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 3 15 fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylatnine. The dinitro Formula VII may be reduced to the diamino Formula VIII using Fe in the presence of N1 4 C, I-CI, or acetic acid, or by treatment with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as BiCl 3 , SbCI 3 , NiC 2 , Cu 2 Cl 2 , or CoC12) in a solvent such as ethanol or THF. 20 Alternatively, Formula VII can be reduced to the product Formula VIII by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. The diamine Formula VIII may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fnoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC/HOB'T, PyBOP, HATU, or DEBP', in a solvent such as THF, DMF, dichloromethane, or 25 DMSO, with or without the addition of an atnine base such as Hunig's base, pyridine, 2,6-lutidine, or triethylamnine, to give Formula IX Removal of the Boc protecting groups to give X may be accomplished by treatment with an acid, such as TFA, HCI, or formic acid. Compounds of the present invention may be prepared by coupling of Formula X with an acid of choice using the standard peptide coupling reagents and conditions described above. Alternately, diamine VIII may be reacted 30 with an N-substituted proline in the presence of a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P, or DEIPT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an atnine base such as Hunig's base, pyridine, 2,6-lutidine, or triethylamine, F to directly give compounds of the present invention (Formula XI). ~ in each Formula within 71 Schemc 11 can he replaced with - where D is defined above, and such compounds can be readily prepared according to the process described in Scheme 1I (including making compound XI directly from compound VIII). N Br NO2 N N2 Br m C)2N 0 02N NO 2NN N NH V X IX 0,N vi S O 0 2 N v iI 5 XI F F~ F N I..C I H~ Schem II N N N 0 BocO ' N O O x Ix H N N'N> 0N 0' 5 X1 Schetme 11 As yet another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula 11 and Formula III as shown in Scheme III, wherc A, B, D, Y, 10 and Z are as described above, using conditions similar to those described above for the preparation of IV in Scheme 1. Similarly, the resulting 1,4-diketone IV may be reduced to the 1,4-diols V using the methods described above for Scheme II. The resultant racenic, enantiomerically enriched, or meso 1,4-diols V may be converted to the dimesylate VI or alternatively to a ditriflate, ditosylate, or dihalide by the methods described above. The dimesylate VI, ditriflate, ditosylate, or dihalide may be 72 reacted with an amine, including but not limited to, aniline, 3,5-difluoraaniline, 3,4-difluoroaniline, 4 fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl antines, cycloalkyl amines, substituted benzylanines, or allylatnine, under the conditions described above the give the compounds of the invention. Alternatively, compounds such as VIII, where R is a 5 group such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, may be treated with reagents useful for the removal of the R group (rhodium catalyst such as Rh(Ph 3

P)

3 C for R = allyl, treatment with an acid such as TFA or HCI for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to generate compounds such as IX. Amine IX may he reacted with an aryl halide or triflate such as X (iodide shown for illustration) employing the Buchwald 10 lartwig reaction in the presence of a palladium catalyst (such as Pd(OAc)2 or Pd 2 (dba)3) and a phosphine ligand (such as triphenylphosphine or XantPhos) and a base (such as sodium bis(trimethylsilyl)amide, potassium tert-butoxide, or K 3

PO

4 ) to give the compounds of the present invention. Alternatively, the compounds of the present invention may be obtained by reaction of IX with an aldehyde or ketone through reductive amnination in the presence of a hydride reducing agent, 15 such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid, such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane. Alternatively the reductive amination may he conducted through the use of hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, amine IX may react with electrophilic reagents, such as alkyl halides, or with aryl electrophiles (suitably electron deficient 20 aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give the compounds of the present invention. 73 Y -Br O Z HO HO vY Y N H 2 Y A 1 Z N Y z Y z NN Ix ViIl R = allyl or substitued benzyl Scheme III 5 As a further non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula 11 and Formula III as shown in Scheme IV, where X 5 in Formula IH and Formula Il1 represents a halogen (e.g., Cl, Br, or F) or a nitro group. The 1,4-diketones such as IV may be prepared using known methods described above for the preparation of IV for Scheme LI. The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of NaBI 4 , LiAIH 4 , or 10 DIBAL. Alternatively, enaniioselecfive reduction of 1,4-diketone such as IV can be accomplished by the methods described above for the preparation of V for Scheme II. The resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be reacted with methansulfonyl chloride to provide the dimesylate VI. Alternatively V may be converted to a ditriflate or ditosylate by the methods described above for Scheme II. The dimesylate, ditriflate, ditosylate, or dihalide may be 15 reacted with an amine including but not limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4 fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl 74 amines, cycloalkyl amines, substituted benzylamines, or allylamine to give VII. When X 5 in Formula VII is nitro, the nitro groups may he reduced to the tetraamino product IX using Fe in the presence of

NH

4 CI, HCI, or acetic acid, or with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as BiCl 3 , SbCl 3 , NiC1 2 , Cu 2

CI

2 , or CoCl 2 ) in a 5 solvent such as ethanol or THF. Alternatively, VII (Xs = nitro) can be reduced to the product LX by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, compounds VII where X.5 = halogen may be reacted with ammonia (R = H) or an amine hearing a suitable protecting group (R = substituted benzyl such as 4-methoxybenzyl or 2,4 dimethoxybenzyl or R = ally]). 'lhe resulting products VIil may be treated with a reagent useful for 10 the removal of the R protecting group (rhodium catalyst such as Rh(Ph 3

P)

3 Cl for R = allyl, treatment with an acid such as TFA or HCI for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to give the product IX. Formula LX may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC/ 103T, PyBOP, IATU, or DEBPT, in a 15 solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base, such as Hunig's base, pyridine, 2,6-lutidine, or triethylanine, to give X as a mixture of the amide products. Conversion to the benzimidazole compound XI may be accomplished by heating X in acetic acid (50-100 "C). Alternatively, XI may be prepared by reaction of IX with an aldehyde, followed by treatment with an oxidant, such as Cu(OAc) 2 or MnO 2 (see Penning, et al., Bloorg. Med. 20 Chemn. 16:6965-6975 (2008). After removal of the Boc protecting groups from XI (accomplished by treatment with an acid, such as TFA, HCI, or formic acid), the compounds of the present invention may be prepared by coupling of the resulting diamine XH with an acid of choice using the standard F peptide coupling reagents and conditions described above for Scheme II. 0 in each Formula within Scheme IV can be replaced with "'* where I) is defined above, and such compounds can 25 be readily prepared according to the process described in Scheme IV. 75 (0 0 , O.N N - 'A Br 02N 0 O.N NN 2 x 5 k) X X5 i OMs S X 5 OH X. o ar 02N o NN NO, .- V1 OMs xi -00 O1 xi V R R X x Nx N N =0N xi 0N NO 511 Vill F R H,N /H C(Y .NI N Ni H.1N NH, o H,N NH, 0 BoC: Ix F 17 N~ N N NTHoN ' NN Anixn SN roc X Bo N N\~I~ NN >= hao0 or1 No, Scheme TV Alternatively IX in Scheme [V Inay be prepared from a compound of Formula 11 as shown in 5 Scheme V. Compound VIII from Scheme II may be treated with an acylating agent such as acetyl chloride or acetic anhydride to give compound 11 (Scheme V). Nitration of compound L1 to provide II may be accomplished using known methods, such as treatment with nitric acid or potassium nitrate in the presence of an acid such as sulfuric acid or treatment with NO2BF 4 . Removal of the acetanide protecting group may be accomplished by treatment with Boc anhydride in the presence of DMAP to 76 give IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or LiOH) to remove the acetyl group and a strong acid such as TFA or HCl to remove the Boc protecting group. The nitro groups in V may be reduced to amino groups using the methods described above for Scheme IV. in each Formula within Scheme V can be replaced with ^ where D is 5 defined above, and such compounds can be readily prepared according to the process described in Scheme V. F F AcHN / N HAc AcHN NAc N NH~ 0,N NO, 1n1 F F Boc Boc

H

2 NN NNH 2 AcN NNAc N' 02,N IN02 0 2 N NO, F

H

2 N NH NXNH HN NH- 2 LX in Scheme tV Scheme V 10 As still another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II as shown in Schetne VI, where A, B, D, Y, and Z are as described above. A 1,4-diketone compound of Formula II (prepared as described in Scheme fit) may be reacted with an atnie, including but not limited to, aniline, 3,5-difluoroaniline, 3,4 difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl 15 atnines, alkyl amines, cycloalkyl aminies, substituted benzylatnines, or allylanie, under acid catalyzed conditions, such as acetic acid, TFA, fortnic acid or HICI, to give the compounds of the invention. 77 YYZ Scheme VI 5 As a further non-limiting example, the compounds of the present invention can be prepared from a compound of Formula II as shown in Scheme VII. A compound of Formula Hl, where Rx is a halogen, such as bromo, chloro, or iodo, or a triflate or a nonaflate may be converted to a boronic acid or ester such as Formula III, where R is hydrogen, methyl, ethyl, or a cyclic pinacolate ester. For 10 example a compound of Formula II can be transformed to a compound of III by treatment with pinacol-borane in the presence of a catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), and a ligand such as, for example, tri-t-butylphosphine, in solvents such as, for example, tetrahydrofuran, dioxane, or toluene at temperatures ranging from ambient to about 130C. Alternatively, compound Il can be reacted with bis(pinacolato)diboron in the presence of a catalyst 15 such as, for example, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA), dichloro[,l' bis(diphenylphosphino)ferrocene] palladium (II) dichloronethane adduct, or palladium acetate in the presence of a ligand such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and a base such as, for example, potassium acetate in solvents such as, for example, toluene, dioxane, tetrahydrofuran, dimethylformainide or dimethyl sulfoxide at temperatures from about 60 to 20 about 130*C to give compound Ill. Alternatively, a compound of Formula II may be reacted with an organolithium reagent, such an n-Bul,i, sec-Bul.i, or t-BuLi, followed by reaction with trimethyl borate or triethyl borate, to give a compound of Formula III. A compound of Formula III in Scheme VII can be coupled with a compound of Formula IV, where Ry is a halogen, such as bromo, chloro or iodo, under Suzuki reaction conditions to provide a 25 compound of Formula V. Such conditions include, for example, use of a palladium catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, or dichloro[l,1'-his(diphenylphosphino)ferrocene] palladium (11) dichloromethane adduct; base such as, for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate, 30 cesium carbonate, or cesium fluoride; and solvent such as, for example, toluene, ethanol, water, or tetrahydrofuran, or mixtures thereof heated in the temperature range from about 40 to about 130'C. Removal of the Boc protecting groups from V may be accomplished by treatment with an acid, such as TFA, I-IC, or formic acid. Compounds of the present invention such as VI may be prepared by coupling the resulting amino compounds with an acid of choice using the standard 35 peptide coupling reagents, such as EDAC/HOBT, PyBOP, HATU, or DEBPT, in a solvent such as 78 THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as Hunig's base, pyridine, 2,6-lutidine, or triethylamine. Each Rz is independently -Ly'-M'-R 0 (e.g., Ly-N(RB")C(0)-Ls-RE), and D, L 3 , RI, R 2 , R 5 , Ly, RB", Ls, RE LY', M' and RD are as defined above. D OR D OR R Rx RO- -OR I - -C II j RY H Bo N

RR

1 N NRR R N . IV R, RN N RR, R N N Rz 5V Scheme VII As another non-limiting example, the compounds of the present invention can be prepared according to Scheme VIII starting from the compound of Formula II, initially cleaving the diol in 10 oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde intermediate is then treated with an aryl boronate or aryl boronic acid (compound IV where A and Y are as described previously, or compound VII) and aniline III (where W is RM or J, and RM and J are as defined above) resulting in the formation of Formula V or Formula VIII respectively. Formula V can be derivatized by deprotonating the hydroxyl groups with a strong base such as sodium hydride, 15 butyl lithium, or potassium hydride, followed by alkylation with Rs-halogen. Alternatively Formula VIll can be dleprotonated with a strong base (e.g., sodium hydride) and alkylated with R 5 -halogen as well, followed by acid hydrolysis of the phenol protecting groups. The sulfonylation of the phenols with nonafluorobutylsulfonyl fluoride in the presence of a neutralizing agent such as potassium carbonate in a polar aprotic solvent such as DMF, followed by beating provides a compound of 20 Formula IX. Boronate of Formula X is produced by heating Formula LX with bis(pinacolato)diboron in the presence of X-phos and a palladium catalyst, such as Pd2(dba)3 and a base such as potassium acetate in an organic solvent such as dioxane. Formula X is further derivatized to final product by heating a suitably substituted heteroarylhalide in the presence of a palladium catalyst such as 79 I1 PdCI2(dppf) in the presence of a base such as sodium carbonate in a mixture of toluene and ethanol. w Rs is as defined above. * in each Formula within Scheme VIII can be replaced with '' where D is defined above, and such compounds can be readily prepared according to the process described in Scheme VIII. W W 1) Phl(OAc)2 NaH 2) H. ' N R,-Halogen N HO HO OH 3) D HO' THFRDMF HgN W W Ww NaH C F~S,.O . \ ,Halogen CFSy Phl(OAc) 2 THF/DMF 3)B.N 0&R2H+Q & -02SC.F6 ) HW 9 K 2 H+ ~~cF 3OH HO OH 3 C4F SO2F R K2CO3, DMF O s R - 4-(CHO)BenzyI ViI Ix III VII ,B- 0 X-Phos, Pd2(dba)3 KOAc. dioxane A Y Y-Br. Pd' N3 2 C0N Y Na2CO3 1 I lolueneVEIOH a 5S "'!0, 5 XI X Scheme VIII As yet another non-limiting example, the compounds of the present invention can be prepared according to Scheme LX starting from the compounds of Formula U1 and Formula Ill. 10 Formula Ill carboxylic acid is activated towards coupling using reagents such as isobutylchloroformale, DCC, EDAC, or HATU in the presence of an organic base, such as diisopropylethylamine. Upon activation, dianiline of Formula II is added to the reaction, with the isolation of an intermediate aide, which is heated in acetic acid, preferably at 60 "C, to yield the compound of Formula IV. The benzimidazole of Formula IV is treated with SEM-Cl in the presence 15 of a base in an aprotic solvent such as TIF, yielding two protected benzimidazole regioisomers V. The boronate esters VI are produced by heating Formula V with bis(pinacolato)diboron in the presence of a palladium catalyst, such as PdCl2(dppf), X-Phos, and a base such as potassium acetate in an organic solvent such as dioxane. Healing yields both bcnzimidazole regioisoners VI. Diol VII 80 is cleaved in oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde intermediate is then treated with an aryl boronate VI and aniline V1II (where W is Rm or J, and RM and J are as defined above) resulting in the formation of the 3 benzinidazole regioisomers of Formula IX. Formula X is produced by deprotonating the hydroxyl groups with a strong base such as 5 sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with Rs-halogen, followed by acid hydrolysis of the pyrollidine and benzimidazole protecting groups, preferably by treatment with mineral acid, such as hydrochloric acid in an alcoholic solvent such as methanol. The carboxylic acid Rz-COOH is activated towards coupling using reagents such as isobutylchloroformatc, DCC, EDAC, or HATU in the presence of an organic base, such as 10 diisopropylethylamine. Upon activation, Formula X is added to the reaction, with the isolation of Formula XI. ' in each Fonnula within Scheme IX can be replaced with where D is defined above, and such compounds can be readily prepared according to the process described in Scheme IX. I5 1) HATU H Oa N IPEA Br'I N SEM -CI B ~N ~ N _____NaH "C , BDMSO N TH 62% Overall NH r 2) HOAC -N - N N (both regloisomers) 60 OC I I v V PinB, PdCI(dppI) KOAc Dioxane S 90 "c, 1 h W\ ON NJ(both regioisorners) N N S I . t O O c N 1H NaH L) oge (3 regiomsomers) Boc W I', - iatogen5\ THF/DMF 2 HCI. MeOH vil NH bH W WI _ C HATU. RzCOOH Hii NHH OH N H 5 or N zO NHN ROR O? RsO X IN X1h R1 ND Scheme IX 81 Compounds of the invention of general formula (8), where R2) is -Ls'-M'-L..s"-R) and ) is as described above, can he prepared according to the methods of Scheme X. The bromoalkylketone (1) can be reacted with an arylalkylketone (2) using the Lewis acid mediated conditions, described above in Scheme 11, to give the diaryldiketone (3). The diketone (3) can be converted to the 5 bisboronate (4) by reaction with bis(pinacolato)diborane in the presence of a base such as potassium acetate, a catalyst such as PdCl(dppf)-C-l 2 Cl:, in a solvent such as DMSO, dimethoxyethane or dioxane with heating to between 60-100 *C. Bisboronate (4) can be converted to the intermediate (5) by Suzuki reaction using, in analogous fashion, the Suzuki conditions described in Scheme VII. The intermediate (5) can be converted to (6) by reaction with an amine D--NIH 2 under the analogous 10 conditions described iin Scheme V I. For example, reaction of (5) with D-NI-1 2 in the presence of an acid such as, but not limited to, TFA, in a solvcnt such as, but not limited to, toluene and with heating up to 110 *C can provide intermediates of general structure (6). Compounds (6) can be converted to compounds of general formulas (7) and then (8) using, in analogous fashion, the methods described in Scheme VII. Br Br Br (1) (2) (3) N O . Bc OH H N N (4) Boc (5) <jN 0' 0 NNJ10 (6) (7) H NH HN NNH C~>~NN NN 15 (() Scheme X The intermediates (6) can also be prepared using the route depicted in Scheme XI. The intermediate (3) can be reacted with an amine D-NIH 2 using, in analogous fashion, the conditions 20 described in Schemes VI and X to provide intermediates (9), which can be converted to (10) using, 82 analogously, conditions as described above in Scheme X; and (10),in turn, can he converted to compounds (6) using the Suzuki reaction conditions described in Scheme VII. (3) Br /Br BB (6) (9) (10) Scheme XI 5 Compounds of the invention of general formula (15), where R 20 is -[-s'-M'-L 5 s"-RD and ) is as described above, can be prepared according to the methods of Scheme XH. Compounds (11) can prepared according to the procedures to convert (3) to (9), using general conditions as described in Scheme VI, such as by reacting an appropriate nitrophenyldiketone with an amine D-NI1 2 with 10 heating in acetic acid to temperature of about 70 *C. The compounds (11) can be converted to (12) using the reduction conditions described in Scheme 1l. Compounds (12) can be converted sequentially to compounds of general formulae (13), (14) and (15) by using, in analogous fashion, the methods described above in Scheme 11. D 0 2 N I NO 2

H

2 N NH 2 - N --------. N ' (11) (12) N H ND/ HY N HH N II- - N Bo0 0 oc (13) (14) -.- _ N / N N R~o 0 0 -R 2 0 (15) 15 Scheme XII Compounds of general formula (19), where D is as described above, can be prepared according to the methods of Scheme XIII. Compounds of general formula (16) can be converted to compounds of general formula (17) using a Buchwald reaction with tert-butyl-2 20 carbamoylpyrrolidine-l -carboxylate. This Buchwald reaction can be conducted in the presence of a base (e.g., cesium carbonate), a palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)), a 83 phosphine ligand (e.g., 4,5-his(diphenylphosphino)-9,9-dimethylxanthene) in solvent such as dioxane with heating to about 80-120 *C. The intermediate (17) can be reduced to (18) and cyclized to (19) using, in analogous fashion, the conditions described generally in Scheme IV. Compounds (19) can be further reacted as illustrated in Scheme IV to provide compounds of the invention. Boce Boc N NON N 020 2 NON NO, (16) (17) BOC Boc N 0 D N D N NHN 5 (18) (19) Scheme XIUI Compounds of the invention of general formula (23), where D is as described above, can be prepared according to the methods of Scheme XIV. Compounds (16) can be reacted with compound 10 (20) using a Buchwald reaction as described generally in Scheme XIII to provide compounds (21). Compounds (21) can be reduced to compounds (22) and cyclized to (23) using, in analogous fashion, the conditions described generally in the foregoing Schemes.

NHCO

2 Me MeO 2 CHN

NH

2 O-N O H HNH N (16) + ON

NHCO

2 Me O 2 N NO 2 (20) (21)

NHCO

2 Mo MeO 2 CHN NO D\ N NK N 0 0NN HNN MeO 2 CHN NHCO 2 Me (22) (23) Scheme XIV 15 Compounds of the invention of general formula (29), where R 20 is -Ls'-M'-Ls"-Ro and D is as described above, can he prepared according to the methods of Scheme XV. Compounds of formula 84 NHC0Me M02C| (24) can he converted to compounds of formula (25) (Sonogashira reaction) by reaction with trimethylsilylacetylene, a palladium catalyst (e.g., his(triphenylphosphine)palladium(l [)chloride), a copper catalyst (e.g., copper()iodide), and a base (e.g., triethylamine) wherein an amine base can also be used as solvent. The compounds (25) can be desilylated to compounds (26) by reaction with a 5 fluoride source (e.g., tetrabutylammonium fluoride) in a solvent such as THF. Compounds (26) can be converted to compounds (27) by formation of the dianion of (26) with n-butyllithium and subsequent reaction with a Weinreb aide (e.g., N-(tert-butoxycarbonyl)-L-proline-N' -methoxy N'methylamide). This reaction can be conducted in an appropriate solvent such as THF or dimethoxyethane. Compounds (27) can be converted to compounds (28) by reaction with hydrazine 10 in a solvent such as ethanol. The compounds (28) can be converted to compounds (29) using the methods described generally in the foregoing Schemes. D TMS Br Br TMS (24) (25) 00 Boo Z Z / -------- N N' N (26) (27) HN-N N-NH HN-N D N-NHI -N .- N "' $N C.Boc oo = R20 R2o (26) (29) Scheme XV 15 Compounds of the invention of general formula (34), where R 20 is -Ls'-M'-Ls"-RD and D is as described above, can be prepared according to the methods of Scheme XVI. Compounds (24) can be converted to compounds (30) by reaction of (24) with CO(g) under pressure (ca. 60 psi) in the presence of a palladium catalyst (e.g., PdCI 2 (dppf)) in methanol as solvent and with heating to around 100 *C. Compounds (30) can be converted to compounds (31) by reaction with hydrazine in a solvent 20 such as methanol with heating to about 60-80 *C. Compounds (31) can be converted to compounds (32) by reaction withN-Boc-2-cyanio-pyrrolidine in the presence of a base (e.g, potassium carbonate) in a solvent such as butanol and with heating to around 150 'C with irradiation in a microwave reactor. Compounds (32) can be deprotected to compounds (33) and acylated to (34) using, in analogous fashion, the conditions described generally in the foregoing Schemes. 85 0 D 0 O D 0 (24) -- + MeO " NOMe -0 H 2 NHN N N NHNH 2 (30) (31) N-N D N-N Boc 80C' (32) N-N D N-N 0- N-N NNN R20 R20 (33) (34) Scheme XVI Compounds of the invention of general formula (38), where R 20 is -Ls'-M'-Ls"-RD and D is 5 as described above, can be prepared according to the methods of Scheme XVIl. Compounds of formula (24) can be converted to compounds (35) by reaction with CuCN in a solvent such as DMF and with heating to about 160 *C with microwave irradiation. Compounds (35) can be converted to compounds (36) by reaction with HCI(g) in anhydrous methanol at 0 *C with warming to room temperature. Compounds (36) can be converted to compounds (37) by reaction with NH 3 (g) in 10 anhydrous methanol at 0 *C with warming to room temperature. Compounds (37) can be converted to compounds (38) by reaction with (41) in THF in the presence of a base (e.g., potassium carbonate). HN D NH (24) NC CNMO OMe (35) (36) FI N Do HN D NH (41)N /\

H

2 N N - NH 2 H - N 20 20= (37) (38) Scheme XVII 15 Compounds of formula (41), where R 20 is -Ls'-M'-L..s"-RD, can be prepared using the methods of Scheme XVI[I. Compounds (39) can be converted to compounds (40) by sequential reaction of (39) with isobutylchloroformate in THF at 0 *C followed by diazomethane. Compounds (40) can be converted to compounds (41) by reaction with IBr in acetic acid. 86 0 0 0

OHN

2 Br -N N -.- N R20 R20 R20 (39) (40) (41) Scheme XVIII Compounds of the invention of general formula (48), where R 2 , is -Ls'-M'-Ls"-RI) and D is 5 as described above, can he prepared according to the methods of Scheme XIX. Compound (42) can he reacted with compound (43) using, in analogous fashion, the Lewis acid mediated conditions described above in Scheme II to provide compound (44). Compound (44) can be converted sequentially to the diol (45), the mesylate (46) and the cyclic intermediate (47) using, in analogous fashion, the conditions of Scheme 11. Compounds (47) can be converted to compounds (48) by 10 reaction with (20) under Buchwald conditions such as those referred to Scheme XIV and described in Scheme XIll. OH HO N- N8C cN N BrN (45) (42) (43) (44) Ms 'Ms C I N C I CI NN (46) (47) RN HN NH R

R

20 C\N 0R (48) Scheme X[X 15 Compounds of the invention of general formula (55), where R 20 is -L..s'-M'-L.,s"-RD and 1) is as described above, can be prepared according to the methods of Scheme XX. Diethyl meso-2,5 dibromoadipate (49) can be reacted with an amine D-NH 2 in a solvent such as 'THF, dioxane, or dimethoxyethane with heating from 50-100 *C to give compounds (50). Compounds (50) can be converted to (51) by alkaline hydrolysis with a base (e.g., NaOHl, KOH) in an alcohol (e.g., methanol, 20 ethanol) and water mixture for solvent. Compounds (51) can be convened to (52) by reaction first with oxalylchloride, and treatment of the intermediate acid chloride with diazomnethane at 0 *C. Compounds (52) can be converted to (53) by reaction with aqueous HBr. Compounds (53) can be 87 converted to compounds (54) by reaction with thiourea in ethanol or like solvent. Compounds (54) can be converted to compounds (55) using, in analogous fashion, the conditions described above in Scheme U1. D D Et02C Br Br Et0 2 C CO 2 Et HO 2 C N CO2H (49) (50) (51) D D 0 1 0 0 I 0

N

2 -. N 2 Br Br (52) (53) H H H2N ND NH2 N D N NNN L= N s)NS<S 0 20 s SR2o -- O OsSOO R2 (54) (55) 5 Scheme XX Compounds of the invention of general formula (60), where R 20 is -Ls'-M'-Ls"-RD and D is as described above, can be prepared according to the methods of Scheme XXI. Compound (56) can be reacted with compound (57) in pyridine with heating to about 135 *C to form compound (58). 10 Compound (58) can be converted to compounds (59) by reaction of an amine 1)-NIH 2 with POCh followed by addition of (58) and heating at about 200 *C in 1,2-dichlorobenzene. Compounds (59) can be converted to compounds (60) using, in analogous fashion, the conditions described above in Scheme VII. Br/ r / Br O-NB Br /- Br HN C1 Br.. \ H. N

HN-NH

2 CI HrN-N (56) (57) (58) (59) H H~ 0 N--N O R20

R

20 (60) 15 Scheme XXI 88 Compounds of the invention of general formula (66), where R 2 , is -Ls'-M'-Ls"-Rj) and ) are as described above, can be prepared according to the methods of Scheme XXII. Compounds of general formula (61) can be reacted with borontribromnide in dichloromethane at 0 *C to give compounds (62), which can be subjected to hydrogenation conditions using platinum(II) oxide to give 5 compounds (63). Coupling between compounds (63) and proline derivatives (64) can be carried out using standard coupling conditions described above to give compounds (65), which can be converted to (66) by the action of diethylazodicarboxylate and triphenylphosphine in TIHF. 0 2 N NO 2 0 2 N NO 2 o0 / HO OH NN (61) (62)

H

2 N NH 2 R2 N HO /\ - OH +R N N O OH (63) (64)

R

20 N N R 2 0 Y Y 0 NH HN O 0 HO / Y -- OH N (65) D0 N N N 0 0--4~

R

2 O O0 2 (66) Scheme XXII 10 Compounds of the invention of general formula (74), where R 20 is -Ls'-M'-Ls"-RD and D is as described above, can be prepared according to the methods of Scheme XXIII. Compound (67) can be converted to (68) by reduction of the nitro group using tin(Il) chloride in ethanol. Compound (69) can be made from (68) by peptide coupling with Boc-proline, followed by heating of the resulting 15 aide in acetic acid at 80 C. Compound (69) can be reacted with SEM-Cl and diisopropylethylamine in dichloromethane to give (70), which can be coupled with (71) using a palladium catalyst such as PXPd using a base such as cesium fluoride in a solvent such as N,N 89 dinethylformanide at 100 "C to give (72). Compound (72) can he converted to (73) by reaction with Selecttluor@ in a mixture of TlHF and water, followed by hydrogenation using 3% Pt on carbon in ethylacetale and then reduction using sodium borohydride in methanol. Compound (73) can be reached with methanesulfonyl chloride and iriethylanine in dichloromethane at -10 *C, followed by 5 addition of an amine (H 2 N-D) to give an intermediate that can be converted to (74) by deprotection using 4N ICI in 1,4-dioxane and then coupling with R 20 C0 2 11 using peptide coupling procedures described above. H BrN(%NO2 Br N 2 r N N NH 2 N NH 2 O-\ (67) (68) (69) O 0 BrNNNOB 0 N 0\0(71) IN>_/ x - \ 0t72) (70) 72 -Si Si 0N N N C-go - N O 73) O R O H 4 R20 20 Scheme XXIII 10 Compounds of the invention of general formula (81), where R 20 is -l s'-M'-Ls"-RD and D is as described above, can be prepared according to the methods of Scheme XXIV. Compound (75) can be converted to (76) using SnC 2 in ethanol. Coupling of (76) with (64) using peptide coupling procedures described above to give an aide that can be heated in acetic acid at 100 0 C to give (77). 15 Compound (77) can be reacted with SEM-CI and diisopropylethylarnine in dichloromethane to give (78), which can be reacted with (71) as described above to give (79). Compound (79) can be converted to (80) using Selectfluor@ in a mixture of THF and water, followed by hydrogenation with Pt on carbon in ethylacetate and reduction with sodium borohydride in methanol. Compound (80) can be converted to compounds (8 1) by mesylation with methanesulfonyl chloride and triethylamine at 90 temperatures less than 0 C, followed by reaction with primary amine 1 2 N-D and deprotection using 4N HCI in 1,4-dioxane. Q-

CO

2 H N /-O H Br NO 2 Br NH 2 (64) Br H ' 'NH- 2 1: NH- 2 F F R20 (75) (76) (77) FF N '0 F Br N N (71) L N N R20 (80 NyN ~ ~ (78)

R

20 (79)R2 F F H H _ _ _ _ _ N N R0 ((81) F F N N NN Kr NN N N H H '2 20 (81) Scheme XXIV 5 Certain amines, D-NH 2 , in the foregoing Schemes are represented by formula (84), and may be prepared according to the general method shown in Scheme XXV, wherein RN is as defined above (e.g., halogen, alkyl, haloalkyl) and Rm is -N(RsRs.) (e.g., -NEt 2 ), heterocyclyl (e.g., pyrrolidin-I-yl, 91 piperidin-l-yl, etc.), or-OR (e.g., -O-t-butyl, -0-isopropyl, etc.). Fluoronitrobeizenes (82) can be reacted with an appropriate amine in the presence of dibasic potassium phosphate in a solvent such as DMSO optionally with heating to give intermediates (83), wherein RM is -N(RsRs') (e.g., -NE1 2 ) or heterocyclyl (e.g., pyrrolidin-I -yl, piperidin-I-yl, etc.). Fluoronitrobenzenes (82) can also be reacted 5 with alkali metal alkoxides (e.g., potassium tert-butoxide) to give intermediates (83), wherein Rm is ORs (e.g., -O-t-butyl, -0-isopropyl, etc.). Intermediates (83) may be converted to (84) using well known nitro reduction conditions. For example, (83) can be converted to (84) by catalytic hydrogenation using palladium on carbon. Alternatively, (83) can be converted to (84) by reaction with iron/ammonium chloride in TH F/methanol/water as solvent. Other conditions for effecting nitro 10 reduction include those described in the foregoing schemes and those generally known to one skilled in the art. F RM RM RN N RN RN RN RN RN RN RN RN RN RN RN

NO

2

NO

2

NH

2 (82) (83) (84) Scheme XXV 15 In the foregoing Schemes, compounds are shown wherein an aromatic ring (e.g., phenyl) is substituted with groups in a particular regiochemistry (e.g., para). A starting material or intermediate with para-substitution provides a final product with para-substitution in the foregoing Schemes. It is understood by one of skill in the art that substitution in the foregoing Schemes of a starting material or intermediate with a different regiochemistry (e.g., meta) would provide a final product with a different 20 regiocheistry. For example, replacement of a para-substituted starting material or intermediate in the foregoing Schemes with a meta substituted starting material or intermediate would lead to a meta substituted product. If a moiety described herein (e.g., -NH 2 or -01-) is not compatible with the synthetic methods, the moiety may be protected with a suitable protecting group that is stable to the reaction 25 conditions used in the methods. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting or deprotecting moieties are well know in the art, examples of which can be found in Greene and Wuts, supra. Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in 30 the reactants used. Solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art based on the present invention. 92 Other compounds of the invention can be similarly prepared according to the above-described schemes as well as the procedures described in following examples, as appreciated by those skilled in the art. It should be understood that the above-described embodiments and schemes and the following examples are given by way of illustration, not limitation. Various changes and modifications within 5 the scope of the present invention will become apparent to those skilled in the art from the present description. Example compounds below were named using either ChemDraw version 9.0 or ACD version 12 (ACD v2). Final compounds for Examples 1-50 were named using ChemlDraw unless otherwise indicated as being named using ACD v12. Final compounds after Example 50 were named using 10 ACD v12. Intermediates were named using ChemDraw, unless otherwise indicated as being named using ACD v12. Certain compounds in the Examples below were purified using reverse-phase FIPLC. Purification was conducted using either a Cl 8 or C8 reverse-phase column. Compounds were cluted using a gradient of about 10-100% acetonitrile in 0.1% aqueous TFA; about 60-100% methanol in 10 15 mM aqueous anunonium acetate; or about 10-95% methanol in 10 mM aqueous annonium acetate. For purifications conducted with 'IFA, the product thus obtained may be in the form of a TFA salt. Compounds may be characterized as the 'IFA salt or as the free base following neutralization, extraction and isolation. Certain compounds in the Examples below were purified using normal phase silica gel 20 chromatography including traditional flash chromatography or an automated purification system (e.g., Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 pim silica gel, Isco gold columns) Typical solvents for silica gel chromatography include: Ethyl acetate in hexanes, Diethyl ether in hexanes, THF' in hexanes, Ethyl acetate in methylene chloride, Methanol in methylene 25 chloride, Methanol in methylene chloride with NH40H, Acetone in hexanes, and Methylene chloride in hexanes. Example I Dimethyl (2S,2'S)- l, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, l 30 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 2,1 -diyl)dicarbamate and Dimnethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylcne))bis(azanediyl)bis(oxotnethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 35 2, 1-diyl)dicarbamate 93 F H H -o HQYN/\YQN N lNHN F .. ~ o C~~ N If. Example IA 1,4-Bis(4-nitrophenyl)butane- 1,4-dione 5 Anhydrous zinc(II) chloride (2.73 g, 20.00 mmol) was stirred in dry benzene (15 ml) while diethylamine (1.558 ml, 15.00 mmol) and t-hutanol (1.435 ml, 15.00 mmol) were added, and the resulting mixture was stirred at room temperature for 90 mini to give a cloudy solution. To this mixture was added 2-broimo-l-(4-nitrophenyl)cthanone (2.44 g, 10.00 mmnol) and 1-(4 nitrophenyl)ethanone (2.477 g, 15.00 nunol), and the resulting mixture was stirred at room 10 temperature overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated. The resulting residue was triturated with dichloromethane to give an orange solid that was collected by filtration and dried to give the title compound (2.0 gi, 61% yield). 15 Example IB l,4-Bis(4-nitrophenyl)butane- 1,4-diol To a solution of the product from Example IA (1.0 g, 3.05 mmol) in anhydrous TI-IF (30 ml) at 0C was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at 50"C overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over 20 Na 2

SO

4 , filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gin, 81% yield). Example IC 25 1,4-Bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonale To a solution of the product from Example 113 (0.80 g, 2.407 mmol) in dry CI-1 2

C

2 (25 mi) at 0*C was added triethylamine (1.007 ml, 7.22 minol), followed by dropwise addition of methanesulfonyl chloride (0.469 ml, 6.02 mmol). The resulting mixture was stirred at 0*C for 30 min, 94 during which time the starting material slowly went into solution. After stirring an additional I h at 0 0 C, a precipitate began to form. Saturated aq NI- 4 CI (4 ml) was added, and stirring was continued at room temperature for 20 min. The mixture was washed with water (2 x 10 iml), and the organic layer was treated with hexanes (10 ml) to give an orange solid that was collected by filtration to give the 5 title compound (0.75 grn, 64% yield). Example ID 1-(4-Fluorophenyl) -2,5-bis(4-n itrophenyl)pyrrolidine The product from Example IC (0.6 gim, 1.228 inmol) and 4-fluoroaniline (2.0 tnl, 20.82 10 inmol) were combined and stirred at 50'C overnight. The resulting mixture was partitioned between 0.2 N HCI (50 mld) and ethyl acetate (3 x 50 ml), and the combined organic layers were dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel.using a solvent gradient of 0-40% ethyl acetate in hexane to give the title compound as a mixture of cis and trans isomers (0.5 gm, 100% yield). 15 Example IE 4,4'-(1 -(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example ID (0.501 g, 1.23 mmol) in ethanol (5 ml) and TIF (5.00 mil) was added iron powder (0.412 g, 7.38 mmol) and a solution of ammonium chloride 20 (0.197 g, 3.69 mtnol) in water (1.0 tnl). The resulting mixture was stirred at 80"C for 45 min. The mixture was cooled, filtered through celite, washed with ethanol, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to give the title compound as a mixture of cis and trans isomers (0.135 gm, 32%). 25 Example IF (2S,2'S)-tert-Butyl 2,2'-(4,4'-(I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azaneliyl)bis(oxomethylene)dipyrrol idine- I -carboxylate To a mixture of the product from Example IE (0.13 gi, 0.374 mmol), (S)-l-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.201 gn, 0.935 minol) and HATU (0.356 gi, 0.935 30 minol) in DMSO (3 ml) was added Hunig's base (0.196 ml, 1.123 mmol), and reaction mixture was stirred at room tempertaure for 90 min. The mixture was poured into water and extracted by ethyl acetate. The organic extract was dried over Na 2

SO

4 , filtered and concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel, cluting with a solvent gradient of 5-100% ethyl acetate in hexane to give title compound (0.28 gm, 100%). 35 Example IG 95 (2S,2'S)-N,N'-(4,4'-(1 -(4-luorophenyl)pyrrolidine-2,5-diyl)his(4, 1 -phenylene))dipyrrolidine-2 carboxamide To the product from Example IF (0.28 gin, 0.377 nunol) in CH 2 Cl 2 (2.0 ml) was added TFA (2.0 ml). The reaction mixture was stirred at room temperature for 45 min and concentrated in vacuo. 5 The residue was partitioned between into 3:1 CH 2

CI

2 :2-PrOH and saturated aq. NaHCO 3 . The organic layer was dried over Na 2

SO

4 , filtered and concentrated to give the title compound (0.195 gin, 95% yield). Example I H 10 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidinc-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimnethyl- I -oxobulane 2, 1-diyl)dicarbamate and Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 15 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,I-diyl))bis(3,3-dimnethyl-l-oxobutane 2,1 -diyl)dicarhamate To a mixture of the product from Example 1G (0.03 gin, 0.055 imol), (S)-2 (methoxycarbonylatmino)-3,3-di methylbulanoic acid (0.0262 gim, 0.138 mmol) and HATU (0.0526 gin, 0.138 mnol) in DMSO (0.5 il) was added Hunig's base (0.029 ml, 0.166 mmnol), and the 20 resulting mixture was stirred at room temperature for 90 min. The mixture was poured into water (2 ml) and extracted by ethyl acetate (2 x 2 ml), and the combined organic layers were concentrated and subjected to HPLC purification on a semi-prep C18 reverse-phased column using a gradient of 10 100% acetonitrile in 0.1% aq TFA. The trans-substituted pyrrolidine isomer was the first of 2 stereolisomers to elute, providing the title compound as a 1:1 mixture of diastereomers (0.014 gin, 25 29% yield): Ili NMR (TFA salt) (400 Mi-z, DMSO-D6) 6 ppm 0.93 - 1.01 (in, J=4.99 Hz, 18 H) 1.62 - 1.68 (n, 2 H) 1.81 - 1.93 (m1, 6 H) 1.94 - 2.04 (in, 2 H) 2.09 - 2.20 (in, 2 H) 3.54 (s, 6 H) 3.59 - 3.69 (in, 2 H) 3.73 - 3.81 (in, 2 H) 4.18 - 4.24 (in, 2 H) 4.43 (dd, 1=7.81, 5.42 Hz, 2 H) 5.16 (d, 2 H1) 6.20 (dd, 1=9.05, 4.39 Iz, 2 H) 6.78 (t, J=8.89 Hz, 2 H1) 7.09 (d, 1=8.89 Hz, 2 H) 7.12 (d, 4 H) 7.50 (d, 1=8.02 Hz, 4 H1) 9.99 (s, 2 H1). The title compound showed an EC 5 o value of less than about 30 0.1 nM in I-CV lb-Coni replicon assays in the presence of 5% FBS. The Ib-Coni replicon assay is described below. Example 2 Dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5R)- I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I 35 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-diiethyl- I -oxobutane 2, 1 -diyl)dicarbamate 96 F -o N NN< 0 0 0 a) To a mixture of the product from Example IG (0.03 gi, 0.055 ininol), (S)-2 (methoxycarbonylaimino)-3,3-dimethylbutanoic acid (0.0262 gi, 0.138 minol) and HATU (0.0526 5 gin, 0.138 iniol) in DMSO (0.5 ml) was added Hunig's chase (0.029 ml, 0.166 inmol), and the resulting mixture was stirred at room temperature for 90 min. The mixture was poured into water (2 ml) and extracted by ethyl acetate (2 x 2 mi), and the combined organic layers were concentrated and subjected to HPLC purification onl a semi-prep C18 reverse-phased column using a gradient of 10 100% acetonitrile in 0.1% aq TFA. The cis-substituted pyrrolidine isomer was the second of 2 10 stereoisomers to elute, providing the title compound (0.018 gin, 37% yield): IH NMR (TF7A salt) (400 MHz, DMSO-D6) 5 ppm 0.93 - 1.01 (in, 1=3.04 Hz, 18 H) 1.75 - 1.94 (in, 6 1-) 1.94 - 2.05 (mn, 2 -1) 2.11 - 2.22 (in, 2 H) 2.31 - 2.35 (in, 1 1-1) 3.54 (s, 6 H) 3.61 - 3.70 (in, 2 H) 3.74 - 3.83 (i, 2 H) 4.22 (d, .1=8.78 Hz, 2 H) 4.46 (dd, .1=8.02, 5.42 H z, 2 H-1) 4.65 (t, 2 H) 6.34 (dd, 2 H) 6.86 (t, .1=8.89 H-lz, 2 H) 7.08 (d, 2 11) 7.43 (d, J=7.81 Hz, 4 H) 7.60 (d, 1=8.57 Hz, 4 H) 10.05 (s, 2 H). The title 15 compound showed an EC 50 value of less than about 0.1 nM in HCV lb-ConI replicon assays in the presence of 5% FBS. Example 3 Diiethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, 1 20 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 2,1 -diyl)dicarbamate F N 0-~ oo The product from Rxample I H was purified by chiral chromatography on a Chiralpak AD-H 25 semi-prep column cluting with a 1:1 mixture of hexanes:(2:1 IPA:EtOH). The title compound was the first of 2 stercoisonmers to elute. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.97 (s, 18 H) 1.61 - 1.67 (in, 1=5.64 Iz, 2 H-) 1.79 - 1.92 (in, 6 11) 1.93 - 2.04 (in, 1=5.86 Iz, 2 11) 2.07 - 2.20 (i, 1=6.51 H z, 2 11) 3.54 (s, 6 11) 3.59 - 3.69 (in, 2 H-) 3.71 - 3.83 (i, 2 H) 4.21 (d, 1=8.89 LIz, 2 11) 4.43 (dd, 97 J=7.97, 5.37 Hz, 2 H) 5.15 (d, J=6.5 1 Hz, 2 H) 6.20 (dd, 2 H) 6.78 (t, 1=8.95 Hz, 2 H) 7.13 (d, J=8.57 Hz, 4 H) 7.50 (d, J=8.57 Hz, 4 H) 9.99 (s, 2 H). lhe title compound showed an lFC. value of less than about 0.1 nM in HCV lb-Coni replicon assays in the presence of 5% FBS. 5 Example 4 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5 R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl- I-oxobutane 2,1 -diyl)dicarbamate F --o oN 10 The product from Example 1HI was separated by chiral chromatography on a Chiralpak AD-I semi-prep column eluting with a 1:1 mixture of hexanes:(2:1 IPA:EtOl 1). The title compound was the second of 2 stereoisomers to elute. I H NMR (400 MHz, DMSO-D6) 5 ppm 0.96 (s, 18 H) 1.64 (d, J=5.53 Hz, 2 H) 1.78 - 1.93 (n, 6 H) 1.94 - 2.06 (m, 2 H) 2.09 - 2.21 (111, 2 H) 3.54 (s, 6 H) 3.59 15 3.69 (in, 2 H) 3.72 - 3.83 (m, 2 H) 4.20 (d, J=8.89 Hz, 2 H) 4.43 (dd, 1=7.92, 5.42 Hz, 2 H) 5.16 (d, J=6.29 Hz, 2 H) 6.20 (dd, J=9.16, 4.39 Hz, 2 H) 6.77 (t, J=8.95 Hz, 2 H) 7.12 (d, 1=8.57 Hz, 4 H) 7.50 (d, J=8.57 Iz, 4 11) 9.99 (s, 2 11). The title compound showed an ECso value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS. 20 Example 5 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylenc)bis(pyrrolidine-2,1 -diyl))bis(I -oxobutane-2, I diyl)dicarbamate and 25 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxonethylene)bis(pyrrolidine-2,1-diyl))bis( I -oxobutane-2,1 diyl)dicarbamate 98 F 0yN,,O0 N F 0 0 Example 5A 4,4'-((2S,5S)- I -(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline and 4,4'-((2R,5R)- 1 -(4 5 Fluorophenyl)pyrrolidine-2,5-diyl)dianiline The product from Example IE was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in hexanes. The title compound eluted as the first of 2 stereoisomers and was obtained as a racemic mixture of trans diastereomers. IH NMR (400 MHz, DMSO-D6) 8 ppm 1.57 (d, 1=5.64 Hz, 2 H) 2.36 - 2.42 (m, 2 H) 4.86 - 4.91 (in, 4 H) 4.96 (d, .1=6.61 10 Hz, 2 -1) 6.17 - 6.25 (in, 2 H) 6.47 (d, 1=8.35 -lz, 4 H) 6.74 (t, 2 H) 6.82 (d, J=8.35 Hz, 4 H). Example 5B (2S,2'S)-iert-Butyl 2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate and (2S,2'S)-tert-Butyl 2,2' 15 (4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate The product from Example 5A (50 mng, 0.144 mmol) was subjected to the conditions described in Example IF to give the title compound as a 1:1 mixture of diastercomers (105 ing, 98%): IH NMR (400 MHz, DMSO-D6) 8 ppm 1.34 (d, 18 1-1) 1.66 (d, J=5.10 Hz, 2 H) 1.74 - 1.89 (n, 6 H) 20 2.07 - 2.23 (in, 2 1) 4.15 - 4.25 (in, 2 H) 5.18 (d, 1=3.47 Hz, 2 1-) 6.18 - 6.25 (m, 2 H) 6.78 (t, 1=8.95 SIz, 2 H1) 7.14 (d, 1=8.24 Hz, 4 H) 7.51 (t, 1=8.29 Hz, 4 11) 9.92 (d, 2 11). Example 5C (2S,2'S)-N,N'-(4,4'-((2S,5S)- I-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylenc))dipyrrolidine 25 2-carboxamide and (2S,2'S)-N,N'-(4,4'-((2R,5R)- I -(4-Fluorophenyl)pyrrolidine-2,5-diyl)his(4, 1 phenylene))dipyrrolidine-2-carboxamide The product from Example 5B was subjected to the conditions described in Example IG to give the title compound as a 1:1 mixture of diastereoiners. 99 Example 5) Dimehyl (2S,2'S)-1,1 '-(( 2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(1-oxobutane-2, I 5 diyl)dicarbamate and Dimethyl (2S,2'S)-1,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4 fluorophenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(I -oxobutane-2,l diyl)dicarhamate To a mixture of the product from Example 5C (0.102 g, 0.188 mmol), (S)-2 10 (mcthoxycarbonyl amino)bulanoic acid (0.064 g, 0.395 iniol) and HATU (0.150 g, 0.395 mmol) in DMSO (2 ml) was added Hunig's base (0.099 ml, 0.565 minol), and the reaction was stirred at room temperature for 45 min. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-4% MeOH in 15 dichloromethane to give the title compound as a 1:1 mixture of stereoisomers (0.158 gin, 94% yield): 1 H NM R (400 M Hz, DMSO-D6) 6 ppm 0.86 - 0.96 (in, 6 H) 1.53 (d, 1=4.34 Hz, 2 H) 1.59 - 1.73 (mn, 2 1-1) 1.80 - 1.96 (m, J=6.29 Hz, 4 H) 1.96 - 2.06 (m, 2 H) 2.08 - 2.20 (i, 2 H) 3.52 (s, 6 I) 3.67 3.79 (i, 2 H) 4.12 - 4.23 (in, 2 H) 4.42 (dd, 1=8.13, 4.66 Hz, 2 H) 5.16 (d, J=6.40 Hz, 2 H) 6.20 (dd, 1=9.22, 4.45 lz, 2 11) 6.77 (t, 1=8.89 Hz, 2 H1) 7.12 (d, 1=7.59 Hz, 4 H-) 7.30 (dd, 1=7.59, 3.25 Hz, 2 20 1-) 7.50 (d, J=8.24 Iz, 4 H-) 8.16 (s, 2 H) 9.95 (s, 2 H-). The title compound showed an EC 50 value of from about 0.1 to about I nM in HCV l b-Con I replicon assays in the presence of 5% FBS. Example 6 Dimethyl (2S,2'S)-1, I'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-diyl)his(4,l 25 phciylcite))bis(azanediyl)bis(oxomttethylcne)bis(pyrrolidinc-2,l-diyl))bis(3-liydroxy-3-mcthyl-1 oxobutaie-2,1-diyl)dicarbamate and Dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylenc))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,I-diyl))bis(3-hydroxy-3-methyl-I 30 oxobutane-2, I -diyl)dicarbamate 100 F 0 N,. ' 0, N'H0 ,o OH F H H OH OH To a mixture of tie product from Example 5C (0.1 g, 0.185 mmnol), (S)-3-hydroxy-2 (methoxycarbonyl amino)-3-methylbutanoic acid (0.074 g, 0.388 innol) and HATU (0.147 g, 0.388 5 inol) in DMSO (2 ml) was added Hunig's base (0.097 ml, 0.554 inmol), and the reaction mixture was stirred at room temperature for 45 min. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient ol0-4% MeOH in dichloromethane to give the title compound as a 1:1 mixture of stereoisoners (0.162 gin, 10 97% yield): I H NMR (400 M-lz, DMSO-D6) 8 ppm 1.15 (d, J=10.19 lz, 12 H) 1.64 (d, J=5.64 Hz, 2 H) 1.87 - 1.98 (m, 6 H) 2.09 - 2.22 (m, 2 H) 3.55 (s, 6 H) 3.58 - 3.66 (m, 2 H) 3.66 - 3.74 (im, 2 1-1) 3.83 - 3.92 (in, 2 1-) 4.37 (s, 2 H) 4.44 - 4.50 (m, 2 H) 5.07 (s, 2 H) 5.11 (s, 2 H) 5.17 (d, 1=6.18 H z, 2 H-) 6.15 - 6.28 (im, 2 H1) 6.78 (t, 1=8.89 Hz, 2 H) 7.13 (d, 1=8.13 Hz, 4 H) 7.51 (d, J=7.81 Hz, 4 H) 8.11 - 8.23 (i, 2 H) 9.67 (d, .1=9.11 Hz, 2 H). The title compound showed an EC,) value of less than 15 about 0.1 nM in HCV I b-Con I replicon assays in the presence of 5% HIS. Example 7 Diiethyl (2S,2'S,3R,3'R)- 1, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I-(4-fluoropheiyl)pyrrolidine-2,5 diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxoiethylene)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1 20 oxobutane-2,1 -diyl)dicarbamate and Diiethyl (2S,2'S,3R,3'R)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5 R)-I-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4, I -phcnylene))bis(azanediyl)bis(oxomet hylcne)bis(pyrrolidine-2,1-diyl))bis(3-imcehoxy-1 oxobulanc-2,1 -diyl)dicarbamatc 101 0l F 0 0o 0 O) O!' O O O ' OH To a mixture of the product from Example 5C (0.025 gi, 0.046 mmol), (2S,3R)-3-methoxy 2-(mnethoxycarbonylamino)butanoic acid (0.01941 gin, 0.102 imol) and HATU (0.0439 gm, 0.115 imnol) in DMSO (0.2 ml) was added Hunig's base (0.024 ml, 0.138 inmol). The mixture was stirred 5 at room temperature for 2 hr, and was then poured into water and extracted with ethyl acetate. The organic phase was dried over Na 2

SO

4 filtered and concentrated in vacu, and the crude product was purified by chromatography on silica gel using a solvent gradient of 0-5%MeOH in C-1 2 Cl 2 to give the title compound (0.040 gin, 93% yield): 1H NMR (400 MHz, DMSO-D6) 6 ppm 1.09 - 1.31 (in, 6 H) 1.64 (d, J=5.10 Hz, 2 H) 1.83 - 1.93 (in, J=12.42, 12.42 Hz, 4 H) 1.93 - 2.03 (in, 2 H) 2.11 - 2.19 10 (m, 2 H1) 3.10 - 3.18 (m, J=6.94 Hz, 2 H-) 3.24 (d, 1=4.99 Hz, 6 11) 3.42 - 3.49 (m, 1=10.84, 6.72 Iz, 2 H) 3.53 (s, 6 H) 3.58 - 3.70 (m, 2 H) 3.79 - 3.89 (m, 2 H) 4.26 (t, .1=7.10 Hz, 2 H) 4.41 (dd, .1=7.97, 4.93 Hz, 2 H) 5.16 (d, .1=6.29 Hz, 2 1-) 6.20 (dd, .=9.11, 4.34 Hz, 2 H) 6.78 (t, J=8.95 Hz, 2 H) 7.12 (d, 4 11) 7.33 (dd, ./=7.70, 3.47 Hz, 2 H) 7.50 (d, .1=8.13 Hz, 4 H) 9.95 (s, 2 1-). The title compound showed an EC5o value of from about 0.1 to about I nM in HCV lb-Conl replicon assays in the 15 presence of 5% FBS. Example 8 dimethyl (2S,2'S,3R,3'R)- 1, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4,I-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1 20 oxobutane-2, 1 -diyl)dicarbamate F 0 H O YN O O 0 O The product from Example 7 was purified by chiral chromatography on a Chiralpak AD-H semi-prep columtn eluting with a 1:3 mixture of hexanes:(I:1 IPA:EtOH). The title compound was the 102 first of 2 stereoisomers to elute. I H NMR (400 MHz, DMSO-D6) S ppm 1.13 (d, J=6.18 Hz, 6 H) 1.64 (d, J=5.64 Hz, 2 H) 1.82 - 1.93 (in, 4 H) 1.95 - 2.04 (m, 2 H) 2.10 - 2.19 (m, 2 H) 3.25 (s, 6 1-) 3.44 - 3.48 (in, 2 H) 3.53 (s, 6 H) 3.62 - 3.71 (in, 2 H) 3.79 - 3.87 (m, 2 H) 4.26 (t, 1=7.75 Hz, 2 H) 4.41 (dd, J=7.92, 4.99 Hz, 2 H) 5.16 (d, J=6.51 Hz, 2 H) 6.20 (dd, 1=9.16, 4.39 Hz, 2 H) 6.78 (t, 5 1=8.89 Hz, 2 H) 7.13 (d, 1=8.57 iz, 4 H) 7.34 (d, J=7.92 Hz, 2 H) 7.50 (d, J=8.57 Hz, 4 H) 9.95 (s, 2 1-). The title compound showed an EC 50 value of less than about 0.1 nM in HCV Ib-Coni replicon assays in the presence of 5% FBS. Example 9 10 dimethyl (2S,2'S,3R,3'R)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I -(4-fluorophenyl)pyrrolidinc-2,5 diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxoneihylene)bis(pyrrolidine-2,1-ciyl))bis(3-methoxy-l oxobutane-2, I -diyl)dicarbamate F H O N N oH yN.. o 0 ' 0 0 The product from Example 7 was purified by chiral chromatography on a Chiralpak AD-H 15 semi-prep column eluting with a 1:3 mixture of hexanes:(1:1 IPA:EtOI). The title compound was the second of 2 stereoisomers to clute. 1H NMR (400 MHz, DMSO-D6) S ppm 1.12 (d, 1=6.18 Hz, 6 H) 1.64 (d, 1=5.64 Hz, 2 H) 1.82 - 1.93 (m, 4 H) 1.95 - 2.06 (in, 2 H) 2.10 - 2.21 (i, 2 H) 3.24 (s, 6 Hl) 3.42 - 3.48 (in, 2 H) 3.53 (s, 6 H) 3.61 - 3.73 (in, 2 H) 3.78 - 3.88 (in, 2 H) 4.26 (t, J=7.75 Hz, 2 H) 4.41 (dd, J=7.92, 4.99 Hz, 2 H) 5.16 (d, 1=6.18 H z, 2 H) 6.20 (dd, 2 H) 6.78 (t, J=8.89 Hz, 2 H) 7.13 20 (d, J=8.46 Hz, 4 H) 7.33 (d, 1=7.81 Hz, 2 1-1) 7.49 (d, J=8.46 H-lz, 4 H) 9.95 (s, 2 H). The title compound showed an EC 50 value of from about 0.1 to about I nM in HCV lb-Con I replicon assays in the presence of 5% FBS. Example 10 25 Dimnethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)his(oxome thylene)bis(pyrrolidine-2, I -diyl))his(3-methyl- I -oxobutane-2, I diyl)dicarbamate and Dimneihyl (2S,2'S)-l, '-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 30 phenylene))bis(azanediyl)bis(oxomnethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-I-oxobutane-2,1 diyl)dicarbamate 103 F N, ,o..... -o 0 . .N 0 F HO H -o,,H N - N H 0 00 To a mixture of the product from Example IG (0.030 g, 0.055 iniol), (S)-2 (methoxycarbonylamino)-3-methylbutanoic acid (0.024 g, 0.14 mmol) and HATU (0.052 g, 0.14 mmol) in DMSO (0.3 ml) was added Hunig's base (0.024 ml, 0.166 iniol), and the resulting mixture 5 was stirred at room temperature for 90 min. The mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated and subjected to -IPLC purification on a semi-prep C18 reverse-phased colunin using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The trans substituted pyrrolidine isomer was the first of 2 stereoisomers to elute, providing the title compound as a 1:1 mixture of diastereomers (9 mg, 16%): IlH NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 10 0.85 - 0.96 (m, 12 H) 1.64 (d, .1=5.75 Hz, 2 H) 1.82 - 1.92 (in, 6 H) 1.95 - 2.06 (m, 2 H) 2.08 - 2.20 (m, 2 11) 3.52 (s, 6 -1) 3.57 - 3.68 (m, 2 H) 3.74 - 3.86 (im, 1=5.86 Hz, 2 H) 4.02 (t, J=8.35 Hz, 2 H) 4.42 (dd, J=7.92, 4.88 Hz, 2 H) 5.16 (d, J=6.18 Hz, 2 H) 6.20 (dd, 1=9.16, 4.39 Hz, 2 H) 6.77 (1, J=8.89 liz, 2 H) 7.12 (dd, J=8.51, 1.68 Iz, 4 H1) 7.31 (dd, 1=8.24, 3.36 Hz, 2 11) 7.50 (d, J=7.26 Hz, 4 H1) 9.99 (s, 2 H1). The title compound showed an EC5 0 value of less than about 0.1 nM in IICV Ib 15 Con I replicon assays in the presence of 5% PBS. Example I I Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5 R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-mcthyl- I -oxobutanc-2, I 20 diyl)dicarbamnate 0 H N- 1 0_N \I -jf:N H 0 0 To a mixture of the product front Example IG (0.030 g, 0.055 niniol), (S)-2 (methoxycarbonylamino)-3-methylbutanoic acid (0.024 g, 0.14 mnmol) and HATU (0.052 g, 0.14 25 mmol) in DMSO (0.3 ml) was added Hunig's base (0.024 ml, 0.166 mnmnol), and the resulting mixture 104 was stirred at room temperature for 90 min. The mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated and subjected to HPLC purification on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The cis substituted pyrrolidine isomer was the second of 2 stereoisomers to elute, providing the title 5 compound (11 mg, 20%): 1H NMR (TFA sal) (400 MHz, DMSO-D6) 6 ppm 9.35 (s, 2 H) 8.26 (s, 2 H-) 7.77 - 7.83 (in, 4 11) 7.68 - 7.73 (in, 4 H) 7.01 (1, J=8.95 Hz, 2 H-) 6.61 - 6.71 (in, 2 H1) 6.23 (d, 1=8.35 Hz, 2 H) 4.87 - 4.97 (im, 2 1-1) 4.67 - 4.78 (in, 2 H) 4.42 - 4.52 (m, 2 -I) 3.99 - 4.09 (m1, 2 H) 3.87 - 3.97 (in, 2 -1) 3.84 (s, 6 H) 1.22 (dd, 1=6.78, 2.11 Hz, 6 H) 1.15 (dd, J=6.72, 2.06 Hz, 6 H). The title compound showed an EC% value of less than about 0.1 nM in HCV 1 b-Con I replicon assays 10 in the presence of 5% FBS. Example 12 Dimethyl (2S,2'S)- 1, l'-((2S,2 S)-2,2'-(4,4'-((2S,5S)- I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxoimethylene)bis(pyrrolidine-2, I -diyl))bis(3-mnethyl- I -oxobutane-2, I 15 diyl)dicarbaiate F N N.< H _ 0 . Ck The product from Example 10 was separated by chiral chromatography on a Chiralpak AD-Hl semi-prep column eluting with a 1:1 mixture of hexanes:(2:1 2-PrOH:EtOH). The title compound eluted as the first of 2 stereoisomers. I H NMR (400 MHz, DMSO-D6) 6 ppm 0.84 - 0.97 (im, 12 H) 20 1.64 (d, 1=5.64 lz, 2 H) 1.88 (s, 6 H) 1.95 - 2.05 (i, 2 H) 2.08 - 2.19 (in, 2 H) 3.52 (s, 6 H) 3.58 3.66 (in, 2 H) 3.76 - 3.85 (in, 2 H) 4.02 (t, 1=8.51 H z, 2 H) 4.42 (dd, 1=8.02, 4.88 Hz, 2 H) 5.15 (d, J=6.51 Hz, 2 H) 6.20 (dd, J=9.16, 4.39 Hz, 2 H) 6.78 (t, 1=8.89 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, 1=8.35 Hz, 2 H) 7.50 (d, 1=8.46 Hz, 4 H) 9.99 (s, 2 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV l b-Con 1 replicon assays in the presence of 5% FBS. 25 Example 13 Dimnethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5 R)-I -(4-fluorophenyl)pyrrolidine-2,5-diyl)his(4,1 phenylenie))bis(azanediyl)bis(oxome thylene)bis(pyrrolidine-2, I -diyl))his(3-mnethyl- I -oxobutane-2, I diyl)dicarbamate 105 F -o 0 0~ k The product from Example 10 was separated by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 1:1 mixture of hexanes:(2:1 2-PrOH:EtOH). The title compound 5 eluted as the second of 2 stereoisomers. IH NMR (400 MHz, DMSO-D6) 8 ppm 0.82 - 0.97 (In, 12 H) 1.65 (d, 2 H-) 1.80 - 2.05 (i, 8 H) 2.08 - 2.20 (m, 2 H) 3.52 (s, 6 H) 3.57 - 3.68 (i, 2 H) 3.76 3.87 (i, 2 H) 4.01 (t, 2 H) 4.42 (dd, 2 H) 5.16 (d, J=6.40 Hz, 2 H) 6.20 (dd, J=9.22, 4.45 Hz, 2 H) 6.77 (t, 1=8.95 Hz, 2 H) 7.12 (d, J=8.57 H-1z, 4 -I) 7.30 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.46 Hz, 4 -I) 9.98 (s, 2 H). The title compound showed an ECo value of less than about 0.1 nM in HCV lb-Conl 10 replicon assays in the presence of 5% FBS. Example 14 Dimethyl (IS, I'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxome thylene)bis(pyrrolidine-2,1-diyl))bis(2-oxo-l-((R) 15 tetraliydrofuran-3-yl)ethaiie-2,1 -diyl)dicarbaiate and Dimethyl (IS, I'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)- 1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomnethylene)bis(pyrrolidine-2, I -diyl))bis(2-oxo- I -((R) tetrahydrofuran-3-yl)ethane-2,1 -diyl)dicarbamate F N, \ :,QKK0 Y j N -. _o 0o 9 2 0 N' 20 .. 0 0 To a mixture of the product from Example 5C (0.013 g, 0.024 mmol), HATU (0.02275 gin, 0.060 minol), and (S)-2-(inethoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yI)acetic acid (0.0107 gin, 0.053 minol) in DMSO (0.200 ml) was added Hunig's Base (0.013 ml, 0.072 mmol). The reaction was stirred at room temperature for 2 hr, poured into water, and extracted with ethyl acetate. The 25 organic extract was dried over Na 2

SO

4 , filtered and concentrated in vacuo, and the crude material was 106 purified on a semi-prep C 18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA to give the title compound (6.9 mg, 28% yield): 1H NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 1.61 - 1.77 (in, 4 H) 1.80 - 1.94 (in, 6 H) 1.93 - 2.06 (in, 2 H) 2.08 - 2.21 (in, 2 H) 3.44 (dd, 1=8.46, 6.29 Hz, 2 H) 3.53 (s, 6 I-) 3.56 - 3.68 (in, 8 H) 3.68 - 3.77 (in, 2 H) 3.80 - 3.90 (m, 2 H) 4.23 5 (t, 1=8.84 Hz, 2 H) 4.43 (dd, 1=8.02, 4.77 Hz, 2 H-1) 5.16 (d, 1=6.29 Hz, 2 H) 6.20 (dd, 1=9.11, 4.45 l z, 2 1H1) 6.77 (t, J=8.95 Iz, 2 11) 7.13 (d, J=8.57 Hz, 4 11) 7.50 (d, J=8.57 Hz, 4 H) 7.60 (d, 1=7.92 lz, 2 H) 9.98 (s, 2 H). The title compound showed an ECo) value of from about 0. 1 to about I nM in HCV I h-Con I replicon assays in the presence of 5% FBS. 10 Example 15 Dimethyl (IS, I'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(2-oxo- I -((R) tetrahydrofuran-3-yl)ethane-2,l -diyl)dicarbainate F N 0 N H _ H O N OOO N OH 0 0 15 The product from Example 14 was separated by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:3 mixture of hexanes:(1:1 2-PrOH:EtOH). The title compound eluted as the first of 2 stereoisomers. I1H NMR (400 MHz, DMSO-D6) 8 ppm 1.59 - 1.78 (im, 4 H) 1.79 - 1.94 (m, 6 H) 1.94 - 2.05 (in, 2 H) 2.09 - 2.23 (in, 1=5.10 Hz, 2 H) 3.44 (dd, 1=8.35, 6.40 Hz, 2 -1) 3.53 (s, 6 H) 3.57 - 3.73 (in, 8 H) 3.7 1 - 3.80 (m, 2 H) 3.81 - 3.89 (m, 2 H) 4.23 (t, J=8.78 Hz, 2 H) 20 4.43 (dd, 1=7.97, 4.83 Hz, 2 H) 5.16 (d, 1=6.07 Hz, 2 H) 6.16 - 6.24 (m, 2 H) 6.78 (t, 1=8.89 Hz, 2 H) 7.13 (d, J=8.57 Hz, 4 H) 7.50 (d, J=8.46 Hz, 4 H) 7.60 (d, 1=8.02 Hz, 2 H) 9.98 (s, 2 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV lb-Con I replicon assays in the presence of 5% FBS. 25 Example 16 Dimethyl (I S, I'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I -(4-fluorophcnyl)pyrrolidine-2,5-diyl)bis(4, I phenyleiie))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(2-oxo- I -((R) tetrahydrofuraii-3-yl)ethane-2,I -diyl)dicarbamate 107 F H O O N O O0O The product from Example 14 was separated by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:3 mixture of hexanes:(1:1 2-P1rOH:EtOH). The title compound eluted as the second of 2 stereoisomers. IH NMR (400 MHz, DMSO-D6) 6 ppm 1.61 - 1.77 (in, 4 H) 5 1.80 - 1.94 (i, 6 H-) 1.93 - 2.06 (i, 2 11) 2.08 - 2.21 (in, 2 H-) 3.44 (dd, J=8.46, 6.29 lz, 2 H-) 3.53 (s, 6 H) 3.56 - 3.68 (n, 8 H) 3.68 - 3.77 (in, 2 H) 3.80 - 3.90 (mn, 2 H1) 4.23 (t, J=8.84 Hz, 2 Hl) 4.43 (dd, J=8.02, 4.77 Hz, 2 -1) 5.16 (d, J=6.29 Hz, 2 H) 6.20 (dd, 1=9.11, 4.45 Hz, 2 H-) 6.77 (t, J=8.95 Hz, 2 H) 7.13 (d, 1=8.57 H z, 4 H) 7.50 (d, .1=8.57 Hz, 4 H) 7.60 (d, 1=7.92 Hz, 2 H) 9.98 (s, 2 H). The title compound showed an ECs) value of from about 0.1 to about I nM in HCV lb-Coni replicon assays in 10 the presence of 5% FBS. Example 17 (R,2S,2'S)-N,N'-(4,4'-((2S,5S)-I-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,I-phenylene))bis(I-((R) 2-phenyl-2-(piperidin- 1 -yl)acetyl)pyrrolidine-2-carboxamide) and 15 (R,2S,2'S)-N,N'-(4,4'-((2R,5R)-I-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1-((R) 2-phenyl-2-(piperidin-I-yl)acetyl)pyrrolidine-2-carboxamide) F HH N.N O 20 To a mixture of (R)-2-phcnyl-2-(pipcridin-l-yl)acetic acid TFA salt (0.0455 ing, 0.137 nunol), the produce from Example IG (0.030 gi, 0.055 nunol), and HATU (0.0526 gm, 0.138 nunol) in DMSO (0.300 mil) was added lunig's base (0.029.0 ml, 0.166 mnmol), and the resulting mixture was stirred at rt for 2 hr. The mixture was partitioned between water and ethyl acetate, the organic layer was dried over Na2SO 4 . filtered and concentrated in vacuo. The crude product was subjected to 25 -PL.C purification on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq IFA (8.3 ing, 11%): 1 H- NMR (TFA salt) (400 MHz., DMSO-D6) 6 ppm 1.20 1.42 (in, 4 H) 1.61 - 2.02 (in, 16 H) 2.62 - 2.81 (in, 4 H) 3.01 - 3.23 (m, J=9.32 Hz, 4 H ) 3.87 - 3.98 108 (in, 2 H) 4.40 - 4.47 (in, J=8.24 Hz, 2 H) 5.14 - 5.24 (in, 2 H) 5.50 (d, J=8.78 Hz, 2 H) 6.23 (dd, J=8.89, 4.34 Hz, 2 H) 6.75 - 6.84 (im, 2 H) 7.16 (d, J=7.8 1 Hz, 4 H) 7.48 - 7.59 (mn, 12 H) 7.62 (d, J=3.69 Iz, 4 H) 9.89 (s, 2 H) 10.17 (s, 2 H). The title compound showed an EC 0 value of from about 0.1 to about I nM in HCV I b-Con I replicon assays in the presence of 5% FBS. 5 Example 18 (R,2S,2'S)-N,N'-(4,4'-((2S,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1-((R) 2-phenyl-2-(piperidin-l-yl)acetyl)pyrrolidine-2-carboxaniide) F N ONo 10 To a mixture of (R)-2-phenyl-2-(piperidin-1-yl)acetic acid TFA salt (0.0455 mg, 0.137 mmol), the product from Example IG (0.030 gin, 0.055 inmol), and HATU (0.0526 gin, 0.138 iniol) in DMSO (0.300 ml) was added Hunig's base (0.029.0 ml, 0.166 mmol), and the resulting mixture was stirred at rt for 2 hr. The mixture was partitioned between water and ethyl acetate, the organic 15 layer was dried over Na.SO,, filtered and concentrated in vacuo. The crude product was subjected to HPIC purification on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA (8.7 mog, 12%): IH NMR (TFA salt) (400 MHz, DMSO-D6) 6 ppm 1.22 1.43 (in, 4 11) 1.62 - 2.03 (m, J=80.02 Hz, 16 H) 2.08 - 2.18 (m, 2 H-) 2.62 - 2.85 (i, 4 11) 3.04 - 3.24 (in, 4 11) 3.88 - 3.99 (m. 2 H) 4.41 - 4.52 (in, 2 H) 4.64 - 4.72 (in, 2 H) 5.52 (d, J=8.24 Hz, 2 H1) 6.36 20 (dd, 1=9.05, 4.50 Hz, 2 H) 6.88 (t, J=8.89 Hz, 2 H) 7.41 - 7.68 (in, 18 H) 9.89 (s, 2 H) 10.23 (s, 2 H-1). The title compound showed an EC 50 value of less than about 0.1 nM in HCV lb-Con I replicon assays in the presence of 5% FBS. Example 19 25 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(I-(4-fluorophenyl)-I H-pyrrole-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxonethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 2, I -diyl)dicarbamate F H H 0 Y \,, C) 0 o 0 +0 109 Example 19A I-(4-Fluoroplienyl)-2,5-bis(4-nitrophenyl)-1H-pyrrole To a slurry of the product from Example I A (1.5 g, 4.57 mmol) in acetic acid (22.85 m.L) was 5 added 4-fluoroaniline (4.33 ml, 45.7 mmol). The mixture was heated to 70 C for 24 h. After cooling to rt the mixture was diluted with water and ether and stirred vigourously, filtered and dried to provide 1.67 g (91%) of the title compound. Example 191 10 4,4'-(l -(4-Fluorophenyl)- I H-pyrrolc-2,5-diyl)dianiline To a solution of example 19A (1.017 g, 2.496 mnnol) in ethanol (15 mL) and THF (15 m1L) was added iron powder (0.836 g, 14.98 mmol) followed by ammonium chloride (0.401 g, 7.49 mmol) and water (3.75 mL). Reaction mixture was refluxed for 45 minutes. Slurry filtered through celite, washed with ethanol, combined filtrate was concentrated and the residue purified by column 15 chromatography (gradient elution from 30% to 50% EtOAc:hexanes) to provide 1.09 g (77%) of the title compound. Example 19C (2S,2'S)-tert-Butyl 2,2'-(4,4'-(1-(4-fluorophenyl)-IH--pyrrole-2,5-diyl)bis(4,1 20 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate To a solution of Example 19B (1.09 g, 3.17 mmol) in DMF (15.87 mL) at rt was added HIATU (2.66 g, 6.98 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.503 g, 6.98 mmol), and Hunig's base (2.218 mL., 12.70 mmol). Stirring was continued overnight. The mixture was partitioned between water and EtOAc added. Organic phase washed with brine, dried (Na 2

SO

4 ) 25 and concentrated. Residue purified by colunn chromatography (gradient clufion from 20% to 50% EOAc/ hexanes). MS (ESI; M+H) m/z = 738. Example 19D (2S.2'S)-N,N'-(4,4'-(I-(4-Fluorophenyl)-1I-H-pyrrole-2,5-diyl)bis(4,1-phenylene))dipyrrolidine-2 30 carboxamide To the product from Example 19C (100 mg, 0.136 mmol) in CH 2 Cl 2 (2.0 ml.) was added TFA (1.0 ml,) and the reaction was stirred I h. Mixture concentrated, the residue was partitioned between water and 25% IPA-CIC1 3 and neutralized with NaHCO 3 . The organic layer was dried over Na 2

SO

4 , filtered and concentrated to give the title compound as a white solid used without further purification. 35 MS (DCI; M+H) m/z = 538. 110 Example 19E I)imethyl (2S,2'S)-I,l'-((2S,2'S)-2,2'-(4,4'-( 1-(4-fluorophenyl)- I H-pyrrole-2,5-diyl)his(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 2, 1-diyl)dicarbamate 5 To a mixture of the product from Example 19D (0.073 g, 0.136 mmol) in CH 2

CI

2 (10 il) at rt was added flunig's base (0.070 mL, 0.407 mmol). To this was then added (S)-2 methoxycarbonylamino-3,3-dimethyl-butyric acid (0.054 g, 0.285 mmol) followed by HATJ (0.114 g, 0.299 mmol). Mixture stirred for 2 hrs then washed with saturated NaHCO 3 and the organic phase concentrated and the residue purified by column chromatography (1% gradient elution from 0% to 3% 10 MeOH-CH 2 Cl 2 ) to provide the desired compound as a light tan solid. MS (ESI; M+H) m/z = 881; 1H NMR (400 MIHz, DMSO-D6) 8 ppm 0.96 (s, 18 H), 1.81-1.89 (in, 4 H), 1.95-2.00 (im, 2 1-1), 2.11-2.16 (m, 2 11), 3.53 (s, 6 H1), 3.61-3.65 (i, 2 H1), 3.75-3.79 (in, 2 H1), 4.20 (d, J=8.85 iz, 2 1H), 4.39-4.42 (in, 2 11), 6.39 (s, 2 H1), 6.96 (d, J=8.69 H z, 4 1-), 7.07-7.10 (i, 4 H), 7.17 (dd, J=8.70, 8.70 Iz, 2 H-1), 7.41 (d, J=8.70 lIz, 4 H1), 10.01 (br s, 2 11). The title compound showed an EC 50 value of less than 15 about 0.1 nM in HCV I b-Con 1 replicon assays in the presence of 5% FBS. Example 20 Dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- -phenylpyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxoiethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimethyl- I -oxobutane 20 2,1 -diyl)dicarbamate and Dimethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-phenylpyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-l-oxobutane 2,1 -diyl)dicarbamate -o rH QH.. / HH -os 25 A Example 20A 2,5-1is(4-nitrophenyl)-1 -phenylpyrrolidine Ill A mixture of the product from Rxample IC (50 mig, 0.102 mmol) and aniline (0.2 ml, 2.19 mmol) were stirred at rt lor 48h. The mixture was partitioned between I N aq. HCI and ethyl acetate, and the organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate 5 in hexanes. The title compound was obtained as a yellow solid (19 mg, 48%). Example 20B (2S,2'S)-tert-Butyl 2,2'-(4,4'-(I-phenylpyrrolidine-2,5-diyl)bis(4,l phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate 10 The product from Example 20A (19 mg, 0.049 mmol) was subjected to the conditions described in Example IE. The crude product was subjected to the conditions described in Example IF to give the title compound (33 mug, 93%). Example 20C 15 Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-l -phenylpyrrolidine-2,5-diyt)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3,3-dimethyl- I -oxobutane 2,1 -diyl)dicarbamate and Dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l -phenylpyrrolidine-2,5-diyl)bis(4, I 20 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-I-oxobutane 2,1 -diyl)dicarbamate The product from Example 20B (30 mg, 0.041 mmnol) was subjected to the conditions described in Example IG, and the crude product was subjected to the conditions described in Example 1 H. The crude product was subjected to H P.C purification on a semi-prep Cl 8 reverse-phased 25 column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The trans-substituted pyrrolidine isomer was the first of 2 stereoisomers to elute, providing the title compound as a 1:1 mixture of diasmereomers (7 mg, 19%): lH NM R (TFA salt) (400 MHz, DMSO-D6) 6 ppm 0.95 (d, J=5.31 Hz, 18 H) 1.59 - 1.67 (in, 2 11) 1.79 - 1.91 (in, 4 H) 1.91 - 2.02 (in, 2 1-1) 2.08 - 2.17 (in, 2 H) 3.52 (s, 6 Hl) 3.58 - 3.68 (in, 2 11) 3.71 - 3.82 (m, 2 H) 4.19 (d, 1=9.00 H z, 2 H) 4.42 (dd, 2 H) 5.17 (d, 1=5.64 Hz, 2 30 H) 6.24 (d, .1=8.35 H z, 2 H) 6.39 (t, .1=7.37 Hz, 2 H) 6.90 (t, .1=7.92 H-z, 2 1-1) 7.07 (d, 2 H) 7.11 (d, 4 I-I) 7.48 (d, J=8.24 1-z, 4 H) 9.98 (s, 2 H). The title compound showed anm EC 5 ( value of less than about 0.1 nM in HCV Ib-Con I replicon assays in the presence of 5% FBS. Example 21 112 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5 R)-I-phcnylpyrrolidine-2,5-diyl)his(4,1 phenylene))bis(azanediyl)his(oxomethylene)bis(pyrrolidine-2,l-diyl))his(3,3-diinethyl-1-oxobutane 2, 1-diyl)dicarbaiate HN 0 H I0 0 5 The product from Example 20B (30 ing, 0.041 mmol) was subjected to the conditions described in Example 1G, and the crude product was subjected to the conditions described in Example Ili. The crude product was subjected to HPLC purification on a semni-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq TFA. The cis-substituted pyrrolidine isomer was the second of 2 stereoisomers to elute, providing the title compound (8.5 mg, 24%): IH 10 NMR (TFA salt) (400 MHz, DMSO-D6) 6 ppm 0.96 (d, 1=3.25 Hz, 18 H) 1.74 - 1.91 (m, 6 I-1) 1.93 2.03 (in, 2 -1) 2.10 - 2.20 (m, 2 H) 3.53 (s, 6 H) 3.58 - 3.69 (m, 2 H) 3.72 - 3.83 (m, 2 H) 4.20 (d, J=8.89 Hz, 2 H) 4.45 (dd, J=7.97, 5.37 Hz, 2 H) 4.68 (1, 1=5.20 Hz, 2 H) 6.37 (d, J=8.24 Hz, 2 H) 6.56 (t, J=7.26 H-z, 2 H) 6.98 (t, 1=7.92 Hz, 2 H) 7.07 (d, 2 H) 7.42 (d, 1=8.02 Hz, 4 H) 7.58 (d, J=8.57 Hz, 4 11) 10.03 (s, 2 H1). The title compound showed an EC 50 value of less than about 0.1 nM 15 in H CV lb-Con! replicon assays in the presence of 5% FBS. Example 22 Dimethyl (I R,I'R)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyrrolidinc-2,5 diyl)bis(4, 1 -phcnylcne))bis(azancdiyl)bis(oxoictliylcnc)bis(pyrrolidinc-2, I -diyl))bis(2-oxo- I 20 phenylethane-2, I -diyl)dicarbamate and Dimethyl (I R, I'R)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxoniethylene)bis(pyrrolidinie-2, 1 -diyl))bis(2-oxo- I phenylethane-2, I -diyl)dicarbamate 113 H H F HH N 0~ r, 10 The product from Example 5C (25 ng, 0.046 mmol) was subjected to the conditions described in Example 51), substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for (S)-2 5 (methoxycarbonyl amino)butanoic acid, to give the title compound as a 1:1 mixture of diastereomners (42 mg, 48%): 1 H NM R (400 MHz, DMSO-D6) 6 ppm 9.83 (s, 2 H) 7.67 (d, 1=7.8 1 Hz, 2 H) 7.51 7.57 (m, 4 1-1) 7.29 - 7.44 (m, 8 H) 7.15 (d, ./=8.46 lz, 4 H) 6.74 - 6.83 (m, 2 H) 6.17 - 6.28 (in, J=9.00, 4.34 Hz, 2 -1) 5.48 (d, J=7.81 Hz, 2 H) 5.12 - 5.24 (m, I H) 4.33 - 4.43 (mn, J=8.13 Hz, 2 H) 3.75 - 3.87 (in, 2 H) 3.54 (s, 6 H) 1.73 - 2.05 (m, 8 H) 1.62 - 1.70 (in, 2 H). Thc titlc compound 10 showed an ECso value of less than about 0.1 nM in HCV lb-ConI replicon assays in the presence of 5% FBS. Example 23 Diinethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5 15 diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3,3-diimethyl-l oxobutanc-2,1 -diyl)dicarbaimate and Di methyl (2S,2'S)- 1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-(trifluoro mehyl)phenyl)pyrrolidline-2,5 diyl)bis(4, I -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3,3-dimnethyl- I 20 oxobutane-2,1 -diyl)dicarbanate 114 CFa H H o N "LjO O N oC-a Example 23A 4,4'-((2S,5S)-lI -(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianiline and 4,4'-((2R,5R)- 1-(4 (Trifluoromethyl)phenyl)pyrrol idine-2,5-diyl)dianiline 5 The product from Example IC (0.74 g, 1.5 nunol) was subjected to the conditions described in Example I D, substituting 4-(trifluoromecthyl)aniline for 4-fluoroaniline. The product thus obtained was subjected to the conditions described in Example LE to give the title compound as a racemic mixture of trans-substituted pyrrolidine stereoisomers (0.0 lg, 17%). 10 Example 23B (2S,2'S)-N,N'-(4,4'-((2S,5S)- I -(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))dipyrrolidine-2-carboxamide and (2S,2'S)-N,N'-(4,4'-((2R,5R)- 1-(4 (Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4, 1-phenylene))dipyrrolidine-2-carboxamnide Tlhe product from Example 23A (0.95 g, 0.24 mmol) was subjected to the conditions 15 described in Example 1F to give a solid (0.166 g, 88%), which was dissolved in 4M HCI in 1,4 dioxane (2 mnt), and the resulting mixture was stirred at rt for 30 min. T1he resulting mixture was concentrated and dried in vacuo to give an HICI salt of the title compound as a 1:1 mixture of stereo somners. 20 Example 23C Dimethyl (2S,2'S)- 1, -((2S,2'S)-2,2'-(4,4'-((2S,5S)-l -I(4-(trifluoromethyl)phenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, -diyl))bis(3,3-dimetyl-1 oxohut ane-2, 1 -diyl)dicar bamate and 15 in Eampe ID, ubsituing -(tiflorotiehylanilne or -floronilne. he rodct husobtine was ubjcte tothecondtios dscrbedin xampe I togiv th tile cmpond s aracin1 Dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-(trifluoroinethyl)phenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(az.anediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))his(3,3-dimethyl- I oxobutane-2,1 -diyl)dicarbamate The product from Example 23B (58 mg, 0.083 nunol) was subjected to the conditions 5 described in Example I H to give the title compound as a colorless solid (30 mg, 39%): 1 H NMR (free base) (400 MHz, DMSO-D6) 6 ppm 10.03 (s, 2 H) 7.52 (d, J=8.46 Iz, 4 H) 7.25 (d, J=8.89 Hz, 2 H) 7.14 (d, .1=7.48 Hz, 4 H) 7.06 - 7.11 (m, 2 H) 6.36 (d, .1=8.35 Hz, 2 H) 5.23 - 5.33 (m, 2 H) 4.39 - 4.48 (in, 2 H ) 4.21 (d, J=8.46 Hz, 2 i) 3.71 - 3.82 (i, 2 1-) 3.58 - 3.69 (in, 2 H) 3.54 (s, 6 H) 2.08 - 2.21 (m, 2 H) 1.93 - 2.06 (mi 2 H) 1.76 - 1.94 (in, 4 H) 1.61 - 1.73 (in, 2 H) 0.96 (m, 18 H). The title 10 compound showed an EC5o value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS. Example 24 Dimethyl (2S,2'S,3S,3'S)- 1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I -(4-fluorophenyl)pyrrolidine-2,5 15 diyl)bis(4,l -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I-diyl))bis(3-iethyl-1 oxopentane-2,1 -diyl)dicarhamate and Dimnethyl (2S,2'S,3S,3'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I -(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4, I-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3-methyl- I 20 oxopentane-2, I -diyl)dicarbamate F H H N N N OO F H H N N N 0 N '[he product from Example IG (20 mg, 0.037 inmol) was subjected to the conditions described in Example IlH, substituting (2S,3S)-2-(imethoxycarbonylamino)-3-mnethylpentanoic acid 116 (15.4 ing, 0.081 minol) for (S)-2-(methoxycarbonylamino)-3,3-diinethylbutanoic acid. The title compound was obtained as a 1:1 mixture of diastereoiers (13.5 ing, 41%) after silica gel chromatography (0-5% MeOl/CH 2

CI

2 ): IH NMR (free base) (400 MHz, DMSO-D6) 8 ppm 9.99 (s, 2 1-) 7.50 (dd, 1=8.46, 1.52 Hz, 4 H) 7.36 (dd, 1=8.35, 3.04 H z, 2 11) 7.13 (dd, 1=8.62, 1.79 Hz, 4 H) 5 6.78 (t, J=8.89 Hz, 2 H) 6.20 (dd, J=9.16, 4.39 -lz, 2 H) 5.16 (d, J=6.29 Hz, 2 H) 4.43 (dd, J=7.92, 4.77 Iz, 2 H) 4.02 - 4.13 (i, 2 11) 3.77 - 3.89 (in, 2 H) 3.57 - 3.67 (m, 2 H) 3.52 (s, 6 HI) 2.08 - 2.21 (m, .1=14.96 Hz, 2 H) 1.94 - 2.05 (m, 2 H) 1.81 - 1.93 (m, J=5.42 Hz, 4 H) 1.60 - 1.79 (m, 4 H) 1.42 1.57 (i, 2 H) 1.04 - 1.18 (i, 2 H) 0.89 (t, J=6.51 Hz, 6 H) 0.76 - 0.85 (in, 6 1-). The title compound showed an EC50 value of less than about 0.1 nM in HICV I b-ConI replicon assays in the presence of' 10 5% FBS. Example 25 Diiethyl (2S,2'S,3R,3'R)- I , l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxonethylene)bis(pyrrolidine-2, I -diyl))bis(3-methyl- I 15 oxopentane-2,1 -diyl)dicarbaiate and Dimethyl (2S,2'S,3 R,3'R)- I, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1 -(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxoimethylcnc)bis(pyrrolidine-2, I -diyl))bis(3-methyl- 1 oxopentane-2, I -diyl)dicarbaiate F H H F HH H I $ QrJI' H 20 The product from Example 1G (25 mng, 0.046 imol) was subjected to the conditions described in Example IH, substituting (2S,3R)-2-(imethoxycarbonylamino)-3-methylpentanoic acid (19.2 ng, 0.102 mmol) for (S)-2-(imethoxycarbonylamino)-3,3-di methylbutanoic acid. The title 25 compound was obtained as a 1:1 mixture of diastereoiners (20.5 ig, 50%) after silica gel chromatography (0-5% MeOH/CH 2

CI

2 ): 1H NMR (free base) (400 MI-lz, DMSO-D6) 8 ppm 9.96 (s, 117 2 H) 7.49 (d, J=8.35 Hz, 4 -) 7.14 (t, J=7.43 Hz, 4 H) 6.77 (t, J=8.89 Hz, 2 H) 6.20 (dd, 1=9.11, 4.45 Hz, 2 H) 5.16 (d, J=6.40 Hz, 2 H) 4.38 - 4.48 (in, 2 H) 4.18 - 4.28 (m, 2 H) 3.69 - 3.82 (in, 2 H) 3.55 3.64 (im, 2 H) 3.52 (s, 6 H) 2.09 - 2.20 (in, 2 H) 1.95 - 2.05 (m, 2 H) 1.72 - 1.95 (m, 6 H) 1.58 - 1.70 (in, J=5.64 Hz, 2 H) 1.40 - 1.55 (in, 2 H) 1.06 - 1.18 (in, 2 H) 0.79 - 0.91 (i, 12 H). The title 5 compound showed an EC5o value of less than about 0.1 nM in HCV lb-ConI replicon assays in the presence of 5% FBS. Example 26 dimethyl (2S,2'S)- 1,1 ((2S,2'S)-2,2'-(4,4'-(4,4'-(I -(4-tert-butylphenyl)- 1 H-pyrrole-2,5-diyl)his(4, I 10 phenylcne))bis(l H-i midazolc-4,2-diyl))bis(pyrrolidine-2, 1-diyl))bis(3-methyl- I-oxobutane-2, 1 cliyl)dicarbamate HN / -~ NH N I\N H NH /0 Example 26A (S)-tert-butyl 2-forinylpyrrolidine-l-carboxylate 15 To an oven-dried 500-mL 3-neck flask purged with nitrogen was added oxalyl chloride (5.32 mL, 60.8 minol) and anhydrous dichloromethane (125 mL), and the solution cooled to -78 C. A solution of anhydrous DMSO (7.30 mL, 103 inmol) in anhydrous dichloromethane (25 mL) was added dropwise from a constant-pressure addition funnel over 20-mimn period. A solution of (S)-tert butyl 2-(hyclroxyiethyl)pyrrolidine- I -carboxylate (9.41 g, 46.8 nunol) in anhydrous dichloromiethane 20 (50 mL) was added dropwise front a constant-pressure addition funnel over 20-imin period, then stirred reaction mixture at -78 C for 30 inn. Added triethylamnine (32.6 mL, 234 nunol) dropwise via syringe over a 5-min period and stirred the thick white mixture in an ice-water bath for 30 minl. Quenched reaction with 10% (w/v) aq. citric acid (30 mL), poured reaction into a separatory funnel with Et:O (550 mL) and 10% (w/v) aq citric acid, separated layers, and washed organic phase with 25 water and brine. Dried the organic phase over anhydrous Na 2

SO

4 , filtered, and concentrated to afford a yellow oil (9.4 g), which was used directly in the next reaction. Example 26B (S)-tert-butyl 2-( 1 1-imidazol-2-yl)pyrrolidine- I -carboxylate 30 The product from Example 26A (20 g, 100 imol) was dissolved in methanol (50.2 mL) and anmonium hydroxide (50.2 mL) was added. To this solution glyoxal (40% in water; 24.08 mL, 211 118 mniol) was added, dropwise, over 10 min. The reaction was stirred at room temperature overnight. Reaction was concentrated under reduced pressure, diluted with 50 mL., of water, and then extracted with ethyl acetate. Washed organic layer with brine, dried (Na 2

SO

4 ) and concentrated to a tan solid. Solid was treated with ether and concentrated. The solid was then triturated with 2:1 diethyl 5 ether:hexanes (150 mL) to afford 17 g of solid, which was used directly in the next reaction. Example 26C (S)-tert-butyl 2-(4,5-dibromo- I H -imidazol-2-yl)pyrrolidine- I -carboxylate N-bromosuccinimide (108 nmol) was added to a cold (0 "C) solution of the product from 10 Example 2613 (12.05 g, 50.8 mmol) in dichloromethane (200 mL). Let stir in ice bath for 2 h and lhen concentrated, dissolved in ethyl acetate (250 mL) washed with water (3 x 150 iL), brine (1 x 100 mL), dried (MgSO 4 ) and concentrated to very dark residue, chased with dichloromethane/hexanes (1:1) to get brown solid (-19 g). Triturated solid with ether (-100 miL), filtered to isolate a tan solid (13.23 g, 65% yield). 15 Example 261) (S)-tert-butyl 2-(5-hroio-l H-imidazol-2-yl)pyrrolidine-1 -carboxylate or (S)-tert-butyl 2-(4-bromo I H-inidazol-2-yl)pyrrolidine- I -carboxylate Dissolved the product from Example 26C (6.25 g, 15.82 mmol) in dioxane (200 mL) and 20 water (200 niL) in a I L round bottom flask equipped with a condenser and glass stopper, added a solution of sodium sulfite (22.38 g, 174 mtnol) in water (200 niL), and heated at reflux with heating mantle for 16 h. Reaction was reddish-amber homogeneous solution. Cooled reaction to room temperature, removed dioxane and some water by rotary evaporation, extracted with dichloromethane, washed the combined organic extracts with brine (50 iL), dried over anhydrous Na 2

SO

4 , filtered, and 25 concentrated by rotary evaporation, co-evaporating with 2:1 hexancs/dichloromethane (100 mL) to give a beige foam (4.38 g). Dissolved foam in dichloroniethane (2 mL), added hexanes (2 mL), applied solution to colunm, and purified by silica gel flash chromatography eluting with 30% to 80% ethyl acetate/hexanes to afford the title compound as a white solid (3.48 g). 30 Example 26E 1,4-bis(4-bromophenyl)butane- 1,4-dione To a solution of zinc(ll) chloride (19.62 g, 144 mmol) in benzene (108 mL) were added diethylamiine (11.16 mL, 108 nunol) and 2-methylpropan-2-ol (10.32 niL, 108 nunol) and the mixture was stirred at room temperature for 2 h. 2-bromo-1-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and 35 l-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion, and the mixture was stirred overnight (18 h). Quenched with 5% Hl2S0 4 (500 mL) and stirred vigorously to induce 119 precipitation of the product, which was collected by vacuum filtration and washed with benzene, water, methanol, then dichloronethane, successively. The product was dried under vacuum to give the title compound as a white solid (11.15 g, 39.1% yield). 5 Example 26F 2,5-bis(4-bromophenyl)-l -(4-tert-butylphenyl)- 1 H-pyrrole To a solution of the product from Example 26E (4.00 g, 10.10 mmnnol) in toluene (40 mL) was added 4-tert-butylaniline (1.81 g, 12.12 mmol) followed by TFA (2.30 g, 20.20 mmol). Mixture heated to 110 'C for 2 h. Mixture cooled to room temperature and water and diethyl ether were 10 added. Stirred for 15 in, filtered, washed with water and dicihyl ether and dried to provide the title compound as a while solid (4.61 g; 90% yield). Example 26G I -(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-I H -pyrrole 15 To a solution of the product from Example 26F (2.32 g, 4.56 mmol) in DMSO (26 mL) at room temperature were added his(pinacolato)diborane (2.54 g, 10.02 mmol), potassium acetate (5.00 g, 36.4 mmol) and PdCI2(dppf) (744 mg, 0.91 mmol). The mixture was degassed and heated to 85 'C. After 4 h, the mixture was cooled to room temperature, diluted with dichloromnelhane and washed with water followed by brine. The organic phase was dried (Na 2

SO

4 ) and concentrated. The residue 20 was taken up in 20% ethyl acetate:hexanes and filtered through a short plug of silica gel (elution with 20% ethyl acetate:hexanes) and concentrated to afford the title compound as a light yellow solid (1.62 g; 59% yield). Example 26I 25 (2S,2'S)-tert-buIyl 2,2'-(4,4'-(4,4'-(l -(4-tcrI-butylphenyl)- 1 H-pyrrole-2,5-diyl)bis(4, I phenylene))bis(I H-imidazole-4,2-diyl))dipyrroliline- I -carboxylate A mixture of the product from Example 26D (664 mg, 2.10 nunol), the product from Example 26G (1.48 g, 2.45 mmol), 2 M sodium carbonate (1400 pL, 2.80 mmnol), and Pd(dppf)C12 (51.2 mg, 0.070 nunol) in DME (2800 pL) was subjected to microwave irradiation at 140 'C for 20 min. The 30 mixture was diluted with ethyl acetate, then washed with water and brine, and dried over Na 2 SO-. The product was purified on silica gel eluted with 30 to 70% ethyl acetate:hexanes to provide the title compound (140 mg; 24% yield). Example 261 35 (2S,2'S)-4,4'-(4,4'-(I-(4-tert-butylphenyl)- I H-pyrrole-2,5-diyl)bis(4,1 -phenylene))bis(2-(pyrrolidin-2 yl)- I 1H-imidazole) 120 To a solution of the product from Example 26H (135 mg, 0.164 mmol) in dichloromethane (2 ml..) at room temperature was added TFA (0.60 mL). After 3 h, the solvent was removed and the residue partitioned between water and 25% isopropyl alcohol:CHC 3 ; neutralized with NaHCO 3 . The organic phase was dried (NaSO 4 ), filtered and concentrated. Residue used directly in the next 5 reaction (98 mng; 96% yield). Example 26.1 Dimethyl (2S,2'S)- I,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-(1 -(4-tert-butylphenyl)-I H -pyrrole-2,5-diyl)bis(4,1 phenylene))bis(I H-iimidazole-4,2-diyl))his(pyrrolidine-2, I -diyl))bis(3-methyl- I -oxobutane-2, I 10 diyl)dicarbamate To a solution of the product from Example 261 (98 mg, 0.158 nniol) in DMF (2 mL) at room temperature was added (S)-2-(nethoxycarbonylamino)-3-methylbutanoic acid (61 mg, 0.347 mmol), EDAC (66 mog, 0.347 nmol) and l-hydroxybenzotriazole hydrate (53 mg, 0.347 nunol). After 3 h, the mixture was transferred to a separatory funnel with ethyl acetate and water. The organic phase 15 was concentrated and the residue purified by chromatography (1% gradient elution from 0% to 4% methanol:dichloromethane) to provide the desired material as a light yellow solid (70 mg; 30% yield). 'HNMR (MeOll-d4; 400 MI-z): 6 7.55-7.30 (in, 6H), 7.25-6.96 (in, 8H), 6.45 (s, 2H), 5.12 (dd, J=5.43, 5.43 Hz, 211), 4.20 (d, J=7.26 Hz, 2H), 4.02-3.90 (tm, 21H), 3.85-3.80 (in, 21H1), 3.64 (s, 61-), 2.36-1.93 (in, 10H), 1.31 (s, 911), 0.97-0.86 (m, 1211). The title compound showed an ECo value of 20 less than about 0.1 nM in ICV Ib-Coni replicon assays in the presence of 5% FBS. Example 27 ditnethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-I-(4-fluorophenyl)-3,4 dimethoxypyrrolidine-2,5-diyl)bis(4,1-phetylene))his(I H-imidazole-4,2-diyl))bis(pyrrolidiie-2, 1 25 diyl))bis(3-mecthyl-l-oxobutane-2,1-diyl)dicarbamnate F HN NH . N / N 0 o-. o r NH HN \ 0 0 Example 27A (2S,3R,4R,5S)-2,5-bis(4-brotmophenyl)-I -(4-fluorophenyl)pyrrolidine-3,4-diol A solution of 3,4-O-isopropylidene-D-mannitol (2.24 g, 10.08 nmol) in 2:1 methanol 30 dichloromethane (45 mL.) was treated with iodobenzene diacetate (7.95 g, 24.19 mmol) followed by stirring at room temperature for 5 i. Tl'he mixture was concentrated by rotary evaporation and the 121 residue was dissolved in 0.1M aq. sulfuric acid solution (20.6 mlL) followed by stirring at room temperature for 18 h1. The mixture was adjusted to pH 6 by addition of solid sodium bicarbonate. The mixture was then sequentially treated with 4-fluoroaniline (1.96 muL, 20.16 nimnol), 4 bromophenylboronic acid (3.64 g, 18.14 mmol), and absolute ethanol (40 mL). The mixture was then 5 heated in an oil bath (110 "C) at reflux for 20 I. The dark brown mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL), washed with water (50 mL), 0.33M aq. potassium phosphate tribasic solution ( 2 x 50 mL), and brine (50 iL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated by rotary evaporation to a dark reddish-brown oil. Dissolved oil in dichloromethane-hexanes, 10 concentrated in vacuo, and dried in vacuo to give a dark brown foam. Purification by silica gel flash chromatography eluting with a step gradient of 10% to 15% ethyl acetate/dichloroinethane afforded pure product as a yellow solid (1.216 g, 24%). Example 27B 15 (2S,3R,4R,5S)-2,5-bis(4-broniophenyl)-I -(4-fluorophenyl)-3,4-dimethoxypyrrolidine Dissolved the product of Example 27A (237 mg, 0.467 mmol) in a mixture of THF (3 ml.) and DMF (I ml.) under a nitrogen atmosphere and cooled to 0 "C. Added 60% sodium hydride dispersion in mineral oil (56.1 ing, 1.402 mmol) in portions and stirred the mixture at 0 "C for 15 miin. Then added neat iodomethane (65 pL., 1.028 mniol), removed the cooling bath, and stirred the 20 reaction at room temperature for 14.5 h. Diluted the reaction in ethyl acetate (50 mL), washed with saturated aq. ammonium chloride solution (25 mL), water (2 x 25 mL), and brine (25 mL). Dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated the filtrate by rotary evaporation. The yellow residue was purified by silica gel flash chromatography eluting with 30% hexanes/dichloromethane to afford the title compound as a white foam (206 mg, 82%). 25 Example 27C (2S,3R,4R,5S)-I-(4-fluorophenyl)-3,4-dimcthoxy-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolai-2-yl)phenyl)pyrrolidine Charged a nitrogen-purged flask with the product of Example 27B (204 mug, 0.381 mmnol), 30 bis(pinacalato)diboron (242 ing, 0.953 mmol), potassium acetate (112 mg, 1.143 mmol), and anhydrous dioxane (2 mL). Sparged the mixture with nitrogen for 30 min, added 1,1' his(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (31.1 ing, 0.038 mmol), sparged the mixture again with nitrogen for 5 min, and heated in ani oil bath at 85 OC for 6 h1. The reaction was vacuum filtered through a small bed of celite 545, the collected solids were 35 thoroughly washed with 5% methanol/dichloromethane, and the filtrate concentrated in vacuo, chasing the residue with dichloromethane/hexanes to give a tati solid. Purification by silica gel flash 122 chromatography eluting with 5% ethyl acetate/dichloromethane afforded the title compound as a salmon-colored solid (238 mg, 99%). Example 27D 5 (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-l -(4-fluorophenyl)-3,4-dimethoxypyrrolidine 2,5-diyl)bis(4,1-phenylene))bis(I --imidazole-4,2-diyl))dipyrrolidine- I -carboxylate A nitrogen-purged 5-nL microwave tube was charged with the product of Example 27C (237 mg, 0.377 mmol), the product from Example 261) (298 mg, 0.941 mmol), and a mixture of absolute ethanol (1.5 ml..) and toluene (1.5 ml..). Sonicated to obtain a cloudy orange mixture, added IM aq 10 sodium carbonate (0.941 mL, 0.941 mmol), and sparged with nitrogen for 20 min. Added 1,1' bis(diphenylphosphino)ferrocene-palladium (1I) dichloride dichloromethane complex (30.8 img, 0.038 mnol), sparged the mixture again with nitrogen for 5 min, sealed the reaction tube with an aluminum crimp cap, and heated in a microwave reactor with stirring at 100 "C for I h. Cooled reaction to room temperature, diluted in ethyl acetate (75 mL), washed with water (2 x 25 mL) and brine (25 mL), 15 dried the organic phase over anhydrous magnesium sulfate, filtered, and concentrated the filtrate by rotary evaporation to a lark yellow solid. Purification by silica gel flash chromatography eluting with 4% inethanol/dichloromethane afforded the title compound as a yellow solid (221 ing, 69%). Example 27E 20 (S)-4,4'-(4,4'-((2S,3R,4R,5S)- I -(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4, I phenylene))bis(2-((S)-pyrrolidin-2-yl)- I H-imidazole) A solution of the product of Example 27D (147.5 mg, 0.174 mmol) in anhydrous dichloromethane (2 mL) under nitrogen was treated with TFA (1 mL) and stirred at room temperature for 30 min. The solvent was removed in vacuo and chased with 1:10 dichloroiethane-hexanes (3 x 25 50 mL) to afford a pale yellow solid (193 ing). The solid TFA salt was dissolved in anhydrous methanol (15 niL), treated with dry Amberlite IRA-400(OH) resin (1.66 g, previously washed 10 g of wet resin (Supelco) with deionized water (3 x 25 iL) and methanol (3 x 25 mL), then dried in vacuo), and stirred for 2 h at room temperature. 'The mixture was then vacuum filtered, the collected resin washed thoroughly with methanol, the filtrate concentrated by rotary evaporation, and the residue 30 chased with 1:10 dichloromethane-hexanes to afford the title compound as a light yellow solid (94 mug, 0. 145 mmol, 83%). Example 27F dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)- I -(4-fluorophenyl)-3,4 35 dimethoxypyrrolidine-2,5-diyl)bis(4, I -phenylene))bis( II I-imidazole-4,2-diyl))bis(pyrrolidine-2, 1 diyl))bis(3-methyl- I -oxobutane-2, I -diyl)dicarbamate 123 In an oven-dried round bottom flask, dissolved the product of' Example 27E (92 mg, 0.142 mmol) in a mixture of I)MF (I ml-) and DMSO (1 ml..) under nitrogen and cooled the solution to 0 *C. Added sequentially (S)-2-(iethoxycarbonylainino)-3-methylbulanoic acid (53.5 mg, 0.305 mmol), EDAC (61.1 mg, 0.312 nmol), l-hydroxybenzotriazole hydrate (47.8 mg, 0.312 nmol), and 5 N-methylmorpholine (47 gL., 0.426 mmol). Removed the cooling bath and stirred at room temperature for 15 h. Diluted the reaction with ethyl acetate (50 nL), washed with saturated aq. sodium bicarbonate solution (25 mL), water (2 x 25 mL), and brine (25 nL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 5% methanol/dichloromethane afforded 10 the title compound as a pale yellow solid (78 mg, 56%). 'H NMR (400 MHz, DMSO-d6) 8 ppm 0.86 (dd, J= 17.67, 6.72 Hz, 12 H), 0.97 - 1.37 (in, 3 H-), 1.41 - 2.29 (in, 11 H), 3.53 (s, 6 H), 3.69 - 3.86 (i, 4 H), 4.04 (q, J=8.02 Hz, 2 H), 4.12 - 4.23 (m, 2 H), 5.07 (d, J=3.80 Hz, 2 H), 5.35 - 5.48 (i, 2 H), 6.31 (dd, J=9.16, 4.39 Hz, 2 H), 6.74 (t, J=8.89 Hz, 2 H), 7.12 - 7.71 (m, 12 H), 11.53 - 12.31 (in, 2 H); MS (ESI+) m/z 963 (M+H)+. The title compound showed an ECSO value of less than about 0.1 15 nM in HCV l b-Con I replicon assays in the presence of 5% FBS. Example 28 dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(5,5'-((2R,5R)- I-(4-tert-butylphenyl)pyrrolidine-2,5 20 diyl)bis(I H-benzo[d]iidazole-5,2-diyl))bis(pyrrolidine-2,1-d iyl))his(3-methyl-I-oxobutane-2, 1 diyl)dicarbaiate and dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)- 1 -(4-tert butylphenyl)pyrrolidine-2,5-diyl)bis( I --benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3 methyl-i -oxobutane-2, I -diyl)dicarbamate HNN NN / N HNN HN .NH N N 00 25 Example 28A 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione 124 Zinc chloride (27.4g, 201 mmol), diethylamine (15.6 ml-, 151 minol) and t-butanol (14.4 mL., 151 inmol) were combined in benzene (151 mil..) at room temperature under a nitrogen atmosphere and stirred for 2 h. I-(4-chloro-3-nirophenyl)eihanone (30.1 g, 151 nunol) and 2-bromo-I-(4-chloro 3-nitrophenyl)ethanone (28 g, 101 nimol) were added. The mixture was stirred vigorously for 20 h, 5 and the solid product was collected by filteration and rinsed with benzene, water, methanol, and dichloromethane. The solid was dried in a vacuum oven. Example 28B 1,4-bis(4-chloro-3-nitrophenyl)butane- 1,4-diol 10 The product of Example 28A (5.75 g, 14.48 mmol) was dissolved in ethanol (150 mL) at room temperature and treated with sodium borohydride (1.21 g, 31.9 miol) portionwise over 5 minutes. The solution was heated at 70 *C for I h and then cooled to room temperature, quenched with water, extracted into ethyl acetate, dried over sodium sulfate, and concentrated to dryness to give 4.81g (83%) of an off-white solid. 15 Example 28C 1,4-bis(4-chloro-3- nitrophenyl)butane-1,4-diyl dimethanesul donate The product of Example 28B (4.81 g, 11.99 mnmol) and triethylamine (5.85 mL, 42.0 nmiol) were dissolved in dichloromethane (80 mL) at room temperature and treated with methanesulfonyl 20 chloride (2.34 mL, 30.0 mmol) dropwise over 10 minutes. The resulting solution was stirred for 2 h then concentrated to dryness and used directly in the next step. Example 28D I-(4-tert-butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine 25 The product from Example 28C (6.6 g, 11.84 nunol) was slurried in DMF (30 mL) and 4-t butyl aniline (18.7 mL, 118 nmmol) was added and the solution was heated at 55 0 C for 2 It then cooled and poured into water and extracted into dichloromnethane. The organics were concentrated and the residue was purified by chromatography on silica gel 120g column, eluting with 0-5%ethyl acetate/hexanes to give 4.41g (72%) of a thick oil. 30 Example 28E 4,4'-(I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxyhenzyl)-2-nitroani line) The product from Example 28D (4.41 g, 8.57 munol) was combined, neal, with p-methoxy benzylamine (8.93 mL, 68.6 mmol) and heated at 145 "C for I h. The mixture was diluted with 35 dichloromethane and filtered. The filtrate was washed with 0.5 M I-IC, then NalHC0 3 soln, then 125 brine, concentrated and purified by chromatography on silica gel with an 80g column, cluting with 0 50% ethyl acetate/hexanes to give 4.1 3g (67%) of an orange foamy solid. Example 28F 5 4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(NI-(4-imethoxybenzyl)benzene- 1,2-diamine) The product from Example 28E (2 g, 2.79 mmol) was dissolved in a mixture of THF (15 niL), ethanol (15 mL), and ethyl acetate (5 mL) then platinum oxide (0.254 g, 1.12 mmol) was added via T-IF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room temperature for 20 h, then filtered through celite, 10 concentrated, and purified by chromatography on silica gel with an 80g column, cluting with 0-40% eihyl acetate/dichloromethane to give the first peak of trans product 0.508 g (28%). Example 28G (2S,2'S)-tert-butyl 2,2'-(5,5'-(1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4 15 methoxybenzylamino)-5, I -phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine- I -carboxylate The product from Example 28F (0.422 g, 0.643 mmol) and diisopropylethylamine (0.674 ml.., 3.86 minol) were dissolved in DMSO (6 mlL) at room temperature and treated with S-Boc-proline (0.319 g, 1.48 mmol) followed by HATU (0.514 g, 1.35 mmol). The solution was stirred for 1 h at room temperature then diluted with water and the solid product was filtered off and purified by 20 chromatography on silica gel with a 40g column, eluting with 0-50% ethyl acetate in dichloromethane to give 0.565 g (84%) of a yellow solid. Example 28H (2S,2S)-tert-hutyl 2,2'-(5,5'-(1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)his(2-amino-5,1 25 pltcnylene)bis(azanediyl)bis(oxoiethylene))dipyrrolidine-I -carboxylate The product from Example 28G (0.565 g, 0.538 mmol) was dissolved in dichloromethane (5 mnL) and water (0.25 tmL) at room temperature and treated with DDQ (0.244 g, 1.076 mnmol) portionwise over 2 minutes. The mixture was diluted with sodium bicarbonate solution, extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 40g column, 30 eluting with 0-15% methanol/dichloromethane to give 0.355 g (81%) of a yellow solid. Example 281 (2S,2'S)-teri-butyl 2,2'-(5,5'-(l -(4-tert-butylphenyl)pyrrolidinc-2,5-diyl)bis(I H benzo[d limidazole-5,2-diyl))dipyrrolidine-I-carboxylate 35 The product from Example 281-1 was dissolved in neat acetic acid (3 mL) and heated at 72 "C for 2 h. The solution was concentrated and then poured into water and adjusted p-I to -7-8 with 126 sodium bicarbonate. The product was extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 40g column, eluting with 0-5%niethanol/dichloromethane to give 0.185 g (55%) of a light yellow solid. 5 Example 28J (S)-5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-l

H

benzo[d]iindazole) lhe product from Example 281 (0.204 g, 0.264 mmol) was dissolved in THF (2 ml-) at room temperature and treated with 4 M hydrochloric acid in dioxane (2 ml.). The mixture was concentrated 10 to dryness and used directly in the next step. Example 28K dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(5,5'-((2R,5 R)- I-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis( I-benzo[d]inidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-I-oxobutane-2,1 15 diyl)dicarbamate and dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)- I -(4-tert butylphenyl)pyrrolidine-2,5-diyl)bis(I H-benzold] imidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3 methyl-I -oxobutane-2,1 -diyl)dicarbamate The product from Example 28J (0.150 g, 0.261 mmol) and diisopropylethylamine (0.365 mL, 2.09 imol) were dissolved in DMSO (3 mL) at room temperature and treated with (S)-2 20 (methoxycarbonylamino)-3-methylbutanoic acid (0.105 g, 0.601 imol) followed by IIATU (0.204 g, 0.536 nniol). The solution was stirred for I h at room temperature then diluted with water and the solid product was filtered off and purified by chromatography on silica gel with a 12g column, eluting with 0-8% methanol in dichloromethane to give 0.143 g (60%) of a yellow solid. 'H NMR (400 M-lz, DMSO-D6) 6 ppm 0.75 - 0.92 (m, 12 H) 1.07 (s, 9 H) 1.64 - 1.76 (m, 2 H) 1.85 - 2.04 (m, 6 H) 25 2.12 - 2.26 (in, 4 1-1) 2.43 (dd, J=7.75, 4.07 Hz, 2 11) 3.53 (s, 6 H) 3.76 - 3.87 (in, 4 H) 4.04 (dd, J= 11.49, 6.51 Hz, 2 H) 5.12 (t, J=7.59 Hz, 2 H) 5.35 (d, J=3.25 Hz, 2 H) 6.25 (d, J=8.46 Hz, 2 H) 6.85 - 6.96 (in, 2 11) 7.07 (t, J=7.97 Hz, 2 H) 7.19 (s, 1 H) 7.28 (d, J=8.35 H z, 3 H1) 7.38 (dd, J=8.19, 1.90 lz, 1 H1) 7.46 (d, J=8.13 Hz17, I H1) 11.97 - 12.09 (in, 2 11). The title compound showed an EC 5 o value of less than about 0.1 nM in ICV lb-Con I replicon assays in the presence of 5% FBS. 30 Example 29 dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5 R)-1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(I H benzo[dliimidazole-5,2-dliyl))bis(pyrrolidiie-2,1-diyl))bis(3-metliyl-1-oxobut ane-2, I -diyl)dicarbamate and dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)- 1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis( 11 35 benzo[dlimidazole-5,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3-methyl-1 -oxobutane-2, 1-diyl)dicarbamate 127 F N- NH HN F NH NH N O N N HN- NH Example 29A 2,5-his(4-chloro-3-nitrophenyl)-I -(4-tluorophenyl)pyrrolidine The product from Example 28C (2.9 g, 5.2 inol) and 4-fluoroaniline (5.0 mL, 52.0 nunol) 5 were combined, ncat, and heated at 45 "C for 20 I then cooled and poured into water and extracted into dichloromethane. The organics were concentrated the residue was purified by chromatography on silica gel with a 120g column, eluting with 0-5% ethyl acetate/hexanes to give 0.5 9 g (24%) of a thick oil. 10 Example 29B 4,4'-(I-(4-fluorophenyl)pyrrolidine-2,5-dliyl)bis(N-(4-mcthoxybenzyl)-2-nitroaniline) The product from Example 29A (0.88 g, 1.86 nunol) was combined with 4-methoxy benzylamine (3.64 mL, 28.0 nunol) and heated at 145 "C for 1 I in a microwave reactor. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by 15 chromatography on silica gel with a 330g column, eluting with 0-60% ethyl acetate/hexanes to give 0.79g (62%) of an orange foam solid. Example 29C 4,4'-(l -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nilroaniline) 20 The product from Example 29B (0.78 g, 1.15 inmol) was dissolved in dichloromethanc (10 tmL) at room temperature and treated with TFA (1.8 mL, 23.0 mmol) for 3 h. The residue was concentrated and partitioned between dichloromethane and sodium bicarbonate solution. The organics were concentrated and purified by chromatography on silica gel with a 40g column, eluting with dichloromethane to give 0.218 g (43%) of the trans isomer. 25 Example 29D 4,4'-(l -(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene- 1,2-diaimine 128 Tlie product from Example 29C (0.218 g, 0.50 mmnol) was dissolved in DMF (5 imL) then platinum oxide (0.226 g, 0.99 inmol) was added via THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room temperature for 20 h. The solution was taken on to the next step without purification. 5 Example 29E (2S,2S)-tert-butyl 2,2'-(5,5'-(I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,l phenylene))bis(azanediyl)bis(oxonethylene)dipyrrolidine- I -carboxylate The crude DMF solution of the product from Example 291) was treated with 10 diisopropylcthylamine (0.296 iL, 1.70 inmol) and S-Boc-proline (0.192 g, 0.89 tmmol) followed by HATU (0.322 g, 0.85 nunol). The solution was stirred for 1.5 I at room temperature then diluted with water and the solid product was filtered off and purified by chromatography on silica gel with a 12g column, eluting with 0-3% methanol in dichloromethane to give 0.235 g (72%) of a yellow solid. 15 Example 29F (2S,2S)-tert-butyl 2,2'-(5,5'-( 1-(4-fluorophenyl)pyrrolidine-2,5-diyl)his(1 H-benzo[djimidazole-5,2 diyl))dipyrrolidine- I -carboxylate The product from Example 29E was dissolved in neat acetic acid (2 nL) and heated at 60 'C for I h. The solution was concentrated then poured into water and adjusted p-1 to -7-8 with sodium 20 bicarbonate. The product was extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 12g column, eluting with 0-20% ethyl acetate in dichloromethane to give 0.124 g (55%) of a light yellow solid. Example 29G 25 (S)-5,5'-(1-(4-fluorophenyl)pyrrol idine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]inidazole) The product from Example 29F (0.120 g, 0.163 mmol) was dissolved in dichloronethane (2 niL) at room temperature and treated with TFA (I niL). The mixture was concentrated to dryness, dissolved in 25%ISOPROPYL ALCOlIOL/dichloromethane and washed with sodium bicarbonate solution. The resulting solids were filtered off and dried and the organics were concentrated and dried 30 to give the title compound (0.062 g 72% yield) of an off-white solid. Example 29H dimnethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(I

H

benzo[d]i midazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate 35 and dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis( 11 benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3-methyl- I -oxobutane-2, I -diyl)dicarbamate 129 The product from Example 29G (0.062 g, 0.116 inmol) and diisopropylethylamine (0.101 mi, 0.58 mnmol) were dissolved in DMSO (2 mL.) at room temperature and treated with (S)-2 (methoxycarbonylamino)-3-methylbutanoic acid (0.051 g, 0.289 inmol) followed by HATU (0.092 g, 0.243 mnmol). The solution was stirred for I h at room temperature then diluted with water and the 5 solid product was filtered off and purified by chromatography on silica gel with a 12g column, eluting with 0-7% methanol in dichloromethane to give 0.021 g (21%) of a yellow solid. 'II NMR (400 MHz, DMSO-D6) 8 ppm 0.78 - 0.90 (m, 12 H) 1.70 (s, 2 H) 1.87 - 2.03 (m, 6 H) 2.13 - 2.26 (m, 4 H) 2.54 2.62 (in, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.03 - 4.11 (in, 2 H) 5.09 - 5.18 (m, 2 H) 5.32 - 5.42 (in, 2 H) 6.28 (dd, J=8.89, 4.34 HIz, 2 H) 6.70 - 6.80 (in, 2 H) 7.01 -7.10 (m, 2 H) 7.20 (d, J=9.32 H47z, I H) 7.27 10 - 7.34 (in, 3 H) 7.38 (dd, J=8.13, 2.71 Hz, I H) 7.45 (d, J=8.02 Hz, I H) 12.03 (s, 2 H). The title compound showed an EC 3 0 value of less than about 0.1 nM in HCV lb-Con I replicon assays in the presence of 5% F3S. Example 30 15 dimethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)- 1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(I H benzo[djimidazole-5,2-diyl))his(pyrrolidine-2,1 -diyl))bis(3-mnethyl-I -oxohutane-2, I -diyl)dicarbaiate F HN .N N HN-/== NH 0 The product from Example 2911 was purified by chiral chromatography on a Chirapak IA column eluting with a mixture of hexane/EtOH/MeOH/1,2 Dichloroethane/diethylamine 20 (25/25/25/25/0.1). 'H NMR (400 MHz, DMSO-D6) 8 ppm 0.75 - 0.89 (m, 12 H) 1.64 - 1.73 (m, 2 1H) 1.85 - 2.03 (in, 6 H) 2.12 - 2.24 (in, 4 H) 2.81 - 2.90 (in, 2 H) 3.52 (s, 6 H) 3.76 - 3.87 (in, 4 H) 4.01 4.09 (in, 2 H) 5.08 - 5.16 (in, 2 1-) 5.34 (q, .1=6.65 Hz, 2 H) 6.26 (dd, J=9.05, 4.50 Hz, 2 H) 6.67 - 6.78 (in, 2 H) 7.03 (t, J=8.02 Hz, 2 H) 7.20 (s, I H) 7.24 - 7.32 (m, 3 H) 7.36 (d, J=8.13 Hz, 1 H) 7.44 (d, J=7.92 Hz, 1 I-I) 12.01 - 12.07 (m, 2 11). The title compound showed an EC 50 value of less than about 25 0.1 nM in 1CV lb-Coni replicon assays in the presence of 5% FBS. Example 31 dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(5,5'-((2R,5R)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1 H benzo[djimidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-mnethyl-1-oxobutane-2,l-diyl)dicarbamate 130 F ,NH N') N Q HN-OO NH The product from Example 291H was purified hy chiral chromatography on a Chirapak IA column cluting with a mixture of hexanc/EtOH/MeOH/1,2 Dichlorocthanc/dicthylamine (25/25/25/25/0.1). 'H NMR (400 MHz, DMSO-D6) 6 ppm 0.74 - 0.93 (m, 12 1-1) 1.69 (1, J=9.65 Hz, 2 5 H) 1.82 - 2.06 (i, 6 H) 2.09 - 2.26 (m, 4 H) 3.04 - 3.23 (i, 2 H) 3.52 (s, 6 1-1) 3.73 - 3.90 (mn, 4 H) 4.06 (t, J=8.46 Hz, 2 H-1) 5.05 - 5.21 (in, 2 11) 5.29 - 5.44 (m, 2 1H1) 6.21 - 6.32 (in, 2 11) 6.67 - 6.86 (mn, 2 H) 7.05 (t, J=8.78 Hz, 2 H) 7.18 (s, 1 H) 7.23 - 7.33 (i, 3 H) 7.37 (d, J=8.13 Hz, I H) 7.45 (d, J=8.02 Hz, 1 H) 12.04 (d, J=14.96 Hz, 2 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV l b-Con I replicon assays in the presence of 5% FBS. 10 Example 32 (I R,4R)- 1,4-bis(4-nitrophenyl)butanc-l,4-diol HO OH 0 2 N NO 2 To (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (2.71 g, 10.70 mmol) was added THF (80 15 inL) at 23 C. The very thin suspension was treated with trimethyl borate (1.44 g, 13.86 inol) over 30 seconds, and the resulting solution was mixed at 23 *C for I h. The solution was cooled to 16-19 'C, and N,N-diethylaniline horane (21.45 g, 132 minol) was added dropwise via syringe over 3-5 min (caution: vigorous -12 evolution), while the internal temperature was maintained at 16-19 'C. After 15 mini, tie H 2 evolution had ceased. To a separate vessel was added the product from Example IA 20 (22.04 g, 95 wt%, 63.8 mmol), followed by THF (80 mL), to form an orange slurry. After cooling the slurry to 11 C, the borane solution was transferred via cannula into the dione slurry over 3-5 min. During this period, the internal temperature of the slurry rose to 16 0 C. After the addition was complete, the reaction was maintained at 20-27 0 C for an additional 2.5 h. After reaction completion, the mixture was cooled to 5 'C and methanol (16.7 g, 521 mnmnol) was added dropwise over 5-10 min, 25 maintaining an internal temperature <20 'C (note: vigorous H 2 evolution). After the exotherin had ceased (ca. 10 min), the temperature was adjusted to 23 'C, and the reaction was mixed until complete dissolution of the solids had occurred. Ethyl acciate (300 miL) and I M HCI (120 iL) were added, and the phases were partitioned. The organic phase was then washed successively with I M HCI (2 x 120 mL), 1120 (65 iL), and 10% aq. NaCl (65 nL). The organics were dried over MgSO 4 , filtered, 30 and concentrated in vacuo. Crystallization of the product occurred during the concentration. The 131 slurry was warmed to 50 'C, and heptane (250 mi..) was added over 15 minl. The slurry was then allowed to mix at 23 "C for 30 minl and filtered. The wet cake was washed with 3:1 heptane:ethyl acelate (75 mL), and the orange, crystalline solids were dried at 45 'C for 24 i to provide the title compound (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer 5 (vs. di isomer). Example 33 (1 S,4S)- l,4-bis(4-nitropheiyl)butane- 1,4-diol

HOCOH

0 2 N NO 2 10 The product from Example IA (30 g, 95 wt%, 91.4 nimol) was subjected to the conditions described in Example 32, substituting (R)-(-)-aa-dipheniyl-2-pyrrolidimiemcthaiol for (S)-(-)-a,a dipheiyl-2-pyrrolidinemethanol, to give the title compound (20.14 g, >99.55 ee, 61% yield) which was contaminated with 9.7% of the meso isomer (vs. dl isomer). 15 Example 34 Dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(4-teri-hutylpheiyl)pyrrolidine-2,5-diyl)his(4,1 phenylene))bis(azanediy)bis(oxomeiCthylene)bis(pyrrolidine-2, I -diyl))bis(3-nicthyl- 1 -oxobutanc-2, I diyl)dicarbamate and 20 Dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomnethylene)bis(pyrrolidine- 2 , I -diyl))bis(3-nethyl- 1 oxobutane-2, I -diyl)dicarbaniate H -o0 N N HO 00 H H -o H ON, N ~ N NI N H Example 34A 25 1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example IC (3.67 g, 7.51 mmol) and 4-iert-butylaniline (11.86 ml, 75 mmol) in DMF (40 nil) was stirred under nitrogen at 50 *C for 4 h. The resulting mixture was diluted 132 into ethyl acetate, treated with IM HICI, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1:9 ethyl acetate/hexane to give 5 a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%). Example 34B 4,4'-((2S,5S)-I-(4-teri-butylphenyl)pyrrolidine-2,5-diyl)dianiline and 4,4'-((2R,5R)-l-(4-tert butylphenyl)pyrrolidine-2,5-diyl)dianiline 10 To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and THF (20 ml) was added PtO 2 (0.22 g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi hydrogen at room temperature for I h. The mixture was filtered through a nylon membrane and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g, 15 54%). Example 34C (2S,2'S)-tert-Butyl 2,2'-(4,4'-((2S,5S)-1-(4-teri-butylphenyl)pyrrolidine-2,5-diyl)bis(4,

I

phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate and (2S,2'S)-tert-Butyl 2,2' 20 (4,4'-((2R,5R)-I-(4-teri-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate To a mixture of the product from Example 34B (250 mg, 0.648 nunol), (S)-1-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 minol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml) was added Hunig's base (0.453 ml, 2.59 mmol). The reaction mixture was 25 stirred at room temperature for I h. The mixture was partitioned with ethyl acclaic and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to give the title compound (500 mg, 99%). 30 Example 34D (2S,2'S)-N,N'-(4,4'-((2S,5S)-I -(4-tert-butylphenyl)pyrrolidin e-2,5-diyl)bis( 4 , I pheniylene))dipyrrolidine-2-carboxamide and (2S,2'S)-N,N'-(4,4'-((2 R,5 R)- I -(4-tert butylphenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylec))dipyrrolidine-2-carboxamide To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was 35 added TFA (6 ml). The reaction mixture was stirred at room temperature for I h and concentrated in vacuo. The residue was partitioned between 3:1 ClICl 3 :isopropyl alcohol and saturated aq. NalHC0 3 . 133 The aqueous layer was extracted by 3:1 CHC 3 :isopropyl alcohol again. The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated to give the title compound (345 ing, 93%). Example 34E 5 Dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3-methyl- I -oxobutane-2, I diyl)dicarbamate and Dimethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5 R)-I-(4-teri-butylphenyl)pyrrolidine-2,5 10 diyl)bis(4,1-phcnylcnc))bis(azancdiyl)bis(oxomethylenc)bis(pyrrolidine-2,1 -diyl))bis(3-imethiyl-1 oxobutane-2, I -cliyl)dicarbamate The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid (19.27 ing, 0.110 mmol), EDAC (21.09 ing, 0.110 iniol), IOBT (16.85 mg, 0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The 15 reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluding with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 ng, 29%). 'H-I NM R (400 M Hz, DMSO-D6) 6 ppm 0.85 - 0.95 (i, 12 H) 1.11 (s, 20 9 H) 1.59 - 1.65 (in, 2 H) 1.79 - 2.04 (i, 8 H) 2.10 - 2.18 (in, 2 H) 2.41-2.46 (i, 21) 3.52 (s, 6 H) 3.57 - 3.67 (m, 2 H-) 3.76 - 3.86 (in, 2 H-) 4.00 (t, J=7.56 lz, 2 H-) 4.39 - 4.46 (i, 2 I-) 5.15 (d, J=7.00 lz, 2 H-1) 6.17 (d, J=7.70 H z, 2 H) 6.94 (d, J=8.78 H z, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20 Hz, 2 H) 7.50 (d, .1=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound showed an EC5o value of less than about 0.1 nM in HCV I b-Coni replicon assays in the presence of 25 5% FBS. Example 35 Dinethyl (2S,2'S)-l, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- I -oxobutane-2, I 30 diyl)dicarbamate The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H seni-prep column cluting with a 2:1 mixture of hexanc:(2:1 isopropyl alcohol:EtOH). The title 134 compound was the first of the 2 diastereomers to elute. 'H NMR (400 MHz, DMSO-D6) 8 ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 H z, 6 1-) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 - 2.04 (m, 8 H) 2.09 - 2.19 (in, 2 H) 2.44 - 2.47 (i, 2 H) 3.52 (s, 6 H) 3.59 - 3.66 (in, 2 H) 3.77 - 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 5 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H-). The title compound showed an EC5 value of less than about 0.1 nM in HCV Ib Con I replicon assays in the presence of 5% FBS. Example 36 10 Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)his(pyrrolidine-2, I -diyl))bis(3-methyl- 1 oxobutane-2,l -diyl)dicarbamate -NN The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H-1 15 semi-prep column eluting with a 2:1 mixture of hexane:(2:1 isopropyl alcohol:EtOH). The title compound was the second of 2 diastereomers to elute. 'H NMR (400 MHz, DMSO-D6) 6 ppm 0.87 (d, J=6.51 Hz, 6 H) 0.92 (d, J=6.72 H z, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 H z, 2 H) 1.82 - 2.04 (in, 8 H) 2.09-2.18 (in, 2 H) 2.41 - 2.47 (n, 2 H) 3.52 (s, 6 H) 3.58- 3.67 (in, 2 H) 3.75 - 3.84 (i, 2 H) 4.02 (, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H) 20 6.94 (d, J=8.67 Iz, 2 H1) 7.12 (d, J=8.46 Hz, 4 11) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H1) 9.98 (s, 2 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV lb-Con I replicon assays in the presence of 5% FBS. Example 37 25 Dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-ieri-hutylphenyl)pyrrolidine-2,5-diyl)his(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3-methyl- I -oxobutane-2, 1 diyl)dicarbanmate ,o 0 0 Example 37A 30 (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate 135 To a mixture of (S)-2-(methoxycarbonylamino)-3-imethylhutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5 *C. Diisopropylcarbodiimide (13.88 g, 110 minol) was added and the reaction mixture was stirred at 0-5 'C for about I hour. The reaction mixture was warmed to room 5 temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50 *C to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield). 10 Example 37B (S)- I -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (10g, 36.7 mmol) in 15 acetonitrile (20 mL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCI (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x 20 10mi). The solvent was evaporated to give a thick oil. Ileptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give the title compound (10.67g) as a white solid. The compound of Example 37R can also be prepreared according to the following procedure: 25 To a flask was charged L-valine (35 g, 299 mmnol), IN sodium hydroxide solution (526 ml, 526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to dissolve solids and then cooled to 15 'C. Methyl chloroformate (29.6 g, 314 mnmol) was added slowly to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15 *C and plH adjusted to -5.0 with concentrated HCI solution. 100 mL of 2-methytetrahydrofuran (2 30 MeTHF) was added and the adjustment of plHl continued until the pH reached ~ 2.0. 150 mnL of 2 MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous layer extracted with 100 ml. of 2-MeTHF. The combined organic layer was dried over anhyd Na 2

SO

4 and filtered, and Na 2

SO

4 cake was washed with 50 mnL of 2-McTHF. The product solution was concentrated to - 100 mL, chased with 120 mL of IPAc twice. 250 ml. of heptanes was charged 35 slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to 45 'C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min, 136 filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 mL). The wetcake was dried at 55 "C for 24 h to give 47.1 g of Moc-L-Val-OH product as a while solid (90%). Moc-L-Val-01H (150 g, 856 minol), HOBI hydrate (138 g, 899 iniol) and DMF (1500 il) were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC 5 hydrochloride (172 g, 899 nunol) was charged and mixed for 20 min. The mixture was cooled to 13 "C and (L)-proline benzyl ester hydrochloride (207 g, 856 minol) charged. Triethylamine (109 g, 1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The reaction mixture was cooled to 15 "C and 1500 mL of 6.7% NaHCO., charged in 1.5 h, followed by the addition of 1200 ml.. of water over 60 min. The mixture was stirred at rt for 30 min, filtered and 10 washed with water/DMF mixture (1:2, 250 mL) and then with water (1500 muL). The wetcake was dried at 55 *C for 24 h to give 282 g of product as a white solid (90%). The resulting solids (40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by TFI (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at 15 room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. -leptane was added (120 ml,), and the solution was stirred until solids formed. After an addition 2 - 3 hours additional heptane was added drop-wise (240 imL), the slurry was stirred for approximately I hour, then filtered. The solids were dried to afford the title compound. 20 Example 37C (IR,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate The product from Example 32 (5.01 g, 13.39 nunol) was combined with 2 methyltetrahydrofuran (70 ml..) and cooled to -5 "C, and N,N-diisopropylethylamine (6.81 g, 52.7 25 mninol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyletrahydrofuran (30 iL) was prepared and added to the diol slurry over 3 tnin., maintaining the internal temperature between -15 'C and -25 *C. After mixing for 5 min at -15 'C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 *C and mixed for 30 minutes. After reaction completion, the crude slurry was carried immediately into the next step. 30 Example 371) (2S,5S)-1 -(4-tert-butylphenyl)-2,5-his(4-nitrophenyl)pyrrolidine To the crude product solution from Example 37C (7.35 g, 13.39 mnmol) was added 4-tert butylaniline (13.4 g, 90 imnol) at 23 C over I minute. The reaction was heated to 65 *C for 2 h. After 35 completion, the reaction mixture was cooled to 23 C and diluted with 2-methyltetrahydrofuran (100 mL) and I M IIC (150 mL). After partitioning the phases, the organic phase was treated with I M 137 HCI (140 ml..), 2-tmethyltetrahydrofuran (50 inL), and 25 wt% aq. NaCl (100 mL.), and the phases were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mil.), dried over MgSO 4 , filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2 inethyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated 5 further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2 methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOl (46 iL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 'C in a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield). 10 Example 37E 4,4'-((2S,5S)-I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of TIHF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig) 15 followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step. 20 Example 37F dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-tert-butylphenyl)pyrrolidinle-2,5-diyl)bis(4, l phenylene)bis(azanediyl)bis(oxonethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- I -oxobutane-2, 1 diyl)dicarhamate 25 To a solution of the product from Example 37E (1.64 g, 4.25 mnol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63 nnol), and H ATU (4.04 g, 10.63 mnol) in DMF (150iL) was added triethylamine (1.07 g, 10.63 nunol), and the solution was stirred at room temperature for 90 min. To the reaction mixture was poured 20 niL of water, and the white precipitate obtained was filtered, and the solid was washed with water (3x5 mL). The solid was blow dried for lh. The crude 30 material was loaded otl a silica gel column and eluted with a gradient starting with ethyl acetate/ heptane (3/7), and ending with pure ethyl acetate. h'lie desired fractions were combined and solvent distilled off to give a very light yellow solid, which was dried at 45 'C ill a vacuum oven with nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 'i- NMR (400 MHz, DMSO D6) 8 ppm 0.88 (d, J=6.61 Hz, 6 11) 0.93 (d, J=6.72 lHz, 6 H1) 1.11 (s, 9 1-1) 1.63 (d, J=5.42 Hz, 2 11) 35 1.80 - 2.04 (in, 8 H1) 2.09 - 2.19 (tll, 2 H1) 2.44 - 2.47 (in, 2 H-) 3.52 (s, 6 11) 3.59 - 3.66 (m, 2 H-1) 3.77 3.84 (n, 2 11) 4.02 (t, J=8.40 lz, 2 H1) 4.42 (dd, J=7.86, 4.83 l1z, 2 11) 5.14 (d, J=6.18 lz, 2 1-) 6.17 138 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 H z, 4 -1) 9.98 (s, 2 H). Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 imol) and the product from example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 5 g, 144 imol) is added and the solution is cooled to O *C. In a separate flask, 1-propanephosphonic acid cyclic anhydride (T3P*) (46.0 g, 50 wt% in EtOAc, 72.2 minol) was dissolved in EtOAc (58.5 mL), and charged to an addition funnel. The 'l3P solution is added to the reaction mixture drop-wise over 3-4 h and stirred until the reaction is complete. The reaction is warmed to room temperature,and washed with IM HCI/7.5 wt% NaCl (100 ml..), then washed with 5% NaHCO 3 (100 mL.), then 10 washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL, EtOH- (300 nL) was added, and the solution was concentrated to 84 g solution. A portion of the EtOl-l solution of product (29 g) was heated to 40 'C, and added 134 g 40 w% EOHl in 1120. A slurry of seeds in 58 wt/wt% EtOHlUI20 was added, allowed to stir at 40 C for several hours, then cooled to 0 C. '[he slurry is then filtered, and washed with 58wt/wt% EtOl-/-1 2 0. 15 The product is dried at 40 -60 'C under vacuum, and then rehydrated by placing a tray of water in the vacuum oven to give the title compound. The title compound showed an ECS) value of less than about 0.1 nM in HCV I b-Con I replicon assays in the presence of 5% FBS. Example 38 20 Dimethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane 2,1 -diyl)dicarbainate F ~H 0 o Example 38A 25 (I S,4S)-1,4-bis(4-nitrophenyl)butane- 1,4-diyl dimethanesulfonate The title compound was prepared using the methods from Example 37C, substituting the product from Example 33 for the product from Example 32. Example 38B 30 (2R,5R)-I-(4-fluorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The title compound was prepared using the methods from Example 37D, substituting 4 fluoroaniline for 4-tert-butylaniline. 139 Example 38C 4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example 38B (2.34 g, 5.74 nunol) in 1:1 ethanol:THF (60 ml) in a 250 ml stainless steel pressure bottle was added PtO 2 (0.47 g, 2.06 mmnol) and the resulting 5 mixture was placed under 1-12 pressure (30 psi) and stirred at rt. for 90 mn. The mixture was filtered through a nylon membrane and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-65% ethyl acetate in hexanes to give the title compound as a solid (0.736 g, 37%). 10 Example 38D (2S,2'S)-Iert-butyl 2,2'-(4,4'-((2R,5R)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate To a solution of the product from Example 38C (3.54 g, 10.19 mmol), (S)-1-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.48 g, 25.5 nunol), and HATU (9.69 g, 25.5 mmol) in 15 anhydrous NMP (50mL) was added N,N-diisopropylethylamine (5.29 ml, 30.6 mmol), and reaction mixture was stirred at room temperature for 30-45 minutes. The reaction mixture diluted with water (500mL). The precipitated product was filtered and washed with water (3xlOOmlL), sodium bicarbonate solution (50mL), and water (50mL). The product dried at 40 *C for 15 h. This material (8.5g) was passed through a pad of silica gel and eluted with ethyl acetate to afford the white solid 20 product (7.9g, 99%). Example 38E (2S,2'S)-N,N'-(4,4'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))dipyrrolidine 2-carboxamide 25 To a solution of the product from Example 38D (7.9 g, 10.65 mmol) in dichloromethane (50miL), was added 5M HCI solution in isopropyl alcohol (50mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated by rotavap under vacuum and crude material taken in dichloromethane containing 20% methanol (200mL). The solution was washed with 5% amnonium hydroxide solution (90mL), brine (50mL) and dried over MgSO 4 . The solution was 30 filtered and concentrated to give 6.5g of crude product. This material was recrystallized from ethyl acetate /heptane (8/2) to give the title compound (5.0 g, 87% yield). Example 38F Dimnethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I-(4-fluoropheniyl)pyrrolidine-2,5-diyl)bis(4, I 35 phenylene))bis(azanediyl)bis(oxonethylene)bis(pyrrolidine-2, 1 -diyl))bis(3,3-dimnethyl- I -oxobutane 2, 1-diyl)dicarbamate 140 To a solution of the product from Example 38E (4.14 g, 7.64 minol), (S)-2 methoxycarbonylamiiio-3,3-dimethyl-butyric acid (3.62 g, 19.11 mmol), and EDAC (3.66 g, 19.11 nnol) in anhydrous DMF (80mtL) was added N,N-diisopropyleihylanine (2.96 g, 22.93 innol) and the solution was stirred at room temperature for 4 h. The reaction mixture poured into 400 mL of 5 water, and the white precipitate obtained was filtered and washed with water (3x50mL), sodium bicarbonate (50mL), water (50ML), and dried at 45 "C in a vacuum oven with nitrogen purge for 15 h to give 7.0 g of the crude product. The crude material was loaded on silica gel column (150g silica) and eluted with a gradient starting with ethyl acetate/ heptane (7/3), and ending with ethyl acetate. Desired fractions were combined and solvent distilled off to give very light yellow oil, which was 10 triturated MTBE /heplane(1:9) for lh. The white solid thus obtained was filtered and dried in a vacuum oven with nitrogen purge to afford 6.lg of product. The solid 5.5 g was dissolved in l6iL of methanol and this solution was added into water (220 mL) in a 500mL flask. The slurry was stirred for 30 minutes, and the solid was collected by filtration, dried at 45 "C with nitrogen purge for 15 h to give the title compound (5.4 g). 'H NMR (400 M Hz, DMSO-D6) 6 ppm 0.96 (s, 18 11) 1.64 (d, J=5.53 15 lz, 2 H) 1.78 - 1.93 (ni, 6 H) 1.94 - 2.06 (m, 2 H) 2.09 - 2.21 (m, 2 H) 3.54 (s, 6 H) 3.59 - 3.69 (m, 2 1-1) 3.72 - 3.83 (i, 2 -1) 4.20 (d, 1=8.89 Hz, 2 -1) 4.43 (dd, J=7.92, 5.42 H-lz, 2 H) 5.16 (d, J=6.29 H z, 2 H) 6.20 (dd, J=9.16, 4.39 Iz, 2 H-1) 6.77 (t, 1=8.95 Hz., 2 H) 7.12 (d, J=8.57 Hz, 4 -1) 7.50 (d, J=8.57 Hz, 4 H-1) 9.99 (s, 2 H-1). The title compound showed an EC 50 value of less than about 0.1 nM in ICV lb-ConI replicon assays in the presence of 5% FBS. 20 Example 39 N-(miethoxycarbonyl)-L-valyl-N-(4-{(2S,5S)- I-(4-fluorophenyl)-5-[4-(2-{(2S)-1-[N (iethoxycarbonyl)-L-valyllpyrrolidin-2-yl}-l H-imidazol-4-yl)phenyl]pyrrolidin-2-yl phenyl)-L prolinamide (ACD v12) 25 and N-(methoxycarbonyl)-L-valyl-N-(4-((2R,5R)-I-(4-fluorophenyl)-5-14-(2-((2S)-l-[N (methoxycarbonyl)-L-valyl]pyrrolidin-2-yl -I H-inidazol-4-yl)phenyl]pyrrolidin-2-ylI phenyl)-L prolinamide (ACD v12) 141 F ~~NH N -0 Example 39A Il-(4-bromophienyl)-4-(4-nitrophenyl)butanc-lI,4-dione Added benzene (108 mnL) to anhydrous zine(II) chloride (19.62 g, 144 mnmol), followed by the 5 addition of diethylamnine (1 1.16 mL, 108 mmnol) and 2-methylpropan-2-ol (10.32 mnL, 108 mmol) and stirred at room temperature for 2 h. Added 2-bromo- I-(4-bromophenyl)ethanone (20 g, 72.0 mmiol) and l-(4-nitrophenyl)cthanone (17.83 g, 108 mnmol) together and stirred mixture for I8 h. Addcd 5% aq. sulfuric acid (50 mL!.) and stirred vigorously, then the product was collected by filtration, rinsed with benzene, water, methanol, dichloromethane and dried under vacuum to provide the product (15.0 10 g, 58% yield, colorless powder). Example 39B Il-(4-bromophenyl)-4 -(4-nitrophenyl)butane- I,4-diol Dissolved the product from Example 39A (3.64 g, 10.05 mnmol) in ethanol (67 mL)j and added 15 sodium borohydride (0.837 g, 22.11 mmol) portionwise. After stirring for I h at room temperature, the mixture was filtered through celite and washed with methanol and ethyl acetate and the filtrate concentrated to a solid. The solid was dissolved in ethyl acetate (200 mnL) and extracted with IN aq. HCI (200 mL), then brine and the organic layer dried and concentrated to a colorless oil (3.68 g, l(00%) that was used directly in the next reaction.

20 Example 39C I -(4-bromophenyl)-4-(4-nitrophenyl)butane- I,4-diyl dimethanesulIfonate Dissolved the product from Example 39B (3.68 g, 10.05 mmol) in dichloromethane (167 mL) and cooled the solution in an ice bath followed by the addition of triethylamine (4.20 moL, 30.1 mnmol) 25 and methancsulfonyl chloride (1.96 mL., 25.1 mmol) dropwisc. After stirring for 15 min the solution was concentrated to a solid (5.25 g, 100%) that was used directly in the next reaction. Example 39D 2-(4-bromophenyl)- I-(4-fluorophenyl)-5-(4-nitrophenyl)pyrrolidine 142

HI

Dissolved the product from Example 39C (5.25 g, 10.05 mmol) in DMF (31 nL) and then added 4-fluoroaniline (9.65 mL, 101 mmol) and heated solution at 50 0 C for 18 h. Solution was cooled to room temperature and IN aq. HCI added (100 mL) then extracted with ethyl acetate (2 x 200 ml..), then combined organic extracts washed with brine, dried and concentrated to an amber oil to 5 which methanol (10 mL) was added and after 3 h a yellow solid (1.05 g, 24%) resulted as the title compound as a 1/l mixture of trans pyrrolidine isomers. Example 39E 1-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 10 yl)phenyl)pyrrolidine Dissolved the product from Example 39D (1.05 g, 2.38 mnol), 4,4,4',4',5,5,5',5'-oclaiethyl 2,2'-bi(l,3,2-dioxaborolane) (0.725 g, 2.86 mmol), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0. 194 g, 0.238 mmol), and potassium acetate (0.35 g, 3.57 nmol) in dioxane (20 niL) and then bubbled nitrogen gas through the solution for 10 15 min, then heated at 100 "C for 1.5 I. Solution was cooled to room temperature then filtered through celite and washed with ethyl acetate (20 iL). The filtrate was dried, concentrated and the residue purified by column chromatography on silica gel, eluting with a solvent gradient of 10-50% ethyl acetate in hexane to give the title compound (1.09 g, 94%) as a yellow solid and a 1/1 mixture of trans stereoisomers. 20 Example 39F (2S)-tert-butyl 2-(4-(4-(1-(4-fluorophenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)-1 H-i midazol-2 yl)pyrrolidine- 1 -carboxylate Dissolved the product from Example 39E (1.05 g, 2.15 nunol), the product from Example 25 26D (0.748 g, 2.365 mmol), [l,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.176 g, 0.215 nunol) in a mixure of toluene (10 mL), ethanol (10 mL) and a IN aq. sodium bicarbonate solution (2.58 mL, 2.58 nnol) and bubbled nitrogen gas through the solution for 10 min, then heated at 90 0 C for 3 h . Solution was cooled to room temperature and water (20 ml.,) added then extracted with dichloromethane (50 mL), then dried, concentrated and the residue purified by column 30 chromatography on silica gel, eluting with a solvent gradient of 0-100% ethyl acetate in hexane to give the title compound (0.28 g, 72%) as a yellow solid and a 1/1 mixture of trans stereoisomers. Example 39G (2S)-tert-butyl 2-(4-(4-(5-(4-aminophenyl)-1-(4-fluorophenyl)pyrrolidin-2-yl)phenyl)-IH-imidazol-2 35 yl)pyrrolidine-l -carboxylae Dissolved the product from Example 39F (300 ing, 0.502 mmol) in ethanol (5 mL) and TIF (5 mL) then added platinum(IV) oxide (22.8 tng, 0.1 mmol) and a hydrogen balloon and stirred the solution at room temperature for 2.5 h. Solution was filtered through celite and washed with 143 methanol (10 mL), then concentrated to give the title compound (285 mg, 100%) as a colorless semi solid and a 1/1 mixture of stereoisomers. Example 39H 5 (2S)-tert-butyl 2-(4-(5-(4-(2-((S)- I -(tert-butoxycarbonyl)pyrrolidin-2-yl)- 1 1-imidazol-4-yl)phenyl)- I (4-fluorophenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine- I -carboxylate Dissolved the product from Example 39G (285 mg, 0.502 innol), (S)-1-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (162 mg, 0.753 mmol), HATI (305 mg, 0.803 mmol) and Ilunig's base (0.263 mL, 1.506 nmol) in DMSO (5 mL) and stirred at room temperature for I h. 10 Dichloromethane (50 mL) was added followed by extraction with water (2 x 50 mL), the organic extract dried, concentrated and the residue dissolved in methanol (10 mnL) followed by the addition of potassium carbonate (400 tmg, 2.89 mmnol) and stirred the bright yellow solution at room temperature for 30 min. The solution was then filtered and the filtrate concentrated to an oil, which was dissolved in a 95/5 dichloromethane/methanol mixture (50 mL) and extracted with water (20 mL). The organic 15 extract was dried and concentrated to give the title product (350 ing, 91%) as a light yellow solid and a I/I mixture of stereoisomers. Example 391 (2S)-N-(4-(I -(4-fluorophenyl)-5-(4-(2-((S)-pyrrolidin-2-yl)-I H-imidazol-4-yl)phenyl)pyrrolidin-2 20 yl)phenyl)pyrrolidine-2-carboxamide hydrochloride salt Dissolved the product from Example 39H (350 mg, 0.458 mmol) in 4M hydrochloric acid in dioxane solution (6 mL) and stirred the solution at room temperature for 30 min then concentrated the mixture under high vacuum to a solid (approx. 310 mg) as a hydrochloride salt that was used directly in the next reaction. 25 Example 39J N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)- 1-(4-fluorophenyl)-5-[4-(2-1(2S)- 1 -[N (methoxycarbonyl)-I.,-valyl]pyrrolidin-2-yl }-I H-i midazol-4-yl)phenyl Ipyrrolidin-2-yl } phenyl)-L., prolinamide (ACD v12) 30 and N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)- I -(4-fluorophenyl)-5-[4-(2-{ (2S)-I -[N (methoxycarbonyl)-L-valyl] pyrrolidin-2-yl }-I H-imidazol-4-yl)phenylJpyrrolidin-2-yl phenyl)-L prolinamide (ACD v12) To a mixture of the product from Example 391 (300 mg, 0.45 nnol), (S)-2 35 (methoxycarboiylamino)-3-metlhylbutanoic acid (173 ing, 0.99 mnol), and HATU (428 mg, 1.125 mmol) in DMSO (5 ml) was added Hunig's base (0.786 mL, 4.5 miol), and the reaction was stirred at room temperature for I h. Dichloromnethane (50 muL) was added followed by extraction with water (2 x 25 mL), the organic extract dried, concentrated and the residue dissolved in methanol (15 mL) 144 followed by the addition of potassium carbonate (300 mg, 2.17 nmnol) and stirred at room temperature for 20 min. The solution was then filered and the filtrate concentrated to an oil, which was dissolved in a 95/5 dichloroimethane/methanol mixture (50 mL) and extracted with water (20 inL). The organic extract was dried and concentrated, and the residue purified by column chromatography on silica gel, 5 eluding with a solvent gradient of 0-25% methanol in dichloromethane to give the title compounds (0.13 g, 33%) as a colorless solid and as a 1/1 mixture of diastereomers. 'H NMR (400 MHz, DMSO D6) 8 ppm 1l1.64 (s, 11H), 9.94 (s, 111), 7.57 (d, J=8.1 Iz, 2H-1), 7.47 (in, 311), 7.33 (d, J=1.7 lz, 11H), 7.24 (m, 211), 7.08 (in, 41-H), 6.72 (in, 21H), 6.17 (in, 2H), 5.15 (m, 2H), 5.01 (m, I H), 4.38 (m, 1 H), 4.0 (in, 211), 3.75 (in, 211), 3.56 (in, I H1), 3.48 (s, 311), 3.47 (s, 311), 2.06 (in, 211), 1.87 (m, 8H-1), 1.63 (in, 10 2H), 0.82 (m, 12H). The title compound showed an ECyo value of less than about 0.1 nM in HCV lb Con I replicon assays in the presence of 5% FBS. Example 40 N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)- 1 -(4-tert-butylphenyl)-5-(4-(2-{(2S)- I -[N 15 (melhoxycarbonyl)-L-valyl]pyrrolidin-2-yl}- IH-imiidazol-4-yl)phenyllpyrrolidin-2-yI }phenyl)-L prolinamide (ACD v12) and N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)- 1-(4-rert-butylphenyl)-5-[4-(2-{(2S)- I -[N (niethoxycarbonyl)-l.,-valyl]pyrrolidin-2-yl - I H-imidazol-4-yl)phenyl]pyrrolidin-2-yl I phenyl)-L 20 prolinamide (ACD v12) H N HNX )=o N -N Example 40A 2-(4-bromnophenyl)-1- (4-mert-butylphenmyl)-5 -(4-nitrophenyl)pyrrolidine 25 The product from Example 39C (10.86 g, 20.79 mmiol), DMF (65 mnL) and 4-tert-butylaniline (26.5 ml., 166 mnmol) was reacted according to the procedure in Example 39D to provide the title compound (5.0 g, 50%, yellow solid) as a mixture of cis and trans pyrrolidine stereoisomners. Example 4013 1 45 011 1-(4-tert-butylphenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl- I 1,3,2-dioxaborolan-2 yl)phcnyl)pyrrolidine The product from Example 40A (2.0 g, 4.17 mmol), 4,4,4',4',5,5,5',5'-octainethyl-2,2' bi(1,3,2-dioxaborolane) (1.27 g, 5.01 inmol), [1,1' 5 bis(di phenylphosphino)ferroceneldichloropalladium(II) (0.681 g, 0.834 mmol), and potassium acetate (0.614 g, 6.26 mmol) in dioxane (35 mL) was reacted according to the procedure in Example 39E to provide the title compound (1.5 g, 68%, yellow solid) as a mixture of stereoisomers. Example 40C 10 (2S)-tert-butyl 2-(4-(4-(I-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)- IH-imidazol 2-yl)pyrrolicine-l -carboxylate The product from Example 40B (0.7 g, 1.33 mmol), (S)-tert-butyl 2-(4-bromo- I H-imidazol-2 yl)pyrrolidine-I-carboxylate (0.462 g, 1.463 mmol), [1,' bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.109 g, 0.133 mmol) in a mixture of toluene 15 (6 mL), ethanol (6 niL) and a IN aq. sodium bicarbonate solution (1.6 mL, 1.6 mnmol) was reacted according to the procedure in Example 39F to provide the title compound (0.66 g, 78%, yellow solid) as a mixture of stereoisomers. Example 401) 20 (2S)-tert-butyl 2-(4-(4-(5-(4-aminophenyl)- 1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenyl)- I II imidazol-2-yl)pyrrolidine- I -carboxylate The product from example 40C (1.37 g, 2.153 mnmol), in ethanol (10 mL) and THF (10 mnL) then added platinum(IV) oxide (196 mg, 0.862 mninol) and a hydrogen balloon and stirred the solution at room temperature for 48 I. The reaction was then treated according to the procedure in Example 25 39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers. Example 40E (2R)-tert-butyl 2-(4-(5-(4-(2-((S)- I -(tert-butoxycarbonyl)pyrrolidin-2-yl)- I H-imidazol-4-yl)phenyl) 1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine- I -carboxylate 30 The product from Example 40D (1.3 g, 2.146 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine 2-carboxylic acid (1.386 g, 6.44 mnol), IIATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL, 6.44 mmol) in DMSO (20 mL) was reacted according to the procedure in Example 39H to provide the title compound (1.01 g, 59%) as a mixture of stereoisomers. 35 Example 40F (2R)-N-(4-( I-(4-tert-butylphenyl)-5-(4-(2-((S)-pyrrolidin-2-yl)- 1 H-imidazol-4-yl)phenyl)pyrrolidin 2-yl)phenyl)pyrrolidine-2-carboxamide hydrochloride salt 146 The product front Example 40E (610 mg, 0.76 minol), in 2M hydrochloric acid in dioxane solution (10 mL) was reacted according to the procedure in Example 391 to provide the title compound (495 mg) as a hydrochloride salt and a mixture of stereoisomers. 5 Example 40G N-(nethoxycarbonyl)-L-valyl-N-(4-{(2S,5S)-I -(4-tert-butylphenyl)-5-[4-(2-{(2S)-1-[N (methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}- I H-imidazol-4-yl)phenyl]pyrrolidin-2-yl }phenyl)-L prolinamide (ACD v12) and 10 N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)- 1-(4-tert-butylphenyl)-5-4-(2-1(2S)-I -[N (melhoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-I H-imidazol-4-yl)phenyllpyrrolidin-2-yl)phcnyl)-L prolinamide (ACD v12) The product from Example 40F (372 mng, 0.617 minol), (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid (324 mng, 1.851 mmol), HATU (821 mg, 2.16 miol) in DMSO (6 ml) and 15 Hunig's base (1.078 ml, 6.17 mmol) was reacted according to the procedure in Example 39J then the reaction was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18), cluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compounds (68 tmg, 12% yield, white solid) as a 1/1 mixture of diastereomers . '1-1 NMR (free base) (400 M H z, DMSO-D6) 6 ppm 0.80 - 0.96 (in, 12 H), 1.10 (s, 9 H), 1.65 (d, J=6.07 Hz, 2 H), 1.82 20 2.04 (in, 8 H-), 2.07 - 2.20 (m, 3 H-), 3.52 (s, 3 11), 3.53 (s, 3 H-), 3.58 - 3.66 (m, 2 11), 3.73 - 3.85 (m, 3 H), 3.99 - 4.08 (in, 2 H), 4.43 (dd, 1=7.97, 4.93 Hz, I I), 5.06 (dd, J=6.99, 2.87 Hz, I H), 5.17 (d, J=6.40 Hz, 2 1-1), 6.20 (d, 1=8.89 H z, 2 H), 6.93 (d, J=8.89 H z, 2 H), 7.14 (dd, J=8.51, 2.87 Hz, 4 H-), 7.30 (t, .1=9. I Hz, 2 H), 7.37 (d, ./=1.84 Hz, 1 H), 7.50 (d, ./=8.02 Hz, 2 1-1), 7.61 (d, ./=8.13 lz, 2 H), 9.98 (s, I H), 11.68 (s, I H). The title compound showed an EC 50 value of less than about 0.1 nM in 25 HCV I b-Con I replicon assays in the presence of 5% FBS. Example 41 N-(methoxycarbonyl)-I..-valyl-N-(4-{(2S,5R)- 1-(4-iert-butylphenyl)-5-[4-(2-{(2S)-i-(N (methoxycarbonyl)-L-valyl]pyrrolidin-2-yI} - I H-imidazol-4-yl)phenyllpyrrolidin-2-ylI phenyl)-L 30 prolinamide (ACD v12) 0 NH HN To the product from Example 40F (493 ng, 0.818 inmol), (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid (430 ig, 2.454 nunol), HATU (1088 tug, 2.86 minol) in DMSO (8.2 mL) and Hlunig's base (1.5 nL, 8.59 mmntol) was reacted according to the procedure in Example 39J then the 147 residue was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (CIS), cluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound (80 mg, 11% yield, white solid). 'H1 NMR (free base) (400 MIHz, DMSO-D6) 8 ppm 0.89 1.04 (i, 12 H), 1.20 (s, 9 H), 1.86 - 2.12 (in, 10 H), 2.15 - 2.27 (in, 3 H), 2.43 - 2.49 (in, 2 1-1), 3.60 (s, 5 3 H1), 3.61 (s, 3 H-), 3.66 - 3.74 (m, 1 11), 3.81 - 3.93 (m, 2 H-1), 4.06 - 4.15 (m, 2 11), 4.52 (dd, 1=7.86, 4.61 Hz, 1 H), 4.74 (d, .1=5.20 Hz, 2 H), 5.14 (dd, .1=6.99, 3.31 Hz, 1 H), 6.40 (d, J=8.78 Hz, 2 H), 7.06 - 7.11 (i, 2 H-), 7.32 - 7.41 (m, 2 11), 7.47 (d, J=1.73 IHz, 1 11), 7.51 (d, J=7.81 1 Hz, 4 11), 7.65 (d, .1=8.46 -lz, 2 1-), 7.77 (d, 1=8.24 Hz, 2 -1), 10.10 (s, I H) ,11.76 (s, 1 H). The title compound showed an EC50 value of less than about 0.1 nM in I-ICV I b-Con I replicon assays in the presence of 5% FBS. 10 Example 42 diiethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I -(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))bis(I H-inidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-iethyl- I oxobutane-2, I -diyl)dicarbamate 15 and diimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-I-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))his( H-imiiidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl- 1 oxobutane-2, I -diyl)dicarbamate H 20~ ExmN 42A N H T N ,NH KCN IN N)"~ ~ N 0p

HN

0 20 Example 42A , i,4-bis(4brounophe-yl)butaie- h,4-diol The product from Example 26F (3.42 g, 8.63 innol) was subjected to the conditions described in Example 39C to provide the title product (3.45 g, 100% yield, colorless oil). 25 Example 42B3 I ,4-bis(4-broiniopheoyl)butane- 1,4-diyl dimethanesulfonate '[he product from Example 42A (3.45 g, 8.63 nunol) was subjected to the conditions described in Example 39C to provide the title product (4.8 g, 100%). 148 Example 42C 2,5-bis(4-bromophenyl)-l -(4-teri-bulylphenyl)pyrrolidine The product from Example 42B (5.2 g, 9.35 mmol) was subjected to the conditions described 5 in Example 39D, substituting 4-tert-butylaniline (11.91 mL, 74.8 imol) for 4-fluoroaniline to provide the title product (3.89 g, 81%) as a mixture of isomers. Example 42D 1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine 10 Dissolved the product from Example 42C (3.88 g, 7.56 imol), 4,4,4',4',5,5,5',5'-octamethyl 2,2'-bi(1,3,2-dioxaborolane) (6.72 g, 26.5 mmol), [1,1' bis(diphenylphosphino)ferroceneldichloropalladium(II) (0.617 g, 0.756 mmol), and potassium acetate (3.34 g, 34.0 nunol) in dimnethoxyethane (70 mL) and bubbled nitrogen gas through the solution for 10 min, then heated at 85 "C for I h. Solution was cooled to room temperature then filtered through 15 celite and washed with ethyl acetate (20 mL), the filtrate dried, then concentrated and the residue purified by column chromatography on silica gel, eluting with a solvent gradient of 0-10% ethyl acetate in hexane followed by trituration of the resultant solid with diethyl ether to give the title compound (1.14 g, 25%) as a /l mixture of trans stereoisomers. 20 Example 42E (2S,2'S)-tert-hutyl 2,2'-(4,4'-(4,4'-(l -(4-tert-hutylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(IH-imidazole-4,2-diyl))dipyrrolidine- I-carboxylate Dissolved the products from Example 42D (0.915 g, 1.506 mmol), the product from Example 26D (1.429 g, 4.52 mninol), [1,l '-bis(diphenylphosphino)ferroceneIdichloropalladiumn(II) (0.123 g, 25 0. 151 mmol) in a mixture of toluene (7 mL), ethanol (7 mL) and a 2N aq. sodium bicarbonate solution (2.64 ml., 5.28 nunol) and bubbled nitrogen gas through the solution for 10 mini, then heated at 100 0 C for 3 h. Solution was cooled to room temperature and water (20 mL) added then extracted with dichloromethane (50 niL), then dried, concentrated and the residue purified by column chromatography on silica gel, eluuing with a solvent gradient of 0-80% ethyl acetate in hexane to give 30 the title compound (0.93 g, 75%) as a 1/1 mixture of trans stereoisomers. Example 42F (S)-4,4'-(4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 -phenylene))bis(2-((S)-pyrrolidin-2 yl)- I H-imidazole) hydrochloride salt 35 To the product from Example 42E (1.11 g, 1.344 inunol), in 4M hydrochloric acid in dioxane solution (5 mL) was reacted according to the procedure in Example 391 to provide the title compound (1.12 g) as a hydrochloride salt and a mixture of stereoisomers. 149 Example 42G dinethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I -(4-tcrt-butylphenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))bis(HI 1l-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl- 1 oxohutane-2, I -diyl)dicarbamate 5 and dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5 R)- I -(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))bis(l I H-inidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-inethyl- I oxobutane-2, I -diyl)dicarbamate To a mixture of the products from Example 42F (1.04 g, 1.662 inmol), (S)-2 10 (imethoxycarbonylamino)-3-methylbutanoic acid (0.728 g, 4.15 mmol), and HATU (1.295 g, 3.41 mniol) in DMSO (20 mL) was added Hlunig's base (2.322 mL, 13.29 nunol), and the reaction was stirred at room temperature for I h. Water (20 miL) was added to form a solid that was dissolved in dichloroiethane and purified by column chromatography on silica gel, eluting with a solvent gradient of 0-5% methanol in dichloromethane to give a solid that was diluted with acetonitrile and water 15 (0.1% TFA) and further purified by reversed phase chromatography (C18), cluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound (92 mg, 6% yield, white solid) as a 1/l mixture of diastereomers. 'H NMR (free base) (400 MHz, DMSO-D6) 6 ppm 0.78 -0.92 (m, 12 H), 1.09 (s, 9 H1), 1.63 - 1.74 (in, 2 11), 1.85 - 2.00 (in, 6 11), 2.05 - 2.16 (m, 2 H-), 3.44 - 3.50 (m, 4 H-), 3.52 (s, 6 H), 3.70 - 3.82 (m, 4 H), 4.02 - 4.09 (m, 2 H), 5.04 (dd, J=6.67, 3.20 Hz, 2 H), 5.19 (t, 20 J=6.18 Hz, 2 H1), 6.21 (d, J=8.57 H z, 2 H-), 6.91 (dd, J=7.16, 1.63 Hz, 2 11), 7.14 (dd, J=8.19, 2.22 H z, 4 H), 7.20 - 7.30 (m, 2 H), 7.36 (d, J= l.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, J=4.01 Hz, 2 H). The title compound showed an EC 5 o value of less than about 0.1 nM in HCV lb-ConI replicon assays in the presence of 5% FBS. 25 Example 43 dimchyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-tcri-butylphcntyl)pyrrolidiine-2,5 diyl)bis(4, I -phenylene))bis( I l1-imsidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl- I oxohutane-2, I -diyl)dicarhamate N N 00 30 The product from Example 42G was purified by chiral chromatography on a Chirapak 1B column eluting with a mixture of hexane/THF/MeOH (80/10110). The title compound was the first of 2 diastereomers to elute.'H NMR (400 MHz, DMSO-D6) 8 ppm 0.78 - 0.92 (in, 12 H), 1.09 (s, 9 H), 1.63 - 1.74 (m, 2 H), 1.85 - 2.00 (m, 6 H), 2.05 - 2.16 (m, 2 H), 3.44 - 3.50 (in, 4 H), 3.52 (s, 6 H), 3.70 - 3.82 (in, 4 H), 4.02 - 4.09 (in, 2 H-), 5.04 (dd, J=6.67, 3.20 Hz, 2 H), 5.19 (i, J=6.18 Hz, 2 H), 35 6.21 (d, J=8.57 Hz, 2 H), 6.91 (dd, J=7.16, 1.63 Hz, 2 1), 7.14 (dd, J=8.19, 2.22 Hz, 4 H), 7.20 - 7.30 150 (m, 2 H), 7.36 (d, J=1.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, 1=4.01 Hz, 2 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV Ib-Coni replicon assays in the presence of 5% FBS. 5 Example 44 dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I -(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))bis(l H l-imidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3-methyl- I oxobutane-2,1 -diyl)dicarbamate N .- o N 0 t 10 The product from Example 42G was purified by chiral chromatography on a Chirapak [B column eluting with a mixture of hexane/T-IF/MeOH (80/10/10). The title compound was the second of 2 diastereomers to elute. 'H NMR (400 MHz, DMSO-D6) 6 ppm 0.78 - 0.92 (m, 12 H), 1.09 (s, 9 H), 1.63 - 1.74 (in, 2 1-1), 1.85 - 2.00 (m, 6 H), 2.05 - 2.16 (in, 2 H), 3.44 - 3.50 (in, 4 H), 3.52 (s, 6 H), 3.70 - 3.82 (in, 4 H), 4.02 - 4.09 (in, 2 1H1), 5.04 (cd, J=6.67, 3.20 Hz, 2 H), 5.19 (1, J=6.18 Hz, 2 H), 15 6.21 (d, J=8.57 Hz, 2 H), 6.91 (dd, J=7.16, 1.63 Hz, 2 H), 7.14 (dd, J=8.19, 2.22 H z, 4 H), 7.20 - 7.30 (in, 2 H), 7.36 (d, J=1.19 Hz, 2 H), 7.61 (d, J=8.13 Hz, 4 H), 11.67 (d, J=4.01 Hz, 2 1-1). The title compound showed an EC 5 o value of less than about 0.1 nM in HCV lb-Coni replicon assays in the presence of 5% FBS. 20 Example 45 dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4, 1 -phenylene))bis( 1-inidazole-4,2-diyl))bis(pyrrolidine-2,1 -diyI))bis(3-methyl- 1 oxobutane-2, I -diyl)dicarbamate 25 and dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5 R)- I-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4,1 -phenylene))his(I H-imidazol-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-imcthyl-l oxobutane-2, I -diyl)dicarbamate 151 N HH H NH o~No HN ~0N Example 45A 2,5-bis(4-broinophenyl)- I -(4-fluorophenyl)pyrrolidine The product from Example 42B (5.2 g, 9.35 minmol) was subjected to the conditions described 5 in Example 39D to provide the title product (6.41 g, 48%) as a mixture of cis and trans isomers. Example 45B 1-(4-fluorophenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxahorolan-2-yl)phenyl)pyrrolidine The product from Example 45A (2.17 g, 4.57 mol) was subjected to the conditions 10 described in Example 421) and purified by column chromatography on silica gel, eluting with a solvent gradient of 0-15% ethyl acetate in hexane to give the title compound (1.65 g, 64%) as a mixture of cis and trans stereoisomers. Example 45C 15 (2S,2'S)-tert-buIyl 2,2'-(4,4'-(4,4'-(I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(I H imidazole-4,2-diyl))dipyrrolidine- I -carboxylate The product from Example 45B (1.0 g, 1.756 inmol) was subjected to the conditions described in Example 42E to provide the title product (1.0 g, 72%) as a mixture of cis and trans isomers. 20 Example 45D (S)-4,4'-(4,4'-( 1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))bis(2-((S)-pyrrolidin-2-yl) I H-imidazole) Dissolved the product from Example 45C (150 ing, 0.19 mmol) in dichloromethane (1 mnL) 25 and TFA (1 mL) and stirred the solution at room temperature for 1 h then concentrated the mixture under high vacuum to give a solid that was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound (62 mg, 55% yield) as a 1/1 mixture of trans diastercomers that eluted before the cis isomer. 152 Example 45E dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I -(4-fluorophenyl)pyrrolidine-2,5 diyl)his(4, I -phenylene))his(I H-imidazole-4,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3-methyl-I 5 oxobutane-2, I -diyl)dicarbainate and dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5 diyl)bis(4, I -phenylene))bis(I H-imidazole-4,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3-methyl-1 oxobutane-2, I -diyl)dicarbamate 10 To a mixture of the product from Example 45D (47 mg, 0.08 nimol), (S)-2 (methoxycarbonylamino)-3-imetliylbutanoic acid (29 ing, 0.168 minol), and HATU (61 mg, 0.16 mmol) in DMSO (0.8 mL) was added Hunig's base (0.035 mL, 0.2 mmol) was reacted according to the procedure in Example 39J then the residue was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water 15 (0.1% TFA) to give the title compound (54 mg, 75% yield, white solid) as a 1/1 mixture of diastereomers . '-I NMR (free base) (400 Miz, DMSO-D6) 6 ppm 11.62 - 12.13 (m, 2 HI), 7.59 - 7.71 (m, J=. 13 Hz, 3 H), 7.46 - 7.57 (i, 1=8.24 Hz, 1 H), 7.38 (d, J=1.84 H1z, 2 1), 7.10 - 7.32 (in, 6 I), 6.72 - 6.83 (in, 2 H-), 6.19 - 6.31 (i, 2 H1), 5.17 - 5.28 (in, 2 H1), 5.02 - 5.11 (in, 1=6.72 lIz, 2 H), 4.05 (t, J=8.40 Hz, 2 H), 3.7 1 - 3.85 (im, 4 I), 3.53 (s, 6 H), 2.05 - 2.21 (m, 4 H), 1.94 (s, 6 H), 1.64 - 1.78 20 (in, 2 H1), 0.77 - 0.95 (in, 12 11). The title compound showed an EC 50 value of less than about 0.1 nM in H(CV I b-Con I replicon assays in the presence of5% FBS. Example 46 dimiethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-I-(4-fluorophcnyl)pyrrolidine-2,5 25 diyl)bis(4,1-phenylene))bis(IH-imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1 oxobutane-2, I -diyl)dicarbamate N The product from Example 45E was purified by chiral chromatography on a Chirapak IB column eluting with a mixture of hexaner'i-IF/MeOI (85/7.5/7.5). 'H1 NMR (400 MIIz, DMSO-D6) 6 30 ppm 11.62 - 12.13 (in, 2 H), 7.59 - 7.71 (m, .1=8.13 H 1z, 3 11), 7.46 - 7.57 (n, J=8.24 H z, I H), 7.38 (d, J=1.84 lz, 2 11), 7.10 - 7.32 (in, 6 H), 6.72 - 6.83 (i, 2 H), 6.19 - 6.31 (in, 2 H), 5.17 - 5.28 (m, 2 1-1), 5.02 - 5.11 (i, ./=6.72 Hz, 2 I), 4.05 (t, .1=8.40 Hz, 2 H), 3.71 - 3.85 (m, 4 H), 3.53 (s, 6 -I), 2.05 2.21 (in, 4 I), 1.94 (s, 6 H), 1.64 - 1.78 (in, 2 H), 0.77 - 0.95 (in, 12 H-). The title compound showed an EC 50 value of less than about 0.1 nM in HCV I b-Coni replicon assays in the presence of 5% FBS. 35 153 Example 47 dimethyl (2S,2'S)- l, '-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)- I-(4-fluorophcnyl)pyrrolidinc-2,5 diyl)bis(4, I -phenylene))bis(l I-I-inidazole-4,2-diyl))bis(pyrrolidine-2, 1 -diyl))bis(3-inethyl- I oxohutane-2, I -diyl)dicarhamate F NN N >-N~ II N N >j N The product from Example 45E was purified by chiral chromatography on a Chirapak 1B column eluting with a mixture of hexanefTHF/MeOH (85/7.5/7.5). 'H NMR (400 MHz, DMSO-D6) 8 ppm 11.62 - 12.13 (in, 2 H), 7.59 - 7.71 (in, J=8.13 Hz, 3 H), 7.46 - 7.57 (m, J=8.24 Hz, 1 H), 7.38 (d, J=1.84 Hz, 2 H), 7.10 - 7.32 (in, 6 H), 6.72 - 6.83 (in, 2 -1), 6.19 - 6.31 (in, 2 H), 5.17 - 5.28 (mu, 2 H), 10 5.02 - 5.11 (i, J=6.72 lz, 2 11), 4.05 (t, J=8.40 Ilz, 2 11), 3.71 - 3.85 (in, 4 11), 3.53 (s, 6 H1), 2.05 2.21 (i, 4 H), 1.94 (s, 6 H), 1.64 - 1.78 (mn, 2 H), 0.77 - 0.95 (in, 12 H). The title compound showed an EC 50 value of less than about 0.1 nM in HCV I b-Con I replicon assays in the presence of 5% FBS. Example 48 I5 dimethyl (2S,2'S)-I, I'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-I-(4-tert-butylphenyl)-3,4 dimethoxypyrrolidine-2,5-diyl)bis(4,1-phenylene))bis( I l1-imid azole-4,2-diyl))bis(pyrrolidine-2,1 diyl))bis(3-methyl-I-oxobutane-2,1-diyl)dicarbamate .N 0-K Example 48A 20 (2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-1 -(4-tert-butylphenyl)pyrrolidine-3,4-diol To a solution of (I R, 'R)-1, l'-((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)diethane-1,2-diol (200 mg, 0.90 mmol) in methanol (6 ml) and dichloromethane (3 ml) was added indobenzene diacetate (696 mg, 2.16 inmol) and the solution was stirred at room temperature for 5 h. Solution was concentrated and to the residue was added 0. 1 M 1-1 2

SO

4 (4 ml) and stirring was continued at room 25 temperature for 18 h. The pH was adjusted to -6 with solid NalHC0 3 , and 4-tert-butylaniline (287 1d, 1.80 mmnol) was added followed by 4-benzyloxyphenylboronic acid (369 mg, 1.62 mmol) and hexafluoroisopropyl alcohol (4 ml) and stirred at 60 *C for 2 h. Solvent was concentrated and the residue dissolved in ethyl acetate, washed with H 2 0, 0.33M K-P0 4 , brine, dried (Na 2

SO

4 ), filtered and 154 concentrated to give crude product which was purified by chromatography on silica gel cluting with 0-20% ethyl acetate/dichloromethane to give title compound (249 mg, 46%). Example 48B 5 (2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-l -(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine To a solution of the product from Example 48A (200 mg, 0.33 mmol) in THF (2.1 ml) and DMF (0.7 ml) at 0 *C was added, in portions, sodium hydride, 60% in mineral oil (40.0 mug, 1.0 mmol) and stirring continued at 0 C for 20 min. lodomethane (0.046 ml, 0.734 mumol) was added and stirring continued at room temperature overnight. Diluted with ethyl acetate, washed with saturated 10 NIH 4 Cl, H 2 0, brine, dried (Na 2

SO

4 ), filtered and concentrated to give crude product which was purified by chromatography on silica gel eluting with 0-20% ethyl acetate/dichloromnethane to give title compound (170 mg, 80%). Example 48C 15 4,4'-((2S,3R,4R,5S)- I-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)diphenol To a solution of the product from Example 48B (168 ng, 0.268mnmol) in ethyl acetate (3 ml) was added 10% palladium on carbon (17 mg) and the flask was evacuated and back-filled with H-12 gas. The solution was stirred under a balloon of H 2 gas for 20 h, filtered through Celite, and washed with ethyl acetate and methanol. The filtrate was concentrated and the residue was azeotroped with ether 20 to give title compound (120 mg, 100%) as a white solid. Example 48D 4,4'-((2S,3R,4R,5S)- I -(4-tert-butylphenyl)-3,4-dimnethoxypyrrolidine-2,5-diyl)bis(4, I -phenylene) bis( 1,1,2,2,3,3,4,4,4-nonalluorobutane- I -sulfonate) 25 To a solution of the product from Example 48C (117 ing, 0.261 mnol) in DMF (1.3 ml) was added K 2

CO

3 (81 mg, 0.588 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonyl fluoride (0.101 mi, 0.575 nunol) and the solution was stirred at 100 "C for I h. The cooled solution was diluted with ethyl acetate, washed with 1120, brine, dried (Na 2

SO

4 ), filtered and concentrated to give an oil which was purified by chromatography on silica gel eluting with 0-20% ethyl acetate/hexane to give title 30 compound (195 mg, 73.7 % yield). Example 48E (2S,3R,4R,5S)-l -(4-tert-butylphenyl)-3,4-climnethoxy-2,5-bis(4-(4,4,5,5-etramethyl-l,3,2 dioxaborolan-2-yl)phenyl)pyrrolidine 35 To a pressure tube was added the product from Example 48D (193 mg, 0.191 mmol), 4,4,4',4',5,5,5',5'-octaimethyl-2,2'-bi(l.3,2-dioxaborolane) (102 mg, 0.401 mmol), dicyclohexyl(2',4',6' 155 triisopropylhiphenyl-2-yl)phosphine (X-Phos) (14.55 mg, 0.031 mmol), potassium acetate (112 mg, 1.145 inmol), and dioxane (1.5 ml) and the solution was degassed with N 2 gas for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (6.99 mng, 7.63 piol) was added and degassing was continued another 10 min. The tube was sealed and heated with stirring at 100 *C overnight. The 5 cooled solution was diluted with ethyl acetate, washed with H 2 0, brine, dried (NaSO 4 ), filtered and the filtrate treated with 3-(imercaptopropyl) silica gel for I h. The solution was filtered and solvent removed to give a yellow solid which was purilied by chromatography on silica gel eluting with 0 20% ethyl acetate/hexane to give title compound (99 mug, 78 % yield) as a white solid. 10 Example 48F (2S,2'S)-teri-butyl 2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-I-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine 2,5-diyl)bis(4, I -phenylene))bis( 1l--imidazole-4,2-diyl))dipyrrolidine- I -carboxylate In a sealed tube was combined the product from Example 48E (97 mug, 0.145 mmol), the product from Example 26D (115 mg, 0.363 mmol), I M Na 2

CO

3 (0.363 ml, 0.363 minol), EtOH (1.0 15 ml) and toluene (1.0 ml) and the solution was degassed with N2 gas for 30 mi. 1,1' lBis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (10.63 mg, 0.015 mmol) was added and degassing was continued an additional 10 miii. The tube was sealed and heated at 100 'C for 3 h. The cooled solution was diluted with ethyl acetate, filtered through Celite and the residue washed with ethyl acetate. The filtrate was concentrated in vacuo and the resulting material 20 was purified chromatography on silica gel using a 12g silica gel column eluting with 0-2% methanol/dichloromethane to give title compound (85 tmg, 66.1 % yield). Example 48G dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)- I-(4-tert-butylphenyl)-3,4 25 dimiethoxypyrrolidine-2,5-diyl)bis(4,1-phcnyleiie))bis(I H-iimidazole-4,2-diyl))bis(pyrrolidine-2,1 diyl))his(3-miethyl-1-oxobutane-2,1-diyl)dicarbamate To a solution of the product from Example 48F (83 mg, 0.094 nunol) in dichloromethane (1.0 ml) was added TFA (1.0 ml, 12.98 mmntol) and the solution was stirred at room temperature for I h. Solvent was concentrated and the residue was azeotroped 2 times with dichloromethane. The residue 30 was placed under vacuum for I h to remove final traces of TFA. To this residue (64.2 mg, 0.094 mmol) was added DNSO (500 pl) followed by (S)-2-(inethoxycarbonylamino)-3-methylbutanoic acid (41.1 mg, 0.234 mumol), HA'U (89 mug, 0.234 mmol) and hunig's base (82 pl, 0.469 mmol). plH was checked and additional Hunig's base was added to adjust pH to -9. Stirring was continued at room temperature for I h. The solution was diluted with ethyl acetate, washed with 1120, brine, dried 35 (Na 2

SO

4 ), filtered and concentrated to give crude residue. Purification was run by chromatography on silica gel eluting with 0-4% methanol/dichloromethane over 60 min to give title compound (7.5 mg, 156 8.01 % yield). I H NMR (400 M Hz, CDCl3) 6 ppm 0.86 (s, 12H) 1.13 (s, 9H) 1.86-2.02 (i, 2H) 2.02-2.12 (in, 21H) 2.12-2.25 (in, 2H) 2.25-2.41 (in, I H) 2.90-3.17 (in, 2H) 3.43 (s, 6H) 3.53-3.65 (in, 21H) 3.70 (s, 6H) 3.74-3.89 (in, 2H) 4.16-4.26 (i, 2H) 4.26-4.37 (in, 1 H) 5.18-5.26 (in, 2H) 5.26-5.32 (m, 2H) 5.33-5.41 (m, 211) 6.28 (d, J=8.78 Hz, 2H) 6.89-6.99 (m, 214) 7.16 (s, 2H) 7.20 (s, 21) 7.22 5 (s, 2H) 7.26 (s, 4H-1) 7.30-7.48 (br s, IH) 7.58-7.82 (br s, 2H) 10.08-10.42 (br s, 1H). The title compound showed an ECo value of less than about 0.1 nM in ICV lb-Con I replicon assays in the presence of 5% FBS. Example 49 10 diiehyl (2S,2'S)-l, I'-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4 diimethoxypyrrolidine-2,5-diyl)bis( I H-benzo[d]iiidazole-5,2-dliyl))bis(pyrrolicline-2,1 -diyl))bis(3 methyl-I -oxobutane-2, I -diyl)dicarbaiate H N H~ NH N Example 49A 15 (S)-tert-hutyl 2-(2-ainino-5-broinophenylcarhaioyl)pyrrolidine- I-carboxylate A solution of the 2-amino-4-bronoaniline (6.0 g, 32.1 iniol), Boc-Pro-OHI (6.90 g, 32.1 iniol) and HATU (13.42 g, 35.3 minol) in dry DMSO (160 iL) was treated with diisopropylethylamine (14.0 mL, 10.4 g, 80 mmol) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (3 x) and saturated sodium 20 chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded a brown solid which was used directly in the next step. Example 49B (S)-tert-hutyl 2-(5-hromo- I H -benzoldl imidazol-2-yl)pyrrolidine- I -carboxylate 25 A solution of the compound of Example 49A in glatial acetic acid (75 mL) was warmed at 60 *C for 3 h. The mixture was cooled and diluted with toluene and concentrated in vacuo. The remainder of the acetic acid was removed by azeotroping with toluene (2 x) and the residue was chromatographed over a 360 g silica gel cartridge, eluting with 25-75% ethyl acetate in dichloromethane. These procedures afforded the product (10.0 g, 85%) as a light beige rigid foam. 30 Example 49C 157 (S)-tert-butyl 2-(6-bromno- I-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-henzo[djimidazol-2-yl)pyrrolidine I -carboxylate A solution of the compound of Example 49B (2.25 g, 6.14 nunol) in dry TIF (25 niL) was treated with sodium hydride (295 mg of 60% in oil, 177 ing, 7.37 ninol) followed by stirring at room 5 temperature for I h. The solution was then treated with SEM-Chloride (1.20 niL, 1.13 g, 6.76 mmol) followed by stirring at room temperature for 18 h. The mixture was quenched by addition of water and the mixture was diluted with ethyl acetate. The mixture was extracted with water and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 20-75% ethyl acetate in hexanes. 10 These procedures afforded the product (2.24 g, 73%) as a heavy oil, which solidified after selling for several days. This mixture of both regioisomeric SEM derivatives was not separated for use in the next step. Example 49D 15 (S)-tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) I H -benzo[dl iimidazol-2-yl)pyrrolidine- I -carboxylate In a resealable pressure tube, a solution of the compound of Example 49C (2.24 g, 4.51 nunol), bis(pinacolato)diboron (1.26 g, 4.96 mmol), and potassium acetate (1.33 g, 13.53 inmol) in dry dioxane (23 mL) was degassed by nitrogen sparge for 30 min. The solution was treated with 1,1' 20 bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (Ill mg, 0.14 mmol) followed by degassing for another 5 min. The pressure tube was sealed and warmed at 90 C for 4 h. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na 2

SO

4 ) and stirred for I h with 3 niercapiopropyl) silica gel. After filtration and concentration in vacuo the brown oil was 25 chroiatographed over a 100 g silica gel cartridge, cluting with 15-70% ethyl acetate in dichloromehane. These procedures afforded the product (1.99 g, 81%) as a white rigid foam. Example 49E (S)-tert-butyl 2-(6-((2S,3R,4R,5S)-5-(2-((S)- I -(tert-butoxycarbonyl)pyrrolidin-2-yl)- 1 -((2 30 (trimethylsilyl)ethoxy)methyl)- I 1l-benzo[djimidazol-5-yl)- 1 -(4-tert-butylphenyl)-3,4 dihydroxypyrrolidin-2-yl)- 1-((2-(tri methylsilyl)ethoxy)methyl) I -l-benzo[d] imidazol-2 yl)pyrrolidine-l -carboxylate A solution of 2,3-0-isopropylidene-D-mannitol (144 tug, 0.65 nunol) and iodobenzenediacetate (501 mg, 1.56 nniol) in 2:1 methanol-dichloromethane (3 mL) was stirred at 35 room temperature for 5 h. The mixture was concentrated in vacuo to a white paste and then suspended in 0. 1 M sulfuric acid solution (1.0 mL) followed by stirring at room temperature for 18 h. 158 The solution was adjusted to p-I 6 by addition of solid sodium bicarbonate followed by addition of 4 tert-butylaniline (206 ptL, 193 mg, 1.30 mmol) the product from Example 491) (634 tmg, 1.17 mmol) and hexafluoroisopropyl alcohol (2.6 mL). The solution was then warmed at 70 "C for 5 h. The solution was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and 5 extracted with 0.33 M tribasic potassium phosphate solution and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded a brown oil, which was chromatographed over a 50 g silica gel cartridge, eluting with 15-85% ethyl acetate in dichloromethane. These procedures afforded the recovered boronate (208 tug) as a viscous brown oil. The column was then re-eluted with 0-20% methanol in dichloromethane to afford the product (159 mg, 23%) as a brown solid. 10 Example 49F (S)-tert -butyl 2-(6-((2S,3R,4R,5S)-5-(2-((S)- I -(ter t-butoxycarbonyl)pyrrolidin-2-yl)- 1 -((2 (trimethylsilyl)ethoxy)nethyl)- I Il-benzo[d]imidazol-5-yl)- I -(4-tert-butylphenyl)-3,4 dimethoxypyrrolidin-2-yl)- I -((2-(trimethylsilyl)ethoxy)methyl)- II -benzo[d]imidazol-2 15 yl)pyrrolidine- I -carboxylate A solution of the product from Example 49E (154 mg, 0.14 mol) in dry THF was treated with sodium hydride (13 mng of 60% in oil, 8 mug, 0.33 mmtuol) followed by stirring at room temperature for 30 min. The mixture was treated with methyl iodide (19 1 iL, 43 mg, 0.30 mmol) followed by stirring at room temperature for 2 h. The mixture was diluted with ethyl acetate and quenched by addition of 20 water. The mixture was extracted with water and saturated sodium chloride solution. Drying (Na2SO 4 ) and concentration in vacuo afforded a brown oil, which was chromatographed over a 25 g silica gel cartridge, eluting with 0-15% methanol in dichloromethane. These procedures afforded the product (121 mg, 77%) as a beige foam. 25 Example 49G (S)-5,5'-((2S,3R,4R,5S)-1 -(4-teri-buiylphcnyl)-3,4-cimethoxypyrrolidine-2,5-diyl)bis(2-((S) pyrrolidin-2-yl)-l H-benzo[d]imidazole) A solution of the compound of Example 49F (Il l tg, 0.10 mmnol) in ethanol (I mL) was treated with 4 N hydrochloric acid solution (2.0 mL) followed by warming at 60 C for 18 h. The 30 solution was cooled and concentrated in vacuo with ethanol-toluene mixtures (2 x) to afford the tetrahydrochloride as a light yellow solid. This material was dissolved in methanol (3 ml..) and stirred with Amberlyte IRA 400 (OH- form, 1.4 mequiv/g, 577 mug, 0.81 mequiv) for I Ih. The resin was removed by filtration and the Filtrate was concentrated in vacuo to afford the product (29 ing, 45%) as a light amber glass. 35 Example 4911 159 dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)- I-(4-tert-butyliphenyl)-3,4 dimethoxypyrrolidine-2,5-diyl)bis(I H-benzo[djimidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))his(3 methyl-I-oxobutane-2, 1-diyl)dicarbamate A solution of the compound of Example 49G (29 ing, 0.046 mmol), H-OBI hydrate (18 mg, 5 0.114 nunol), EDAC (22 mg, 0.114 mmol) and (S)-2-(methoxycarbonylamino)-3-nethylbutanoic acid (20 mg, 0.114 mmol) in dry DMF (0.5 mL) at 0 C was treated with N-methylmorpholine (15 pL, 14 mug, 0.137 mmol) followed by stirring at 0 0C for 30 min and warning to room temperature for 2 h. The mixture was diluted with ethyl acetate and extracted with water (3 x) and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded an oil which was dissolved 10 in methanol and treated with a small amount of potassium carbonate. After stirring I h, the mixture was filtered and concentrated in vacuo to afford a yellow oil, which was chronatographed over a 25 g silica gel cartridge, cluting with 0-15% methanol in dichloromethane to give the product (14 mg, 32%) as a white solid. 'I I NM R (400 MH z, DMSO-d6) 6 7.39 (in, 4 H-), 7.30 (in, 4 HI), 7.07 (t, J = 9.1 lz, 2 H-), 6.87 (in, 2 H1), 6.31 (d, J = 8.9 Hz, 1 H), 5.54 (in, 2 H), 5.14 (dd, J = 7.6, 4.6 Hz, 2 H-), 4.14 15 (in, 2 H), 3.77 (m, 4 1-1), 3.51 (in, 6 H), 3.28 (i, 6 H), 2.15 (in, 4 H), 1.04 (s, 9 H), 0.86 (m, 12 H). The title compound showed an ECy 1 value of from about 0.1 to about 1 nM in HCV I b-Con I replicon assays in the presence of 5% FBS. Example 50 20 dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-( I -(4-(pentafluorothio)phenyl)- I l-pyrrole-2,5 diyl)bis(4,1-phenylene))bis( IH-imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-imethyl-1 oxobutane-2,1 -diyl)dicarbamate SF, H N NH N N / o Example 50A 25 2,5-bis(4-bromophenyl)-] -(4-(pentafluorothio)phenyl)- IH-pyrrole Title compound was prepared from the product from Example 26E using the methods from Example 26F substituting 4-aminophenylsulfur pentalluoride for 4-tert-butylaniline to provide the desired compound. 30 Example 50B 1-(4-(pentafluorothio)phenyl)-2,5-bis(4-(4,4,5,5-tetranethyl-1,3,2-dioxaborolan-2-yl)phenyl)-I H pyrrole 160 Title compound was prepared using the methods from Example 260 substituting the product from E example 50A for tile product from Example 26F to provide the desired compound. Example 50C 5 tert-butyl 2,2'-(4,4'-(4,4'-(l-(4-(pentafluorothio)phenyl)- IH-pyrrole-2,5-diyl)bis(4,1 phenylene))bis( IlH-i midazole-4,2-diyl))dipyrrolidine- I -carboxylate Title compound was prepared using the methods from Example 26H substituting the product from Example 50B for the product from Example 26G to provide the desired compound. 10 Example 50D 4,4'-(4,4'-(1 -(4-(pcntafluorthio)phenyl)- I 1-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(2-(pyrrolidin-2 yl)- I 1H-imidazole) Title compound was prepared using the methods from Example 261 substituting the product from Example 50C for the product from Example 261-1 to provide the desired compound. 15 Example 50E Diimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-(4,4'-(I -(4-(pentalluorothio)phenyl)-I H-pyrrole-2,5 diyl)bis(4, Ilphenylene))bis(1lH-imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1 oxobutane-2,1 -diyl)dicarbamate 20 Title compound was prepared using the methods from Example 26J substituting the product from Example 50D for the product from Example 261 to provide the desired compound. 'HNMR (DMSO-d6; 400 MIH z): 8 11.75 (br s, 2H), 7.88 (m, 2H), 7.56 (app d, J=8.35 iz, 4H), 7.45 (br s, 2H), 7.27 (m, 41-), 6.96 (app d, J=8.35 Hz, 411), 6.50 (s, 211), 5.04 (m, 2H), 4.03 (m, 2H), 3.78 (in, 4H), 3.53 (s. 6H), 2.11-1.85 (i, 10H), 0.86 (d, J=6.72 Hz, 6H), 0.82 (d, J=6.72 H7, 6H). 'he title 25 compound showed an EC 5 o value of less than about 0.1 nM in HCV lb-ConI replicon assays in the presence of 5% FBS. C) 0 0 Example 51 30 dimneihyl ([1-(4-fluorophenyl)- I l--pyrrole-2,5-diyl]bis( benzene-4, I -diylcarbaioyl(2S)pyrrolidine 2,1 -diyl[(2S)-3-mnethyl- I -oxobutane- l,2-diyl]} )biscarbamate Example 191) (150 mg) and (S)-2-(methoxycarbonylanino)-3-methylbutanoic acid were processed using the method of Example 19E (substituting DMF as solvent) to provide the title compound which was purified using gradient silica gel chromatography (30-70% EtOAc in 161 hexanes)(70 mg). 'H NMR (500 Mliz, i)MSO-)6) 69.76 (s, 2H), 7.16 (d, J = 8.7, 4H), 7.06 (d, J = 8.4, 2H), 6.92 (t, J = 8.7, 2H), 6.83 (dd, J = 5.0, 8.9, 2H), 6.71 (d, J = 8.7, 4H), 6.14 (s, 21H), 4.15 (dd, J = 5.1, 7.9, 2H), 3.77 (t, J = 8.5, 2H), 3.59 - 3.50 (in, 2H), 3.40 - 3.31 (in, 21H), 3.27 (s, 6H), 1.95 1.82 (i, 2H), 1.79 - 1.52 (m, 8H), 0.67 (d, J = 6.8, 61-1), 0.62 (d, J= 6.7, 6H). MS (ESI; M+H) I/z = 5 853. F Example 52 dimethyl ([1-(4-fluoro-2-methylphenyl)- 1 H-pyrrole-2,5-diyl]bis{ benzene-4, 1 10 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dinethyl-i-oxobutane-1,2-diyll])biscarbamate Example IA was processed using 4-fluoro-2-methylaniline and the methods from Examples 19A, 19B, 19C, 191), and 51 ((S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid was used) to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 6 9.98 (s, 2H), 7.44 - 7.36 (mn, 5H), 7.09 - 6.96 (m, 8H), 6.42 (s, 2H), 4.39 (dd, J = 5.5, 8.1, 2H), 4.19 (d, J = 8.7, 2H), 3.80 - 3.70 (m, 2H), 15 3.65 - 3.56 (m, 2H), 3.52 (s, 6H), 2.20 - 2.06 (m, 2H), 1.97 - 1.91 (in, 2H), 1.90 - 1.76 (i, 4H), 1.63 (s, 311), 0.94 (s, 1811). MS (ESI; M+1H) n/z = 895. Example 53 20 dimethyl ({(2S,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl }bisi benzene-4,I diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl] ))biscarbamate Example 53A dincthyl ({(2S,5S)-I-[4-(trinuoromcthyil)phenyl]pyrrolidinc-2,5-diylIbis{bcnzene-4,1 25 cliylcarbamoyl(2S)pyrrolidine-2, I-diyl[(2S)-3-imethyil-I-oxobut ane-1,2-diyi ]})biscarbamate and dimethyl ({(2R,5R)- I-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diylbis{benzene-4, 1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-l -oxobutane-1,2-diyl]))biscarbamate To a solution of the product from Example 23B (84 ng, 0.142 imnol) in DMSO (1.5 niL) was added (S)-2-(iethoxycarbonylamino)-3-methylbutanoic acid (62.2 ig, 0.355 inmol), HATIJ (135 30 ing, 0.355 inmol), and Hunig'sBase (0.074 mL, 0.426 imol), and the resulting mixture was stirred at rt for 90 min and then partitioned between 20 (I nL..) and .tOAc (2 x 2 mL). The combined organic 162 layers were dried over Na 2

SO

4 , filtered and concentrated in vacuo. The drying agent was filtered off, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 1-3% MeOH in CH 2 Cl2 to give the title compounds as a 1:1 mixture. Example 53B 5 dimethyl ({ (2S,5S)-l -[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl }bis (benzene-4, 1 diylcarbamoyl(2S)pyrrolidine-2, I -diyl[(2S)-3-methyl- 1 -oxobutane- 1,2-diyl] ))biscarbamate The product from Example 53A was separated on a Chiralpak AD-H column using 1:1 hexanes:(1:I EtOH:2-PrOH). '[he title compound was the first component to elute. 'H NMR (400 MHz., DMSO-D6) 6 ppm 0.88 (d, 1=6.61 Hz, 6 H), 0.93 (d, J=6.61 Hz, 6 H), 1.63 - 1.72 (i, 2 -1), 10 1.78 - 2.06 (i, 8 H), 2.06 - 2.20 (i, 2 1-1), 3.52 (s, 6 H), 3.56 - 3.67 (m, 2 H), 3.73 - 3.86 (i, 2 H), 4.03 (i, J=8.51 Hz, 2 H), 4.42 (dd, J=7.92, 4.88 Hz, 2 H), 5.27 (d, J=6.61 Hz, 2 I-), 6.36 (d, J=8.67 Slz, 2 H1), 7.14 (d, 1=8.57 H z, 4 H-), 7.25 (d, 1=8.89 Hz, 2 H-), 7.31 (d, J=8.35 H z, 2 11), 7.52 (d, 1=8.57 Hz, 4 H-), 10.01 (s, 2 1-); MS (ESI) m/z 906.3 (M+H)*. 0 0 15 Example 54 dimethyl (((2R,5R)-l -14-(trifluoromethyl)phcnyl]pyrrolidine-2,5-diylIbis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidi ne-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]))biscarbaimate The product from Example 53A was separated on a Chiralpak AD-H column using 1:1 20 hexanes:(l:1 EtOH:2-PrOH). The title compound was the second component to elute. I1H NMR (400 MlHz, DMSO-D6) 6 ppmn 0.87 (d, J=6.61 Hz, 6 H), 0.92 (d, 1=6.72 Hz, 6 11), 1.64 - 1.74 (m, 2 11), 1.78 - 2.06 (i, 8 11), 2.06 - 2.22 (i, 2 H-), 3.52 (s, 6 1-), 3.56 - 3.67 (i, 2 H-), 3.75 - 3.86 (i, 2 11), 3.97 - 4.08 (in, 2 H), 4.37 - 4.48 (in, 2 H), 5.28 (d, J=6.51 Hz, 2 H-), 6.36 (d, J=8.78 Hz, 2 H-), 7.14 (d, ./=8.57 Hz, 4 H), 7.25 (d, .=8.89 liz, 2 1-1), 7.30 (d, .=8.24 Hz, 2 H), 7.52 (d, .1=8.57 Hz, 4 H), 10.01 25 (s, 2 H); MS (ESI) mn/z 906.3 (M+H)*. Example 55 163 dimethyl ([(2R,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyljbis { benzene-3,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-I-oxobutane-1,2-diylj))biscarbamate Example 55A 5 l,4-bis(3-nitrophenyl)butane- 1,4-dione Anhydrous zinc(II) chloride (5.42 g, 39.7 mmol) was stirred in dry benzene (50 mL) under nitrogen while diethylamine (3.10 nL, 29.8 mmol) and t-butanol (2.85 nL, 29.8 mmol) were added. The resulting mixture was stirred at room temperature for 90 mini to give a cloudy solution. To this was added 1-(3-nitrophenyl)ethanone (4.97g, 29.8mmol) followed by 2-bromo-l-(3 10 nitrophenyl)ethanone (5.00g, 19.87mmnol) and the resulting mixture allowed to stir at room temperature overnight. A large portion of the benzene was subsequently removed by decantation. The resulting mixture was then treated with 5% sulfuric acid (25m.L) in a separatory funnel and the aqueous phase drawn off. The organic phase was washed with water (2x25mL). A third washing resulted in an emulsion. The contents of the funnel were emptied into a large volume of water 15 (750niL) to which was added sodium chloride and the oil in water mixture rapidly stirred. Methanol was added (75miL) in portions to try and disperse the oil and promote solidification of the product. After nearly forty eight hours of stirring the product solidified and was collected by vacuum filtration. The filter cake was water washed, dried first in air and then a vacuum oven at 55 *C to provide the title compound (5.85g, 90% yield) as a pale yellow solid that was used directly in the next step. 20 Example 55B 1,4-bis(3-nitrophenyl)butane- 1,4-diol Sodium borohydride (0.6173 g, 17.74 minol) was added to a suspension of Example 55A (2.71 g, 8.26 mmnol) in ethanol (150 mL.) and stirred at ambient temperature for 3 hours. The reaction 25 was quenched with water (-50 mL) and concentrated to a paste which was taken up in 1:1 McOH:THF. This suspension was filtered through a celite plug and concentrated. The residue was taken up in toluene and heated with stirring to form a white paste which was then sonicated and scraped until a filterable solid formed. This was filtered, rinsed with toluene and dried under vacuum to afford 2.84 g (100%) of the title compound as an off white solid. MS (DCI) m/z 350 (M+NI14)*. 30 Example 55C I,4-bis(3-nitrophcnyl)hutane-I,4-diyl dimethanesulfonate Mcthanesulfonyl chloride (0.3 mL, 3.87 mmol) was added dropwise to a cold (0 "C) solution of Example 55B (0.5089 g, 1.531 mmol) and tricihylamine (0.65 iL, 4.66 ninol) in THF (10 niL). 35 The reaction was removed from the ice bath and stirred at ambient temperature for 30 minutes. 164 Solvent was removed under vacuum to provide the title compound as a solid that was used without purification. Example 55D 5 1-(4-fluorophenyl)-2,5-bis(3-nitrophenyl)pyrrolidine Example 55C (0.733 g, 1.5 mmol) was mixed with 4-fluoroaniline (1.5 mL, 15.63 mmol) and DMF (3 mL). The reaction was stirred at 50 *C for 24 hours. The reaction mixture was partioned between EtOAc and water. The organic portion was washed with water (2 x), shrine (1 x), dried (MgSO 4 ), concentrated. Purification by flash chromatography (silica gel, 0-50% EtOAc/Hexanes). 10 The material was dissolved in EtOAc and washed with 1 M HCI (2 x) to remove residual aniline, water (1 x), sat aqueous NaHC03 (1 x) and brine (1 x) dried (MgSO 4 ) and concentrated to afford the title compound as a mixture of trans and cis isomers (0.45 g, 73%). Example 55E 15 3,3'-(1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline A suspension of Pd/C (0.0527 g, 0.050 minol) in THF (2 mL) was added to a solution of Example 551) (0.45 g, 1.105 imol) in TIF (7 mL)/EtOH (7 ml..) under N 2 . he flask was flushed with H 2 and stirred under I atm H 2 for 20 hours. The reaction was filtered through a celite plug, rinsed with -100 mL (1:1 EtOll:THF) and solvent was removed under vacuum. The material was used 20 without purification. MS (DCI) m/z 348 (M+H)+. Example 55F (2S,2'S)-tert-butyl 2,2'-(3,3'-((2S,5R)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1 phenylene))bis(azanediyl)bis(oxomnethylene)dipyrrolidine- I -carboxylate 25 Diisopropylethylamine (0.8 mL, 4.58 mmnol) was added to a mixture of Example 55E (0.382 g, 1.1 inmnol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carhoxylic acid (0.5950 g, 2.76 mmol) and HATU (0.9196 g, 2.419 mmol) in dichloromethane (12 mlL). The reaction was stirred at rt for I hr, diluted with dichloroinelhane, washed with water (2 x), brine (I x), dried (MgSO 4 ) and concentrated to give a brown residue. The residue was taken up in ether, sonicated and filtered to afford the title 30 compound as a tail solid. The trans isomers remained in the ether solution and are described further in Example 83. LC/MS Rt 2.27 m/z 742 (M+H)+. Example 55G (2S,2'S)-N,N'-(3,3'-((2S,5R)-I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3, 1-phenylene))dipyrrolidine 35 2-carboxamide 165 TFA (3 mL, 38.9 mmnol) was added to a solution of Example 55F (0.4033 g, 0.544 nmol) in dichloromethane (10 inL). After 90 minutes the reaction was concentrated. The residue was sequentially dissolved in and concentrated in vacuo from the following solvents: dichloromethane (2x), methanol (2x), and ether (lx). This semi-solid was taken up in dicholormethane and washed 5 with sat aq NaHC0 3 (2 x) water (lx) brine (lx) dried (MgSO4) and filtered to provide the title compound. LC/MS Rt 1.31 m/z 542 (M+H)+. Example 55H] dimethyl (|(2R,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyllbis{ benzene-3,1 10 diylcarbamoyl(2S)pyrrolidine-2, l-diyl[(2S)-3,3-dinethyl-1-oxobutane-1,2-diyl]))biscarbamate Diisopropylcthylamine (0.5 ml-, 2.86 mmol) was added to a mixture of Example 55G, (S)-2 mnethoxycarbonylamino-3,3-dimethyl-butyric acid (0.2600 g, 1.374 nunol) and HATU (0.4527 g, 1.191 mmol) in dichloromethane(15 m.L). The reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with dichloromethane, washed with water (2x), brine (lx), dried 15 (MgSO 4 ), concentrated and purified by flash chromatography (silica gel, 0-30% EtOAc/dichloromethane) to afford 0.14 g (30%) of the title compound. 11-1 NMR (400 MHz, DMSO d6) 6 0.96 (s, 911), 0.98 (s, 911), 2.06 - 1.71 (in, 811), 2.25 - 2.07 (i, 211), 2.42 (t, J = 7.1, 211), 3.54 (d, J = 3.2, 6H), 3.72 - 3.59 (m, 2H), 3.86 - 3.72 (m, 2H), 4.22 (d, .1 = 8.9, 2H), 4.51 - 4.37 (m, 21), 4.69 (t, . = 11.9, 2H), 6.42 - 6.28 (m, 2H), 6.96 - 6.83 (in, 2H), 7.08 (t, J = 8.5, 2H), 7.39 - 7.18 (in, 41-1), 20 7.76 -7.54 (in, 4H), 10.03 (d, J = 9.8, 2H). MS (ESI) m/z 884 (M+H)+, 882 (M-H)+. Co NN H . 0NN Example 56 dimethyl ([1 -(4-chlorophenyl)- 11 -pyrrole-2,5-diyl]bis{ benzene-4,1-diylcarbanioyl(2S)pyrrolidine 25 2,1 -diyl[(2S)-3-inethyl-I-oxobutane-1,2-diyl]})biscarbainate Example IA was processed using 4-chloroaniline and the methods from Examples 19A, 19B, 19C, 191), and 51 to provide the title compound (72 ing).'H NMR (400 MHz, l)MSO-d6) 5 10.00 (s, 2H), 7.45 - 7.36 (in, 6H), 7.31 (d, J = 8.3, 2H), 7.04 (d, J = 8.4, 21), 6.96 (d, J = 8.6, 4H), 6.39 (s, 2H), 4.44 - 4.37 (i, 2H), 4.06 - 3.99 (in, 21-), 3.85 - 3.74 (m,2H), 3.67 - 3.56 (in, 21-1), 3.52 (s, 6H), 30 2.20 - 2.06 (in, 211), 2.04 - 1.79 (m, 811), 0.92 (d, J = 6.7, 61-), 0.88 (d, J = 6.7, 611). MS (ESI; M+H1-) m/z = 869. 166 Example 57 dimethyl (I 1-(4-fluorophenyl)- I H-pyrrole-2,5-diyljhisibenzene-3, I -diylcarbamoyl(2S)pyrrolidine 2,1 -diyl[(2S)-3-iethyl-l -oxobutane-1,2-diyl I})hiscarbamatc 5 Example 55A was processed using the methods of Example 19A, 19B, 19C, 191), and 19E to provide the title compound. I H NM R (400 MHz, DMSO-d6) 6 0.99 - 0.84 (m, 12H), 2.05 - 1.76 (m, 8H), 2.22 - 2.05 (in, 2H), 3.53 (s, 6H), 3.70 - 3.56 (in, 2H), 3.88 - 3.71 (in, 2H), 4.11 - 3.93 (m, 2H), 4.42 (dd, J = 4.9, 7.9, 214), 6.40 (s, 2H), 6.54 (d, J = 7.9, 2H), 7.18 - 6.98 (m, 6H), 7.34 (dd, J = 8.3, 15.4, 41-), 7.55 (s, 2H), 9.96 (d, J = 11.2, 2H). MS (ES I) n/z 852 (M+H)+. 10 F F F Example 58 dimethyl ({ 1-[4-(trifluoromethyl)phenyll-I H-pyrrole-2,5-diyl Ibis{( benzene-4, Il diylcarbamoyl(2S)pyrrolidine-2,1I-diyl[(2S)-3-mnethyl- I -oxobutane-1I,2-diylj}))biscarbamate I5 Example 58A 2,5-bis(4-nitrophenyl)-I-(4-(trifluoromethyl)phenyl)- IH-pyrrole To a slurry of the product from Example IA (1.00 g, 3.05 mmol) in acetic acid (30 nL) was added 4-(triluoronethyl)aniline (1.9 mL, 15 innol). The mixture was heated to 170 *C for 15 20 minutes under microwave irradiation. The cooled mixture was diluted with water and diethyl ether and stirred vigorously for 15 minutes and then filtered. The crude product was purified by chromatography on silica gel eluting with a solvent gradient of 0-30% ethyl acetate in hexane. Product containing fractions were combined and concentrated under reduced pressure and then triturated with diethyl ether to give the title compound (110 mg, 8% yield). 25 Example 581B 167 dimethyl (Il -[4-(trifluoroimethyl)phenylJ- I -I H-pyrrole-2,5-diyl }bis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl- 1 -oxobutane- 1,2-diyl]})biscarbamate Example 58A was processed using the methods of Examples 19B, 19C, 19D, and 51 to provide the title compound (44 ing). 'I NMR (400 MHz, DMSO-d6) 6 10.01 (s, 211), 7.71 (d, J = 5 8.6, 21-I), 7.42 (d, J = 8.7, 4H), 7.31 (d, J = 8.2, 2H), 7.22 (d, J = 8.3, 2H), 6.95 (d, J = 8.6, 41-1), 6.43 (s, 211), 4.39 (dd, J = 5.2, 8.1, 21-I), 4.03 (d, J = 8.3, 211), 3.85 - 3.75 (m, 21-), 3.66 - 3.56 (m, 21-), 3.52 (s, 6H), 2.18 - 2.08 (in, 2H), 2.01 - 1.79 (i, 81-), 0.92 (d, , = 6.7, 6H), 0.87 (d, .1 = 6.6, 6H). MS (FS1; M+H) n/z = 903. H 10 Example 59 methyl {(2S)-I-[(2S)-2-(4-(4-[(2R,5S)-5-(4-(2-((2S)-1-((2S)-2-[(methoxycarbonyl)ainol-3 methylbutanoyl pyrrolidin-2-yll-ll-imidazol-4-yl}phenyl)-l-phenylpyrrolidin-2-yiJphenyl)-1I iimidazol-2-yl)pyrrolidin-1-yl]-3-mcthyl-1-oxobutan-2-ylcarbamaic 15 N Example 59A (2S,2'S)-tcrt-butyl 2,2'-(4,4'-(4,4'-(l -phenylpyrrolidine-2,5-diyl)his(4, 1 -phcnylene))bis( I H-imidazole 4,2-diyl))dipyrrolidine- I -carboxylate 20 Example 42B and aniline were processed using the methods of Examples 39D, 42D, and 42E to provide the title compound as a mixture of stereoisomers. MS (ESI) i/z 770 (M+-1)+. Example 59B 4,4'-{1(2R,5S)-1 -phcnylpyrrolidine-2,5-diyl]dibenzene-4,1 -diyl Ibis{2-[(2S)-pyrrolidin-2-ylJ-I H 25 imidazole} (ACD v12) To the product of Example 59A (30 mg, 0.039 minmol) was added dimethoxyethane (1.5 mnL) and a solution of 4N hydrochloric acid in dioxane (3 inL) and the resultant solution stirred at room temperature for 1.5 hr. The solvent was then removed under vacuum and the resultant residue was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18), 30 eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 9.8 mug (44%) of the title compound 168 and 8.5 ing of a mixture of the trans diastereomers (MS (ESI) mI/z 570 (M+H)+) that were processed further as described in Example 89. For the title compound: MS (ES!) m/z 570 (M+H)+. Example 59C 5 methyl {(2S)-I-[(2S)-2-(4-{4-[(2R,5S)-5-(4-(2-[(2S)-1-1(2S)-2-[(mnethoxycarbonyl)aiminol-3 methylbutanoyl}pyrrolidin-2-yl]- 11-imidazol-4-yl Iphenyl)-1-phenylpyrrolidin-2-yl]phenylI }-Il inidazol-2-yl)pyrrolidin-1-yll-3-methyl-1-oxobutan-2-ylcarbamate The product from Example 59B (9.8 mg, 0.012 nmol), (S)-2-(methoxycarbonylamino)-3,3 dimethylbutanoic acid (5.4 mg, 0.031 minol) and HATU (10.3 mg, 0.027 mimol) in DMSO (1 ml..) 10 was added Hlunig's base (0.017 inL, 0.098 ininol), and the reaction mixture was stirred at room temperature for I hr. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 4.5 mg (41%) of the title compound. 1ll NMR (TFA salt) (400 MHz, DMSO-D6) 8 15 ppm 14.50 (bs, 2 H), 7.99 (s, 2 H), 7.78 (in, 4 H-), 7.65 (m, 4H), 7.32 (m, 2H), 7.02 (t, ./=8.0 H z, 2 H), 6.63 (t, 1=7.4 Hz, I H), 6.40 (d, 1=8.2 -Iz, 2 H), 5.11 (t, 1=6.9 Hz, 2 -1), 4.83 (in, 2H), 4.10 (t, 1=7.7 Hz, 2 H), 3.82 (in, 6 -1), 3.48 (s, 6 H), 2.40 (in, 2 -1), 2.08 (in, 2 H), 2.00 (m, 6 H), 1.85 (m, 2 H ), 0.85 (in, 2 H), 0.80 (in, 12 1-1); MS (ESI) m/z 884 (M+H)+. 20 10 Example 60 dimethyl ([(2S,5S)-I -(4-tert-buiylphenyl)pyrrolidine-2,5-diyl]bis (beizene-4, 1 cliylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dinethyl-1-oxobut ane-1,2-diyl]))biscarbamate 25 Example 60A dimethyl ([(2S,5S)- I-(4-tert-butylphenyl)pyrrolidine-2,5-diyllbis{benzene-4,1 diylcarbaimoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-diimethyl-I-oxobutanIc-I,2-diyl]})biscarbamate and dimethyl ([(2R,5R)-I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{ benzenc-4,1 30 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-diiethyl-I-oxobutane-1,2-diyl]})biscarbamiate The product from Example 34D (29.0 mg, 0.05 mmol), (S)-2-(methoxycarbonylainino)-3,3 dinethylbutanoic acid (20.81 mg, 0.110 minol), EDC (21.09 mg, 0.110 innol), H1OB' (16.85 mg, 169 0.110 mmol) and N-methylmorpholine (0.027 nil.., 0.250 mmol) were combined in DMF (2 mL). The mixture was stirred at room temperature for 3 hours. lie reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluding with ethyl 5 acetate/hexane (50% to 80%) to give the title compound (32 ng, 69%) as a mixture of trans diastereomers. Example 60B dimethyl ([(2S,5S)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diy Jbis{ benzene-4,1 10 diylcarbaimoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-dimcthyl- I -oxobutane- 1,2-diyl]})biscarbaiatc The product from Example 60A was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 3:1 mixture of hexane:(2:1 IPA:EtOll). The title compound was the first of the 2 diastereomers to elute. 'I1. NMR (400 MHz, DMSO-D6) 6 ppm 0.97 (s, 18 H-) 1.11 (s, 9 1-) 1.60 - 1.65 (in, 2 1-1) 1.79 - 1.91 (m, 4 H-) 1.94 - 2.03 (m, 2 H-) 2.10 - 2.18 (m, 2 H-) 2.44 - 2.50 (in, 2 15 H) 3.54 (s, 6 H) 3.59 - 3.67 (m, 2 H) 3.71 - 3.82 (in, 2 H) 4.21 (d, J=8.89 Hz, 2 H) 4.43 (dd, .1=7.92, 5.42 lz, 2 H) 5.14 (d, J=6.40 Hz, 2 H) 6.18 (d, J=8.89 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.08 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.57 Hz, 4 H) 7.50 (d, J=8.46 Hz, 4 H) 9.99 (s, 2 1); MS (ESI+) i/z 923 (M+H)+. 20 Example 61 dimethyl ([(2R,5R)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diylJbis I benzene-4, diylcarbamoyl(2S)pyrrolidine-2, 1 -diyl [(2S)-3,3-dimeihyl-1 -oxobutane- 1,2-diyl]))biscarbamate The product from Example 60A was purified by chiral chromatography on a Chiralpak AD-H 25 semi-prep column eluting with a 3:1 mixture of hexane:(2:1 IPA:EtO-1). The title compound was the second of the 2 diastereomers to elute. 'H NMR (400 MHz, DMSO-D6) 6 ppm 0.96 (s, 18 H) 1.11 (s, 9 1-1) 1.60 - 1.66 (m, 2 H) 1.78 - 1.92 (in, 4 H) 1.94 - 2.04 (i, 2 H) 2.08 - 2.19 (m, 2 H) 2.42 - 2.50 (in, 2 H) 3.54 (s, 6 H) 3.59 - 3.67 (i, 2 H) 3.74 - 3.81 (in, 2 -1) 4.20 (d, .1=8.89 Hz, 2 H) 4.43 (dd, J=7.97, 5.37 Hz, 2 H) 5.15 (d, J=6.29 Hz, 2 H) 6.17 (d, J=8.89 Hz, 2 H) 6.94 (d, J=8.89 lz, 2 H) 7.07 (d, 30 J=8.89 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H-1) 7.50 (d, J=8.57 Hz, 4 H) 9.99 (s, 2 H); MS (ESI+) m/z 923 (M+H)+. 170 o/ Example 62 methyl { (2S)-I1-[(2S)-2-(4- {4-[(2R,5S)- I-(4-fluorophenyl)-5-(4- {2-[(2S)-1I- ((2S)-2 [(methoxycarbonyl)amino]-3-methyl butanoyl } pyrrolidin-2-yl) -1 H -imnidazol-4-yl lphenyl)pyrrolidin 5 2-yl~phenyl } -I H -iidazol-2-yl)pyrrol idin-1I-yl]-3-methyl-1I-oxobutan-2-yl }carbamate Example 62A 4,4'-{ [(2R,5S)- I-(4-fluorophenyl)pyrrolidine-2,5-diyljdibenzene-4, I-diyl }his (2-l(2S)-pyrrol idin-2 yl]-l1H-imnidazole } (ACD v12) 10 The product from Example 45C (0.15 g, 0.190 mmol) in CH- 2 C1 2 (I mnL) was treated with TFA (I mnL), and the resulting mixture was stirred at rt for Ih and then concentrated in vacuo. The crude product was purified by column chromnatography on CI8 silica using a solvent gradient of 10 100% CH2CN in 0.1% aq TFA. The desired cis-pyrrolidine isomer was the second of 2 components to elute. Fractions containing pure cis-isomer were pooled and concentrated in vacuo. The residue 15 was partitioned between saturated aq. NaHCO2 and a 3:1 mixture of CH 2

CI

2 :2-PrOH (3x). The combined organic layers were dried over Na 2

SO

4 , filtcrcd and concentrated in vacuo to give the title compound (32 mng, 28%). Example 62B 20 methyl { (2S)- I-[(2S)-2-(4- {4-[(2R,5S)- 1-(4-fluorophenyl)-5-(4- {2-[(2S)- I-{I(2S)-2 [(methoxycarbonyl)aminol-3-mnethyl butanoyl Ipyrrolidin-2-yll -l H-imnidazol-4-yI } phenyl)pyrrolidin 2-yl~phenyl}I-1I H -imidazol-2-yl)pyrrolidin-lI -yl]-3-methyl- I-oxobutan-2-yl Icarbamate Tlhe product from Example 62A (32 mng, 54 mnmol) was subjected to the method described in Example 5D, substituting (S)-2-(methoxycarbonylamuino)-3-methylbutanoic acid for (S)-2 25 (mnethoxycarbonmyl amino)butanoic acid, to give the title compound (34 mig, 69%). 'H NMR (400 M Hz, DMSO-D6) 6 ppm 0.78 -0.93 (in, 12 H), 1.78 -2.24 (in, 12 H), 2.37 - 2.46 (mn, 2 H), 3.54 (s, 6 H-), 3.68 - 3.87 (in, 4 H-), 4.66 - 4.79 (mn, 2 H). 5.02 - 5.13 (in, 2 H), 6.39 (dd, J=9.l6, 4.50 H z, 2 H), 6.81 -6.92 (mn, 2 H), 7.23 -7.34 (m, 2 H-), 7.39 - 7.80 (in, 12 H), 11.67 - 12.12 (in, 2 H); MS (ESI) m/z 902.7 (M+H)*. 30 17l Example 63 methyl f(2S)-1-{(2S)-2-[4-(4-{(2R,5S)-5-(4-(2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)aminol-3 methylbutanoyl )pyrrolidin-2-yl I-I H-imidazol-4-yl) phenyl)- I -[4-(trifluoromethyl)phenyllpyrrolidin 5 2-yl phenyl)- I H-imidazol-2-yl]pyrrolidin-1-yll-3-methyl-1-oxobutan-2-yl]carhanate Example 63A (2R,5S)-2,5-bis(4-bromophenyl)- I -(4-(trifluoromethyl)phenyl)pyrrolidine The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (Aldrich, 10 32.2 g, 200 mmol) were combined in DMF (50 mL), stirred at 50 *C under nitrogen for 16 hours, cooled and concentrated. The residue was diluted with ethyl acetate, treated with IM ICI, stirred for 10 minutes and filtered to remove solids. The organic layer of the filtrate was washed with brine, dried (Na 2

SO

4 ), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 1% ethyl acetate/hexane) to give the title compound (1.0 g, 10 %) as the second eluting 15 stercoisomer. MS (ESI+) nz 526 (M+H)*. Example 63B methyl [(2S)-1 -{(2S)-2-[4-(4-{(2R,5S)-5-(4-{2-{(2S)-I-{(2S)-2-[(methoxycarbonyl)aminol-3 methylbutanoyl }pyrrolidin-2-yll- I H-imidazol-4-yl ) phenyl)- I -[4-(trifluoromethyl)phenyllpyrrolidin 20 2-yl phenyl)-1l-1-imidazol-2-yllpyrrolidin-1-yl}-3-methyl-I-oxobutan-2-yllcarbamate The product from Example 63A (1.0 g, 1.90 mnimol) was processed using the methods described in Example 42D, 42K, 42F, and 420 to afford the title compound. 'H NMR (free base) (400 MHz, )MSO-da) 6 0.80 - 0.95 (in, 12 H) 1.83 - 2.18 (in, 14 H) 3.54 (s, 6 H) 3.79 (d, J=6.18 Hz, 3 -I) 3.97 - 4.15 (in, 3 H) 4.87 (d, J=4.88 H z, 2 H) 5.02 - 5.14 (in, 2 H) 6.54 (d, J=8.67 Hiz, 2 H) 7.15 - 7.80 25 (in, 14 11) 11.56 - 12.30 (m, 2 H-); MS (ESI+) m/z 953 (M+1H). /7 172 Example 64 methyl {(2S)-I -l(2S)-2-(4-14-|(2R,5S)- I-(4-tert-butylphenyl)-5-(4-{2-l(2S)-I-{(2S)-2 [(metlioxycarbonyl)aminol-3- methylbutanoyl pyrrolicin-2-yll-IH-i midazol-4-yl} phenyl)pyrrolidin 2-yl]phenyl)-l H-inida 5 zol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl carbamate Example 64A (2S,2'R)-2,2'-(4,4'-(4,4'-(i -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, 1 -phenylene))his(l H imidazole) his trifluoroacetate salt 10 Example 42C was processed using the methods of Examples 42D, 42E, and 42F to provide a mixture of cis/trans pyrrolidine isomers. The mixture of stereoisoners was dissolved in 10 ml of 80% (0.1% TFA/water):20% CHI 3 CN and applied to a 13 g C18 silica column. The column was eluted with a gradient of 0.1% TFA(aq):CIH3CN; 80/20 to 50:50 over 25 minutes, giving the cis steroisomer of the title compound as a light yellow solid triluoroacetate salt, 88.6 mg, 58%. 15 Example 64B methyl ((2S)-I -[(2S)-2-(4-{4-I(2R,5S)-I-(4-tert-butylphenyl)-5-(4-{2-t(2S)-1-((2S)-2 [(methoxycarboiyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-4-yl I phenyl)pyrrolidin 2-yliphenyl}-l l-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl- I-oxobutan-2-yl}carbanmate 20 The product from Example 64A was dissolved in I ml DMF and added dropwise to a chilled (0-5 "C) solution containing (S)-2-(methoxycarbonylanino)-3-methylbutanoic acid (0.41g, 0.232 mmole), HOBt (0.036g, 0.232 mmole), EDAC (0.045 g, 0.232 mmole) and 4-methylmorpholine (0.138g, 0.150 ml, 1.364 mole) in 0.5 ml DMF. The pH of the solution was measured and found to be 8. The reaction was stirred a total of 3.5 hr in the ice bath. The reaction mixture was diluted with 25 50 ml EOAc and washed with 10% NaHC0 3 , 10% NaCl, dried over anhydrous Na2S0 4 (s), filtered and solvent removed in vacuo leaving a pinkish oil. The oil was dissolved in 5 ml CH 2

C

2 and applied to a 12 g silica gel column. The column was eluted with a gradient of CH 2 Cl2/MeOH, 99/1 to 94/6 over 25 minutes giving the title compound as a white solid, 12.5 mg, 11%. 1H- NMR (400 MHz, DMSO-D6) d ppm 0.85 (s, 12 1-1) 1.13 (s, 9 H) 1.95 (s, 6 H) 2.15 (s, 4 H) 2.50 (s, 3 H-) 3.43 (s, 1 H) 30 3.54 (s, 5 H) 3.80 (s, 4 H) 4.05 (s, 2 H) 4.70 (s, 2 H) 5.07 (s, I H) 6.36 (d, J=8.78 H z, 2 H) 7.01 (s, 2 H) 7.28 (s, 2 H) 7.47 (s, 6 H) 7.70 (s, 4 H) 11.71 (s, 2 H) 12.09 (s, 2 H)ES1+:940.8 173 Example 65 methyl {(2S)-1-t(2S)-2-(4-{4-t5-(4-{2-[(2S)-1-((2S)-2-((methoxycarbonyl)amino]-3 methylbutanoyl pyrrolicin-2-yl]-1H-imidazol-4-yl)phenyl)-I-phenyl-1H-pyrrol-2-yl]phenyl)-1H imi(azol-2-yl)pyrrolilin-1-yll-3-methyl-I-oxobutan-2-yl carbamate 5 Example 65A (2S,2'R)-tert-butyl 2,2'-(4,4'-(4,4'-(1 -phenyl- 1 H-pyrrole-2,5-diyl)bis(4, 1 -phenylene))bis(1 H inidazole-4,2-diyl))dipyrrolidine-l -carboxylate Example 26F and aniline were processed using the methods of Examples 19A, 26G, and 26H 10 to provide the title compound (150 mg). Example 65B (S)-4,4'-(4,4'-( I-phenyl- I H-pyrrole-2,5-diyl)bis(4, I -phenylene))bis(2-((S)-pyrrolidin-2-yl)- Hl imidazole) 15 To a suspension of the product from Example 65A (186 mg, 0.243 nnol) in dioxane (5 mL) was added HCI/dioxane (5 ml, 20 mmol). The mixture was stirred for 30 minutes and then concentrated under reduced pressure to provide the title compound as a hydrochloride salt. Example 65C 20 methyl {(2S)-I-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-l -{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl}pyrrolidin-2-yl]-l-I-imidazol-4-yl phenyl)-I-phenyl- IH-pyrrol-2-yllphenyl}-l1H imidazol-2-yl)pyrrolidil--yll-3-methyl-I-oxobutan-2-yl carbamate A solution consisting of NI -((ethyl imino)methylene)-N3,N3-dinethylpropane- I,3-diamine hydrochloride (90 mg, 0.47 mmol), I H-benzoldJ[l,2,3]triazol-I-ol hydrate (72 ing, 0.47 mmol), (S) 25 2-(mctlhoxycarbonylaminto)-3-mcthylbutanoic acid (82 ng, 0.47 mmol) and 4-mnethylnorpholine (0.28 mL, 2.6 ninol) in DMF (1.6 mnL) was cooled in an icebath. To this mixture was added dropwise a solution of the product from Example 65B (150 mg, 0.23 mnol) in DMF (0.5 nL). Additional 4 tnethylmorpholine was added to the mixture until the pi was adjusted to 8. The reaction was stirred for 3.5 hours and then the icebath was removed and the reaction was stirred for an additional 16 30 hours. Water was then added to the reaction mixture and the resulting precipitate was recovered by filtration. The residue was washed with copious amounts of water followed by diethyl ether. The crude product was purified by chromatography on silica gel eluting with a solvent gradient of 0-5% methanol in CH 2

CI

2 to provide the title compound. 'H NMR (400 MHz, DMSO-d6) 8 12.12 - 11.64 (tm, 211), 7.57 - 7.45 (in, 411), 7.42 - 7.36 (m, 211), 7.36 - 7.29 (m, 311), 7.29 - 7.05 (m,4Hl), 7.04 35 6.91 (n, 411), 6.54 - 6.43 (tn, 21-1), 5.06 - 4.96 (m, 211), 4.06 - 3.96 (m, 211), 3.84 - 3.67 (in, 411), 3.52 (s, 6H-1), 2.17 - 1.80 (m, 101-I), 0.91 - 0.76 (m, 121-I). MS (ESI; M+-) m/z = 881. 174 Example 66 methyl [(2S)-I -1 (2S)-2-[4-(4-((2S,5S)-5-(4-12-[(2S)-I-((2S)-2-l(methoxycarbonyl)aminol-3 5 methylbut anoyl }pyrrolidin-2-ylj -I H -i midazol-4-yl }phenyl)- I -I4-(trifluoromethyl)phenyl Ipyrrolidin 2-yllphenyl)-1 I-imidazol-2-yljpyrrolidin-I-yl}-3-methyl-I-oxobutan-2-yljcarbamate Example 66A (2R,5R)-2,5-bis(4-bromophenyl)- 1-(4-(trifluoroimethyl)phenyl)pyrrolidine 10 and (2S,5S)-2,5-bis(4-bromophenyl)- I -(4-(trifluoronethyl)phenyl)pyrrolidine The product from Example 42B (11.13 g, 20.0 mmnol) and 4-(trifluoromethyl)aniline (32.2 g, 200 mumol) were combined in DMF (50 mL). The mixture was stirred at 50 'C under nitrogen overnight. The reaction muixturc was evaporated and the residue was diluted with ethyl acetate, treated 15 with I M -IC1, stirred for 10 minutes, and filtered to remove the solid. The organic layer of filtrate was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (0 to 1%). The title compounds (500 mug, 5%) were eluted as the first of 2 stereoisomers and were obtained as a mixture of trans diastereomers. 20 Example 6611 (2R,5R)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxahorolan-2-yl)phenyl)-1-(4 (triluoromnethyl)phenyl)pyrrolidine and 25 (2S,5S)-2,5-bis(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)- 1-(4 (trifluoromethyl)phcnyl)pyrrolidine The products from Example 66A (500 mg, 0.952 mmuol), bis(pinacolato)diboron (725 mg, 2.86 mmuol), potassium acetate (374 mug, 3.81 mmol) and bis(triphenylphosphine)palladium(11) chloride (66.8 mug, 0.095 mnol) were combined in 1,2-dimethoxyethane (10 ml.). The mixture was 30 purged with nitrogen for 15 minutes and stirred at 85 'C for 2 hours. The reaction mixture was partitioned between ethyl acetate and IM HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by 175 chromatography on silica gel eluting with hexane to ethyl acetate/hexane (10%) to give a solid which was triturated with dichloromethane/hexane (1:3) to give the title compounds (370 ing, 63%). Example 66C 5 (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-((2R,5R)-I -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4, 1 phenylene))bi s( t1--imidazole-4,2-diyl))dipyrrolidine- I -carboxylate and (2S,2'S)-tert-hutyl 2,2'-(4,4'-(4,4'-((2S,5S)-I-(4-(trilluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))his(I H-imidazole-4,2-diyl))dipyrrolidine-I-carboxylate 10 The products from Example 66B (257 mg, 0.415 nnol), the product from Example 26D (341 mg, 1.079 mmol), potassium phosphate Iribasic (352 mg, 1.660 mmol) and 1,1'-bis(di-tert butylphosphine)ferrocene palladium dichloride (27.0 mg, 0.041 nmol) were combined in TIF (4.5 mL)/ water (1.5 mnL). The mixture was purged with nitrogen for 15 minutes and stirred at 70 'C for 6 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. 15 The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with methanol/dichloromethane (1% to 3%) to give the title compounds (286 mg, 82%) as a solid. Example 66D 20 (S)-4,4'-(4,4'-((2R,5R)- I -(4-(triluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))bis(2 ((S)-pyrrolidin-2-yl)-I H-imidazole) and (S)-4,4'-(4,4'-((2S,5S)- I -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))bis(2 ((S)-pyrrolidin-2-yl)- I H-imidazole) 25 To the products from Example 66C (385 mg, 0.459 iunol) in dioxane (6 miL) was added 4M hydrochloric acid in dioxane (10 niL, 40.0 ninol) and the reaction stirred at room temperature for I hour. The solvent was evaporated under high vacuum to give the title compounds (approx. 360 mg) as hydrochloride salts. 30 Example 66E methyl ((2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-(methoxycarbonyl)amino j-3 methylbut anoyl }pyrrolidin-2-yl]- IH-imidazol-4-yl }phenyl)- I-[4-(trifluoromethyl)phenylJpyrrolidin 2-yl ) phenyl)-1 -1-inidazol-2-ylpyrrolidin-1-yl -3-methyl-I-oxobut an-2-yl]carbanate and 176 methyl [(2S)-l -((2S)-2-[4-(4-((2R,5R)-5-(4-{2-[(2S)-I-((2S)-2-[(methoxycarbonyl)aminoj-3 methylbut anoyl } pyrrolidin-2-ylJ -I H -i midazol-4-yl } phenyl)- 1 -(4-(triluoromethyl)phenylJpyrrolidin 2 -yl}phenyl)-I H-imidazol-2-yllpyrrolidin-1 -yl}-3-methyl-I-oxobutan-2-yl]carbamate The product from Example 66D (360 mg, 0.459 immol), (S)-2-(methoxycarbonylamino)-3 5 mnethylbutanoic acid (161 mg, 0.919 mmol), 4-methylmorpholine (0.404 mL, 3.68 mmol), NI ((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (194 mg, 1.011 mmol) and IH-benzotdJ[l,2,3Jtriazol-I-ol hydrate (155 mg, 1.011 mmol) were combined in DMF (10 mL). The mixture was stirred at room temperature for 20 hours. lie reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, 10 brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluding with methanol/dichloromethane (1% to 6%) to give the title compounds (223 mug, 51%) as a solid. Example 66F 15 methyl [(2S)-I -((2S)-2-[4-(4-((2S,5S)-5-(4-{2-[(2S)-I-((2S)-2-[(nethoxycarbonyl)aminol-3 methylbut anoyl }pyrrolidin-2-ylI- I - -imidazol-4-yl } phenyl)- I -[4-(trifluoromethyl)phenyl]pyrrolidin 2-yl ) phenyl)- I -l-imidazol-2-ylIpyrrolidin-1-yl}-3-methyl-I-oxobutan-2-ylJcarbamate The product from Example 66E was purified by chiral chromatography on a Chiralpak LB column eluting with a mixture of hexane/lIF/methanol (8/1/1). The title compound was the first of 20 the 2 diastereomers to elute. 'II NMR (400 MHz, DMSO-D6) 6 ppm 0.78 - 0.90 (m, 12 1-1) 1.71 - 1.77 (in, 2 H) 1.86 - 2.02 (in, 6 H) 2.09 - 2.18 (m, 4 H) 2.51 - 2.54 (in, 2 H) 3.53 (s, 6 H) 3.74 - 3.84 (in, 4 1-1) 4.04 (t, J=8.35 H-1z, 2 H) 5.06 (dd, J=6.83, 3.14 Hz, 2 H) 5.28 - 5.41 (m, 2 H) 6.41 (d, J=8.67 Hz, 2 H) 7.12 - 7.33 (in, 8 H) 7.36 - 7.72 (m, 6 H) 11.62 - 12.13 (in, 2 H); MS (ESI+) m/z 953 (M+H)+. 25 Example 67 methyl [(2S)-I-((2S)-2-[4-(4-{(2R,5R)-5-(4-(2-[(2S)-1-((2S)-2-[(methoxycarbonyl)aminoj-3 nethyl but anoyl } pyrrolidin-2-yl] -I H -imidazol -4-yl } phenyl)- 1 -[4-(tri fluoromethyl)phenyl]pyrrolidin 2-yl} phenyl)- I l--imidazol-2-yllpyrrolidin-1-yl} -3-methyl-I-oxobutan-2-yllcarbamate 30 The product from Example 66E was purified by chiral chromatography on a Chiralpak IB column eluting with a mixture of' hexanefl'HF/mnethanol (8/1/1). ie title compound was the second of the 2 diastereomers to clute. 'H NMR (400 MHz, DMSO-D6) 6 ppm 0.79 - 0.91 (in, 12 H) 1.71 177 1.77 (im, 2 H) 1.88 - 2.01 (in, 6 H ) 2.08 - 2.17 (in, 4 H) 2.51 - 2.54 (m, 2 H) 3.53 (s, 6 H) 3.74 - 3.82 (in, 4 H) 4.05 (1, J=8.40 Hz, 2 H) 5.00 - 5.13 (in, 2 H) 5.29 - 5.40 (in, 2 H) 6.40 (d, J=8.57 Hz, 2 H) 7.12 - 7.31 (in, 8 H) 7.36 - 7.72 (m, 6 H) 11.52 - 12.15 (mn, 2 H); MS (ESI+) m/z 953 (M+H)+. 5 Example 68 methyl {(2S)-I-[(2S)-2-(4-(4-[(2R,5S)-I-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-1-((2S)-2 [(methoxycarbonyl)amino]-3-methyl butanoyl}pyrrolidin-2-yl]-1 1-inidazol-4-yl }phenyl)pyrrolidin 2-yl]phenyl)-ill-imidazol-2-yl)pyrrolidin-i-yl]-3-methyl-1-oxobutan-2-yI carbamate 10 Example 68A 2,5-his(4-bromophenyl)-l -(4-cyclopropylphenyl)pyrrolidine The product from Example 421B (3.14 g, 5.64 mmol) and 4-cyclopropylaniline (6.01 g, 45.2 mmol) were combined in DMF (20 mL). The mixture was stirred at 50 "C under nitrogen for 3 hours. 15 The reaction mixture was partitioned between IM HCI and ethyl acetate. The organic layer was washed with brine three times, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (0.5% to 1%) to give the title compound (2.12g, 76%) as a mixture of stereoisoners as a sticky solid. 20 Example 68B 1-(4-cyclopropylphenyl)-2,5-bis(4-(4,4,5,5-(ctramethlyl-l,3,2-dioxaborolan-2-yl)phcnyl)pyrrolidine The product from Example 68A (2.12 g, 4.26 nunol), bis(pinacolato)biboron (3.25 g, 12.79 mnmol). potassium acetate (1.674 g, 17.05 mnmol) and bis(triphenylphosphine)palladiumn(II) chloride (0.299 g, 0.426 minol) were combined in 1,2-dimnethoxyethane (40 mL). The mixture was purged with 25 nitrogen for 15 minutes and stirred at 85 *C for 2 hours. The reaction mixture was partitioned between ethyl acetate and I M HCL. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with hexane to ethyl acetate/hexaie (10%) to give a solid that was triturated with diethyl ether/hexane (1/3) to give the title compound (1.05, 42%) as a mixture of stercoisomers as a 30 white solid. Example 68C 178 (2S,2'S)-tert-hutyl 2,2'-(4,4'-(4,4'-(1 -(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))his( I H-i midazole-4,2-diyl))dipyrrolidine- I -carboxylate The product from Example 68B (1.04 g, 1.759 tiunol), the product from Example 26D (1.446 g, 4.57 mmol), PdCI(dppf) (0.129g, 0.176 imol) and 1.0 M sodium carbonate (4.57 mL, 4.57 mmol) 5 were combined in the mixed solvent of ethanol (5 mL)/toluene (5 mL). The mixture was purged with nitrogen for 15 minutes and stirred at 80 *C for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluding with methanol/dichloromnethane (1% to 3%) to give the title compound (1.28 g, 90%) as a mixture of 10 stereoisomers as a solid. Example 68D (S)-4,4'-(4,4'-((2R,5S)- 1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,1 -phenylene))bis(2-((S) pyrrolidin-2-yl)-1 I-imidazole) 15 The product from Example 68C (1.27 g, 1.568 mrmol) was dissolved in dichloromethane (12 ml,). The mixture was cooled to 0 'C and trifluoroacetic acid (8 ml-, 104 mmol) was added slowly. The mixture was warmed to room temperature and stirred for Ih. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with methanol/dichloromethane (1% to 10%). The title compound (310 mg, 32%) eluted as the second of 2 stereoisomers. 20 Example 68E methyl {(2S)-I-[(2S)-2-(4-{4-[(2R,5S)-I-(4-cyclopropylphenyl)-5-(4-{2-1(2S)-1-{(2S)-2 [(methoxycarbonyl)aninol-3-methylbutanoyl pyrrolidin-2-yl]-1 H-imidazol-4-yl }phenyl)pyrrolidin 2-yll phenyl )-l H-imi dazol-2-yl)pyrrolidin- I -yll-3-methyl-1-oxobutan-2-yl }carbamnate The product of Example 681) (90 mg, 0.148 mmol), (S)-2-(methoxycarbonylamino)-3 25 muethylbutanoic acid (51.7 mug, 0.295 inuol), 4-miethylnorpholine (0.130 niL, 1.181 mnol), NI ((ethyli mino)methylene)-N3,N3-di methylpropane- 1,3-diamine hydrochloride (62.2 mg, 0.325 mol) and 1-1-benzo[d][1,2,3]iriazol-1-ol hydrate (49.7 mug, 0.325 nunol) were combined in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, 30 brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with methanol/dichloromnethane (1% to 4%) to give the title compound (40 mg, 29%) as a solid. 'H NM R (400 M H., DMSO-D6) 6 ppm 0.39-0.47 (mn, 2 H) 0.71 0.78 (m, 2 H) 0.82 - 0.92 (m, 12 H) 1.65 - 1.72 (m, I H) 1.82 - 2.03 (in, 8 H) 2.09 - 2.17 (tm, 4 H) 2.40 - 2.45 (m, 2 H1) 3.54 (s, 6 11) 3.75 - 3.83 (tn, 4 H) 4.02 - 4.09 (im, 2 11) 4.64 - 4.75 (mi, 2 H) 5.03 - 5.11 35 (i, 2 11) 6.32 (d, J=8.67 H z, 2 11) 6.73 (d, J=8.35 l z, 2 11) 7.29 (d, J=8.02 H z, 2 H) 7.37 - 7.81 (m, 10 H) 11.47 - 12.17 (n, 2 11); MS (ESI+) m/z 924.7 (M+H1)+. 179 Example 69 methyl {(2S)-I-[(2S)-2-(4-{4-[(2S,5S)-I-(4-tert-butylphenyl)-5-(4-{2-(2S)-1-{(2S)-2 5 [(methoxycarbonyl)aininoJ-3,3-dimethylbutanoyl)pyrrolidin-2-yl]-I H-imidazol-4 yl } phenyl)pyrrolidin-2-yllphenyl ]-1 H-imidazol-2-yl)pyrrolidin-1-ylI-3,3-dimethyl-l -oxobutan-2 yl }carbamate Br -0 Br 10 Example 69A (1 R,4R)- 1,4-bis(4-bromophenyl)butane-i,4-diol To (S)-(-)-alpha, alpha-diphenyl-2-pyrrolidinemethanol (3.81 g, 15.04 rnmol) was added THF (140 mi) at 23 "C. The thin slurry was treated with trimethyl borate (2.189 mL, 19.63 mmol) to form a clear solution. After stirring for 1.5 h, the solution was cooled to 10-15 'C, and N,N-diethylaniline 15 borane (33.1 mL, 186 mmol) was added over 5-10 min via a syringe. A slight exotherm and 112 evolution were observed. To a separate vessel was charged Example 26E (35.045 g, 88 mmol), followed by TIHF (140 mL), to form a slurry. The slurry was cooled to 10 C. The cooled borane solution was transferred via cannula into the dione slurry over approximately 5 minutes, maintaining the internal temperature <25 *C. After the transfer was complete, the slurry was held at 15 'C for 5 20 in and then the temperature was maintained at 23 C for 3 h. After reaction completion, the solution was cooled to 5 "C, and methanol (31.6 mlL, 780 mnmol) was added slowly to maintain a temperature <20 'C (note: vigorous evolution of hydrogen). The hazy solution was mixed for an additional I h in order to ensure complete quenching. The hazy solution was diluted with EtOAc (500 mL) and I M H-CI (220 mL). The phases were partitioned, and the organic phase was washed successively with 1 M 25 HCi (2 x 220 mL), 1-120 (l 10 miL), and 25% aq. NaCl (110 nL). The organic layer was concentrated in vacuo, then dissolved in EtOAc, filtered, concentrated and crystallized from EtOAc/hexane to provide the title compound (16.92 g; 100% ee; 47% isolated yield). Example 69B 30 (2S,5S)-2,5-bis(4-bromophenyl)-I-(4-tert-butylphenyl)pyrrolidine 180 To a mixture of the product from Example 69A (0.60 g, 1.500 mmol) in anhydrous CH 2

CI

2 (15 mL) at 0 *C was added Et 3 N (0.627 mL, 4.50 mmol), and the resulting mixture was stirred at 0 *C for 10 ino until a homogenous solution was obtained. To the cooled solution was added methanesulfonyl chloride (0.292 mL, 3.75 mmol) dropwise, and the resulting mixture was stirred at 0 5 *C for 1.5 h until the reaction was complete as determined by ''LC (1:1 EtOAc:hexanes). Solvent was removed in vacuo to give a solid, which was dried in vacuo. The solid was dissolved in anhydrous DMF (5 mL), and 4-tert-butylaniline (2.39 mL, 15 mmol) was added. The resulting mixture was stirred at 40 *C for 4h and then was partitioned between IN aq. HCl (30 mL) and EtOAc (30 niL). The organic layer was washed with 1-120 and dried over Na 2

SO

4 . The drying agent was filtered off, 10 the solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes. The title compound was obtained as a colorless solid (0.71 g, 92%). 'H NMR indicated this material was a 87:13 mixture of trans:cis pyrrolidine isomers. 15 Example 69C (2S,5S)-I -(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetranethyl-1,3,2-dioxaborolan-2 yl)phenyl)pyrrolidine The product from Example 69B (0.71 g, 1.38 mnmol) was subjected to the conditions described in Example 42D to give the title compound as a colorless solid (0.56 g, 66%). 20 Example 69D (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-((2S,5S)- I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phetnylene))bis( lH-ii midazole-4,2-diyl))dipyrrolidine-l-carboxylate The product from Example 69C (0.55 g, 0.91 mmol) was subjected to the conditions 25 described in Example 42E to give the title compound (0.27 g, 36%). Example 69E (S)-4,4'-(4,4'-((2S,5S)-I -(4-tert-hutylphenyl)pyrrolidine-2,5-diyl)his(4, I -phenylene))bis(2-((S) pyrrolidin-2-yl)-l H-imnidazole) 30 A solution of the product from Example 69D (0.27 g, 0.33 mnmol) in a 1:1 mixture of

CH

2 CI:TFA (4 mnL) was stirred at rt for 40 min and then concentrated in vacuo. The residue was partitioned between saturated aq NaHCO 3 and a 3:1 mixture of CH 2

CI

2 :2-PrO-l (2x), and the combined organic layers were dried over Na 2

SO

4 . The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as an amorphous solid (0.18 g, 87%). 35 Example 69F 181 methyl {(2S)-I-[(2S)-2-(4-{4-[(2S,5S)-I-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [i(methoxycarbonyl)ainino]-3,3-di methylbutanoyl pyrrolidi n-2-yl]-IH-iinidazol-4 yl )phenyl)pyrrolidin-2-yllphenyl}-lH-inidazol-2-yl)pyrrolidin-1-yl]-3,3-diimethyl-i-oxobutan-2 yl)carbamate 5 To a mixture of the product from Example 69E (0.10 g, 0.16 mmol) and (S)-2 (methoxycarbonylamino)-3,3-diimethylbutanoic acid (76 mg, 0.40 nmol) in anhydrous DMSO (1.6 mL) was added HATU (152 mg, 0.40 mmol) and Hlunig's base (84 lL, 0.48 mrnmol). The resulting mixture was stirred at rt for 90 min, and was then partitioned between H 2 0 (5 mL) and EtOAc (2 x 5mL). The combined organic layers were concentrated in vacuo, and the residue was dissolved in 10 MeOH (I mL..). To the solution was added solid K 2 C0 3 (1-2 mg) and the resulting mixture was stirred at rt for 30 mini. The mixture was filler and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH 2 C1 2 to give the title compound (0.12 g, 78%). 'H NMR (400 MHz, DMSO-D6) S ppm 0.94 (s, 18 H), 1.10 (s, 9 H), 1.63 - 1.77 (in, 2 H), 1.84 - 2.25 (m, 10 H), 3.55 (s, 6 H), 3.66 - 3.87 (m, 2 H), 4.16 - 4.28 (mn, 2 15 H), 5.03 - 5.12 (i, 2 H), 5.15 - 5.28 (m, 2 H), 6.22 (d, 1=8.46 Hz, 2 H), 6.93 (d, 1=8.67 Hz, 2 H-1), 7.07 (d, 2 -1), 7.15 (d, 1=8.13 Hz, 4 H), 7.23 (d, I H-), 7.38 (d, J=1.41 Hz, 2 H), 7.52 (d, 1 H), 7.62 (d, .1=8.02 Hz, 4 H-), 11.66 - 12.10 (in, 2 H). MS (ESI) m/z969.1 (M+H)*. 0 NH HN .- 0 20 Example 70 dimethyl ([(2S,3R,4R,5S)-I-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyllbis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2, 1-diyl[(2S)-3-mnethyl-I-oxobutane-1,2-diyl]})biscarbamate Example 70A 25 Tert-butyl 4,4'-((2S,3 R,4R,5S)-1 -(4-fluorophenyl)-3,4-dihydroxypyrrolidine-2,5-diyl)his(4, 1 phenylenc)clicarbamate A solution of 3,4-0-isopropylidene-D-mannitol (444 mg, 2.0 imol) in 2:1 methanol dichloromethane (8 ml.) was treated with iodobenzene diacetate (1.54 g, 4.79 minol) followed by stirring at RT for 5 h. The mixture was concentrated in vacuo to remove organic solvents, and the 30 residue was suspended in 0.1 M sulfuric acid solution (4 mL) followed by stirring at RT for 18 h. The mixture was adjusted to pH 6 by addition of solid sodium bicarbonate. The mixture was then sequentially treated with 4-fluoroaniline (383 gL, 444 ig, 4.00 mmol), 4-(tert 182 butoxycarbonylanino)phenylboronic acid (853 mg, 3.60 mmol) and hexafluoroisopropyl alcohol (8 mL.). 'he mixture was warmed at 50 "C for 2 h. The solution was cooled and concentrated in vacuo. The mixture was dissolved in ethyl acetate and extracted with water, 0.33 M tribasic potassium phosphate solution, and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in 5 vacuo afforded a brown solid, which was chromatographed over a 100 g silica gel cartridge, eluding with 5-70% ethyl acetate in dichloromethane. These procedures afforded the title compound (770 mg, 67%) as a nearly white solid. 'H NMR (400 M Hz, CDCl 3 ) 8 7.35 (d, . = 8.3 Hz, 4 H), 7.11 (d, J = 8.4 Hz, 4 -1), 6.67 (t, J = 8.8 Hz, 2 H), 6.51 (s, 2 H), 6.22 (dd, J = 9.1, 4.3 H z, 2 H), 5.15 (d, J = 6.3 Hz, 2 H), 4.26 (d, J = 5.7 Hz, 2 H), 1.51 (s, 18 H). MS +ESI m/z (rel abundance) 580 (100, M+H), 602 (15, 10 M+Na), 1159 (18, 2M+H). Example 70B (2S,3R,4R,5S)-2,5-bis(4-(tert-butoxycarbonylamino)phenyl)-I -(4-fluorophenyl)pyrrolidine-3,4-diyl diacetate 15 A solution of the compound of Example 70A (314 mg, 0.54 imol), triethylaniine (227 gL, 164 mg, 1.65 inol), and DMAP (13 mg, 0.11 mnol) in 1:1 ethyl acetate-tetrahydrofuran (2.8 niL) was treated with acetic anhydride (128 ptL, 138 tng, 1.35 mnmol) followed by stirring at RT for I h. The mixture was treated with water followed by stirring at RT for 30 min. The mixture was diluted with ethyl acetate and extracted with water, saturated sodium bicarbonate solution and saturated 20 sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded the title compound (330 mg, 92%) as a cream-colored solid, sufficiently pure for further use. 'H NMR (400 MHz, CDCl 3 ) 8 7.32 (d, J = 8.4 Hz, 4 H), 7.07 (d, J = 8.5 Hz, 4 H), 6.66 (t, J = 8.8 H z, 2 H), 6.47 (s, 2 H-), 6.25 (dd, J = 9.2, 4.3 lz, 2 H), 5.53 (dd, J = 5.5, 1.9 Hz, 2 11), 5.46 (d, J = 7.2 Hz, 2 H), 1.83 (s, 6 11), 1.51 (s, 18 1-1). MS +ESl mn/z (rel abundance) 664 (100, M+H). 25 Example 70C (2S,3R,4R,5S)-2,5-bis(4-aiinophcnyl)- 1 -(4-fluorophenyl)pyrrolidine-3,4-diyl diacetate dihydrochloride A solution of 4 N hydrogen chloride in dioxane (8 mL) was treated with the compound of 30 Example 70B (136 mg, 0.21 mmol) followed by stirring at RT for 2 h. (During this time, the mono deprotection product started precipitating, and ca. 4 mlL of dichloromethane was added to speed the reaction by solublizing the mono-hydrochloride) The mixture was added to excess ether and the product collected by filtration and washed with ether. After drying in a vacuum oven at 50 "C for 18 h, these procedures afforded the title compound (92 mg, 84%) as an off-white powder. 'H NMR (400 35 MH z, DMSO-d 6 ) 8 7.28 (in, 8 1-1), 6.81 (t, J = 8.9 Hz, 2 H), 6.33 (in, 2 H), 5.63 (m, 2 11), 5.51 (dd, J = 5.5, 1.9 lz, 2 H), 1.79 (s, 6 H). 183 Example 701) (2S,3R,4R,5S)-2,5-bis(4-aiinophenyl)-I-(4-fluorophenyl)pyrrolidine-3,4-diol In a 25-nL round bottom flask, was dissolved Example 70C(160.5 mg, 0.299 mmol) in 5 MeOH (3 mL), added potassium carbonate (165 mg, 1.197 mmol), and stirred at 25 C for 1.5 hr. Filtered off the solids, washed with MeOll, and concentrated the filtrate by rotary evaporation to dryness. Purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 8% MeO-l/CH 2

CI

2 ) to afford the title compound as a yellow solid (85 ing, 75%). 'H NMR (400 MH., DMSO-D6) 6 ppm 4.10 - 4.19 (in, 2 H), 4.73 (d, 1=2.71 Hz, 2 H-1), 4.80 - 4.88 (i, 2 H), 4.84 (s, 4 H), 10 6.21 (dd, 1=9.22, 4.55 Hz, 2 H), 6.45 (d, 1=8.35 Hz, 4 H), 6.72 (t, 1=8.95 Hz, 2 11), 6.77 (d, J=8.24 Hz, 4 H); MS (DCI+) 380 (M+H)*. Example 70E 4,4'-((2S,3R,4R,5S)- I-(4-fluorophenyl)-3,4-diniethoxypyrrolidine-2,5-diyl)dianiline 15 In an oven-dried 25-mL round bottom flask, dissolved the product of Example 70D (83.6 mg, 0.220 inmol) in anhydrous THF (3 ml.,) under nitrogen, cooled to 0 C in an ice water bath, added 60 wt% NaH dispersion in mineral oil (18.51 mg, 0.463 inmol), and stirred at 0 C for 15 min. Then added iodomethane (0.028 mL, 0.441 mmol) via microsyringe and stirred at 0 "C for I hr, then at 25 C for 3 hr. Removed the solvent by rotary evaporation and dried the residue in vacuo. Purified by 20 flash chromatography (silica gel, Alltech Extract-Clean 1Og column, gradient of 1% to 2% MeOH/CH 2

CI

2 ) to afford the title compound as a yellow solid (59 mg, 66%). 'H NMR (400 MHz, DMSO-D6) 6 ppm 3.25 (s, 6 1-1), 3.92 - 4.17 (in, 2 11), 4.91 (s, 4 H), 5.07 - 5.24 (in, 2 H), 6.28 (dd, .1=9.16, 4.50 H z, 2 H), 6.47 (d, .1=8.46 Hz, 4 H), 6.73 (t, J=8.95 Hz, 2 H), 6.86 (d, .1=8.35 Hz, 4 H); MS (DCI+) n/. 408 (M+H)*. 25 Example 70F (2S,2'S)-tert-butyl 2,2'-(4,4'-((2S,3R,3R,5S)- I -(4-fluorophenyl)-3,4-diniethoxypyrrolidine-2,5 diyl)bis(4, I-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate In a 10-miL round bottom flask, dissolved the product of Example 70E (57 mg, 0.140 mmol) 30 in anhydrous DMSO (1.2 mL) under nitrogen, added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2 carboxylic acid (76 mg, 0.350 minol), HATU (137 ing, 0.350 nimol), and diisopropylethylamine (0.073 ml., 0.420 mnmol), and stirred the bright yellow solution at 25 'C for I hr. Diluted the reaction with EtOAc (50 niL), washed with 120 (3 x 25 mL) and brine (15 niL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a yellow residue. Purified by 35 flash chromatography (silica gel, Alltech Extract-Clean lOg column, 3% MeOIH/C1 2 Cl 2 ) to afford the title compound as a yellow solid (118 mg). 'H NMR (400 MHz, DMSO-D6) 8 ppm 1.29 (s, II 1), 184 1.39 (s, 7 H), 1.72 - 1.95 (m, 6 H), 2.08 - 2.25 (in, 2 H), 3.29 (s, 6 H), 3.35 - 3.49 (in, 3 H), 4.12 (d, J=0.87 Hz, 2 H), 4.15 - 4.29 (in, 2 H), 5.30 - 5.45 (m, 2 H), 6.28 (dd, 1=9.22, 4.45 Hz, 2 H), 6.75 (t, 1=8.89 Hz, 2 H), 7.19 (d, J=8.35 H z, 4 H), 7.50 (t, 1=8.89 Hz, 4 H), 9.70 - 10.14 (im, 2 H); MS (Al'I(+) mi/z 802 (M+H)*. 5 Example 70G (2S,2'S)-N,N'-(4,4'-((2S,3R,4R,5S)- 1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis((4, 1 phenylene))dipyrrolidine-2-carboxamide Dissolved the product of' Example 70F (112 mg, 0.140 mmol) in anhydrous CH 2

C

2 (1 mL.) 10 under nitrogen, added TFA (I mL), and stirred at 25 UC for 30 min. Removed the solvent by rotary evaporation, redissolved in 1:5 v/v CH 2 CIz/hexanes, and concentrated in vacuo. Took up the residue in EtOAc (50 inL), washed with sat'd aq NalHC0 3 (2 x 15 mL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to afford the title compound as a yellow solid (72 mg, 84%). 'I NMR (400 MlHz, DMSO-D6) 8 ppm 1.57 - 1.69 (n, 4 H), 1.70 - 1.85 15 (in, 2 H-), 1.96 - 2.10 (m, 2 H), 2.82 - 2.95 (m, 4 H), 3.28 (s, 6 H), 3.66 (dd, 1=8.84, 5.58 Hz, 2 H), 4.07 - 4.17 (i, 2 H), 5.30 - 5.49 (in, 2 H-1), 6.28 (dd, J=9.16, 4.39 Hz, 2 -1), 6.75 (t, J=8.89 Hz, 2 H), 7.18 (d, 1=8.57 Hz, 4 H-1), 7.56 (d, J=8.57 H z, 4 H), 9.90 (s, 2 H); MS (ESI+) inz 602 (M+H)*. Example 7011 20 dimethyl (((2S,3R,4R,5S)-I-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl]bis{benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]))biscarbamate Dissolved the product of Example 70G (69.3 mg, 0.115 nunol) in anhydrous DMF (1.2 iL) under nitrogen, cooled to 0 C, then sequentially added (S)-2-(iethoxycarbonylamino)-3 methylbutanoic acid (50.4 mg, 0.288 mmnol), HOBT monohydrate (44.1 ng, 0.288 iniol), EDAC 25 (56.3 ing, 0.288 nimol), and N-incthylmorpholinc (0.038 inL, 0.346 nunol). Removed the cooling badh and stirred at 25 *C for 13 hr. Diluted the reaction with EtOAc (50 nL), washed with sat'd aq NaHCO 3 (25 mL), H 2 0 (2 x 25 mL), and brine (25 mL). Dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation. Purified by flash chromatography (silica gel, 2.5 cm x 15 cm, 6% MeO1/CH 2 Cl 2 ) to afford the title compound as a white solid (48 ing, 85%). 30 'H NMR (400 M Hz, DMSO-D6) 8 ppm 0.88 (d, .1=6.61 lz, 6 I), 0.93 (d, 1=6.72 Hz, 6 H), 1.80 2.05 (n, 8 H), 2.08 - 2.22 (in, 2 H), 3.28 (s, 6 H), 3.52 (s, 6 H), 3.56 - 3.69 (in, 2 H), 3.77 - 3.88 (in, 2 -1), 4.03 (t, 1=8.51 Hz, 2 H), 4.07 - 4.16 (m, 2 H), 4.43 (dd, J=7.97, 4.83 Hz, 2 H), 5.29 - 5.44 (in, 2 H), 6.27 (dd, 1=9.22, 4.45 Hz, 2 H), 6.75 (t, J=8.89 Hz, 2 H), 7.17 (d, 1=8.46 Hz, 4 H), 7.31 (d, J=8.46 Ilz, 2 11), 7.49 (d, 1=8.57 [iz, 4 H1), 9.99 (s, 2 H1); MS (ESI+) n/z 408 (M+1)*. 35 185 NM HN.O 0 0 Example 71 dimethyl ([(2S,3R,4R,5S)-I-(4-fluorophenyl)-3,4-dinethoxypyrrolidine-2,5-diyllbis ( benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,l -diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-diyl]))biscarbaiate 5 Dissolved the product of Example 701) (58.5 ing, 0.097 mnol) in anhydrous DMF (I ml..) under nitrogen, cooled to 0 "C, then sequentially added (S)-2-(methoxycarbonylamino)-3,3 dimcthylbuianoic acid (46.0 ing, 0.243 mnimol), HOBt ionohydrate (37.2 ing, 0.243 mmol), EDAC (47.5 mg, 0.243 mmol), and 4-methylmorpholine (0.032 mL, 0.292 mnmol). Removed the cooling bath and stirred overnight at 25 *C for 16 hr . Diluted the reaction with EtOAc (50 mL), washed with 10 sat'd aq NalHCO 3 (25 mL), HO (2 x 25 mL), and brine (25 mL). Dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation. Purified by flash chromatography (silica gel, 2.5 cm x 15 cm, 4% MeOHl/C1 2 Cl 2 ) to afford the title compound as a cream-colored solid (66 mg, 72%). 'H NMR (400 Mzli, DMSO-D6) 8 ppm 0.96 (s, 18 H), 1.79 1.94 (in, 4 H), 1.94 - 2.06 (m, 2 H), 2.10 - 2.22 (in, 2 H), 3.28 (s, 6 I), 3.54 (s, 6 H), 3.58 - 3.70 (m, 2 15 -1), 3.71 - 3.86 (in, 2 H), 4.06 - 4.15 (in, 2 H), 4.21 (d, J=8.89 Hz, 2 H), 4.44 (dd, J=7.92, 5.31 Hz, 2 -1), 5.31 - 5.39 (in, 2 H), 6.27 (dd, J=9.22, 4.45 H-z, 2 H-), 6.75 (t, 1=8.89 H-z, 2 H), 7.08 (d, 1=8.78 Hz, 2 H-), 7.17 (d, 1=8.57 iz, 4 11), 7.49 (d, J=8.57 Iz, 4 11), 9.99 (s, 2 H-); MS (ESI+) nVz 945 (M+H-1)*. 20 Example 72 diiethyl ([1-(4-teri-butylphenyl)-i H-pyrrole-2,5-diyl]bis{benzene-4,1-cliylcarbaimoyl(2S)pyrrolidine 2,1-diyl[(2S)-3-imethyl-I-oxobutane-1,2-diyl]})biscarbainate Example 72A 25 4,4'-(I-(4-tert-butylphenyl)-l I H-pyrrole-2,5-diyl)dianiline Example IA was processed using the methods described generally in Examples 26F and 19B to provide the title compound. MS (EST; M+H) m/z = 382. Example 72B 186 (2S,2'S)-tert-hutyl 2,2'-(4,4'-(] -(4-tert-butylphenyl)- I H-pyrrole-2,5-diyl)his(4,1 phenylene)his(azanediyl)his(oxomethylene))dipyrrolidine- I -carboxylate To a solution of the product from Example 72A (0.310 g, 0.813 nimol) in DMF (5 niL) was added (S)- I -(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.385 g, 1.79 mmol) 1 5 hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) and N-(3-dimethylamiinopropyl)-N' ethylcarbodiiimide hydrochloride (0.343 g, 1.79 mmol) and the mixture stirred overnight. The mixture was poured into water and extracted CH 2 Cl 2 . The organic extract was dried (Na 2

SO

4 ), filtered and concentrated to give a crude product that was purified by trituration with ether to give 325 ing (51 %) of the title compound. 'H NMR (400 MHz, DMSO-D6) 8 1.25 (s, 24 H) 1.83 (s, 6 H) 2.15 (s, 2 H) 10 3.45 (n, 4 1-) 4.18 (s, 2 1-1) 6.40 (s, 2 I-I) 6.98 (s, 6 H) 7.37 (s, 6 H) 9.98 (s, 2 H). Example 72C (2S,2'S)-N,N'-(4,4'-(1 -(4-tert-butylphenyl)- I HI-pyrrole-2,5-diyl)bis(4, I -phenylene))dipyrrolidine-2 carboxamide 15 To a solution of the product from Example 72B (0.325 g, 0.419 mnmol) in CH 2 Cl 2 (5 mL) at rt was added TFA (1.0 mL) and stirring continued for 5 h. The reaction was concentrated and the residue partitioned between water and 25% isopropyl alcohol-CHC1 3 . The organic phase was dried (Na 2

SO

4 ), filtered and concentrated to provide the title compound used directly in the next reaction. MS (DCI; M+l 1) mi/z = 576. 20 Example 72D dimethyl ([I -(4-tert-butylphenyl)- H l-pyrrole-2,5-diyllbis ( benzene-4,1-diylcarbamoyl(2S)pyrrolidine 2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyll))biscarbainate The product from Example 72C and the product from (S)-2-(iethoxycarbonylamino)-3 25 methylbutanoic acid were processed using the method described in Example 72B. The crude residue was purified by silica gel chromatography (1% gradient elution from 0% to 4% MeOH:CH 2

CI

2 ) to provide 129 mg (35%) of the title compound. 'H NMR (400 MHz, DMSO-D6) 50.89 (s, 12 H) 1.25 (s, 9 11) 1.89 (s, 6 H) 1.98 (s, 2 H) 2.13 (s, 2 H) 3.52 (s, 6 H) 3.61 (s, 2 H) 3.80 (s, 2 H) 4.00 (s, 2 H) 4.39 (s, 2 H1) 6.38 (s, 2 11) 6.95 (s, 6 H1) 7.34 (s, 8 H-) 9.96 (s, 2 H1). 30 co- Example 73 187 methyl [(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-I -{(2S)-2-j(methoxycarbonyl)aminoj-3 methyibutanoyl }pyrrolidin-2-ylj- IH-i midazol-4-yl phenyl)-i-14-(methylsulfonyl)phenyl]- IH-pyrrol 2-yli phenyl)-I H-iidazol-2-yl]pyrrolidin-1-yl}-3-methyl-I-oxobutan-2-yl]carbamate Example 26E and 4-(methylsulfonyl)aniline were processed using the methods of Examples 5 26F, 26G, 26H, 653, and 65C to provide the title compound (78 mg). 'H NMR (400 MHz, DMSO d6) 8 12.17 - 11.67 (m, 211), 7.92 - 7.82 (i, 211), 7.62 - 7.49 (m, 411), 7.48 - 7.40 (im, 211), 7.39 7.15 (m, 4H), 7.08 - 6.92 (m, 4H), 6.59 - 6.47 (m, 2H), 5.08 - 4.99 (i, 2H), 4.08 - 3.98 (in, 2H), 3.84 - 3.69 (m, 41-), 3.53 (s, 6H), 3.24 (d, J = 1.9, 3H), 2.20 - 1.81 (nm, IOH), 0.91 - 0.77 (m, 12H). MS (HS1; M+H) m/z= 959. 10 Example 74 methyl {(2S)- I-[(2S)-2-(5-{4-[ I -(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)amino]-3-methyl butanoyl pyrrolidin-2-yl]- l H-imidazol-5-yl)phenyl)-l H -pyrrol 15 2-yllphenyl }-lH-imidazol-2-yl)pyrrolidin-I-yl]-3-mnethyl-I-oxobutan-2-ylIcarbamate Example 74A 2,5-bis(4-bromophenyl)- I -(4-cyclohexylphenyl)-1 H-pyrrole The product from Example 26E and 4-cyclohexylaniline (Alfa) were processed using the 20 method described in Example 26F to provide 1.23 g (91%) of the title compound. 'H NMR (400 M Hz, benzene-D6) 61.09 (s, 5 H) 1.60 (s, 5 H) 2.14 (s, I H) 6.52 (s, 2 H) 6.67 (s, 4 H) 6.84 (s, 4 H) 7.1 1 (s, 4 11). Example 74B 25 1-(4-cyclohexylphenyl)-2,5-bis(4-(4,4,5,5-tetraiethyl-1,3,2-dioxahorolan-2-yl)phenyl)- 1 H-pyrrole The product from Example 74A was processed using the method described in Example 26G to provide 1.58 g (60%) of the title compound. MS (ESI; M+H) mi/z = 630. Example 74C 30 (2S,2'S)-tert-butyl 2,2'-(5,5'-(4,4'-(I-(4-cyclohexylphenyl)- I H-pyrrole-2,5-diyl)bis(4,1 phenylene))bis( I H-im idazole-5,2-diyl))dipyrrolidine- I -carboxylate 188 A solution of the product from Example 741 (0.400 g, 0.635 mmol) and the product from Example 261) (0.442 g, 1.40 minol) in toluene (3 mL) and ethanol (3 mL) was treated with I M sodium carbonate (2 iL) followed by 1,1 -bis(diphenylphosphino)ferrocene-palladium(U)dichloride dichloromethane complex (0.052 g, 0.064 mmol), the mixture degassed (3 x vacuum/purge N 2 ) and 5 then heated to 90 C for 4 h. The reaction was concentrated and the residue partitioned between 25% isopropyl alcohol-CIC1 3 . The organic phase was dried (Na 2

SO

4 ) concentrated and the residue taken up in ether, sonicated, filtered and dried to provide 499 mg (93%) of the title compound. MS (ESI; M+Hl) m/z = 848. 10 Example 74D (S)-5,5'-(4,4'-(I -(4-cyclohexylphenyl)-l H-pyrrole-2,5-diyl)bis(4,1-phcnylenc))bis(2-((S)-pyrrolidin-2 yl)- I H-imidazole) The product from Example 74C was processed using the method described in Example 19D to provide the title compound. MS (ESI; M+H) tn/z = 648. 15 Example 74E methyl {(2S)-l-[(2S)-2-(5-14-41-(4-cyclohexylphenyl)-5-(4-(2-[(2S)-l-1(2S)-2 [(methoxycarbonyl)aminol-3-imethylbutanoyl}pyrrolidin-2-ylJ-Hl- -imidazol-5-yl iphenyl)- IH-pyrrol 2-yl]phenyl}- IH-imidazol-2-yl)pyrrolidin-l-yl]-3-methyl-1-oxobutan-2-ylIcarbamate 20 To a solution of the product from Example 74D (0.190 g, 0.293 mmol) in DMF (5 mL-) was added (S)-2-(methoxycarbonylamino)-3-imethylbutanoic acid (0.113 g, 0.645 mmol), 1 hydroxybenzotriazole hydrate (0.099 g; 0.645 tmmol) and N-(3-dinethylaminopropyl)-N' ethylcarbodiimide hydrochloride (0.124 g, 0.645 mmol) and the imxture stirred for 3 h. The mixture was poured into water and extracted CH 2

C

2 . The organic layer was concentrated and the residue 25 purified by chromatography (gradient elation from 0% to 4% MeOH-CH 2 Cl 2 ) to provide 100 mg (35%) of the title compound. 'H NMR (400 MHz, DMSO-D6) 6 0.84 (d, J=6.62 Hz, 6 H) 0.87 (d, J=6.72 Hz, 6 H) 1.20 (in, 2 H) 1.35 (in, 4 1H) 1.78 (in, 4 H) 1.92 (in, 6 1) 2.10 (in, 4 H) 3.52 (s, 6 H) 3.76 (tm, 4 H) 4.02 (m, 2 H) 5.03 (i, 2 H) 6.47 (in, 2 H) 6.99 (m, 6 H) 7.18 (in, 3 H) 7.27 (in, 2 H) 7.41 (in, 2 IH) 7.51 (in, 4 11) 11.74 (s, 2 11). 30 N89 189 Example 75 methyl {(2S)-1 -1(2S)-2-(5-(4-[ I -(4-cyclohexylphenyl)-5-(4-(2-1(2S)-l-i(2S)-2 [(nelthoxycarbonyl)aiino]-3,3-diimethylbutanoyl )pyrrolidin-2-yl]-I H -imidazol-5-yl i phenyl)-I H pyrrol-2-yl phenyl )-Il-l-iidazol-2-yl)pyrrolidin-i 1-yl]-3,3-dimethyl-1-oxubutan-2-yl]carbamnate 5 The product from Example 74D and (S)-2-methoxycarbonylaiino-3,3-dimethyl-butyric acid (Org. Process Res. Develop. 2008, 12, 69) was processed using the method described in Example 74E to provide 165 mng (57%) of the title compound. 'H NMR (400 MHz, DMSO-D6) 8 0.86 - 0.96 (m, 18 H) 1.23 (m, 2 H) 1.36 (in, 4 H) 1.78 (in, 4 H) 1.88 - 2.00 (m, 4 H) 2.10 (m, 4 H) 3.54 (s, 6 1-) 3.77 (m, 4 H) 4.21 (m, 2 H) 5.05 (m, 2 H) 6.46 (s, 2 H) 6.96 - 7.03 (m, 6 H) 7.19 (m, 2 H) 7.38 - 7.55 (in, 7 10 1-) 7.70 (d, J=8.35 Hz, I H) 7.97 (d, J=8.46 Hz, I H) 11.76 (s, 2 H). ,o~ Example 76 N-(methoxycarbonyl)-L-valyl-N-(4-{ l -(4-tert-butylphenyl)-5-[4-(2-{(2S)--I [N-(methoxycarbonyl)-L 15 valyllpyrrolidin-2-yl }-I 1-imidazol-5-yl)phenyl]-I lH-pyrrol-2-yl}phenyl)-L-prolinamnide Example 76A 2-(4-bromophenyl)-I -(4-tert-butylphenyl)-5-(4-nitrophenyl)-1H-pyrrole TFA (0.6 ml-, 7.79 mmol) was added to a mixture of the product from Example 39A (1.2335 20 g, 3.41 miol) and 4-tert-butylaniline (0.8 ml., 5.07 minol) in toluene (30 mL) and heated at 110 "C for 17 hours. The cooled reaction mixture was poured into ether/water and stirred until nice solid formed. The mixture was filtered to afford the title compound. 'H NMR (400 MHz, BENZENE-D6) 8 1.02 (s, 9H), 6.48 (d, J = 3.8, IH), 6.52 (d, J = 3.8, 11), 6.63 (d, J = 8.5, 2H), 6.80 (d, J = 8.5, 2H), 6.84 (d, J = 8.9, 211), 6.89 (d, J = 8.5, 2H), 7.10 (d, J = 8.5, 2H), 7.70 (d, J = 8.9, 2H). 25 Example 76B N-(niethoxycarbonyl)-L-valyl-N-(4-{ I -(4-tert-butylphenyl)-5-[4-(2-{(2S)-I -[N-(methoxycarbonyl)-L valyllpyrrolidiii-2-yl }-I H-imidazol-5-yl)phenyl]-I H-pyrrol-2-yl }phenyl)-L-prolinaiide Example 76A was processed using sequentially the methods of Examples 19B, 55F, 39E (reaction temperature = 85 *C), 39F, 55G, and 26J (reaction solvent = dichloronethane) to provide the 30 title compound (0.14 g). 'H NMR (400 MHz, METHANOL-D4) 8 0.94 (dldd, J = 21.1, 19.5, 6.7, 1211), 1.30 (s, 10-l), 2.36 - 1.92 (m, 10Hl), 3.63 (s, 611), 3.76 - 3.67 (im, 11H), 3.89 - 3.78 (m, IH), 4.02 - 3.89 (in, 211), 4.19 (d, J = 7.9, 211), 4.50 (dd, J = 8.1, 5.3, 111), 5. 11 (dd, J = 7.6, 5.5, 11-H). 6.39 (d, J 190 = 3.7, I H), 6.43 (d, J = 3.6, I H), 7.01 (dt, J =28.2, 8.3, 6H), 7.20 (s, I H), 7.40 (ddd, J= 19.1, 11.9, 5.7, 6H). MS (ESI) m/z 913 (M+H)+. F F F 5 Example 77 N-(methoxycarbonyl)-L.,-valyl-N-(4-{5-14-(2-{(2S)-I-N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl} I H-inidazol-5-yl)phenyl]- 1-[4-(pentafluoro-lambda-6--sulfanyl)phenyl]-I H-pyrrol-2-y )phenyl)-L prolinaimide Example 39A and 4-aininophenylsulfurpentafluoridewere processed using sequentially the 10 methods of Examples 76A, 19B, 55F, 39E (reaction temperature = 85 *C), 39F, 55G, and 261 (reaction solvent = DMF) to provide the title compound (0.36 g). H NMR (400 MHz, DMSO-D6) 6 0.86 (ddd, J = 6.9, 15.8, 21.6, 12H), 2.04 - 1.76 (in, 711), 2.24 - 2.04 (m, 3H), 3.53 (d, J = 3.0, 6H), 3.61 (dd, J = 6.7, 16.0, I FI), 3.88 - 3.67 (in, 3H), 4.03 (dd, J = 8.3, 14.1, 2H), 4.40 (dd, J = 5.0, 8.0, 1 H), 5.12 - 4.92 (in, I H), 6.49 (ddd, J = 3.6, 14.2, 18.1, 2H), 7.09 - 6.84 (in, 4H), 7.38 - 7.12 (m, 4H), 15 7.50 - 7.38 (in, 3H), 7.58 (dd, J = 8.3, 16.7, 2H), 7.89 (t, J = 8.7, 2H), 10.01 (d, .1 = 20.9, 1 H), 12.16 11.66 (in, I H). MS (ES[) m/z 983 (M+H)+, 981 (M-H)+. Example 78 20 methyl {(2S)-I-[(2S)-2-(5-(3-[1 -(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(miethoxycarbonyl)aimino]-3-imethyl butanoyl pyrrolidin-2-yl]-l lH-iimidazol-5-yl phenyl)-lI H-pyrrol 2-ylIphenyl )-1l-inidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbaiate 2,4'-Dibromoacetophenone and 3-bromoacetophenone were processed using sequentially the methods of Examples 26E, 26F, 26G, 74C, 19D, and 74E to provide the title compound (232 ing). 'H 191 NMR (400 MHz, DMSO-D6) 6 0.81 - 0.91 (in, 12 H) 1.25 (s, 9 H) 1.93 (im, 4 H) 2.11 (m, 4 Hl) 3.53 (s, 6 H) 3.78 (in, 4 -1) 4.04 (in, 2 H) 5.03 (im, 2 H) 6.49 (im, 2 H) 6.90 - 7.08 (m, 5 H) 7.11 - 7.21 (im, I H) 7.27 -7.55 (in, 9 H) 7.71 (d, J=8.35 Hz, I H) 7.94 - 8.01 (in, 2 H) 11.72 (br s, 2 H). 5 Example 79 methyl {(2S)-I-[(2S)-2-(4-{4-[(2R,3S,4S,5R)--(4-tert-butylphenyl)-3,4-dimethoxy-5-(4-{2-[(2S)-I {(2S)-2-I(methoxycarbonyl)aimino]-3-imethylbutanoyl} pyrrolidin-2-ylJ-I H -iimidazol-4 yl } phcnyl)pyrrolidin-2-yl]phenyl }-I H-iinidazol-2-yl)pyrrolidin-I-yl]-3-imethyl-i-oxohutan-2 10 yl Icarbainate Example 79A 1,2:3,4:5,6-Tri-O-isopropylidene-L-imannitol A solution of L-mannonic acid 7-lactone (9.87 g, 55.4 mmol) in methanol (150 mL) at 0 *C 15 was treated with lithium borohydride (2.1 g, 97 nnol) over 30 min. After addition was complete, the mixture was warmed to RT for 30 min. The mixture was then cautiously treated with a solution of hydrogen chloride in dioxane (4 N, 2 mL). The solution was then concentrated in vacuo, first on the rotary evaporator and then under high vacuum (0.3 nun Hg) while warming with a heal gun to remove the last traces of methanol. The solid obtained was then suspended in acetone (50 mnL) and treated 20 with 2,2-dinethoxypropane (41 mL, 34.6 g, 332 nunol) and a solution of hydrogen chloride in dioxane (4 N, 42 mL, 166 mmnol) followed by stirring at RT for 18 h. The mixture was concentrated in vacuo to ca. 20% of original volume, and the inhomogeneous mixture was added to saturated sodium bicarbonate solution (200 mL) followed by stirring for 48 h. The precipitate was collected by filtration and washed with water and air dried. The white solid was dissolved in ethanol (200 proof, 25 175 niL) and filtered through celite to remove particulate matter. The solution was cooled to -78 *C to effect crystallization. The solid was collected by filtration, and the mother liquors concentrated to ca. half volume, and re-cooled to -78 *C. The second crop of crystals was collected by filtration and washed with ethanol. After drying in a vacuum oven at 50 0 C for 3 h, these procedures afforded the title compound (9.88 g, 59%) as a fluffy white solid. '-1 NMR (400 MHz, CDCl 3 ) 6 4.19 (dt, J = 6.0, 30 3.0 Hz, 2 -1), 4.08 (dd, J = 8.3, 6.4 Hz, 2 H), 3.99 (m, 2 H), 3.95 (in, 2 H), 1.43 (s, 6 11), 1.39 (s, 6 H), 1.36 (s, 6 II). MS (+ESI) m/z (rel abundance) 303 (100, M+1), 320 (43, M+NI14). 192 Example 79B 3,4-0-Isopropylidene-L-inannitol The compound of Example 79A (9.88 g, 32.7 mmol) was suspended in 60% (v/v) acetic acid 5 in water (150 mL) in a I L roundbottom and the flask placed on the rotory evaporator and rotated in the heating bath at 45 *C for 1.5 h. The heating bath was reduced in temperature to 40 *C and a line to the vacuum pump was attached to the rotory evaporator. The mixture was concentrated under ca. I mm Hg pressure to a wet solid. This material was diluted with dichloromethane (100 imL) and stirred at RT for 10 min. The solution was filtered through celite, and the filtrate concentrated in vacuo. The 10 residue was dissolved in toluene and concentrated in vacuo (2 x) to remove residual acetic acid. The white solid was then triturated with ether (60 mL) and collected by filtration. After drying in a vacuum oven for 18 h, these procedures afforded the title compound (2.46 g, 34%) as a white solid. 'H NMR (400 MHz, DMSO-d 6 ) 6 5.07 (d, J = 4.5 Hz, 2 H), 4.45 (t, J = 5.7 Hz, 2 H-), 3.86 (dd, J = 4.9, 1.5 Hz, 2 H), 3.54 (ddd, J = 10.9, 5.5, 3.1 Hz, 2 H), 3.48 (d, J= 4.6 Hz, 2 H), 3.37 (m, 2 H), 1.28 15 (s, 6 H). Example 79C (2R,3S,4S,5R)-l -(4-tert-butylphenyl)-2,5-bis(4-(4-niethoxyhenzyloxy)phenyl)-pyrrolidine-3,4-diol To a solution of Example 79B (1.0g, 4.5 mmol) in CH 3 0H (12.0 mL) and CH 2

CI

2 (6.0 inL) 20 was added iodobenzene diacetate (3.48g, 10.8 mmol) and the solution was stirred at room temperature for 5 h. Solvent was removed in vacuo and to the residue was added 0.1 M 1 2

SO

4 (4 imL) and the solution was stirred at room temperature for 18 h. The pH was adjusted to -6 with solid NaHCO 3 , and 4-tert-butylaniline (1.43 mL, 9.0 tmol) was added followed by 4-(4 methoxybenzyloxy)phenylboronic acid (2.09g, 8.1 mmol) and hexafluoroisopropyl alcohol (8 mL). 25 The solution was heated at 50 *C for 2 h, cooled and solvent removed in vacuo leaving the aqueous layer which contained quite a bit of solid material. The mixture was diluted with H 2 0 and 0.33 M

KYO

4 was added and the mixture was stirred vigorously. The resulting white solid was collected by filtration and dried in a vacuum oven to give title compound (1.49g, 2.26 nunol, 50%).'H NMR (400 MHz, DMSO-d6) S ppm 1.10 (s, 9H) 3.75 (s, 61-) 4.21 (s, 2H) 4.95 (s, 2H) 5.02 (d, J=6.9 Hz, 2H) 30 5.75 (s, 2H) 6.20 (d, J=8.9 Hz, 2H) 6.85-6.97 (m, 101-) 7.05 (d, J=8.6 Hz, 4H) 7.37 (d, J=8.7 Hz, 4H). Example 79D (2R,3S,4S,5 R)-l -(4-tert-butylphenyl)-3,4-di methoxy-2,5-bis-(4-(4 methoxybenzyloxy)phenyl)pyrrolidine 35 To a solution of Example 79C (1.49g, 2.26 mmol) in THF (17 mL) and DMF (5.7 il) at 0 *C was added, in portions, NaH, 60% in mineral oil (0.27g, 6.77 mmnol) and the mixture was stirred at 0 193 *C for 20 min. lodomethane (0.31 mL, 4.97 mmol) was added and the reaction mixture was stirred at room temperature for 18 h, diluted with EtOAc, washed with saturated NI-1 4 C, H 2 0, and brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo to give an oily product. The oil was diluted with minimal ether and the oil began to solidify and the title compound was isolated as a colorless solid 5 (1.55g, 2.25 minol, 100%). 'H NMR (400 MHz, CDCl 3 ) 8 ppm 1.16 (s, 6H) 3.44 (s, 6H) 3.82 (s, 6H) 4.12-4.17 (in, 211) 4.94 (s, 411) 5.22 (dd, J=5.2, 1.63 Hz, 211) 6.29 (d, J=8.9 Hz, 21-) 6.88-7.00 (in, 10H) 7.12 (d, J=8.6 Hz, 4Hf) 7.34 (d, J=8.6 Hz, 4H). MS (ESI) m/z 688 (M+H)*. Example 79E 10 4,4'-((2R,3S,4S,5R)-I -(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)diphenol To a solution of Example 79D (1.55g, 2.25 mmol) in CH 2 Cl 2 (9 iL) was added trifluoroacetic acid (9 mL, 117 mmol) and stirring was continued at room temperature for I h. Solvent was removed and the crude residue was dissolved in 1:1 EtOAc/ saturated NaHCO 3 . The organic layer was separated, washed with brine, dried (Na 2

SO

4 ), filtered and solvent removed in 15 vacuo to give title compound (1.0 g, 2.23 imol, 99%). MS (ES1) n/z 448 (M+H)*. Example 79F 4,4'-((2R,3S,4S,5 R)-1 -(4-tert-butylphenyl)-3,4-di methoxypyrrolidine-2,5-diyl)his(4, I phenylene)bis(1,1,2,2,3,3,4,4,4-nonafluorobutane- I -sulfonate) 20 To a solution of Example 79E (l.Og, 2.23 minol) in DMF (12 mL) was added K 2

CO

3 (0.695 g, 5.0 nmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-l -sulfonyl fluoride (0.86 mL, 4.9 mmol) and the solution was stirred at l00 *C for I I. The cooled solution was diluted with EtOAc, washed with 1120, brine, dried (Na2S0 4 ), filtered and solvent removed in vacuo to give crude product which was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexane to give the title 25 compound (1.63 g, 1.61 minol, 72%). H NMR (400 MHz, CDC 3 ) 8 ppm 1.17 (s, 9H) 3.42 (s, 6H) 4.10 (dd, .J=5.3, 1.90 Hz, 2H) 5.30 (dd, J=5.2, 1.9 Hz, 2H) 6.19 (d, J=8.8 Hz, 2H) 6.99-7.03 (m, 2H) 7.21-7.29 (in, 81H1). MS (ES1) nz 1012 (M+H)*. Example 79G 30 (2R,3S,4S,5R)-1 -(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetramethyl- 1,3,2 dioxaborolan-2-yl)phenyl)pyrrolidine To a pressure tube was combined Example 79F (216 mug, 0.21 mmol), 4,4,4',4',5,5,5',5' octamethy-2,2'-bi(1,3,2-dioxaborolane) (114 mg, 0.45 mnol), dicyclohexyl(2',4',6' triisopropylbipheiyl-2-yl)phosphine (16.3 mg, 0.034 mmol), potassium acetate (126 mg, 1.28 mnmol) 35 and dioxane (2 mL) and the mixture was de-gassed with N 2 gas for 30 min. Tris(clibenzylideneacetone)dipalladium(0) (7.8 mg, 8.54 minnol) was added and de-gassing was 194 continued for 10 min. The tube was sealed and heated at 100 *C for 30 min. The cooled solution was diluted with EtOAc, washed with H 2 O, brine, dried (Na 2

SO

4 ), filtered and the filtrate treated with 3 inercaptopropyl functionalized silica gel for I h, filtered and solvent removed in vacuo to give the title compound (143 ing, 100%). 5 Example 7911 (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-((2R,3S,4S,5R)- I -(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine 2,5-diyl)bis(4,1 -phenylene)bis(l H -imidazole-4,2-diyl))dipyrrolidine- I -carboxylate To a pressure tube was combined Example 79G (140 mg, 0.21 nnol), (S)-tert-butyl-2-(4 10 bronio-l-1-imidazrol-2-yl)pyrrolidine-l-carboxylate (Example 26D) (166 ing, 0.524 mnol), I M Na 2

CO

3 (0.524 mL, 0.524 imol), EtOH (I iL), and toluene (1 mL) and the mixture was de-gassed with N 2 gas for 30 min. 1, l'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (15.3 mng, 0.021 mmol) was added and de-gassing was continued for 10 min. The tube was sealed and heated at 100 *C for 3 h, then stirred at room temperature for 16 h. The solution was 15 diluted with EtOAc, filtered through Celite and the filtrate washed with brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo. Purified by fash chromatography on silica gel eluting with 0-100% EtOAc/hexane to give title compound (119 mg, 0.135 mmol, 64%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.13 (s, 9H) 1.49 (s, 18H) 1.88-2.02 (in, 2H) 2.06-2.22 (in, 4H) 2.99 (s, 2H) 3.33-3.48 (in, 4H) 3.43 (s, 6H) 4.23 (s, 2H) 4.96 (d, J=5.3 Hz, 2H) 5.29 (d, J=6.9 Hz, 21-1) 6.29 (d, J=8.9 H-z, 2H) 6.94 (d, 20 J=8.4 Hz, 2H) 7.13-7.29 (tn, 8H). MS (ESI) mi/z 886 (M+H)*. Example 791 methyl {(2S)-I -((2S)-2-(4-(4-[(2R,3S,4S,5R)-I-(4-tert-butylphenyl)-3,4-dimnethoxy-5-(4-{2-[(2S)-i ((2S)-2-[(methoxycarbonyl)amninol-3-methylbutanoyl } pyrrolidin-2-yll-l H -imidazol-4 25 yl phenyl)pyrrolidin-2-yll phenyl }-1 H-imidazol-2-yl)pyrrolidin-1 -yll-3-mnethyl-1-oxobutan-2 yl ]carbamate To a solution of Example 79H (30 tmg, 0.034 minol) in CH 2 Cl 2 ( mL) was added trifluoroacetic acid (1 nL) and the solution was stirred at room temperature for I h. Solvent was removed in vacuo and then dissolved in DMSO (0.5 mL). N,N-diisopropylethylamine was added 30 until pH 9-10, then (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14.8 mg, 0.085 mmol) was added followed by HATU (32 ing, 0.085 nunol) and the solution was stirred at room temperature for I h. The solution was diluted with EtOAc, washed with H 2 0, brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo. Dissolved the residue in CH3OH (2 mL), added solid K 2 C0 3 and stirred at room temperature for 30 min. Solid was filtered off and the filtrate was concentrated in vacuo and the 35 residue purified by flash chromatography on silica gel eluting with 0-5% CH 3 0H/CH 2

CI

2 to give title compound (21.6 mug, 0.022 nunol, 63%). 'H NMR (400 MHz, CDCl 3 ) 8 ppm 0.85 (s, 121-1) 1.13 (s, 195 9H) 1.82-2.03 (m, 2H) 2.02-2.24 (m, 4H) 2.32 (br s, 21H) 3.04 (br s, 2H) 3.43 (s, 6H) 3.53-3.65 (in, 2H) 3.70 (s, 6H) 3.75-3.90 (m, 2H) 4.22 (s, 2H) 4.31 (d, J=15.7 Hz, 2H) 5.16-5.33 (mn, 4H) 5.37 (d, J=9.1 Hz, 2H) 6.29 (d, J=8.9 Hz, 2H) 6.94 (s, 211) 7.16 (s, 2H) 7.22 (d, J=8.0 Hz, 4H) 7.3 1-7.52 (mn, 211) 7.60-7.87 (i, 2H) 10.26 (s, IH) 10.64 (s, 1H). MS (ESI) m/z 1000 (M+H)*. 5 N" Example 80 methyl 1(2S)-1 -1(2S)-2-15-(4-{ I -[4-(di methylainno)phenyl]-5-(4-{2-l(2S)-1-{(2S)-2 [(imethoxycarbonyl)amino]-3-methylbutanoyllpyrrolidin-2-yl]-1 H -iimidazol-5-yl }phenyl)-I H-pyrrol 10 2-yl iphenyl)-I1H-iiidazol-2-yl]pyrrolidin-l-yI}-3-imetiyl-I-oxobutan-2-yl]carbaimate Example 26E and N,N-dimethyl-p-phenylenediainine were processed using sequentially the methods of Examples 76A, 39E, 39F, 55G (25% isopropylalcohol/chloroforin used for extraction), and 26J (reaction solvent = dichloromethane) to provide the title compound (5.6 ng). I1H NMR (400 M 1z, DMSO-d6) 6 0.94 - 0.75 (i, 12H), 2.04 - 1.78 (m, 6H), 2.21 - 2.03 (in, 4H), 2.89 (s, 6H), 3.38 15 (s, 1 H), 3.53 (s, 6H), 3.84 - 3.68 (m, 3H), 4.10 - 3.96 (i, 2H), 5.04 (dd, J = 2.9, 6.7, 21-), 6.53 - 6.37 (in, 2H), 6.70 - 6.54 (m, 2H), 7.12 - 6.85 (in, 6H), 7.33 - 7.12 (in, 21H1), 7.46 - 7.34 (in, 211), 7.60 - 7.46 (i, 4H), 12.11 - 11.64 (m, 2H). MS (ESI) rm/ 923 (M+H)+. OH 20 Example 81 dimethyl ([(2S,5S)-l -(4-fluorophenyl)pyrrolidine-2,5-diyllbis{ benzene-4, I -diylcarbamoyl[(2S,4S)-4 hydroxypyrrolidine-2, 1-diyl][(2S)-3,3-diiethyl-1 -oxobutane-1,2-diyl]})biscarbainate and dimethyl ([(2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{ benzene-4,I-diylcarbaioyl[(2S,4S)-4 25 hydroxypyrrolidine-2,1-diyl][(2S)-3,3-dimethyl-I-oxobutane-1,2-diyl]})biscarbaiate Example 81 A (2S,4S)-I -(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 196 To a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (3.9 g, 29.7 mmol) in THF (26.7 mul..) and water (13.3 mL) was added di-tert-butyl bicarbonate (7.14 g, 32.7 mmol) and sodium hydroxide (2.0 N, 22.9 mnL, 45.8 nuiol) and the mixture stirred at room temperature overnight. The mixture then had 10% citric acid (50 nL) added followed by EtOAc and extraction with water and 5 brine. The organic extract was dried, filtered and concentrated to afford 5.31 g (77%) of the title compound. MS (ESI) m/z 232 (M+l 1)+. Example 81 B (2S,4S)-I-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid 10 To a solution of Example 81A (5.31, 22.96 nunol) and imidazole (7.82 g, 115 nuol) in dichloronethane (106 nL) and DMF (21.3 tmL) was added tert-butyllimethylsilyl chloride (7.61 g, 50.5 mmol) and the mixture stirred at room temperature overnight. The mixture then had water (425 tmL) added and the solution was extracted with EtOAc and the organic extract concentrated to a residue that was dissolved in 25% EtOAc and 75% hexanes then extracted with brine and the organic 15 extract concentrated to a solid. The resultant solid was dissolved in methanol (65 nL) and water (85 iL..) then lithium hydroxide monohydrate (1.93 g, 46 tnmol) added and the solution stirred at room temperature for 2 h. Afterwards water (106 mL) and a solution of IN aqueous hydrochloric acid was added until a pH of 2 was reached. The mixture was then extracted with a mixture of 25% EtOAc and 75% hexanes, the organic extract dried, filtered and concentrated to a colorless solid. MS (ESI) m/z 20 346 (M+HI)+. Example 81C (3S,3'S,5S,5'S)-tert-butyl 5,5'-(4,4'-((2S,5S)-] -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))his(azanediyl)his(oxomethylene)his(3-(tert-butydimetliylsilyloxy)pyrrolidine-l 25 carboxylate) and (3S,3'S,5S,5'S)-iert-butyl 5,5'-(4,4'-((2R,5R)- I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azanediyl)bis(oxonethylene)bis(3-(tert-butyldimethylsi lyloxy)pyrrolidine- I carboxylate) 30 The product of Example 81B (149 mg, 0.432 mmol) and the product from Example 5A (50 mug, 0.144 mol) were processed using the method described in Example I F to afford 74 tmg (51%) of the title compound as a 1:1 mixture of diastereomers. MS (ESI) m/z 1002 (M+H)+. Example 81D 35 (2S,2'S,4S,4'S)-N,N'-(4,4'-((2S,5S)- 1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))bis(4 hydroxypyrrolidine-2-carboxamnide) 197 and (2S,2'S,4S,4'S)-N,N'-(4,4'-((2R,5R)- I -(4-tluorophenyl)pyrrolidine-2,5-diyl)bis(4, 1 -phenylene))bis(4 hydroxypyrrolicline-2-carboxamide) The product of Example 81C (74 ing, 0.074 rmnol) was dissolved in trifluoroacetic acid (4 5 inL), water (0.2 nL) and dichloromeihane (0.2 mL) and the mixture stirred at room temperature for 3 hours. Afterwards the mixture was concentrated to an oil which was dissolved in 75% CHC 3 and 25% isopropyl alcohol then extracted with a saturated aqueous sodium bicarbonate solution, the organic extract separated, dried, filtered and concentrated to a colorless solid. MS (ESI) m/z 574 (M+H)+. 10 Example 81 E dimnethyl ([(2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,I-diylcarbanoyl[(2S,4S)-4 hydroxypyrrolidine-2,1 -diyl][(2S)-3,3-dimnethyl-1-oxobutane-1,2-diyl]))biscarbamate and 15 dimnethyl (1(2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyLlbis (benzene-4,1-diylcarbamoyl[(2S,4S)-4 hydroxypyrrolidine-2,1-diyl][(2S)-3,3-di methyl-I-oxobutane-1,2-diyl]))biscarbamate To the product from Example 811) (40 mng, 0.072 mmnol), (S)-2-(methoxycarbonylamio)-3,3 dimethylbutanoic acid (34.1 mg, 0.18 mmol) and HATU (60.2 mg, 0.158 imnol) in DMSO (3 mL) was added Hunig's base (0.063 mL, 0.36 mol), and the reaction mixture was stirred at room 20 temperature for I hr. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% MeOH in dichloromethane to give the title compound as a 1:1 mixture of stereoisomers (21 mg, 32% yield): 'H NMR (400 MHz, DMSO-D6) 6 ppm 9.94 (s, 2 H), 7.44 (d, J=8.4 Hz, 4 H), 7.07 (in, 6 H) 6.74 (t, 25 J=8.9 Hz, 2 H), 6.15 (dd, 1=9.1, 4.4 H z, 2 H), 5.26 (dd, 1=6.1, 3.3 Hz, 2 H), 5.11 (d, 1=5.5 Hz, 2 H), 4.33 (1, J=7.8 H-z, 2H), 4.19 (in, 2 H), 4.07 (in, 2 H), 3.93 (in, 2 H), 3.48 (s, 6 H), 2.34 (in, 2 H4), 1.66 (n, 2 H), 1.59 (in, 2 H), 1.20 (in, 2 H), 0.91 (in, 18 H). F 30 Example 82 dimethyl ([(2S,5S)-1 -(3-luorophenyl)pyrrolidine-2,5-diyl Ibis 1 benzene-4, I diylcarhamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimncthyl-l -oxobutane-1,2-diyl]])biscarbamat and 198 dimethyl ([(2R,5R)- I-(3-fluorophenyl)pyrrolidine-2,5-diylJbis benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-di methyl-l -oxobutane-I,2-diyl]})biscarbamate Example IC and 3-fluoroaniline were processed using sequentially the methods of Examples ID, 1E, IF, 1G, and IH to provide the title compounds. The trans diastereomers were separated from 5 the cis diastereomer at the stage of 4,4'-(1-(3-fluorophenyl)pyrrolidine-2,5-diy)dianiline. Data for the title compounds. 'H NMR (free base) (400 MHz, DMSO-d 6 ) 6 ppm 0.96 (d, 1=2.17 Hz, 18 H-), 1.75 1.92 (m, 7 H), 1.93 - 2.05 (in, 2 H), 2.10 - 2.21 (m, 2 H), 2.31 - 2.44 (tn, 2 H), 3.43 - 3.51 (m, 4 H), 3.53 (s, 6 H-1), 3.59 - 3.73 (m, 6 H), 3.73 - 3.82 (i, 2 H), 4.21 (d, 1=8.89 Hz, 2 H), 4.46 (dd, J=7.92, 5.31 Hz, 2 H), 4.70 (t, J=4.66 Hz, 2 H), 6.07 (d, 1=12.90 H z, I H), 6.19 (dd, J=8.35, 1.63 Hz, I H), 10 6.37 (dt, J=8.35, 2.06 Iz, I H), 6.97 - 7.05 (in, 2 H), 7.08 (d, J=8.67 H z, 2 H), 7.41 (d, J=7.26 Hz, 4 H), 7.60 (d, 1=8.57 Hz, 4 H), 10.07 (s, 2 11). MS (ESI) nIz 885 (M+H)* Example 83 15 diiethyl ([(2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyllbis{benzene-3,l diylcarbaioyl(2S)pyrrolidine-2, I-diyl((2S)-3,3-dimnethyl- I-oxobulane-1,2-diyl]})biscarbamate and dimethyl (I(2R,5R)- 1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis (benzene-3, I diylcarbamoyl(2S)pyrrolidine-2, I -diyl[(2S)-3,3 -dimethyl -I -oxobutane- 1,2-diyl] })biscarbamate 20 Example 83A (2S,2S)-tert-butyl 2,2'-(3,3'-((2S,5S)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1 phetiylenc))his(azaticdiyl)bis(oxoinethyleic)dipyrrolidinc- I -carboxylate and 25 (2S,2'S)-tert-butyl 2,2'-(3,3'-((2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3, I phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I -carboxylate The ether fraction from the work up of Example 55F was purified using flash chromatography (silica gel, 0-30%EtOAc/dichloromethane) to afford the title compound as a mixture of trans diastereoiers. MS (ES 1) m/z 742 (M+H)+. 30 199 Example 83B dimethyl ([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diylJbis henzene-3,l diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-di methyl-l -oxobutane-1,2-diyl]})biscarbaimate and 5 dimethyl ([(2R,5R)-I-(4-uorophenyl)pyrrolidine-2,5-diyl]bis(benzene-3,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-di methyl-I -oxobutane-1,2-diyl] })biscarbaiate The product from Example 83A was processed using the methods described in Examples 55G and 55H to afford the title compound (0.18 g, 27%). 1 H NMR (400 MHz, DMSO-D6) 8 0.97 (d, J = 4.5, 181-1), 1.73 - 1.60 (n, 2H), 1.92 - 1.75 (m, 5H), 2.05 - 1.92 (m, 3H), 2.23 - 2.05 (m, 2H), 3.54 (d, J 10 = 1.5, 6H), 3.71 - 3.59 (in, 2H), 3.85 - 3.71 (in, 2H), 4.21 (d, J = 8.9, 211), 4.50 - 4.37 (in, 2H), 5.14 (d, J = 5.7, 21-), 6.30 - 6.19 (im, 2H), 6.85 - 6.75 (in, 2H), 6.88 (d, J = 7.7, 2H), 7.09 (d, J = 8.7, 2H), 7.23 (t, J = 7.9, 2H), 7.40 - 7.30 (in, 2H), 7.58 (d, J = 8.1, 2H), 10.07 - 9.96 (in, 2H). MS (ESf) m/z 884 (M+H)+, 882 (M-H)+. o 15 Example 84 diiethyl ([(2S,5S)- I-(4-methylphenyl)pyrrolidine-2,5-diyllbis { benzene-4, I diylcarbamoyl(2S)pyrrolidine-2, I -diyl[(2S)-3-imethyl-1-oxobutane-1,2-diylI )biscarbamate and 20 diicthyl (((2R,5R)-I-(4-iethylphenyl)pyrrolidine-2,5-diyl]bisbcnzene-4,1 diylcarbaioyl(2S)pyrrolidine-2, I -diyl[(2S)-3-niethyl- I -oxobutane- 1,2-diyl] )biscarbaiate The title compound was prepared using the procedures described for the synthesis of Examples 34A, 34B, 34C, 34D, and 34E, substituting 4-inethylaniline for 4-tert-butylaniline. 11-1 NMR (500 MHz, DMSO-D6) 8 ppm 0.85 - 0.90 (in, 6 H), 0.90 - 0.95 (in, 6 H), 1.61 - 1.65 (n, 2 H), 25 1.82 - 2.01 (in, 8 H), 2.03 (s, 3 H), 2.09 -2.16 (m, 2 H), 3.52 (s, 6 H), 3.58 - 3.66 (m, 2 H), 3.77 - 3.84 (in, 2 H), 4.02 (t, 2 H), 4.40 - 4.45 (in, 2 H), 5.14 (d, J=6.6 Hz, 2 H), 6.13 - 6.18 (im, 2 H), 6.72 (d, 1=8.4 Hz, 2 H), 7.08 - 7.14 (in, 4 11), 7.29 - 7.34 (in, 2 H), 7.46 - 7.51 (in, 4 H), 9.98 (s, 2 H); MS mn/z 852.3 (M+H)*. 30 200 Example 85 dimethyl ([(2S,5S)-I-(4-chlorophenyl)pyrrolidine-2,5-diylJbis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-imehyl-1-oxobutane-1,2-diyl]))biscarbamate and 5 dimethyl ( (2R,5 R)- I -(4-chlorophenyl)pyrrolidine-2,5-diyl ibis{ benzene-4, I diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl]))biscarbamate Example 85A 1-(4-chlorophenyl)-2,5-his(4-nitrophenyl)pyrrolidine 10 The product of Example IB (0.50 g, 1.51 mnol) was suspended in CH 2 Cl 2 (15 mL). Triethylamine (0.626 mL,, 4.51 mmol) was added at 0 'C, the resulting mixture was stirred for 30 miin, and methanesulfonyl chloride (0.293 mL, 3.76 mmol) was added. The mixture was stirred at rt for I hr and then concentrated in vacuo to give a light yellow solid. The solid was dissolved in DMF (6 mL), 4-chloroaniline (1.92 g, 15.05 innol) was added, and the resulting mixture was stirred at 50 *C 15 overnight. The mixture was partitioned between EtOAc and IN aq IICI, and the organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give the title compound (0.226 g, 35%). 20 Example 85B 4,4'-(trans- I-(4-chlorophenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product of example 85A (0.214 g, 0.505 mmol) in EtOll (2.52 mL) and TIIF (2.52 mL) was added platinum(IV) oxide (0.115 g, 0.505 mmol), and the resulting mixture was stirred at rt under I atm H 2 overnight. The mixture was filtered through celite, and the filtrate was 25 concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EIOAc in hexane to give a-mixture of the title compound and some dechlorinated product (4,4'-(trans- I -phenylpyrrolidine-2,5-diyl)dianiline). Example 85C 30 diniethyl ([(2S,5S)-I-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis Ibenzene-4,1 diylcarbamoyl(2S)pyrrolidine-2, 1-diyl[(2S)-3-niethyl-I-oxobutane-1,2-diyll})biscarbamate and dimethyl ([(2R,5R)-I-(4-chloroplienyl)pyrrolidine-2,5-diylibis { benzeie-4,l diylcarbamoyl(2S)pyrrolidiie-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl] I)biscarbamate 35 A mixture of the product from Example 85B was subjected to the procedures described in Examples 34C, 341), and 34E to give the title compounds free of dechlorinated product. 11- NMR 201 (TFA salt) (400 M H z, DMSO-D6) 6 ppm 0.84 - 0.89 (i, 6 H), 0.89 - 0.94 (in, 6 H), 1.61 - 1.66 (in, 2 -I), 1.80 - 2.03 (in, 8 H), 2.06 - 2.18 (m, 2 H), 3.51 (s, 6 H), 3.56 - 3.65 (n, 2 H ), 3.74 - 3.84 (mn, 2 H), 4.01 (1, J=8.4 Hz, 2 H), 4.36 - 4.44 (in, 2 H), 5.16 (d, 1=6.3 Hz, 2 1H1), 6.21 (d, J=8.9 Hz, 2 H), 6.93 (d, 1=9.0 -lz, 2 H), 7.08 - 7.13 (in, 4 H), 7.26 - 7.31 (m, 2 H), 7.46 - 7.51 (m, 4 H), 9.99 (s, 2 H). MS 5 m/z 872.3 (M+H)*. B, Example 86 dimethyl ([(2S,5S)-I-(4-bromophenyl)pyrrolidine-2,5-diylJbis{ benzene-4,I 10 diylcarbainoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl- I -oxobutane- 1,2-diyl] })biscarbamate and diiethyl ([(2R,5R)-I-(4-broimophenyl)pyrrolidiiie-2,5-diyl]bis{ benzene-4, I diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl]})biscarbainate 15 Example 86A 1-(4-broimophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example IC (0.7 g, 1.433 mmol) and 4-bromoaniline (2.54 g, 14.33 nmmol) were suspended in DMF (6mL) and stirred at 50 *C overnight. The resulting mixture was partiiioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with IN -ICI 20 (2x5OmL) followed by a brine wash then dried over MgSO 4 filtered and concentrated. The crude product was purified by chromatography on silica gel.using a solvent gradient of 2-50% ethyl acetate in hexane to give the title compound as a mixture of stereoisomers (74.4mg, I I% yield). Example 86B 25 (2S,2'S)-N,N'-(4,4'-(I-(4-broiophenyl)pyrrolidine-2,5-diyl)bis(4,I-phenylene))dipyrrolidine-2 carboxanide Example 86A was processed using the methods of Examples I E, IF, and I G to provide the title compound as a mixture of stereoisomers. 30 Example 86C dimeihyl ([I-(4-broimophenyl)pyrrolidinc-2,5-diyllbis (bcnzcne-4,1-diylcarbaimoyl(2S)pyrrolidine 2,1-diyll(2S)-3-mehyl-1-oxobulane-1,2-diyl]})biscarbamnale The product from Example 86B (78.0mng, 0.129nunole) was combined with EDAC (67.0mng, 0.347 mmnol), I -hydroxybenzotriazole hydrate ( 49.0mng, 0.323imole) and (S)-2 202 (methoxycarhonyl amino)-3-methylbutanoic acid (61.0ng, 0.346mnmole) in diinethylformnamide (I.4ml.) at room temperature under a nitrogen atmosphere. To this solution was added diisopropylethylamine (0.113 mL, 0.645 iniol). The mixture was allowed to stir overnight at room temperature followed by partition between ethyl acetate (20nl) and water (5mL). The organic phase 5 was washed with water (3x5iL) then dried over MgSO 4 , filtered and evaporated to dryness. The crude product was chrotnatographed by reverse phase (Cis) HIPLC providing the title compound as a 1:1 mixture of (trans) diastereotmers (0.045g, 38% yield) as an off white solid. IH NMR (free base) (400 MHz, DMSO-D6) 6 ppm 0.72 - 1.03 (tn, 12 H) 1.65 (s, 2 H) 1.79 - 2.19 (in, I1 H) 3.52 (s, 6 -1) 3.58 - 3.67 (in, 2 H) 3.75 - 3.86 (tn, 2 H) 3.95 - 4.09 (n, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.08 10 5.25 (n, 2 H) 6.19 (d, 1=8.89 Hz, 2 H) 7.06 (d, 1=8.89 Hz, 2 H) 7.12 (d, 1=7.16 Hz, 4 H) 7.31 (dd, J=8.29, 3.96 Hz, 2 1-) 7.51 (dd, J=8.46, 1.52 Hz, 4 Fl) 10.00 (s, 2 H). MS ESI(+) nz@916.6 (M+I 1)+. 15 Example 87 methyl {(2S)-I-[(2S)-2-{5-[(2S,5S)-I-(4-fluorophenyl)-5-(2-[(2S)-1-{(2S)-2 [(mnethoxycarbonyl)amino]-3,3-ditmethylbutanoyl }pyrrolidin-2-yl]- IH-henzimidazol-5-yl }pyrrolidin 2-yll- IH-benzimidazol-2-yl }pyrrolidin-I-yll-3,3-dimethyl-1-oxobutan-2-yl carbaiate and 20 methyl {(2S)-I-[(2S)-2-i5-[(2R,5R)-I-(4-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2 |(mnethoxycarbonyl)amitto]-3,3-dimnethylbutanoyl pyrrolidin-2-yl]- IH-benzimnidazol-5-ylIpyrrolidin 2 -yl]- IH-benzimidazol-2-yl pyrroliditn-1-yl]-3,3-diimethyl-1-oxobutan-2-yl carbatmale The product from Example 29G (0.045 g, 0.084 mnol), (S)-2-methoxycarbonylaiino-3,3 dimethyl-butyric acid (0.037 g, 0.193 nnol), 4-iethylnorpholine (0.037 niL, 0.336 mmol), 1H 25 benzo[d][l,2,3]triazol-l-ol hydrate (0.028 g, 0.185 inmol) and Nl-((ethylimino)mnethylene)-N3,N3 diimethylpropane-1,3-diamine hydrochloride (0.035 g, 0.185 tnmol) were combined in 2 mL DMF and stirred for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed 3 X 20 niL with brine, dried (Na 2

SO

4 ), filtered and concentrated. The crude material was flash chromatographed on a 4 g Isco Gold silica cartridge eluting with 1.5-8% McOH in tmethylene 30 chloride. A second reverse phase C-18 preparative chromatography eluting with 9:1 water/acetonitrile --> 100% acetonitrile afforded the title compounds (29 tmg, 28%; mix of trans diastereomers) as a light tan powder. '1 NMR (TFA salt) (400 MIHz, DMSO-d 6 ) 6 0.84 - 0.95 (m, 18 1-) 1.21 - 1.46 (tn, 4 203 H) 1.75 - 2.27 (m, 8 H) 3.56 (s, 6 H) 3.86 (t, J=5.26 Hz, 4 H) 4.22 (dd, J=8.57, 4.45 H z, 2 -1) 5.15 5.24 (in, 2 1-) 5.53 (d, J=4.88 Hz, 2 1-1) 6.30 (dd, J=9.1 1, 4.34 Hz, 2 H) 6.75 - 6.83 (n, 2 H) 7.29 (d, J=8.57 Hz, 2 H) 7.35 (d, J=8.46 Hz, 2 H) 7.48 (d, J=7.92 Hz, 2 H) 7.69 (d, J=7.37 Hz, 2 H). MS (ESL+) m/z 879 (M+H)*. 5 Example 88 dimethyl ([(2S,5S)-I-(4-methoxyphenyl)pyrrolidine-2,5-diyllbis{ benzene-4, I diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbaimate 10 and dimethyl (1(2R,5R)-I-(4-inethoxyphenyl)pyrrolidine-2,5-diyllbis{benzene-4,1 diylcarbanoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diylJ)biscarbamate The title compound was prepared using the procedures described for the synthesis of Examples 34A, 3413, 34C, 34), and 34E, substituting 4-icthoxyaniline for 4-tert-butylaniline. IH 15 NMR (TFA salt) (400 M Hz, DMSO-D6) 6 ppm 0.85 - 0.90 (im, 6 H), 0.90 - 0.95 (in, 6 H), 1.60 - 1.66 (in, 2 11), 1.81 - 2.04 (in, 8 11), 2.08 - 2.19 (m, 2 1-), 3.52 (s, 9 11), 3.57 - 3.66 (in, 2 H-), 3.77 - 3.85 (m, 2 1-1), 4.02 (t, 2 H), 4.39 - 4.46 (m, 2 H), 5.12 (d, .1=6.3 Hz, 2 H-), 6.18 (d, ./=9.0 H z, 2 H), 6.56 (d, ./=9.0 Hz, 2 H), 7.09 - 7.15 (in, 4 H), 7.28 - 7.34 (m, 2 H), 7.46 - 7.52 (in, 4 H), 9.97 (s, 2 H); MS n/z 868.5 (M+H)*. 20 N /0 Example 89 methyl {(2S)-I-[(2S)-2-(4-{4-l(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-l(methoxycarhonyl)amino]-3 icihylbutanoyl) pyrrolidin-2-yl] -I H-imidazol-4-yl I phenyl)- I -phenylpyrrolidin-2-yl]phenyl) - H 25 imidazol-2-yl)pyrrolidin- I-yll-3-methyl-1-oxobutan-2-yl}carbaina(e and methyl {(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-5-(4-{2-[(2S)-I -{(2S)-2-[(methoxycarbonyl)aiino]-3 methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-4-yl}phenyl)-I-phenylpyrrolidin-2-yl]phenyl}-IH imidazol-2-yl)pyrrolidin-l -yll-3-methyl-I-oxobutan-2-yl carbamate 30 204 The trans diastereomers obtained in Example 59B (8.5 mng, 0.0107 inmol), (S)-2 (methoxycarbonylamino)-3-mcthylbutanoic acid (4.67 mng, 0.027 mmol) and HATU (8.9 mg, 0.023 nunol) in DMSO (I mL) was added -unig's base (0.015 mL, 0.085 nunol), and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between water and 5 ethyl acetate, and the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 5.0 mg (53%) of the title compound as a mixture of trans diastereomers. Il- NMR (TFA salt) (400 M H z, DMSO-D6) 6 ppm 14.45 (bs, 2 H), 7.97 (s, 2 -1), 7.66 (in, 4 H), 7.38 (in, 4H). 7.31 (d, 1=7.4 Hz, 2 H), 6.92 (t, J=7.6 Hz, 2 H), 6.43 (in, I H), 6.28 (d, 1=8.1 10 Hz, 2 H), 5.37 (in, 2H), 5.09 (t, 1=6.7 Hz, 2 H), 4.09 (1, 1=7.7 Hz, 2 H), 3.81 (in, 6 H), 3.53 (s, 6 H), 2.40 (in, 2 H), 2.08 (m, 2 1-), 2.02 (in, 6 H), 1.85 (in, 2 H), 0.85 (in, 2 H), 0.80 (in, 12 H); MS (ESI) m/z 884 (M+Hl)+. N O.

15 Example 90 dimethyl ([(2S,5S)-1-(biphenyl-4-yl)pyrrolidine-2,5-diyllbis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2, I -diyl[(2S)-3-methyl- I-oxobutane-1,2-diyll I)biscarbamate and dimethyl ([(2R,5R)-I-(hiphenyl-4-yl)pyrrolidine-2,5-diyl Jbis ( henzene-4,1 20 diylcarhamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxohutanc-I,2-diyl]})hiscarhamate The product from Example 86C (24.9mg, 0.027nunole) dissolved in a THF (ItmL) and water (0.3tL) solution was combined in a microwave tube with phenylboronic acid (6.90mg, 0.0541nmole), tribasic potassium phosphate (13.37mg, 0.063mmole) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.42mng, 2.17pnole). The tube was sealed and nitrogen bubbled through at 25 room temperature for five minutes. All gas lines were subsequently removed and the reaction vessel inmmersed in a 50 *C oil bath and heated for two and one half hours. The contents of the tube were partitioned between ethylacetate (5mL.) and brine (ImL). The organic phase was washed with brine (2 x imJL) then dried over MgSO 4 , filtered and concentrated. The crude product was purified by silica gel chromatography cluting with 5% EtOAc - hexane and progressing to (75% EtOAc-hexane ) + 3% 30 methanol to provide as a 1:1 mixture of (trans) diastereomers the title compound (18.6mg, 75% yield) as a cream colored solid. 1-1 NMR (400 MHz, DMSO-D6) 6 ppm 0.76 - 0.99 (m, 12 H) 1.67 (s, 2 H) 1.77 - 2.19 (in, 11 11) 3.52 (s, 6 1-1) 3.58 - 3.65 (m, 2 H-) 3.74 - 3.86 (in, 2 H-) 3.96 - 4.08 (i, 2 H) 4.44 (d, J=4.99 Hz, 2 H) 5.25 (s, 2 H) 6.35 (d, 1=8.02 Hz, 2 H) 7.17 (d, 1=7.26 Hz, 5 H) 7.24 - 7.34 (m, 6 205 H) 7.45 (d, J=7.92 Hz, 2 H) 7.52 (d, J=7.81 Hz, 4 H) 10.00 (s, 2 H). MS ESI(+) m/z@ 915.1 (M+H)+, m/z@ 972.3 (M+CH 3 CN+NH4)+. F F N N NN 5 Example 91 incthyl ((2S)-I-[(2S)-2-(5-((2S,5S)-5-(2-[(2S)-1-((2S)-2-[(mcthoxycarbonyl)anino)-3 mcthylbutanoyl pyrrolidin-2-yl]- IH-benzi midazol-5-yl}-1-[4-(trifluoromcthyl)phcnyl]pyrrolidin-2 yl l-I H-beniirndazol-2-yl)pyrrolidin-1-yl]-3-mihyl-1-oxobutaii-2-ylcarbamate and 10 methyl {(2S)-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(inethoxycarbonyl)amino]-3 methylbutanoyl pyrrolidin-2-yl]- IH-benzi midazol-5-yl}-I-[4-(trifluoromethyl)phenyl]pyrrolidin-2 yl l-IH-benziiidazol-2-yl)pyrrolidin- I-yl]-3-methyl- I-oxobutan-2-yl carbamate Example 91 A 15 (2S,2'S)-2,2'(6,6'-( I -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(I H-benzo[d]imidazole 6,2-diyl))dipyrrolidinium chloride Example 28C and 4-trifluoromethylaniline were processed using the methods of Examples 28D-28J to provide the title compound as a mixture of cis and trans stereoisoiners. 20 Example 91B methyl ((2S)-I-I(2S)-2-(5-((2S,5S)-5-(2-1(2S)-lI -(2S)-2-I(methoxycarbonyl)aminol-3 methylbutanoyl }pyrrolidin-2-yl]- IH-henzimidazol-5-yl 1-1 -[4-(Irifluoromcthyl)phcnyl]pyrrolidin-2 ylI- IH-bcnzimidazol-2-yl)pyrrolidin-1-yl]-3-meihyl-1-oxobutan-2-yl}carbaiate and 25 methyl {(2S)-I-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoylIpyrrolidin-2-yl]-IH-benzimidazol-5-yl)-I-[4-(trifluoromethyl)phenyl]pyrrolidin-2 yl}-I H-benzimidazol-2-yl)pyrrolidin-I-yll-3-methyl-I-oxobutan-2-yl carbamate The product from Example 91A (1: 1 mixture of cis and trans isomers), 0.018 g, 0.027 mnmnole), HORt (0.013 g, 0.082 mmolc), EDAC (0.016 g, 0.082 minnIole) and (S)-2 30 (methoxycarbonylamino)-3-methylbutanoic acid (0.014 g, 0.082 minole) were combined in a 20 mi round bottom flask and dissolved in 1 ml DMF at room temperature, added 4-methylmorpholine 206 (0.015 ml, 0.137 mmole) and the resulting clear slightly brown solution was stirred at room temperature for 2 hr. The reaction mixture was analyzed by LC-MS and determined to be complete. The reaction mixture was diluted with 50 ml EtOAc, washed with 10% Nal-C0 3 and 10% NaCl, dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving the title compound as a light 5 brown solid. The material was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100A AXIA column (30mm x 75mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10 95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A). The product fractions were collected and evaporated to dryness in vacuo leaving the title compound as a tan solid, (I I tg, 44%) 10 and a mixture of diastercomcric trans isomers. IH NMR (TFA salt) (400 MHz, DMSO-D6) d ppn 0.67 - 0.94 (in, 12 H) 1.95 (in, 18 H) 3.79 - 3.89 (in, 6 H) 4.10 (s, 2 H) 5.19 (s, I H) 5.64 (s, 2 H) 6.45 (s, 2 H1) 7.28 (s, 4 H-) 7.47 (s, 4 H) 7.69 (s, 4 11), 12.1 (b, 2l)ESI+(m/z):900.6, ESI-(m/z):898.8.

.

'OYH 00 15 Example 92 dimethyl ([(2S,5S)-I-(4-hydroxyphenyl)pyrrolidine-2,5-diyl]bis benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl] ))biscarbamate and dimethyl (I(2R,5R)-1-(4-hydroxyphenyl)pyrrolidine-2,5-diyllbis{ benzene-4,1 20 diylcarbamoyl(2S)pyrrolidine-2,l-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl] )biscarbamate To a solution of the product from Example 88 (0.050 g, 0.058 mmol) in CH 2 Cl 2 (I ml-) at -78 * was added a 1.0 M solution of borontribromide in CH 2 Cl 2 (0.29 mL, 0.29 mmol). The resulting dark red color solution was stirred at -78 *C for 4 h, and then warmed to rt and washed with water. The organic layer was dried over sodium sulphate, filtered, and concentrated in vacuo. The crude 25 product was purified by column chromatography on silica gel using a solved gradient of 0-7.5% MeOH in CH2C1 2 to give the title compound (5.5 tmg, 12%) as a mixture of trans diasiereomners. 11-1 NMR (400 MHz, DMSO-D6) 8 ppm 0.86 - 0.90 (i, 6 H), 0.90 - 0.95 (m, 6 H), 1.58 - 1.63 (m, 2 H), 1.82 - 2.04 (in, 8 H-1), 2.08 - 2.19 (in, 2 H), 3.52 (s, 6 H), 3.58 - 3.66 (mn, 2 H), 3.77 - 3.84 (i, 2 H), 4.02 (t, .1=8.5 Hz, 2 H-1), 4.40 - 4.46 (in, 2 1-1), 5.08 (d, .1=6.3 Hz, 2 1), 6.08 (d, .1=8.8 Hz, 2 H), 6.38 (d, 30 .1=8.8 Hz, 2 H), 7.08 - 7.13 (in, 4 H), 7.29 - 7.34 (m, 2 H), 7.45 - 7.51 (m, 4 H), 8.27 (d, .1=1.2 Hz, 1 H), 9.96 (s, 2 H); MS n/z 854.4 (M+H)*. 207 A H Example 93 dimethyl ({ (2S,5S)- I -[4-(propan-2-yl)phenylJpyrrolidine-2,5-diyl }his{ benzene-4, I diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-imethyl-1-oxobutane-1,2-diyl]})biscarbamate 5 and dimethyl ({ (2R,5R)- I -[4-(propan-2-yl)phenyl]pyrrolidine-2,5-diyl }bis{ benzene-4, 1 diylcarbamoyl(2S)pyrrolidine-2, l-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate The title compound was prepared as a mixture of trans diastereomers using the procedures described for the synthesis of Examples 34A, 34B, 34C, 341), and 34E, substituting 4-isopropylaniline 10 for 4-eri-hutylaniline. I H NMR (TFA salt) (400 MI-Iz, DMSO-D6) 8 ppm 0.85 - 0.90 (m, J=5.8, 5.8 H z, 6 H), 0.90 - 0.96 (m, 6 H), 1.02 - 1.06 (in, 6 H), 1.60 - 1.65 (m, 2 H), 1.81 - 2.04 (in, 8 H), 2.08 - 2.19 (m, 2 H), 2.56 - 2.65 (i, I H), , 3.52 (s, 6 H), 3.58 - 3.66 (m, 2 H), 3.76 - 3.85 (m, 2 1-1), 4.02 (I, J=8.3 Hz, 2 11), 4.40 - 4.45 (in, 2 1-), 5.14 (d, 1=6.5 Iz, 2 1-), 6.15 - 6.20 (i, 2 11), 6.79 (d, J=8.7 Liz, 2 11), 7.09 - 7.16 (i, 4 11), 7.29 - 7.34 (in, 2 H), 7.47 - 7.52 (m, 4 H-), 9.97 (s, 2 11); MS m/z 880.5 15 (M+H)*. F N N Example 94 methyl ((2S)-1-[(2S)-2-(4-14-I(2S,5S)-I-(4-fluorophenyl)-5-(4-{2-(2S)-1-{(2S)-2 20 [(imethoxycarbonyl)atninoJ-3,3-dimethylbutanoyl pyrrolidin-2-yl]-1H-imidazol-4 yl }plienyl)pyrrolidin-2-yl]phenyl}-IH-iiidazol-2-yl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobulan-2 yl carbamate and methyl {(2S)- I-[(2S)-2-(4- 4-[(2R,5R)-I-(4-fluorophenyl)-5-(4-(2-[(2S)-1-{(2S)-2 25 [(mnethoxycarbonyl)ainino]-3,3-di methylbutanoyl pyrrolidin-2-yl]-IH-imtnidazol-4 yl phenyl)pyrrolidin-2-yl]phenyl}-1H-inidazol-2-yl)pyrrolidin-1-yll-3,3-dimnethyl-1-oxobutan-2 yl Icarbamate The product from Example 45D (28 mg, 0.048 mmnol) was subjected to the conditions described in example 45E, substituting (S)-2-(methoxycarbonylanino)-3,3-diinethylbutanoic acid for 208 (S)-2-(imethoxycarhonylaniino)-3-methylbutanoic acid, to give the title compound (18 mg, 41%) as a mixture of diasterconers. I H NMR (TFA salt) (400 MHz, DMSO-D6) 6 ppm 0.86 (s, 9 H), 0.87 (s, 9 H), 1.70 - 1.81 (in, 2 H-1), 1.94 - 2.25 (m, 6 H), 2.34 - 2.44 (in, 2 H), 3.55 (s, 6 11), 3.72 - 3.95 (in, 4 H), 4.19 (d, J=8.7 Hz, 2 H), 5.09 (t, J=7.2 Hz, 2 H), 5.35 (d, 1=6.1 H z, 2 H), 6.26 (dd, 1=9.1, 4.4 Hz, 2 5 -1), 6.81 (t, J=8.9 Hz, 2 H), 7.29 (d, J=8.0 Hz, 2 H), 7.37 (d, 1=7.2 Hz, 4 H), 7.68 (dd, 1=7.8, 5.4 Hz, 4 H-), 7.97 (s, 2 H1), 14.46 (br s, 2 H-); MS in/z 930.8 (M+H-)*. HN NH NANN N H0 Example 95 10 methyl {(2S)-I-[(2S)-2-(4-{4-[(2S,5S)-I-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(mnethoxycarbonyl)amino)-3-methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-4-yl }phenyl)pyrrolidin 2-yllphenyl}-IH -imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl carbamate and methyl {(2S)- I-[(2S)-2-(4-{4-[(2R,5R)- I-(4-cyclopropylphcnyl)-5-(4-{2-[(2S)-I-{(2S)-2 15 [(methoxycarbonyl)aminol-3-methylbutanoyl}pyrrolidin-2-yll-1H-imidazol-4-ylipheiyl)pyrrolidin 2-yl]phenyl) - H-i midazol-2-yl)pyrrolidin- I -yl]-3-methyl- I -oxobutan-2-yl carbamatee Example 95A (S)-4,4'-(4,4'-((2R,5R)- I -(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,1 -phenylene))bis(2-((S) 20 pyrrolidin-2-yl)-I H-imidazole) and (S)-4,4-(4,4'-((2S,5S)- I -(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,1 -phenylenc))bis(2-((S) pyrrolidin-2-yl)- I H-iinidazole) 'he product from Example 68C (1.27 g, 1.568 mmol) was dissolved in dichloromethane (12 25 mL). The mixture was cooled to 0 oC and trifluroacetic acid (8 mL, 104 mmol) was added slowly. The mixture was warmed to room temperature and stirred for lh. The solvent was evaporated and the residue was purified by chromatography on silica gel cluting with methanol/dichloromethane (1% to 10%). The title compound was eluted as the first of' 2 stereoisomers and was obtained as a mixture of trans diastercomers (510 mg, 53%). 30 Example 95B 209 methyl {(2S)-i -t(2S)-2-(4-{4-[(2S,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-I -{(2S)-2 [(me thoxycarbonyl)amino j-3-methylbutanoyl)pyrrolidin-2-yl J-I H-iinidazol-4-yl }phenyl)pyrrolidin 2-yllphenyl }- IH-iiidazol-2-yl)pyrrolidin-1-yl]-3-imethyl-I -oxobuian-2-yi Icarbaniate and 5 methyl {(2S)- I -[(2S)-2-(4-(4-[(2R,5R)-I-(4-cyclopropylphenyl)-5-(4-(2-[(2S)-1-((2S)-2 [(imethoxycarbonyl)ainino]-3-iethylbutanoyl pyrrolidin-2-yI-I H-iimidazol-4-yl}phenyl)pyrrolidin 2-ylIphenyl I - H-inidazol-2-yl)pyrrolidin- I -ylI-3-methyl- 1 -oxobutan-2-yl Icarbamate The product from Example 95A (150 ing, 0.246 mnmol), (S)-2-(netlioxycarbonylanino)-3 methylbutanoic acid (86 ing, 0.492 mmol), 4-methylmorpholine (0.216 mL, 1.968 imol), N1 10 ((ethyli i no)mnthylcnc)-N3,N3-di mneihylpropane- 1,3-diaminc hydrochloride (104 ing, 0.541 inmiol) and IH-benzo[d][l,2,3]triazol-I-ol hydrate (83 ing, 0.541 innol) were combined in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by 15 chromatography on silica gel eluting with methanol/dichloromethane (1% to 4%) to give the title compound (78 mug, 34%) as a solid. I H NM R (400 MHz, DMSO-D6) 6 ppm 0.35 - 0.41 (in, 2 H) 0.65 - 0.72 (in, 2 H) 0.81 - 0.92 (in, 12 H) 1.58 - 1.64 (m, I H) 1.66 - 1.72 (in, 2 H) 1.86 - 2.03 (mn, 6 H-1) 2.07 - 2.17 (in, 4 H) 2.24 - 2.30 (in, 2 H-1) 3.53 (s, 6 H) 3.74 - 3.82 (in, 4 H) 4.04 (t, J=7.86 Hz, 2 H) 5.06 (dd, J=6.72, 2.93 Iz, 2 H) 5.14 - 5.26 (in, 2 H-) 6.19 (d, J=8.67 Iz. 2 H-) 6.64 (d, J=8.24 i z, 2 H1) 20 7.10 - 7.30 (in, 6 H) 7.34 - 7.69 (i, 6 H) 11.64 - 12.11 (m, 2 H-1); MS (ESI+) nz 924.8 (M+1)+. ~H HN 0 NoH Example 96 diiethyl ([(2R,5R)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1 25 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl]})biscarbamate Example 38A and 4-cyclopropylaniline were processed using sequentially the methods of Examples 34A, 34B, 34C, 66D, and 66E to provide the title compound (62 ig). 'II NMR (400 MHz, DMSO-d,) S 0.36 - 0.46 (i, 2 H) 0.63 - 0.77 (in, 2 H-) 0.87 (d, .1=6.61 Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.52 - 2.46 (i, 15 H) 3.52 (s, 6 H) 3.57 - 3.66 (in, 2 1-1) 3.75 - 3.85 (in, 2 1-1) 4.02 (t, J=8.46 Hz, 2 30 H) 4.42 (dd, 1=8.02, 4.88 Hz, 2 -I) 5.14 (d, .1=6.40 Hz, 2 H) 6.14 (d, J=8.78 Hz, 2 H) 6.65 (d, J=8.67 210 Hz, 2 H) 7.10 (d, J=8.57 Hz, 4 H) 7.30 (d, J=8.35 Hz, 2 H) 7.48 (d, J=8.57 Hz, 4 H) 9.97 (s, 2 H). MS (APCI) nilz 878 (M+H)*. HO H NH 5 Example 97 methyl {(2S)- 1-1(2S,4S)-2-{5-t(2S,5S)-1 -(4-fluorophenyl)-5-{2-[(2S,4S)-4-hydroxy- 1 {(2S)-2 [(methoxycarbonyl)aminol-3-nethylbutanoyl pyrrolidin-2-ylJ-IH-henzimidazol-5-yllpyrrolidin-2 yI]-l H-henzimidazol-2-yl }-4-hydroxypyrrolidin- I -yl] -3-methyl- I -oxohutan-2-yl Icarbamate and 10 methyl {(2S)- I-[(2S,4S)-2-(5-[(2R,5R)- I-(4-fluorophenyl)-5-{2-[(2S,4S)-4-hydroxy-l -{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]- IH-benzinidazol-5-yl pyrrolidin-2 yl]-l-H-benzimidazol-2-yl}-4-hydroxypyrrolidin-I-yl]-3-methyl-1-oxobutan-2-yl)carbamate COH 0r Example 97A 15 (2S,4S)-I-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 minol) and imidazole (7.82 g, 115 mnmol) were combined in dichlorormethane (106 nL) and dimethylformamidce (22 mL) at ambient temperature and treated with portionwise addition of tert butylchlorodimethylsilanc (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted 20 with water and extracted into ethyl acetate and concentrated to provide the title compound. Example 97B The product from Example 29D (0.906 g, 2.62 mmol) was processed as in Examples 29E, 29F, 29G, and 2911, substituting Example 97A for S-Boc-proline in step 29E to give the title 25 compounds (0.012 g, 13%).1 H NMR (400 MHz, DMSO-D6) 8 ppm 0.69 - 0.85 (in, 12 H) 1.27 - 1.39 (in, I H) 1.53 (dt, J=21.31, 6.64 Hz, I H) 1.71 (s, 4 H) 1.80 - 1.90 (i, 2 H) 2.02 (d, J=7.70 Hz, 2 H) 2.54 - 2.62 (i, 2 H) 3.53 (s, 6 H) 3.68 (t, J=10.63 Hz, 2 H) 3.93 - 4.00 (i, 2 H) 4.39 (s, 2 H) 5.13 (s, 2 H) 5.38 (s, 2 H) 6.19 - 6.38 (in, 4 H) 6.74 (d, J=2.60 Hz, 2 H) 7.08 (s, 2 1) 7.21 - 7.36 (i, 4 1-1) 7.40 - 7.51 (in, 2 H) 12.21 - 12.38 (m, 2 1-1); MSTFA+ mi/z 882.5 (M+-1)+. 211 H H Example 98 dimethyl ({ (2R,5R)-1- [4-(morpholin-4-yl)phenyllpyrrolidine-2,5-diyl Ibis { benzene-4, 1 5 diylcarbamoyl(2S)pyrrolidine-2, I-diyl [(2S)-3,3-dimethyl-l -oxobutane- I,2-diyl] })biscarbamate Example 98A 4-(4-((2R,5R)-2,5-bis(4-nitrophenyl)pyrrolidin- I-yl)phenyl)mnorpholine The product from Example 38A and 4-morpholinoaniline were processed using the method 10 descrihcd in Example IID using NMP~ for the solVent to afford thc title compound. MS (ESI) mn/z 475 (M +H)+. Example 98B 4,4'-((2R,5R)--(4-morpholinophenyl)pyrrolidine-2,5-diyl)dianiline 15 The product from Example 98A in tctrahydrofuran (20 muL) was added to Ra-Ni (water wet, A-7000, 0.8 g, 12.63 mnol) in a 50 nt pressure bottle and stirred for 2 hours at ambient temperature under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated to afford the title compound (0.31 g, 44%). MS (DCI) m/ 415 (M+H)+. 20 Example 98C (2S,2'S)-tert-buyl 2,2'-(4,4'-((2R,5R)- -(4-morpholinophenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(azancdiyl)bis(oxomethylene)dipyrrolidine- I -carboxylate The product from Example 9813 was processed using sequentially the methods of Examples 55F, 55G, and 26J (with (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid) to afford the title 25 compound (0.13 g). 'H NMR (400 MHz, DMSO-D6) 0.93 (d, J = 20.5, 17H), 1.92 - 1.79 (m, 4H), 2.05 - 1.93 (mn, 3H), 2.21 - 2.08 (in, 2 H), 2.43 (t, .1= 6.1, 31H), 2.84 - 2.75 (mn, 41H), 3.54 (s, 6H), 3.68 3.58 (in, 6 H), 3.83 - 3.70 (mn, 21HI), 4.20 (d, I = 8.9, 2 H), 4.43 (dd, J = 7.9, 5.3, 2H ), 5.1I2 (d, I = 6.3, 2H-I), 6.17 (di, J = 9.1, 21-I), 6.60 (di, J = 9.1, 2H-), 7.07 (dI, I = 8.8, 21-), 7.1 I , I = 8.5, 4H), 7.48 (d, J = 8.5, 4H), 9.98 (s, 2H). Impunity 'H NMR (400 MIHI, DMSO-D6) 1.63 (d, = 5.6, 2H), 3.17 (d, 30 = 5.3, 311), 4.09 (q, J = 5.3, I -). MS (ESI) m/z 952 (M+HI+). 212 N N O H Q N NH OQy N , O Example 99 dimethyl ([(2S,5S)-l-{ 4-[6-(dimethylainino)pyridin-3-yl]phenyl } pyrrolidine-2,5-diyllbis{ benzene 4,1-diylcarbaioyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-l-oxobut ane-1,2-diyl]})biscarhamnate 5 and dimethyl ([(2R,5R)-I-{4-[6-(diinethylamino)pyridin-3-ylJphenyl pyrrolidine-2,5-diylJbis{ benzene 4,1 -diylcarhamoyl(2S)pyrrolidinc-2,1-diyl[(2S)-3-methyl-1-oxobutanc-I,2-diyl] })hiscarhamate Example 99A 10 5-(4-(2,5-bis(4-nitrophenyl)pyrrolidin- I -yl)phenyl)-N,N-dimethylpyridin-2-amine The product from Example 86A (25.7ig, 0.055miole) was combined in a microwave tube with 6-(di methylamino)pyridine-3-ylboronic acid (17.49mg, 0.105imole), tribasic potassium phosphate (24.70mg, 0.1 l6mole) and 1,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.504mg, 3.84pmole). The tube was scaled and a solvent mixture of THF (2mL) and water (0.6mL) 15 added via syringe. The reaction mixture was sparged with nitrogen at room temperature for three minutes during which time the solution turned black in color. Chromatographic analysis indicated that the reaction was complete. The contents of the microwave tube were partitioned between brine (3mL) and ethyl acetate (3mL). The water was drawn off and the organic phase dried over MgSO 4 , filtered and concentrated. The crude product was purified by chromatography on silica gel from 2 up to 20% 20 ethyl acetate in hexane to provide the title compound (26.8mg, 96% yield) as an orange solid as a mixture of stereoisomers. MS ESI(+) m/z @ 510.4 (M+H)+. Example 99B 4,4'-(I-(4-(6-(di methylainino)pyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline The product from Example 99A (26.8mg, 0.053mmnole) was dissolved in THF (526pL) in a 25 round bottom flask to which was subsequently added ethanol (526pL) resulting in a yellow precipitate. To this suspension was added platinum (IV) oxide (3.16mg, 0.014nmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture allowed to stir at room temperature for two and one half hours. The reaction mixture was vacuum filtered through a sand and celite plug, which was rinsed with THF and methanol 213 until the filtrate was u.v.(-). The filtrate was concentrated in vacuo to provide the title compound in quantitative yield as a white solid as a mixture of stereoisomers. MS ESl(+), m/z @ 450.7 (M+1-)+. Example 99C 5 (2S,2'S)-tert-butyl 2,2'-(4,4'-(I-(4-(6-(dimnethylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5 diyl)bis(4, I-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- I-carboxylate The product from Example 99B (23.83mg, 0.053mmole) was reacted with (S)-l-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (27.8mg, 0.129mmole) as described in Example IF with minor modification. The crude product was recovered by partition of the reaction mixture 10 between ethyl acetaie(I0mL) and water(3nL). The organic phase was washed with water (3x3mL), dried over MgSO 4 , Filtered and concentrated. Chromatography on silica gel using a solvent gradient of 2-100% ethyl acetate in hexane provided the title compound (32.6ng, 73% yield) as a cream colored solid as a n-ixture of stereoisomers. 15 Example 99D (2S,2'S)-N,N'-(4,4'-(I-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))dipyrrolidine-2-carboxamide The product from Example 99C (32.6mg, 0.039mnole) was reacted with trifluoroacetic acid (0.071mL, 0.927mmnole) as described in Example IG to provide the title compound (22.5mg, 90% 20 yield) as a cream colored solid as a mixture of stereoisomers. Example 99E dimethyl ([(2S,5S)-I-(4-[6-(dinethylamino)pyridin-3-yllphenyl)pyrrolidine-2,5-diyll bis{ benzene 4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxohutane-1,2-diyl]j)biscarhamnate 25 and dimethyl ([(2R,5R)-l -{4-[6-(diimethylamino)pyridin-3-yl]phenyl pyrrolidine-2,5-diyl]bis{ benzene 4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-I,2-diyl]})biscarbamate The product from Example 99D (22.5mg, 0.035mmole) was reacted with (S)-2 (methoxycarbonylaimino)-3-mnethylbutanoic acid (19.41mg, 0.11mmole) as described in Example 30 86C. Chromatography on silica gel (10% ethyl acetate / 90% hexane to 100% ethyl acetate / 4% methanol) provided the title compound (14.5mg, 43.3% yield), an orange yellow solid that darkened somewhat on standing, as a 1:1 mixture of trans diastereomers. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.77 - 0.99 (in, 12 H) 1.67 (s, 2 H) 1.76 - 2.24 (in, I I H) 2.98 (s, 6 H) 3.52 (s, 6 H) 3.58 - 3.65 (n, 2 H1) 3.76 - 3.90 (m, 1=9.54 Iz, 2 11) 3.95 - 4.11 (m, 2 11) 4.36 - 4.47 (m, 2 11) 5.19 - 5.27 (m, 2 35 11) 6.30 (s, 2 H1) 6.58 (d, J=9.00 H Iz, 1 H) 7.17 (t, J=8.08 l z, 4 -I) 7.30 (d, 1=8.02 Iz, 3 H1) 7.52 (d, 214 J=7.37 Hz, 4 H) 7.57 - 7.63 (i, I H) 7.63 - 7.68 (m, I H) 7.91 (s, I H ) 8.18 - 8.22 (m, I H) 10.00 (s, 2 H). MS ESl(+) n/z @ 959.4 (M+H)+. 0 H H O N ON 5 Example 100 diiethyl ({(2R,5R)-I-14-(iethylsulfonyl)phenyllpyrrolidine-2,5-diyl )bis{ benzene-4, I diylcarhanoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimnethyl-l -oxobutane-1,2-diylJ })biscarbamate Example 38A and 4-(mnethylsulfonyl)aniline were processed using sequentially the methods of Examples 98A, 98B, 55F, 55G, and 26J (with (S)-2-(methoxycarbonylarmino)-3,3 10 dimethylbutanoic acid; reaction solvent = dichloroimethane) to provide the title compound (55 mg). 'H NMR (400 MIlz, DMSO-D6) 80.96 (d, J = 5.1, 1811), 1.24 (s, 111), 1.69 (d, J = 5.7, 211), 2.04 - 1.74 (i, 71), 2.22 - 2.07 (m, 211), 2.98 (s, 311), 3.54 (s, 611), 3.70 - 3.58 (in, 211), 3.83 - 3.70 (m, 211), 4.20 (d, . = 8.9, 2H), 4.43 (dd, J = 7.8, 5.4, 2H), 5.32 (d, . = 6.1, 21), 6.39 (d, J = 9.0, 2H), 7.08 (d, . = 8.8, 21), 7.15 (d, J = 8.6. 4H), 7.43 (d, J = 9.0, 2H), 7.53 (d, J = 8.6, 4H), 10.03 (s, 2H). MS (ESI) m/z 15 966 (M+Na)+, 943 (M-H)+. Q0 H N. Example 101 dimiethyl ([(2S,5S)-1-{4-[6-(imorpholin-4-yl)pyridin-3-yl]phenyl )pyrrolidine-2,5-diyl]bis{ benzene 20 4,1-diylcarbanioyl(2S)pyrrolidine-2,1-diyl[(2S)-3-nethyl-1-oxobutane-1,2-diyll})biscarbamate and dimethyl ([(2R,5R)-l -{4-[6-(norpholin-4-yl)pyridin-3-ylJphenyl }pyrrolidine-2,5-diyllbislbenzene 4,1-diylcarhanoyl(2S)pyrrolidinc-2,1 -diyl[(2S)-3-nethyl-1-oxobutane- l,2-diyl] })biscarbamnate Example 86A and 4-(5-(4,4,5,5-tctraicthyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)imorpholine 25 were processed using sequentially the methods of Examples 99A, 99B, IF, IG, and 86C to provide the title compound as a 1:1 mixture of trans diastereotners. 11-1 NMR (free base) (400 MI-Iz, DMSO D6) 8 ppn 0.78 - 1.00 (n, 12 H1) 1.67 (s, 2 H-) 1.75 - 2.20 (n, 111) 3.36 - 3.41 (i, 4 H-) 3.52 (s, 6 H-) 215 3.57 - 3.65 (in, 2 H) 3.65 - 3.72 (in, 4 1-1) 3.79 (s, 2 H) 4.02 (s, 2 H) 4.36 - 4.48 (i, 2 H) 5.24 (s, 2 H) 6.32 (d, J=7.70 Hz, 2 H) 6.78 (d, 1=9.00 H z, I H ) 7.12 - 7.18 (in, 4 H) 7.21 (d, 1=8.78 Hz, 2 H) 7.31 (d, 1=8.35 Hz, 2 H) 7.52 (d, 1=7.48 Hz, 4 H) 7.63 - 7.69 (in, 1 H) 8.22 - 8.27 (in, I H) 10.00 (s, 2 H). MS ESI(+) m/z @1000.6 (M+H)+. 5 N NH 0oH NH Example 102 dimethyl ({(2S,5S)-I-[4-(pyridin-3-yl)phenyljpyrrolidine-2,5-diyl }bis (be nzcne-4,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-i-oxobulane-1,2-diyl]})biscarbamate 10 and dimethyl ({(2R,5R)-1 -[4-(pyridin-3-yl)phenyllpyrrolidine-2,5-diyl Ibis{ benzene-4,I diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-mnethyl-l-oxobutane-I,2-diyl]})biscarbamate Example 86A and pyridin-3-ylboronic acid were processed using sequentially the methods of Examples 99A, 99R, IF, IG, and 86C to provide the title compound as a 1:1 mixture of trans I5 diastereomers ( 35.8mg). IH NMR (free base) (400 MHz, DMSO-D6) 6 ppm 0.71 - 1.05 (m, I I H) 1.68 (s, 2 H) 1.87 (s, 8 H-1) 2.06 - 2.21 (in, 2 H) 3.52 (s, 6 H) 3.56 - 3.67 (in, 2 1-1) 3.80 (s, 2 H) 4.02 (d, J=1.73 Hz, 2 H) 4.43 (dd, 1=7.97, 4.93 Hz, 2 H) 5.26 (d, 1=6.29 Hz, 2 H) 6.37 (d, J=7.92 HIz, 2 H) 7.17 (dd, 1=8.57, 1.95 i z, 4 11) 7.28 - 7.36 (n, 5 1-) 7.52 (d, 1=7.8 l Iz, 4 11) 7.82 - 7.87 (in, 1 11) 8.36 (dd, 1=4.72, 1.36 Iz, 1 11) 8.69 (s, 1 11) 10.00 (s, 2 1). MS ESI(+) m/z @ 915.6 (M+1)+ 20 N N Example 103 methyl [(2S,3S)-I-{(2S)-2-[5-(4-((2S,5S)-I-(4-tert-butylphcnyl)-5-[4-(2-((2S)-I-[N (methoxycarbonyl)-O- methyl-D-threonyl]pyrrolidin-2-yi }- IH-i midazol-5-yl)phenyl]pyrrolidin-2 25 yl}phenyl)-IH-imidazol-2-yllpyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yllcarbamate and 216 methyl [(2S,3S)-- -{(2S)-2-[5-(4-{(2R,5R)- I-(4-tert-hutylphenyl)-5-[4-(2-{(2S)-I-[N (methoxycarbonyl)-O-methyl-)-threonyl]pyrrolidin-2-yI }-l H-i midazol-5-yl)phenyl pyrrolidin-2 y Iphenyl)-1 H-imiidazol-2-yl]pyrrolidin-1-yl)-3-methoxy-1-oxobut an-2-yl]carbamtate The product from Example 201A (0.122 g, 0.639 umol), and IIOBI ( 0.098 g, 0.639 mmole) 5 were combined and dissolved in 2 ml DMF then cooled in an ice bath between 0-5 0 C. To this solution was added EDAC (0.123g, 0.639 mmol) followed by 4-methylmorpholine (0.211 ml, 1.917 mmole) and the mixture was stirred 5 minutes, then added dropwise the mixture of the products from Example 42F (0.2 g, 0.320 mmol), in DMF (2 ml) with a DMF wash (I ml). The pH of the solution was adjusted with additional 4-methylmnorpholine (0.1 ml, 0.96 mole) and the mixture was stirred a 10 total of 90 minutes in the ice bath. The reaction mixture was analyzed by LC-MS at 90 min and determined the reaction to be complete. The reaction mixture was diluted with 100 ml EtOAc and washed with 25 ml water. The layers were separated and the aqueous layer was extracted with another 100 ml EtOAc. The combined organic extracts were washed with 10% Nal-C0 3 and 10% NaCI, dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving a purple oil. 15 The oil was dissolved in 10 ml CH 2

CI

2 and applied to a 12 g silica gel column. The column was eluted with a gradient of CH 2

CI

2 /MeOH, 99/1 to 95/5 over 25 minutes. The title compounds were isolated as a light yellow solid, 60 mg, 19%.AH NMR (400 MHz, DMSO-D6) d ppm 0.86 (in, 2 H) 1.00 - 1.18 (in, 15 1) 1.27 (i, 2 H) 1.70 (in, s I-) 1.99 (m, 2H) 2.15 (in, 4 H) 3.18 (d, J=10.08 Hz, 6 H) 3.54 (s, 6 H) 3.81 (in, 4 H) 4.27 (m, 2 H) 5.06 (m, 2 H1) 5.21 (d, 2 H) 6.21 (d, 2 H) 6.94 (d, 2 11) 20 7.17 (d, 2 H) 7.29 (d, 2 1) 7.38 (d, J=1.73 Hz, 2 11) 7.51 (d, 2 H) 7.62 (d, J=8.02 Hz, 2 H) 1l1.68 (s, 2 H), 12.01 (i, 2H);ESI+:972.6 MN N Example 105 25 methyl {(2S)-1-t(2S)-2-(3-{4-[(2S,5S)-I-(4-tert-butylphenyl)-5-(4-{5-t(2S)-l-((2S)-2 [(mnethoxycarbonyl)amino]-3-mnethylbutanoyllpyrrolidin-2-yl]-IH-pyrazol-3-yllphenyl)pyrrolidin-2 yl]phcnyl)-1H-pyrazol-5-yl)pyrrolidin-1-yl]-3-miethyl- -oxobuian-2-yl}carbamate and methyl {(2S)-I-[(2S)-2-(3-{4-[(2R,5R)-I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-2 30 [(methoxycarbonyl)aniino]-3- methylbutanoyl)pyrrolidin-2-yl]-IH-pyrazol-3-ylIphenyl)pyrrolidin-2 yl]phenyl)-IH-pyrazol-5-yl)pyrrolidin-1-yI]-3-mnethyl-1-oxobutan-2-yl carbaniate 2l7 Example 105A 1-(4-tert-butylphenyl)-2,5-bis(4-((trimethylsilyl)ethynyl)phenyl)pyrrolidine To an oven-dried microwave tube (Size M, 5 mL) purged with nitrogen, added the product of 5 Example 42C (340 mg, 0.662 mmol), bis(triphenylphosphine)palladium(II) dichloride (18.60 mg, 0.026 mmol), THF (2 mL), and triethylamine (2 mL). Stirred at room temperature for 5 min, then added copper(l) iodide (2.52 mg, 0.013 mmol), stirred the yellow mixture for 2 min, then nitrogen bubbled through for 15 min. Added trimethylsilylacetylene (0.374 ml-, 2.65 mmol), sealed the tube with an aluminum crimp cap, and heated in an oil bath at 70 *C for 20 hr. Cooled the reaction to 10 room temperature, added fresh bis(triphenylphosphine)palladium(II) dichloride (18.60 ing, 0.026 nnol) and copper(l) iodide (2.52 mg, 0.013 nunol), added additional trimnethylsilylacetylene (0.374 mL, 2.65 mmol), and continued heating at 80 *C for 24 hr. Cooled the reaction to room temperature, diluted with Et 2 O (50 nL), washed with 1120 (2 x 25 mL) and brine (25 mL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a light tan foam (470 mg). 15 Purified by flash chromatography (silica gel, 2.5 cm x 10 cm, 2% Et 2 0/hexanes) to afford the title product as a yellow foam (324 mug, 89%) as a mixture of stereoisomers. MS (ESl+) ni/. 548 (M+H)'. Example 105B 1-(4-tert-hutylphenyl)-2,5-bis(4-ethynylphenyl)pyrrolidine 20 Dissolved the product of Example 105A (322 mg, 0.588 mmol) in anhydrous TIIF (5 mL) under nitrogen, added IM TBAF in TIF (1.322 mL, 1.322 minol), and stirred at 25 *C for 30 min. The reaction darkened immediately upon addition and remained a brown color throughout the reaction. Removed solvent by rotary evaporation, dissolved the residue in Et 2 0 (50 mL), washed with

H

2 0 (2 x 25 ml.,) and brine (25 ml..), dried the organic phase over anhydrous MgSO 4 , filtered, and 25 concentrated by rotary evaporation to a light tan foam (289 ing). Purified by flash chromatography (silica gel, 3.8 cm x 14 cm, 20% CH 2 Cl 2 /hexanes) to the title compound as a light yellow foam (176 ing, 74%) as a mixture of stereoisomners. MS (ESI+) mu/z 404 (M+H)*. Example 105C 30 (S)-3,3'-(4,4'-(1-(4-tert-butylpheiyl)pyrrolidine-2,5-diyl)bis(1-(4,1-phenylene))bis(1-(N-Boc-(S) pyrrolidin-2-yl)prop-2-yn-I-one In a flame-dried 10-il.. round bottom flask, dissolved the product of Example 105B (94.3 mug, 0.234 nunol) in anhydrous TIF (2 muL) under nitrogen and cooled to -78 'C, added 1.6 M n-BuLi in hexanes (0.365 mL, 0.584 munol) slowly in a dropwise manner via gas-tight syringe, and stirred the 35 greenish-yellow solution for I hr at -78 'C. In a separate flame-dried 10-niL round bottom flask purged with nitrogen, was prepared a solution of N-(tert-butoxycarbonyl)-L-proline N'-methoxy-N' 218 mnethylamide (166 mg, 0.631 mmol) in anhydrous THF (1 ml-), and cooled to -78 "C. Added the dianion mixture dropwise via a gas-tight syringe fitted with a 16G needle to the Weinreb amide solution and stirred at -78 0 C for 30 min, replaced the dry ice-acetone bath with an ice-waler bath, and stirred at 0 *C for I hr. Removed the cooling bath and stirred at room temperature for I hr, the cloudy 5 yellow mixture became a dark yellow solution. Quenched the reaction with sat'd aq NH 4 Cl (10 nL), extracted with Et 2 O (2 x 25 mL), washed the combined ethereal extracts with 1120 (2 x 25 mL) and brine (25 mL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a yellow oil (214 tng). Purified by flash chromatography (silica gel, Alltech Extract Clean log column, gradient of 5% to 7% EtOAc/CH 2

CI

2 ) to afford the title compound as a yellow 10 solid (77 mg, 41%) as a mixture of stereoisomers. MS (ESI+) n/iz 798 (M+H)*, 1595 (2M+H)*. Example 105D (2S,2'S)-tert-butyl 2,2'-(3,3'-(4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, I phenylene))bis(1H-pyrazole-5,3-diyl))dipyrrolidine-l -carboxylate 15 Dissolved the product of Example 105C (75 mg, 0.094 mmnol) in anhydrous absolute EtOH (1 ml..) under nitrogen, added hydrazine hydrate (0.023 ml., 0.235 mmol), and stirred the yellow solution at room temperature for I hr. Removed the solvent by rotary evaporation, azeotroped the yellow oil with toluene (2 x 5 mL), redissolved in 1:5 v/v CH 2 Cl 2 /hexanes, concentrated, and dried the light yellow solid in vacuo. Purified by flash chromatography (silica gel, 2.5 cm x 15 cm, 4% 20 MeOHI/C1 2 Cl 2 ) to afford the title compound as a white solid (59 tng, 76%) as a mixture of stereoisomers. MS (ESI+) m/z 826 (M+H)+, 848 (M+Na)*. Example 105E (S)-3,3'-(4,4'-(1-(4-iert-hutylphenyl)pyrrolidine-2,5-diyl)his(4,1-phenylene))bis(5-((S)-pyrrolidin-2 25 yl)- I H-pyrazole Dissolved the product of Example 105D (57.5 mog, 0.070 nunol) in anhydrous CH 2

C

2 (2 niL) under nitrogen, added TFA (I mL, 12.98 miol), and stirred at 25 'C for 30 min. Removed the solvent by rotary evaporation, took up the residue in 1:5 v/v CI1 2 Cl 2 /hexanes, concentrated to a yellow residue, and dried in vacuo (83 mg). The TFA salt was dissolved in anhydrous MeOll (7 mL) under 30 nitrogen, treated with pre-washed (H20 and MeOH-) and dried Amberlite IRA-400(OH) resin (750 mug, -15 equivs of OH- based oi ~1.4 mequiv/g dry resin) and stirred at 25 "C for 2 hr. Vacuum filtered in a RBichner funnel and washed the resin thoroughly with MeOH1. The filtrate was concentrated by rotary evaporation, the residue taken up in 1:5 v/v CH 2

CI

2 /hexanes, and concentrated in vacuo to give the title compound as a light yellow solid (41 mg, 94%) as a mixture of 35 stereoisomers. MS (ESI+) m/z 626 (M+H)*, 1251 (2M+Hl)*. 219 Example 105F methyl {(2S)-I-[(2S)-2-(3-{4-[(2S,5S)-I -(4-teri-hutylphenyl)-5-(4-{5-[(2S)-I-{(2S)-2 [(methoxycarbonyl)aimino]-3- methylbutanoyl}pyrrolidin-2-yl]- IH-pyrazol-3-yl)phenyl)pyrrolidin-2 yliphenyl)-1H-pyrazol-5-yl)pyrrolidin-1-yl]-3-methyl-I-oxobulan-2-yl carbamate 5 and methyl {(2S)-1-[(2S)-2-(3-{4-[(2R,5R)- I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-I-{(2S)-2 [(methoxycarbonyl)aminoj-3-methylbutanoyl pyrrolidin-2-ylj-I H-pyrazol-3-yllphenyl)pyrrolidin-2 ylJphenyl)-I H-pyrazol-5-yl)pyrrolidin-1-ylJ-3-methyl- -oxohutan-2-yl carhainate In an oven-dried 10-mL round bottom flask purged with nitrogen, dissolved the product of 10 Example 105E (39.7 ig, 0.063 nunol) in anhydrous DMF (I mL) and cooled to 0 "C. Added sequentially (S)-2-(imethoxycarbonylamino)-3-mnethylbutanoic acid (23.89 mg, 0.136 minmol), HOBIt hydrate (21.37 mg, 0.140 mmol), EDAC (27.3 mg, 0.140 nmmol), and N-methylmorpholine (0.021 mL, 0.190 mmol). Removed the cooling bath and stirred the dark yellow solution at 25 'C for 1 hr. Diluted the reaction with EtOAc (50 mL), washed with 120 (3 x 25 mL) and brine (25 mL), dried the 15 organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a light peach solid (63 mng). Dissolved the crude material in CH 2 C1 2 and purified by flash chromatography (silica gel, 2.5 cm x 10 cm, 5% MeOH/CH 2

CI

2 ) to afford a 1:1.25 trans:cis product mixture (34 mg, 94% purity). Dissolved the residue in 1:1 v/v DMSO/MeOH (2 mL) and purified by RP-Cs HPLC (Waters Prep LC, 40mm Module with Nova Pak HR C1 8 6pm 40xlOOnun Prep Pak cartridge) eluting 20 with a 30 min gradient of 90:10 0.1% TFA in 1 2 0/AcCN to 100% AcCN at 20 mL/nin. Fractions containing a mixture of the trans diastereomers were concentrated by rotary evaporation, the residue taken up in 1:5 v/v CH 2 Cl2/hexanes and evaporated (5 times), and dried in vacuo to afford the title compounds as a cream-colored solid (12 mg, 16%). 'H NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.76 - 0.94 (m, 12 H), 1.10 (s, 9 H), 1.13 - 1.31 (m, 3 H), 1.71 (d, 1=5.42 Hz, 2 1-1), 1.82 - 2.17 25 (im, 9 H), 3.53 (s, 6 H), 3.70 - 3.85 (in, 4 H), 4.05 (t, J=8.08 Hz, 2 H), 5.09 - 5.19 (in, 2 H), 5.26 (d, 1=5.96 Hz, 2 H), 6.22 (d, J=8.78 HIz, 2 1-1), 6.39 (d, 1=1.30 Hz, 2 H), 6.94 (d, 1=8.67 Hz, 2 H), 7.20 7.31 (in, 6 H), 7.62 (d, J=7.92 Hz, 4 H); MS (ESI+) m/z 940 (M+-1)*. 30 Example 106 220 methyl {(2S)-I-[(2S)-2-(3-{4-l(2R,5S)-I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-1(2S)-2 [(methoxycarbonyl)aminol-3-imethylbutanoylipyrrolidin-2-yl]-1H-pyrazol-3-yl pheiyl)pyrrolidin-2 yl] phenyl}-lHIi-pyrazol-5-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-ylIcarbamate From the preparative HPLC separation of Example 105F was obtained the title compound 5 (cis) as a yellow solid (16 mg, 21%). 'H NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.77 - 0.93 (in, 12 11), 1.14 (s, 9 H-), 1.17 - 1.31 (m, 2 11), 1.80 - 2.18 (i, 1I 1-), 3.35 (d, 1=8.02 Hz, 1 11), 3.54 (s, 6 H), 3.72 - 3.85 (in, 4 H), 4.06 (t, .1=8.29 Hz, 2 H), 4.71 - 4.79 (n, 2 H), 5.13 - 5.20 (m, 2 H), 6.35 (d, J=8.78 Hz, 2 H), 6.43 (s, 2 1), 7.03 (d, 1=8.78 Hz, 2 H), 7.28 (d, J=8.35 Hz, 2 H), 7.55 (d, J=8.24 Hz, 4 H), 7.71 (d, J=7.59 Hz, 4 H); MS (ES I+) n/z 940 (M+H)*. 10 0N Example 107 methyl {(2S)-I-[(2S)-2-(3-{4-[1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-2 [(methoxycarbonyl)anino] -3-methylbutanoyl)pyrrolidin-2-yl]-IH-pyrazol-3-yl phenyl)-IH-pyrrol-2 15 yl phenyl}-1--pyrazol-5-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-ylcarbamate In an oven-dried 5-miL round bottom flask purged with nitrogen, dissolved the product of Example 105E (5.1 mg, 8.15 pmol) in anhydrous DMF (400 pL) and cooled to 0 C. Added sequentially (S)-2-(mnethoxycarbonylanino)-3-methylbutanoic acid (3.07 ing, 0.018 minol), H-lOlt hydrate (2.75 tmg, 0.018 minol), EDAC (3.51 mg, 0.018 minol), and N-methylinorpholine (2.69 pL, 20 0.024 mnol). Removed the cooling bath and stirred the dark yellow solution at 25 "C for 18 hr. Diluted the reaction in EtOAc (50 mL), washed with H20 (2 x 10 nL) and brine (10 mL), dried the organic over anhydrous MgSO,, filtered, and concentrated by rotary evaporation to a yellow solid (9.6 mg). Dissolved in 1:1 v/v MeOH/DMSO (1.5 mL) and purified by RP-C 8 IPLC (Waters Prep LC, 40mm Module with Nova Pak HR C1 8 6pm 40xl00mm Prep Pak cartridge) eluting with a 30 min 25 gradient of 90:10 0.1% TFA in H 2 0/AcCN to 100% AcCN at 20 mnL/nin. Pure fractions were concentrated by rotary evaporation, azeotroped with toluene (25 m.L), the residue was taken up in 1:5 v/v CH 2 Clicxancs and evaporated (3 times), then dried in vacuo to afford the title compound as an off-white solid (2.5 mg, 25%). 'H NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.76 - 0.92 (in, 12 I-I), 1.27 (s, 9 H), 1.80 - 2.15 (m, 10 H), 3.53 (s, 6 H), 3.69 - 3.84 (m, 4 1-1), 4.05 (t, 1=8.24 Hz, 2 H), 30 5.08 - 5.16 (m, 2 11), 6.39 (s, 2 H-), 6.53 (s, 2 11), 7.06 (dd, 1=8.29, 2.87 lz, 6 1-1), 7.26 (d, 1=8.35 lz, 2 H), 7.37 (d, J=8.46 Hz, 2 H), 7.44 - 7.55 (in, 4 H), 12.92 (s, 2 H); MS (ESI+) m/z 936 (M+H)*. 221 N N HN NH HN-NH NH o H /0 Example 108 N-(methoxycarbonyl)-L-valyl-N-(4-[(2S,5R)-5-(4-{[N-(methoxycarbonyl)-L-valyl] amino}phenyl)- 1 (4-[6-(morpholin-4-yl)pyridin-3-ylJphenyl}pyrrolidin-2-yl]phenyl}-L-prolinamide 5 and N-(methoxycarbonyl)-L-valyl-N-{4-l(2R,5S)-5-(4-I [N-(nethoxycarbonyl)-L-valyJamino iphenyl)-l (4-[6-(morpholin-4-yl)pyridin-3-ylJphenyl}pyrrolidin-2-yljphenyl}-L-prolinamide Example 108A 10 4-(5-(4-(2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morplioline In a microwave tube (size L, 20 mnL) purged with nitrogen and sealed with a rubber septum, dissolved the product of Example 86A (160 mg, 0.342 mmol) and 4-[5-(4,4,5,5-tetramnethyl-1,3,2 dioxaborolan-2-yl)pyridin-2-yllmorpholine (153 mg, 0.512 mumol) in THF (6 mL), added a solution of potassium phosphate (176 mg, 0.803 mmol) in water (2 mL), and sparged the reaction solution with 15 nitrogen for 5 min. Added 1,l'-bis(di-tert-butylphosphino)fcrrocene palladium dichloride (12.02 mg, 0.018 mninol) and stirred at 25 4C for 15 min . During this process, the reaction darkened quickly to a brown color. Diluted the reaction with EtOAc (50 miL), washed with brine (10 mL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation. Dissolved the residue in CH 2

C

2 and purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 20% 20 EtOAc/CH 2

CI

2 ) to afford the title compound as a solid (176 mg, 93%) as a mixture of stercoisomners. 'H NMR (400 MIHz, DMSO-D6) 8 ppm 1.82 - 1.94 (in, 2 H), 2.53 - 2.62 (m, 2 H), 3.37 - 3.47 (m, 4 H), 3.64 - 3.74 (m, 4 H), 5.03 (t, .1=5.37 Hz, 2 H), 6.40 (d, .1=8.89 Hz, 2 H), 6.82 (d, .1=9.00 Hz, I H), 7.34 (d, 1=8.78 H z, 2 H), 7.69 (dd, J=8.84, 2.55 H lz, I H), 7.83 (d, J=8.78 Hz, 4 H), 8.28 (d, J=8.78 Hz, 4 H-), 8.29 - 8.31 (in, I H); MS (ES[+) m/z 552 (M+H)*. 25 Example 108B 4,4'-(l -(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline Charged a 100-mL round bottom flask with the product of Example 108A (174.7 mg, 0.317 mnmol), partially dissolved in 1TIF (12.50 mL) and absolute EtOH (2.50 mL), evacuated on house 30 vacuum and filled flask with nitrogen, then added platinum (IV) oxide (14.38 mng, 0.063 mmnol), 222 evacuated flask on house vacuum and filled with hydrogen from a balloon, repeated evacuation/filling cycle 3 times, and stirred heterogeneous reaction mixture vigorously under hydrogen (I atm). After 2 hr, charged reaction with additional platinum (IV) oxide (14.38 mg, 0.063 immol) and continued to vigorously stir under hydrogen at 25 C. After 5 hr, added additional platinum (IV) oxide (14.38 mg, 5 0.063 mmol). The reaction mixture was then vacuum filtered through a bed of Celite 545 in a Buchner funnel, the filter pad was washed with CHC1 3 (100 inL) and hot CHlC 3 (2 x 50 nL), and the filtrate concentrated by rotary evaporation to give the title compound as a yellow solid (101 mg, 65%) as a mixture of stereoisomers. 'H NM R (400 MHz, l)MSO-l)6) 6 ppm 1.71 - 1.87 (im, 2 H), 2.24 2.31 (in, I H), 3.37 - 3.45 (in, 4 H), 3.64 - 3.74 (in, 4 H), 4.57 (t, 1=4.99 -lz, 2 1-1), 4.95 (s, 4 H), 6.42 10 6.53 (in, 3 H), 6.57 (d, J=8.35 Hz, 4 H), 6.76 - 6.89 (im, 2 H), 7.15 (d, J=8.35 Hz, 4 H), 7.26 (d, J=8.78 Hz, 2 H), 7.68 (dd, J=8.84, 2.44 Hz, 1 H), 8.29 (d, J=2.39 Hz, I H); MS (ESI+) m/z 492 (M+ 1I)+. N N HN H2N0 N NH 15 Example 108C methyl (2S)-I-(4-(5-(4-aminophenyl)-I-(4-(6-inorpholinopyridin-3-yl)phenyl)pyrrolidin-2 yl)phteiylainino)-3-imethyl-1-oxobuian-2-ylcarbaimate In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 108B (70 tmg, 0.142 nuol) and (S)-2-(inethoxycarbonylamino)-3-methylbutanoic acid (26.2 20 ing, 0.150 minol) in anhydrous DMSO (1.5 m.L), added IIATIU (58.6 ing, 0.150 minol) and diisopropylethylainine (0.050 imL, 0.285 nnol), and stirred dark yellow solution at 25 C for 15 min. Diluted the reaction with MeOH (1.5 iL) and purified by RP-C, 8 HPLC (Waters Prep LC, 40mm Module with Nova Pak IR C1 6pm 40xlOOmm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H 2 0/AcCN to 25:75 0.1% TFA in H 2 0/AcCN, then 10 mini to 100% AcCN at 20 25 niL/min. Pure fractions were concentrated by rotary evaporation (water bath 350) to a small volume, partitioned between 20% iPrOI/CllCl 3 (50 mL), and sat'd aq NaHCO 3 (15 mL), separated layers, dried organic extract over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (48 mg, 52%). IH NMR showed the material to be -3:1 trans:cis mixture; MS (ESI+) m/z 649 (M+-)*, 1297 (2M+H)*. 30 Example 1081) 223 N-(methoxycarbonyl)-L..-valyl-N-{4-[(2S,5R)-5-(4-{ [N-(nethoxycarbonyl)-L-valyljamino }phenyl)- I {4-[6-(morpholin-4-yl)pyridin-3-ylIphenyl I pyrrolidin-2-ylIphenyl -.- prolinamide-ACID vi 2 and N-(melhoxycarbonyl)-L-valyl-N- {4-[(2R,5S)-5-(4-{ [N-(methoxycarbonyl)-L-valyllamino )phenyl)- I 5 {4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl pyrrolidin-2-yl]phenyl )-L-prolinamide ACD v1 2 In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved 3:1 trans/cis mixture of Example 108C (44 mg, 0.068 minol) and the product of Example 37B (20.31 ing, 0.075 mmol) in anhydrous DMSO (I mL), added HATU (29.2 mg, 0.075 mmol) and diisopropylethylamine (0.024 mL, 0.136 mmol), and stirred yellow solution at 25 C for 30 mini. Diluted the reaction with 10 McOH (1 mL) and purified by RP-C 18 HPLC (Waters Prep LC, 40mm Module with Nova Pak HR C 18 6pm 40xOOmnm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H 2 0/AcCN to 25:75 0.1% TFA in H120/AcCN, then 10 min to 100% AcCN at 20 mUmin. The earlier eluting compound (18.8 mg, 31%) was determined by '11 NMR to be the trans diastereomers. The fractions of the later eluting peak were concentrated by rotary evaporation (water bath 35 *C) to small volume, 15 partitioned between 20% iPrOH/CIC1 3 (50 mL) and sat'd aq NaHCO 3 (15 mL), separated layers, dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to afford a 2:3 trans:cis mixture as an off-white solid (10 mg). The mixture was dissolved in 1:1 v/v MeOH/DMSO (1.5 nL) and purified by RP-C 18 HPLC (Phenomenex Luna C 8 (2) 5 pm IOOA AXlA column (30mm x 75mm)) eluting with a gradient of 90:10 10 mM NHl 4 OAc:MeOl to 100% MeOll 20 to afford the title cis compounds as a light beige solid (2 tmg, 3%). 'Hl NMR (400 MI-z, DMSO-D6) 8 ppmn 0.85 - 0.98 (in, 12 H), 1.77 - 2.06 (m, 7 H), 2.09 - 2.21 (i, 1 H), 2.36 - 2.45 (tn, 1 1-1), 3.37 - 3.42 (n, 4 -1), 3.51 (s, 3 H), 3.53 (s, 3 H), 3.59 - 3.70 (in, 6 H), 3.75 - 3.86 (m, 1 H), 3.95 (t, J=8.13 Hz, 1 H-), 4.02 (t, 1=8.57 Hz, I H), 4.44 (dd, J=8.19, 4.72 Hz, I H), 4.73 (s, 2 H), 6.43 (d, ./=8.89 Hz, 2 H), 6.80 (d, 1=8.89 Hz, I H), 7.27 (d, J=8.78 H-z, 2 H), 7.29 - 7.38 (m, 2 H), 7.44 (dd, 1=8.57, 2.71 lFlz, 4 25 H-), 7.54 - 7.64 (im, 4 H), 7.67 (dd, 1=8.89, 2.49 Hz, I H), 8.27 (d, J=2.49 H z, I H), 10.04 (s, 2 H); MS (ESI+) nz 903 (M+H1)*, 920 (M+NH4)*, 961 (M+AcCN+NH 4)*. Example 109 30 methyl ((2S)-I-[(2S)-2-{5-[(2R,5R)-I-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2 [(imethoxycarbonyl)aiinoj-3-iethylbutanoyl }pyrrolidin-2-ylJ-l H-henzimidazol-5-yl }pyrrolidin-2 yll-I i-bcnzimindazol-2-yl ) pyrrolidin-1 -yl]-3-nethyl-1 -oxobut an-2-ylcarbamaie 224 Example 109A 2-bromo- 1-(4-chloro-3-nitrophenyl)ethanone Method A: 5 To a flask equipped with a magnetic stir bar and under an atmosphere of N 2 was added 4' chloro-3'-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was added portion-wise phenyltrimethylainonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes time period. The resultant mixture was then stirred with monitoring every hour via LCMS. After 3 hr the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then 10 concentrated, H20 and 10% aq. NaHC0 3 added and washed with EtOAc (2 x 300 mL). The combined organic layers were then washed with Brine, dried (MgSO 4 ), filtered and concentrated. The residue material was then subjected to purification via crystallization (dissolved material in 100 muL EtOAc and slowly added hexanes until cloudy - let stand for a few hours) to yield 9.81 g (70%) of 2-bromo-l-(4-chloro-3-nitrophenyl)ethanone as an off white colored solid product. IH NMR (500 15 MlHz, DMSO-D6) 6 ppm 5.00 (s, 2 H) 7.98 (d, J=8.54 Hz, I H) 8.24 (dd, J=8.54, 2.14 Hz, I H) 8.61 (d, J=1.98 H z, I H). Method B: In a 500 mL round-bottomed flask was added 1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 20 60 mmol) in benzene (75 ml) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. Stirred for I hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate to give 2 bromo- I -(4-chloro-3-nitrophenyl)ethanone as yellow needles. 25 Example 109B 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione Zinc (11) chloride (14.68 g, 108 mmol) was added to toluene (81 mL), then diethylamnine (8.35 mL, 81 mmol) and tert-butanol (7.73 mL, 81 nunol) were added and the resultant heterogenous solution stirred at rt for approx. 2 h. Afterwards Example 109A (15.0 g, 53.9 mmol) and 4'-chloro-3' 30 nitroacetophenone (16.13 g, 81 inmnol) were added to the solution in one portion, and the resultant mixture stirred at rt for 42 h). The reaction was then quenched with 5% aqueous sulfuric acid (500 niL) and stirred vigorously to induce solid formation. The resultant solid was vacuum filtered, then washed with toluene, water, and methanol successively. Then the solid was added to a solution of hot ethyl acetate and resulting heterogeneous solution was stirred for 30 minutes and then the solid was 35 collected and dried overnight in a vacuum oven to provide 16.6 g (78%) of the title compound. 'H 225 NMR (400 M-iz, DMSO-d6) 6 8.61 (d, J = 1.9 117, 2H), 8.27 (dd, J = 8.4, 1.9 H z, 2H), 7.96 (d, J = 8.3 Hz, 2H), 3.48 (s, 4H). Example 109C 5 (1 S,4S)- 1,4-bis(4-chloro-3-nitrophenyl)butane- 1,4-diol (R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08g, 4.28mmol) was dissolved in 70 iL of -THF at ambient temperature in a dry flask under nitrogen and the timethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hr. The solution was cooled in a cold bath to ~ 10 C and the N,N-diethylaniline horane (9.18 mL, 51.6 mmol) was added dropwise 10 with some bubbling. After 15 itdn, this solution was transferred to an addition funnel and added dropwise Io 1,4-bis(4-chloro-3-nirophenyl)butane-1,4-dione (Example 109B) (10.0g, 25.2 inmol) suspended in 200 nL of TIF and cooled to ~ 10 *C. Bubbling was observed. After the addition, mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL MeOl- was added dropwise till bubbling stopped, then the mixture was let stir at ambient 15 temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The filtrate was concentrated, poured into I M HCI and extracted into ethyl acetate, dried over sodium sulfate; concentrated to give the title compound (9.9g, 99%) as a yellow waxy solid. Chiral HPILC e.e. >99.9% (RR diol was undetectable). 'H NMR (400 MHz, DMSO-d6) 6 7.94 (d, J = 1.9 Hz, 21-1), 7.69 (d, J = 8.4 lz, 211), 7.60 (dd, J = 8.4, 1.9 lz, 211), 4.65 (m, 211), 1.62 (ni, 411). 20 Example 109D The product of Example 109C was processed as in Example 1 13A, 1 13B, 113C, and 113D, substituting 4-t-butylaniline for 4-cyclohexylaniline in the step I 13A procedure to give 0.212 g (22%) of the title compound. I H NMR (400 MHz, DMSO-D6) 6 ppm 0.74 - 0.92 (m, 12 H) 1.07 (s, 9 1-1) 25 1.69 (d, J=4.01 Hz, 2 H) 1.86 - 2.05 (in, 6 H) 2.13 - 2.24 (m, 4 H) 2.54 (d, J=2.60 Hz, 2 H) 3.51 - 3.56 (im, 6 H) 3.81 (s, 4 1) 4.05 (1, J=8.13 Hz, 2 H) 5.09 - 5.18 (in, 2 H) 5.35 (d, J=3.47 Hz, 2 H) 6.25 (d, J=8.78 Hz, 2 H) 6.86 - 6.96 (i, 2 H) 7.07 (t, J=7.81 Hz, 2 H) 7.20 (s, I H) 7.26 - 7.32 (in, 3 H) 7.38 (d, J=8.24 lz, I H-) 7.46 (d, J=8.24 lHz, 1 11) 11.98 - 12.08 (in, 2 11); MS TFA+ m/z 889. HN N UN> 30 Example 110 226 methyl [(2S)-1-[(2S)-2-{5-[(2S,5S)-I-(4-tert-butylphenyl)-5-{2-[(2S)-i-{(2S)-2 (methoxycarbonyl)aminloJ-3-nethylbutanoyl) pyrrolidin-2-yI]-I H-heiizimida.ol-5-yl }pyrrolidin-2 yl]-I H-benzinidazol-2-yl Ipyrrolidin-I -yl]-3-methyl-1-oxobutan-2-yl carbamate The product from Example 28K was purified by chiral chromatography on a Chirapak IA 5 column eluding with a mixture of hexane/methanol/tetrahydrofuran (3:1:1) to give the title compound. 111 NMR (400 MIH z, DMSO-D6) 8 ppm 0.78 - 0.91 (in, 12 1-) 1.07 (s, 9 11) 1.64 - 1.73 (in, 2 H-) 1.89 2.00 (m, 6 H) 2.12 - 2.23 (in, 4 H) 3.14 - 3.24 (in, 2 -1) 3.52 (s, 6 H) 3.76 - 3.85 (in, 4 H) 4.05 (td, J=8.38, 2.33 H z, 2 H) 5.07 - 5.16 (m, 2 H) 5.30 - 5.39 (m, 2 H) 6.23 (d, J=8.78 Hz, 2 H) 6.90 (ddd, J=8.95, 4.72, 4.55 Hz, 2 H) 7.06 (t, J=9.22 Hz, 2 H) 7.17 (s, I H) 7.23 - 7.31 (in, 3 H) 7.37 (d, J=8.13 10 lz, I H) 7.44 (d, J=8.24 Hz, I H) 12.02 (d, J=23.42 H-z, 2 H); MS ESI+ n/z 888 (M+H)+. H H o i- HN N Example III dimethyl ([(2S,5S)-I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis( benzene-4,1-diylcarbamoyl(3S)-2 15 azabicyclo[2.2. I Iheptuane-3,2-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyll))biscarbanate OH Example I II A (3S)-2-((S)-2-(imethoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.I]heptane-3-carboxylic acid 20 (3S)-ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (1.25 g, 7.39 minmol), (S)-2 (inethoxycarbonylainino)-3-methylbutanoic acid (1.42 g, 8.13 mmol), diisopropylethylaimine (6.45 mL, 36.9 iniol), and HATU (2.95 g, 7.76 iniol) were combined in dimethylformaimide (40 mL) at ambient temperature and stirred for 2 hours. The solution was diluted with water and the product filtered and dried. The dried ester (l.0g, 3.06 nunol) was taken up in water (15 mL) and ethanol (15 25 niL) and treated with sodium hydroxide (0.5 g, 12.5 nmnol) at ambient temperature for 17 hours. The solution was washed with ether then the aqueous was neutralized with concentrated ICI to pI 7 and the product extracted into ethyl acetate, dried over sodium sulfate, and concentrated to give the title compound as a waxy solid. 30 Example I l 11B 227 dimethyl ([(2S,5S)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl Jhis I benzene-4,1 -diylcarbamoyl(3S)-2 arabicyclo[2.2.I Jheptane-3,2-diylt(2S)-3-methyl-I-oxobutane-1,2-diyl]})biscarbamate The product from Example 37E (0.05g, 0.13 inol), the product from example 11A (0.097 g, 0.324 mmol), diisopropylethylamine (0.113 ml, 0.648 nuinol), and HATU (0.104 g, 0.272 mmol) 5 were combined in dimethylformanide (2 miL) at ambient temperature and stirred for 3 hours. The solution was poured into brine, extracted into ethyl acetate, concentrated, and purified by conbi-flash 12g silica column, eluting with 0-6% methanol in dichloromethane to give the title compound as a solid. I l NMR (400 MHz, DMSO-D6) 6 ppm 0.91 (d, J=6.72 Hz, 6 H) 0.98 (d, J=6.72 Hz, 6 H) 1.1 I (s, 9 H) 1.32 (d, J=8.89 Hz, 2 H) 1.36 - 1.46 (mn, 2 H) 1.59 - 1.74 (tm, 6 H) 1.76 - 1.84 (n, 2 H) 1.90 10 (td, J=13.88, 6.94 lz, 2 H) 2.01 - 2.09 (i, 2 H) 2.40 - 2.47 (tm, 2 H) 2.60 (d, J=1.19 Hz, 2 H) 3.52 (s, 6 H) 3.94 (s, 2 1-1) 4.04 - 4.15 (i, 2 -1) 4.46 (s, 2 1-1) 5.15 (d, J=6.51 Hz, 2 1-1) 6.17 (d, J=8.78 H z, 2 1H) 6.94 (d, J=8.78 l z, 2 HI) 7.13 (d, J=8.57 lz, 4 H1) 7.22 (d, J=8.46 Hz, 2 H-) 7.49 (d, J=8.57 Hz, 4 H) 9.95 (s, 2 H) 15 Example 112 methyl {(2S)-I-[(2S)-2-(4-{4-[(2R,5R)- I-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(mnethoxycarbonyl)(nethyl)anino] -3-methylbutanoyl pyrrolidin-2-yl]-1H-iinidazol-4 yl phenyl)pyrrolidin-2-yllphenyl}-1H-imidazol-2-yl)pyrrolidin-l-yll-3-methyl-I-oxobutan-2 20 ylmethylcarbamate The product from Example 126H was processed as in Example 42B-42G, substituting (S)-2 (mnetlioxycarbonyl(mnetliyl)amiino)-3-methylbutanoic acid for (S)-2-(methoxycarbonylamino)-3 tmethylbutanoic acid in step 42G, to give 0.07 g (40%) of the title compound as a white solid. lH NMR (free base) (400 MHz, DMSO-D6) 8 ppm 0.76 (d, J=6.61 lHz, 6 H) 0.83 (d, J=6.51 lHz, 6 H) 25 1.09 (s, 9 11) 1.63 - 1.75 (tm, 2 H1) 1.86 - 2.00 (m, 4 HI) 2.03 - 2.21 (m, 6 11) 2.77 (s, 6 11) 3.10 - 3.22 (i, 4 H) 3.63 (s, 6 H) 3.74 - 3.84 (n, 2 H) 4.98 - 5.07 (n, 2 -I) 5.16 - 5.23 (i, 2 H) 6.21 (d, J=8.78 Hz, 2 1) 6.88 - 6.96 (m, 2 H) 7.15 (d, J=8.24 Hz, 4 H) 7.22 (d, .1=8.35 Hz, 1 H) 7.36 (d, J=1.52 Hz, 2 H) 7.51 (d, J=8.24 HIz, I I-) 7.61 (d, J=8.13 Hz, 4 H) 11.70 (s, 2 H); MS FSl+ m/z 968.7 (M+H)+; MS ESI+ nlz 968.7 (M+H)+. 30 228 Example 113 methyl {(2S)-1-[(2S)-2-{5-[(2R,5R)- I-(4-cyclohexylphenyl)-5-(2-[(2S)-1-{(2S)-2 [(niethoxycarbonyl)aminol-3-niethylbutanoyl)pyrrolidin-2-yll- IH-benziimidazol-5-yl)pyrrolidin-2 5 yll-i H-benzinidazol-2-yl}pyrrolidin-l -yll-3-methyl-I-oxobutan-2-yl carbamate Example I I 3A (2R,5 R)-2,5-his(4-chloro-3-nitrophenyl)- I -(4-cyclohexylphcnyl)pyrrolidine The product of Example 109C (2.0g, 4.99nnol) and triethylanine (1.51 nL, 14.96 minol) 10 were dissolved in dichloromethane (50 mL) and cooled in an ice bath. Methanesulfonyl chloride (0.855 nL, 10.97 minol) in dichloromethane (2 niL) was added dropwise and the resulting mixture was stirred at ambient temperature for 2 hours. The solution was concentrated to dryness and dissolved in dinmethylformarnide (8 mL). 4-Cyclohexylaniline (5.24 g, 29.9 mmol) was added and the solution was heated at 65 'C for 2 hours then poured into I M HCI and extracted into 15 dichloromethane, concentrated, and purified by combi-flash 80g silica colunm, cluting with 0-20% ethyl acetate in hexanes to give 1.38 g (51%) of the title compound. NI o-1- oON- ,, NO, OX 0 2 N NO0 2 Example 113B 20 (2S,2'S)-icrt-butyl 2,2'-(4,4'-((2R,5R)-I-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1 phenylene))bis(azanediyl)bis(oxomnethylene)dipyrrolidine-1-carboxylate The product from Example I 13A (1.

2 9 g, 2.39 mnol), (S)-tert-butyl 2-carbanoylpyrrolidine l-carboxylate (1.53 g, 7.16 mnmol), cesium carbonate (2.33g, 7.16 mmol), 4,5 bis(diphenylphosphino)-9,9-di methylxanthene (0.33 g, 0.573 mmol), and 25 tris(dibenzylideneacetone)dipalladium(0) (0.328 g, 0.358 nimol) were combined in dioxane (18 mL) and nitrogen was hubbled through the solution for 15 mini, then the flask was capped with a reflux condenser and the solution healed at 100 "C for 8 hours. After filtering through celite and 229 concentrating, the residue was purified by combi-fIlash 80g silica column, eluting with 0-20% ethyl acetate in dichlorornethane to give 1.71 g (80%) of the title compound. o HN N O O >i HN .N NH0

H

2 N 6aH 5 Example 113C (2S,2'S)-tert-butyl 2,2'-(4,4'-((2R,5R)- I -(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-4, I phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- 1 -carboxylate The product from Example I13B (1.71 g, 1.91 mmol) was dissolved in ctrahydrofuran (10 niL) and ethanol (10 mL) at ambient temperature and treated with Platinum (IV) oxide (0.11 g, 0.48 10 mmol). The flask was evacuated and opened to a hydrogen balloon and stirred for 18 hours then filtered through celite and concentrated to give the title compound. Example 113D methyl {(2S)- l-[(2S)-2-{5-[(2R,5R)-l -(4-cyclohexylphenyl)-5-{2-[(2S)-1-((2S)-2 15 [(iethoxycarboiiyl)amino]-3-methylbutanoyl }pyrrolidin-2-ylJ-l H-benzimidazol-5-yl pyrrolidin-2 yl]- I H-benziiclazol-2-yl pyrrolidin-1 -yl]-3-methyl-I -oxobutan-2-y}carbamate Example 113C was processed using the methods of Examples 281, 28J, and 28K to provide the title compound. 1H1 NMR (400 MHz, DMSO-D6) 8 ppm 0.76 - 0.91 (in, 12 H-) 1.03 - 1.29 (m, 6 H-) 1.55 - 1.74 (in, 7 11) 1.84 - 2.06 (in, 6 H-) 2.11 - 2.25 (m, 6 HI) 3.53 (s, 6 Hl) 3.81 (s, 4 11) 4.02 - 4.13 20 (tm, 2 H) 5.08 - 5.18 (in, 2 H) 5.32 - 5.38 (m, 2 H) 6.24 (d, J=8.57 Hz, 2 H) 6.68 - 6.77 (m, 2 H-1) 7.06 (t, J=7.54 Hz, 2 H-) 7.19 (s, 1 H) 7.26 - 7.32 (in, 3 H) 7.37 (d, J=8.24 Hz, I H1) 7.45 (d, J=8.35 H z, 1 H) 11.98 - 12.05 (in, 2 H); MS ESI+ m/z 914.5. N

N

25 Example 114 230 methyl {(2S)-I-[(2S)-2-(6-((2R,5R)-5-{2-1(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl}pyrrolidin-2-yli-1I H-benzimidazol-5-yl1-1-4-(4-methylpiperazini-l yI)phenyl]pyrrolidin-2-yl}-IH-henzimidazol-2-yl)pyrrolidin-1-yl]-3-metiyl-I-oxobutan-2 yl Icarbanate 5 The product of Example 109C (1.0g, 2.49mmol) was processed as in Examples 113A-1 131), substituting 4-(4-methylpiperazin-l-yl)aniline for 4-cyclohexylaniline in the procedure of Example II 3A and substituting Raney Nickel in tetrahydrofuran for platinum(IV) oxide in tetrahydrofuran and ethanol in the procedure of Example I 13C to give 0.028 g (50%) of the title compound as a solid. I NM R (400 MHz. DMSO-D6) 6 ppm 0.77 - 0.90 (in, 12 H) 1.65 - 1.72 (m, 2 H) 1.85 - 2.04 (in, 8 H) 10 2.13 (s, 3 H) 2.15 - 2.23 (m, 4 H) 2.32 (s, 2 H) 2.77 (s, 6 H) 3.54 (s, 6 H) 3.82 (d, J=4.66 Hz, 4 H) 4.02 - 4.08 (in, 2 H) 5.09 - 5.18 (in, 2 H) 5.28 - 5.37 (m, 2 H) 6.23 (d, J=8.78 Hz, 2 H) 6.54 (ddd, J=9.00, 4.66, 4.55 lz, 2 1) 7.02 - 7.08 (m, 2 H-) 7.19 (s, 1 11) 7.26 - 7.31 (m, 3 H) 7.36 (d, J=8.13 Hz, 1 11) 7.44 (d, J=8.35 Hz, 1 11) 12.01 (s, 2 1-); MS ESI+ m/z 556 (M+l1)+. 15 Example 115 methyl {(2S)-I-[(2S)-2-(6-[(2R,5R)-I-(1,3-benzothiazol-2-yl)-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbony)aLminJo-3-methylbutanoyl}pyrrolidin-2-yi]- IH-benzimidazol-5-yl pyrrolidin-2 yl}-l H -benzi midazol-2-yl } pyrrolidin-I -yI 1-3-methyl-I -oxobutan-2-y1 Icarbamate 20 Example I15A (2R,5R)-1-allyl-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine The product from Example 109C (5.0 g , 12.46 mnol) and allylamine were processed as in Example II 3A to give 1.5 g (39%) of the title compound as a thick oil. 25 Example 115B (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine The product from Example I15A (2.0 g, 4.74 nmol) was dissolved in acetonitrile (40 mL) and water (4 mL) and treated with Tris(triphenylphosphine)rhodium(l) chloride (0.219 g, 0.237 30 mmol). The mixture was heated at 100 'C and nitrogen was bubbled through the solution for 3 hours. The mixture was partitioned between 5% sodium bicarbonate solution and ethyl acetate, then the 231 organics were concentrated and the product purified by combiflash 80g silica column eluting with dichloromethane to give 1.33 g (74%) of the title compound. Example I15C 5 2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)benzo[d]thiazole The product from Example 115B (0.335 g, 0.877mmnol), 2-bromobenzo[dlthiazole (0.281 g, 1.32 mmol), tris(dibenzylideneacetone)dipalladium(0) 0.08 g (0.088 mmol), BINAP (0.055 g, 0.088 inmol), and sodium tert-hutoxide (0.126 g, 1.32 mmol) were combined in dioxane (8 ml-) and nitrogen was bubbled through the solution for 10 minuets. The tube was sealed and heated at 100 "C 10 for 18 hours. The reaction mixture was partitioned between brine and dichloroniethane and the organics were concentrated and purified by combi-flash 24 g silica column, eluding with 1: I hexanes: dichloromethane, followed by 100% dichloromethane to give 0.165 g (37%) of the title compound. Example I15D 15 methyl {(2S)-I-[(2S)-2-{6-[(2R,5R)-I-(I,3-benzothiazol-2-yl)-5-(2-[(2S)-l-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl) pyrrolidin-2-yl]-I H -benzimidazol-5-yl pyrrolidin-2 ylJ-l- -benzi midazol-2-yl} pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl carbamate The product from Example I15C was processed as in Examples 113B, 113C, and 113D to give 0.040 g (38%) of the title compound. IlI NM R (400 MHz, DMSO-D6) 8 ppm 0.74 - 0.88 (in, 12 20 H1) 1.76 - 1.84 (m, 2 H1) 1.85 - 1.94 (ni, 3 11) 1.95 - 2.07 (m, 4 11) 2.14 - 2.26 (m, 4 11) 2.61 - 2.71 (in, 2 H-1) 3.53 (s, 6 H) 3.76 - 3.85 (i, 4 1-1) 4.05 (t, J=8.51 Hlz, 2 H) 5.10 - 5.18 (m, 2 H) 6.90 (t, J=7.54 H z, 2 H) 7.07 - 7.16 (m, 3 H) 7.22 - 7.35 (in, 4 H) 7.40 (d, J=8.13 Hz, 2 H) 7.47 (d, J=8.35 Hz, 1 H) 7.52 7.59 (n, I H) 12.07 (s, 2 H); MS ESI+ m/z 889. N. N O H NH 25 Example 116 methyl {(2S)-I-[(2S)-2-16-[(2R,5R)-5-(2-t(2S)-1-((2S)-2-[(niethoxycarbonyl)aiino] -3 iethylbutanoyl )pyrrolidin-2-yl]-liH-benziiidazol-5-yl}-I-(4,5,6,7-tetrahydro-I,3-benzothiazol-2 yl)pyrrolidin-2-yl]-ll-benzimidazol-2-yl pyrrolidin-1-yl]-3-imethyl- I-oxobutan-2-yl carbainate 30 Example 116A 232 (S)-pyrrolidine-2-carboxamide hydrochloride salt To (S)-tert-hutyl 2-carhamoylpyrrolidine-l-carboxylate (29.8 g, 139 mmol) was added a solution of 4N HC in dioxane (209 niL, 836 inmol) and the resultant mixture stirred at room temperature for 18 hrs. The mixIure was then concentrated and triturated with diethyl ether then 5 vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid. Example 116B (S)-2-( methoxycarbonylamino)-3-methylbutanoic acid 10 To (S)-2-amino-3-miethylbutanoic acid (57 g, 487 mmol) dissolved in dioxanc (277 niL) was added a 2N aqueous sodium hydroxide solution (803 miL, 1606 mmol) followed by the dropwise addition of methyl chloroformate (75 mL, 973 nmol) over I hr which caused warming of the solution to occur. After the addition, the mixture was heated at 60 *C for 22 hrs, then cooled and extracted with dichloromethane (400 mL). The resultant aqueous layer was cooled in an ice bath then 12N 15 hydrochloric acid was added dropwise until the pH was 2. The resultant mixture was stirred at 0 *C for 2 hrs then the resultant solid was vacuum filtered and dried in a vacuum oven to provide 80g (94%) of the title compound as a colorless solid. 'H NMR (400 MHz, DMSO-d6) 8 12.50 (bs, IH), 7.34 (d, J = 8.6 11z, 1 H), 3.84 (dd, J = 8.6, 6.0 Hz, 1 H), 3.54 (s, 3H), 2.03 (m, I H), 0.86 (t, J = 7.0 Hz, 6-1). 20 H I NH 2 0 Example 116C methyl (S)- I -((S)-2-carbamoylpyrrolidin- I -yl)-3-methyl- I -oxobutan-2-ylcarbamate To the product of Example 1 16A (21.6 g, 144 imol), the product of Example I16B (29.1 g, 25 166 mmnol), I H-benzo[d][l,2,3]triazol-I-ol hydrate (27.6 g, 180 mmol), Nl-((ethylimino)mnethylene) N3,N3-dimethylpropane- 1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL, 578 mmol) was dissolved in dichloromethane (960 muL) and stirred at room temperature for 18 hrs. The resultant solution was then concentrated to a residue, water was then added and the solution extracted with a 25% isopropanol in chloroform solution (2 x 2000 mL..) the organic layer 30 washed with brine then the organic extract dried over MgSO 4 , then concentrated to a yellow oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to provide 25 g (64%) of the title coompound as a colorless solid. 'H NMR (400 MHz, DMSO-d6) 6 7.28 (m, 21H), 6.81 (s, 1H), 4.24 (dd, J = 8.1, 4.4 Hz, 1H), 4.00 (t, J = 8.4 Hz, 1H), 233 3.75 (in, I H), 3.55 (in, I H), 3.50 (s, 3H), 2.02 (i, I H), 1.97 (mn, 211), 1.80 (in, 21-), 0.92 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 8.6 Hz, 3H). S N C1 / 1 CI 0 2 N NO 2 5 Example 116D 2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole The product from Example 109C (0.80 g, 1.489mmol) and 4,5,6,7-tetrahydrobenzo[d]thiazol 2-amine were processed using the method of Example 113A to give 0.375 g (50%) of the title compound 10 Example 116E dimethyl ([(2R,5R)-I-(4,5,6,7-tetrahydro-I,3-benzothiazol-2-yl)pyrrolidine-2,5-diyl]bis{(2 nitrobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-imethyl-I-oxobutane-1,2 15 diyl]})biscarbamate (ACD v12)) The product from Example 116D (0.375 g, 0.722 mmol) was processed as in Example 113B, substituting the product from Example I 16C for (S)-tert-butyl 2-carbainoylpyrrolidine-l-carboxylate to give 0.59 g (83%) of the title compound. H O ONH N 20 O H 2 N NH 2 OK 0 Example I 16F dimethyl ([(2R,5R)-I-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)pyrrolidine-2,5-diyl]bis{(2 aininobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-iethyl-1-oxobulane-1,2 diyl]))biscarbarnate (ACD v12)) 25 The product from Example I 16E (0.59 g, 0.596 minol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney Nickel slurry in water (0.25 nL). The flask was evacuated and opened to 234 a hydrogen balloon and stirred at ambient temperature for I hour. The solution was filtered through a silica plug and concentrated to dryness to give the title compound. Example I 16G 5 methyl {(2S)- I-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl lpyrrolidin-2-yl]- IHl-benziindazol-5-yl)-I-(4,5,6,7-tetrahydro-1,3-benzothiazol-2 yl)pyrrolidin-2-yl]-1 H-benzimidazol-2-ylpyrrolidin-1-ylj- 3 -methyl-1-oxobutaii-2-yl}carbamate The product from Example I 16F (0.55 g, 0.592 mmol) was dissolved in toluene (6 mL) and treated with acetic acid (0.34 ml., 5.92 mmol) and heated to 65 "C for 4 hours. The solution was 10 concentrated to dryness and purified by coibi-flash 12g silica colunm, cluting with 0-6% meihanol in dichloroniethane to give 0.245 g (48%) of the title compound. tH NMR (400 MI-Iz, DMSO-D6) 8 ppm 0.78 - 0.92 (m, 12 11) 1.53 - 1.61 (i, 4 H) 1.67 - 1.75 (m, 2 H) 1.88 - 2.07 (m, 6 H) 2.15 - 2.27 (n 6 H) 2.41 - 2.47 (i, 2 H) 2.59 (d, J=1.63 Hz, 2 H) 3.54 (s, 6 H-) 3.79 - 3.87 (n, 4 H-) 4.07 (t, J=8.57 lIz, 2 11) 5.12 - 5.20 (m, 2 H-1) 5.38 - 5.46 (i, 2 11) 7.05 (dd, J=12.79, 9.00 Hz, 2 H-) 7.22 - 7.33 15 (m, 4 H) 7.39 (d, 1=8.46 iz, I H) 7.46 (d, J=8.46 Hz, I H) 12.06 (d, .1=6.83 -lz, 2 H); MS ESI+ m/z 893.5. N NN Fxaiple 117 20 methyl {(2S)-1-[(2S)-2-(4-{4-[(2S,3R,4R,5S)-I -(4-tert-bulylphenyl)-3,4-dieithoxy-5-(4-(2-[(2S)-1 {(2S)-2-[(methoxycarbonyl)aiino]-3-methylbutanoyl}pyrrolidin-2-yl]-IH-iimidazol-4 yl}phenyl)pyrrolidin-2-yl]phenyl}-lIH-inidazol-2-yl)pyrrolidin-1-yl]-3-methyl-l-oxobutan-2 yi carbaimate 3.4-O-isopropylidene-D-mannitol was processed using the methods of Examples 79C, 79D, 25 79E, 79F, 79G, 79H, and 791 to provide the title compound, wherein iodoethane was used in the 0 alkylation step (method of Example 79D) instead of iodomethanc. 'I NMR (400 MHz, CDC 3 ) 6 ppm 0.86 (t, J=7.4 lz, 12H) 1.04 (t, J=7.0 lz, 6H) 1.13 (s, 9H) 1.85-2.03 (m, 4H) 2.03-2.13 (in, 2H) 2.13 2.24 (m, 2H) 2.24-2.40 (in, 21-) 3.03 (i, 2H) 3.54-3.89 (in, 9H) 3.69 (d, J=1.7 Hz, 6H) 4.25 (d, J=5.3 Hz, 2H) 4.31 (br s, 2H) 5.19-5.29 (in, 41-1) 5.36 (br s, 2H) 6.28 (d, J=8.8 lz, 21) 6.90-6.98 (m, 4H) 30 7.12-7.23 (i, 6H). MS (ESI) m/z 1029 (M+H)*. 235 Example 118 methyl {(2S)-I-[(2S)-2-(5-((2R,5R)-5-(2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 iethylbulanoyl)pyrrolidin-2-yll-l H-benziindazol-5-yl}-1-[6-(pyrrolidin-1-yl)pyridin-3 5 yl]pyrroliclin-2-yl}-1H-benziridazol-2-yl)pyrrolidin-I-yl]-3-methyl-1-oxobutan-2-ylIcarbamate Example 1 18A 5-nitro-2-(pyrrolidin-1-yl)pyridine To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room 10 temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70 *C for 18 h. The cooled solution was concentrated in vacuo and the residue partitioned between CH 2 C1 2 and I M NaOH. The organic layer was dried (Na 2

SO

4 ), filtered and solvent removed in vacuo to give title compound (9.52g, 78%). MS (ESI) r/z 194 (M+H)*. 15 Example 118B 6-(pyrrolidin- I -yl)pyridin-3-amine Material from Example I18A (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and DMF (40 iL) and added to a pressure bottle containing Raney Nickel 2800, water slurry (45%) (9.52g, 162 mmol) stirred for 2 h at 30 psi under H 2 gas. The solution was filtered through a nylon membrane, 20 washed with CH 3 0H and the filtrate concentrated in vacuo to give the title compound (7.78 g, 97%). 'H NMR (400 MHz, DMSO-d6) 6 ppim 1.81-1.91 (in, 4H) 3.17-3.29 (in, 4H) 4.30 (s, 2H) 6.25 (d, J=8.7, I H), 6.90 (dd, J=2.8, 8.7, 1 H), 7.55 (d, J=2.6, I H). MS (ESI) m/z 164 (M+H)*. Example II 8C 25 (2S,2'S)-tert-butyl 2,2'-(5,5'-((2R,5R)-I-(6-(pyrrolidin-1-yl)pyridine-3-yl)pyrrolidine-2,5 diyl)bis(I H-benizo[d]iimidazole-5,2-diyl)dipyrrolidine- I -carboxylate Example I18B and Example 109C were processed using sequentially the methods of Examples 113A, 113B, I16F, and 281 to provide the title compound. 30 Example I 18D 236 methyl {(2S)-I-[(2S)-2-(5-((2R,5R)-5-{2-[(2S)-I-{(2S)-2-[(methoxycarbonyl)aminoJ -3 methylhutanoyl }pyrrolidin-2-ylJ-l] H-henzi midazol-5-yl }1-[6-(pyrrolidin-I-yl)pyridin-3 yl]pyrrolidin-2-yl}-1 H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl carbamate To a solution of Example 118C (741 mg, 0.94 mmol) in dioxane (4 mnL) was added 4 M HCI 5 in dioxane (4.0 minL) and the solution was stirred at room temperature for 30 min. Solvent is removed in vacuo and the residue is dissolved in DMF (9.4 mL). Added N,N-diisopropyethylamine (0.99 mL, 5.65 mmol) followed by (S)-2-(methoxycarbonyl-amino)-3-methylbutanoic acid (379 mg, 2.16 mmol), HOBT (331 mg, 2.16 mnmol), and EDC (415 mug, 2.16 mmol) and stirred at room temperature for 18 h. Poured into EtOAc, washed with H 2 0, brine, dried (Na 2 SO.), filtered and removed solvent 10 in vacuo to give crude product which was purified by flash chromatography on silica gcl eluting with 0-6% CH 3 0-1/CH 2

CI

2 to give the title compound (165 mug, 0.183 inniol, 19%). 1H NMR (400 MHz, DMSO-d6) 6 0.73-0.95 (in, 1211) 1.66-2.27 (in, 1211) 3.09 (br s, 511) 3.53 (s, 611) 3.81 (br s, 411) 4.06 (t, J=8.4 Iz, 211) 5.13 (br s, 211) 5.33 (br s, 211) 6.12 (br s, 1H1) 6.64 (br s, 1H1) 7.00-7.47 (in, 1011) 12.02 (s, 211). MS (ESI) m/z 903 (M+1)*. 15 Example 119 methyl 4-(4-[(2R,5 R)-2,5-bis(2-{ (2S)-I -[N-(methoxycarbonyl)- L-valylJpyrrolidin-2-y}I 1 H benz.imidazol-5-yl)pyrrol idin- I -yl]-2-fluorophenyl I piperazine- I -carboxylate 20 Example 119A 1-(2-fluoro-4-nitrophenyl)piperazine To a warm solution of piperazine (7.78 g, 90 nnol) in DMSO (40 mL) was added dropwise 1,2-difluoro-4-nitrobenzene (2.0 mL, 18.07 mmol). The solution was stirred at 70 *C for 2 h, cooled 25 to room temperature, diluted with EtOAc, washed with H 2 0, brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo to give the title compound (4.05 g, 17.98 mnmol, 100%). 'H NMR (400 MHz, CDCl 3 ) 8 ppm 3.03-3.09 (in, 41H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, IH) 7.91 (dd, .=13.1, 2.6 H z, I H) 7.96-8.01 (in, 11-1). MS (ESr) mn/z 226 (M+H)*. 30 Example 119B 237 Methyl 4-(2-fluoro-4-nitrophenyl)piperazine- I -carboxylate To a solution of Example 1 19A (4.0 g, 17.76 mol) in dioxane (40 mL) at 0 *C was added 2 M NaOH (29.3 mL, 58.6 inol) followed by dropwise addition of methyl chloroforiate (2.75 mL, 35.5 mmol). The solution was warmed to room temperature and stirred for 2 h. Diluted with EtOAc 5 and added I N HCI until all solid had dissolved, separated the phases and washed the organic phase with I N HCI, 120, brine, dried (Na 2

SO

4 ), filtered and removed solvent in vacuo to give the title compound (4.69 g, 16.56 mmol, 93%). 'H NMR (400 MHz, CDCl 3 ) 8 ppm 3.20-3.31 (m, 4H) 3.62 3.71 (m, 4H) 3.75 (s, 3H) 6.92 (t, .1=8.8 Hz, I H) 7.93 (dd, J=12.9, 2.6 Hz, I H) 7.98-8.02 (in, I H). MS (ESI) m/z 284 (M+-)*. 10 Example 119C Methyl 4-(4-amino-2-fluorophenyl)piperazine- I -carboxylale To a solution of Example 119B (3.0 g, 10.59 nmol) in EtOAc (40 nL) was added 10% palladium on carbon (300 mg) and the solution was stirred under a balloon of H 2 gas for 1.5 h. The 15 solution was filtered through Celite, the catalyst washed with EtOAc, and the filtrate concentrated in vacuo to give the title compound (2.68g, 10.59 mnmol, 100%). Example 1191) methyl 4-(4-[(2R,5R)-2,5-bis(2-{(2S)-I-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-l H 20 benzimidazol-5-yl)pyrrolidin- I -yl]-2-fluorophenyl) piperazine- I -carboxylate Example I19C and Example 109C were processed using sequentially the methods of Examples I 13A-l 13C, 261, and I 18D to provide the title compound. 'H NMR (400 MHz, DMSO-d6) 8 ppm 0.75-0.93 (in, 12H) 1.69 (br s, 2H) 1.82-2.07 (in, 7H) 2.10-2.28 (in, 41-I) 2.61-2.73 (in, 5H-1) 3.54 (s, 6H) 3.56 (s, 3H) 3.82 (br s, 4H) 3.99-4.11 (m, 2H) 5.09-5.19 (m, 2H) 5.29-5.41 (in, 2H) 6.01 25 6.13 (m, 2H) 6.61-6.72 (in, 11-1) 7.06 (s, 2H) 7.20 (s, lIH) 7.29 (d, J=9.1 Hz, 3H) 7.38 (d, .1=8.1 Hz, I H) 7.46 (d, I H) 12.04 (s, 2H). MS (ESI) nz 993 (M+H)*. N Example 120 238 methyl {(2S)-I-[(2S)-2-{5-l(2R,5R)-I-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2 [(niethoxycarbonyl)aninoJ-3-methylbutanoyl)pyrrolidin-2-ylj-I H-henzimidazol-5-ylpyrrolidin-2 yl]-l H -benziiidazol-2-ylpyrrolidin-1-yl]-3-imethyl-I -oxobutan-2-yl}carbanate 5 Example 120A 4-(2-Fluoro-4-nitrophenyl)mnorpholine A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and dibasic potassium phosphate (9.44 g, 54.2 mmol) in DIMSO (27 ml.,) was treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g, 27.1 mmol) was warmed at 60 *C for 18 h. The solution was cooled and diluted with ethyl acetate 10 and extracted with water (3 x) and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded the title compound (6.32 g, ca. 100%) as a yellow solid. 'H NMR (400 MHz, CDC 3 ) 8 8.00 (ddd, J = 9.0, 2.6, 0.9 liz, I H), 7.92 (dd, J = 13.1, 2.6 Hz, I H), 6.92 (t, J = 8.8 Hz, I H), 3.88 (in, 4 H), 3.29 (dd, J = 5.5, 4.0 H z, 4 H). MS +DCI m/z (rel abundance) 227 (10, M+H), 244 (100, M+NI-4). 15 Example 120B 3-Fluoro-4-morpholinoaniline A solution of the compound of Example 120A (2.26 g, 10.00 inmol) in ethyl acetate (35 ml-) was treated with 10% palladium on carbon (300 mg) followed by hydrogenation under one 20 atmosphere pressure for 6 h. The mixture was filtered through celite and concentrated in vacuo to afford the title compound as a white solid. Example 120C 4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin--yl)-2-fluorophenyl)morpholine 25 A solution of the compound of Example 109C (2.00 g, 4.99 mmol) and triethylamine (4.17 mL, 3.03 g, 29.9 mmol) in dry dichloromethane (25 niL) at 0 *C was treated with methanesulfonyl chloride (1.17 mL, 1.71 g, 14.96 mnol) followed by stirring at 0 *C for 30 min. The solution was warned to RT and then concentrated in vacuo. The residue was combined with the compound of Example 120B and N,N-dinethylaniline (1.26 mL, 1.21 g, 9.98 inniol) and dissolved in dry DMF (14 30 niL) followed by warming at 50 C for 2 i. The solution was cooled and diluted with ethyl acetate, followed by extraction with water (3 x) and I N hydrochloric acid solution (2 x) and saturated sodium chloride solution. Drying (Na 2

SO

4 ) and concentration in vacuo afforded an orange oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-80% ethyl acetate in hexanes. These procedures afforded the title compound (1.39 g, 50%) as an orange rigid foam. 'H NMR (400 35 MHz, CDC 3 ) 8 7.92 (in, 2 1-1), 7.58 (i, 9 H-), 7.31 (dd, . = 8.3, 2.1 Hz, 2 H), 6.69 (s, 1 1H1), 5.99 (m, 2 H), 5.20 (d, J= 7.1 Hz, 2 H), 3.79 (i, 4 H), 2.92 (in, 6 H), 2.54 (m, 2 H), 1.88 (in, 2 H). 239 Example 1201) Diiethyl (2R,2'R)- 1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)- 1-(3-fluoro-4-morpholinophenyl)pyrrolidin-2,5 diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3 5 methyl-I -oxobutane-2, I -diyl)dicarbamate In a microwave tube, a suspension of the Example 120C (1.39 g, 2.48 mmoL), the compound of Example I 16C (2.02 g, 7.43 mmol), XantPhos (129 mg, 0.22 mmol) and cesium carbonate (2.42 g, 7.43 mmoL) in dioxane (14 ml..) was degassed by nitrogen sparge for 30 mini. The mixture was treated with tris(dibenz.ylideneacetone)dipalladium (0) (68 mg, 0.074 mmol) followed by degassing 10 for another 5 min. The microwave tube was sealed and the mixture was warmed at 100 *C for 2 h. The mixture was cooled and diluted with ethyl acciate and extracted with water (3 x) and saturated sodium chloride solution. The solution was dried (Na 2

SO

4 ) and stirred overnight with 3 (mercaptopropyl) silica gel. Filtration and concentration in vacuo afforded a solid, which was chromatographed over a 340 g silica gel cartridge, eluding with 0-10% methanol in dichloromethane. 15 These procedures afforded the title compound as an orange solid. 'H NMR (400 MHz, DMSO-d6) 6 ppm 0.80-0.90 (in, 12H) 1.74 (br s, 21-) 1.82-2.03 (in, 10H) 2.08-2.20 (in, 2H) 2.71-2.81 (m, 41H) 3.52 (s, 6H) 3.62 (in, 4H) 3.76 (s, 2H) 4.02 (m, 2H) 4.50 (d, J=4.4 Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H) 6.72-6.81 (im, I H) 7.32 (d, J=8.4 Hz, 2H) 7.47-7.60 (mn, 4H) 7.80 (d, J=1.5 Hz, 2H) 10.41 (s, 2H). MS (ES) i/z 1031 (M+H)*. 20 Example 120E Dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(3-fluoro-4-morpholinophenyl)pyrrolidine 2,5-diyl)bis(2-amino-4,1-phenylene)bis(azanediyl)bis(oxoniethylene)bis(pyrrolidine-2,1diyl)bis(3 methyl- I -oxobutane-2, I -diyl)dicarbamate 25 To a solution of Example 120D (640 mg, 0.621 mninol) in EtOH (4 mL) and THF (4 iiiL) was added PMO 2 (35 ing) and the solution was stirred under a balloon of 1-12 gas for 16 h. The solution was filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound (322 mg, 0.332 imol, 53%). 30 Example 120F methyl ((2S)-I-[(2S)-2-(5-[(2R,5R)-l-[3-fluoro-4-(imorpholin-4-yl)phenyl]-5-(2-[(2S)-1-((2S)-2 [(imcthoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-IH-benziimidazol-5-yl pyrrolidin-2 yI]-I H-bentzi midazol-2-yIlpyrrolidin-1-yl]-3-methyl- I -oxobutai-2-yl}carbamate To a solution of Example 120E (320 img, 0.33 mniol) in toluene (1.5 iL) was added glacial 35 acetic acid (0.057 mL, 0.99 minol) and the solution was stirred at 50 *C for 3 h. The cooled solution was concentrated in vacuo and azeotroped 2 times with toluene. The crude product was purified by 240 flash chromatography on silica gel eluting with 0-4% CH 3

OH/CH

2

C

2 to give the title compound (100 mg, 0.107 mmol, 32%). 'H NMR (400 MIHz, DMSO-d6) 6 ppm 0.72-0.92 (i, 12H) 1.69 (br S, 2H) 1.81-2.10 (im, 8H) 2.11-2.28 (in, 4H) 2.64-2.78 (im, 4H) 3.54 (s, 6H) 3.59 (s, 4H) 3.73-3.92 (in, 41-1) 4.06 (s, 2H) 5.02-5.21 (in, 2H) 5.36 (s, 2H) 6.03-6.14 (m, 2H) 6.60-6.73 (m, H) 7.00-7.15 (in, 2H) 5 7.15-7.37 (i, 4H) 7.36-7.61 (m, 2H) 12.06 (br s, 21-). MS (ES[) nz 935 (M+H)*. Example 121 methyl [(2S)- 1-((2S)-2-[5-(4-{(2S,3R,4R,5S)-I-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 10 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl]-I H-itmidazol-5-yl }phenyl)-3,4-bis[2 (2-imethoxyethoxy)ethoxylpyrrolidin-2-ylphenyl)-Il-imidazol-2-yl]pyrrolidin-1-yi}-3-methyl-I oxobutan-2-yl]carbamate 3.4-0-isopropylidene-D-mannitol was processed using sequentially the methods of Examples 79C, 791) (1-bromo-2-(2-methoxyethoxy)ethane as the alkyating agent with added sodium iodide), 15 79E-79G, 791-1 (18 hour reaction time), 66D, and 66E to provide the title compound (46 ig) as a light yellow solid. 'H NMR (400 MHz, DMSO-d 6 ) 6 7.60 (d, J = 7.9 H-z, 4 H), 7.50 (d, J = 8.4 Hz, 2 -I), 7.38 (s, 2 H), 7.29 (d, J = 8.6 H z, 2 1-), 7.19 (s, 4 H), 6.90 (in, 2 H), 6.27 (d, J = 8.6 H z, 2 H), 5.37 (s, 2 11), 5.07 (d. J = 3.6 lIz, 2 11), 4.32 (s, 2 H1), 4.06 (i, 2 H-), 3.78 (d, J = 6.0 lz, 2 1H1), 3.66 (d, J= 4.2 l z, 4 11), 3.53 (s, 6 1), 3.17 (s, 6 11), 2.10 (in, 4 11), 1.93 (m,4 H1), 1.07 (s, 9 11), 0.86 (m, 12 H-). MS 20 (+ESI) m/t (rel abundance) 1177 (100, M+1), 1199 (5, M+Na). Example 122 methyl {(2S)-I-[(2S)-2-(5-(4-[(2S,3R,4R,5S)- I-(4-icrt-butylphcnyl)-5-(4-{2-[(2S)-I-f(2S)-2 25 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-5-yllphenyl)-3,4-bis(3 241 methoxypropoxy)pyrrolidin-2-yl]phenyl}-I H-imidazol-2-yl)pyrrolidin-1 -ylI-3-methyl- I -oxobutan-2 yl Icarhamate 3.4-0-isopropylidene- D-mannitol was processed using sequentially the methods of Examples 79C, 79D (1-bromo-3-methoxypropane as the alkyating agent with added sodium iodide), 79E-79H, 5 66D, and 66E to provide the title compound. 'H NMR (400 MHz, DMSO-d 6 ) 6 7.60 (s, 4 H), 7.52 (in, 2 H), 7.37 (in, 2 1-1), 7.30 (i, 4 11), 7.18 (d, J = 7.1 Hz, 4 11), 6.91 (m, 2 11), 6.24 (n, 2 H-), 5.40 (in, 2 H-1), 5.06 (m, 2 H), 4.31 (m, 2 H), 4.11 (m, 2 H), 3.78 (s, 4 H), 3.66 (m, 4 H), 3.56 (in, 10 H), 3.14 (in, 14 -), 2.14 (m, 6 H), 1.94 (d, J= 3.5 Hz, 8 H), 1.43 (m, 6 H), 1.07 (s. 10 H), 0.89 (d, = 6.1 Hz, 6 H), 0.84 (d, = 5.9 Hz, 6H). 10 /10 Example 123 methyl ((2S)-I-[(2S)-2-(5-{4-[(2S,3R,4R,5S)- I-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(imethoxycarbonyl)anino]-3-iethylbutanoyl}pyrrolidin-2-yl]-IH-itnidazol-5-yl}phenyl)-3,4-bis(2 15 methoxyethoxy)pyrrolidin-2-yl]phenyl}- I H-imidazol-2-yl)pyrrolidin-1-yl]-3-iethyl-1-oxobutan-2 yl carbamate 3.4-O-isopropylidene-D-imannitol was processed using sequentially the methods of Examples 79C, 79D (-bromo-2-methoxyethane as the alkyating agent with added sodium iodide), 79E, 79F, 79G, and 791-1, wherein Examnple 1 26C replaced (S)-ten-bunyl-2-(4-broio- III .iniidazol-2 20 yl)pyrrolidinc-l-carboxylatc in applying the method of Example 791H, to provide the title compound (43 mg) as a light beige solid. 'H NMR (400 MHz, DMSO-d 6 ) 6 7.60 (d,I= 8.0 Hz, 4 H), 7.47 (in, 2 H), 7.37 (n, 2 1-1), 7.27 (m, 4 H), 7.19 (s, 4 H), 6.90 (d, J= 8.6 Hz, 2 H), 6.26 (d, J = 8.7 Hz, 2 H), 5.37 (s, 2 HI), 5.06 (d, J = 3.7 Iz, 2 11), 4.30 (s, 2 1-1), 4.03 (in, 2 11), 3.79 (s, 4 11), 3.66 (m, 6 I-), 3.53 (s, 6 H), 3.25 (in, 6 H), 3.12 (s, 6 H), 2.13 (in, 4 H), 1.94 (m, 6 1-1), 1.07 (s, 9 H), 0.89 (d, J = 6.6 H z, 6 25 H), 0.84 (d,./ = 6.6 Hz, 6 H). MS +ESI m/7 (rel abundance) 1088 (100, M+H). 242 0 Example 124 methyl [(2S)-I-(2S)-2-(6-((2R,5R)-5-12-I(2S)-1-{(2S)-2-|i(methoxycarbonyl)aiino l-3 imethylbut anoyl }pyrrolidin-2-yll -lI H-benzimidazol-6-yl ) -- [6-(morpholin-4-yl)pyridin-3 5 ylJpyrrolidin-2-yl} -i--henzimidazol-2-yl)pyrrolidin-I-ylJ-3-methyl-1-oxobutan-2-yl carbamate Example 109C and Example 154B were processed using the methods of Examples 113A, 1 13B, 116F, 281 (reaction conducted at 50 *C for 4 h), 66D, and 66E to provide the title compound (120 ing) as a light beige solid. 'H NMR (400 MIHz, DMSO-d 6 ) 8 12.03 (s, I H), 7.46 (d, J = 8.2 lz, I H), 7.45 (s, I H), 7.31 (d, J = 6.4 Hz, 3 H), 7.21 (s, 1 1-1), 7.06 (t, i = 8.0 Hz, 2 H), 6.64 (i, 1 H), 10 6.49 (in, I H), 5.36 (d, J = 6.2 Hz, 2 H), 5.13 (s, 2 H), 4.04 (in, 2 H), 3.77 (in, 3 H), 3.55 (m, 9 H), 3.04 (s, 4 H), 2.19 (s, 3 H), 1.95 (m, 5 1-1), 1.73 (s, 3 H), 0.82 (i, 12 H). MS +ESI m/z (rel abundance) 918 (100, M+H). Hb- 0 t H- / 15 Example 125 methyl {(2S)-I-[(2S)-2-(5-{4-[I-(2,3-dihydro-1H-inden-5-yl)-5-(4-{2-[(2S)-1-{(2S)-2 f(methoxycarbonyl)aminol-3-methylbutanoyl pyrrolidin-2-yl1-11l-imidazol-5-yl phenyl)- IH-pyrrol 2-yljphenyl}l- l-imidazol-2-yl)pyrrolidin-1-ylJ-3-methyl-I-oxobutan-2-ylicarbamate Example 26E and 5-aminoindan were processed using the methods of Examples 76A, 39E, 20 39F, 55G, and 26J (reaction solvent = dichloromethane) to provide the title compound (0.1446 g). '-1 NMR (400 MHz, DMSO-D6) 8 0.91 - 0.79 (i, 121-1), 2.18 - 1.87 (tn, 12H), 2.74 (t, J = 6.7, 21-1), 2.86 (t, J = 6.8, 211), 3.53 (s, 611), 3.84 - 3.68 (m, 411), 4.10 - 3.98 (m, 2H), 5.03 (dd, J = 6.8, 2.9, 211), 6.54 - 6.40 (m, 2H), 7.10 - 6.86 (m, 5H), 7.22 - 7.13 (in, 2H), 7.33 - 7.22 (m, 2H), 7.45 - 7.35 (m, 21-1), 7.53 (dd, J= 13.7, 8.5, 41-1), 11.70 (s, 111), 12.07 - 11.96 (in, 111). MS (ESI) m/z 920 (M+1-1)+, 918 (M-1)+. 25 243 F F, I F F F 0 H 0 T Example 126 methyl [(2S)-i-((2S)-2-[5-(4-((2R,5R)-5-(4-{2-[(2S)-1-((2S)-2-[(imethoxycarbonyl)amino]-3 methylbutanoyl }pyrrolidin-2-yl]-1 H-imidazol-5-yl }phenyl)-I-[4-(pentafluoro-lambda-6- 5 sulfanyl)phenyllpyrrolidin-2-yl1phenyl)-l --imidazol-2-yl]pyrrolidin-1-yl )-3-me thyl-1-oxobutan-2 yl]carbamate Example 126A (S)-2-(methoxycarbonylanino)-3-nethylbutanoic acid 10 A mixture of (S)-2-amino-3-methylbutanoic acid (10.0 g, 85.0 mmol), NaOl- (3.41 g, 85.0 mmol) and NaHCO 3 (4.7 g, 44.4 nmol) in H 2 0 (85 mL) was cooled to 0 *C. A mixture of methyl chloroformate (7.3 mL, 94.0 mmol) dissolved in Et20 (40 ml-) was slowly added to the aqueous mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pl- 2.0 with HCI (conc). The mixture was extracted with CH1 2

CI

2 (3 x 100 m.L) and then dried (MgSO 4 ), filtered 15 and concentrated to afford 7.5 g (50%) of the title compound. MS (ESI) m/z 176 (M+l)*. Example 126B (S)-tert-butyl 2-formnylpyrrolidine-l -carboxylate A mixture of oxalyl chloride (14.1 mL, 161 nmol) in Cll 2

C

2 (331 mL) was cooled to -75 *C. 20 Dimethylsulfoxide (19.4 ml., 273 mmol) in CH 2

CI

2 (70 ml..) was slowly added over 30 minutes followed by stirring at -75 *C for an additional 15 minutes. At -75 *C (S)-tert-butyl 2 (hydroxymethyl)pyrrolidine- I -carboxylate (25.0 g, 124 mmol) in CH 2

CI

2 (132 tnL) was added slowly over one hour, followed by a further 15 minutes of stirring. Then, still at -75 *C, Et 3 N (87 mL, 621 nmol) was added over 30 minutes followed by another 15 minutes of stirring. Mixture was then 25 allowed to stir at 0 *C for 90 minutes. Mixture was quenched with 10% aqueous Citric acid at 0 *C. The mixture was diluted with 10% aqueous Citric acid and partitioned. Organic was washed with 1120 (5 x 150 muL) and Brine. The organic was then dried (MgSO 4 ), filtered and concentrated to afford 24.7g (100%) of the title compound. MS (ESI) m/z 200 (M+H)*. 30 Example 126C 244 (S)-tert-butyl 2-(1 H-iimidazol-2-yl)pyrrolidine-I -carboxylate A mixture of Example 1261B (24.7g, 124.0 inmol) and NH 4 0H (62.0 mL, 497 nimol) in methanol (62 mL) was stirred at 0 *C followed by slow addition of glyoxal hydrate (29.9 nL, 262 nitol) over 10 minutes. Mixture was stirred for 16 hours at ambient temperature. The mixture was 5 concentrated, diluted with H 2 0 and extracted with EtOAc (3 x 200 mL). The organic was then dried (MgSO 4 ), filtered and concentrated. Purification by trituration with IBuOMe afforded 15.5g (53%) of the title compound. MS (ESI) n/z 238 (M+H)*. Example 126D 10 (S)-tert-butyl 2-(4,5-dibromo- IH-iimidazol-2-yl)pyrrolidine-1-carboxylate A mixture of Example 126C (15.5 g, 65.4 nunol) in CH 2

CI

2 (260 mL) was stirred at 0 'C followed by portion-wise addition of 1-bromopyrrolidine-2,5-dione (24.5, 137.0 nunol) over 10 minutes. Mixture was stirred 0 *C for 90 minutes. Mixture was concentrated, diluted with EtOAc (600 miL) and washed with H12O (3 x 200 mL) and brine. The organic was then dried (MgSO,), 15 filtered and concentrated. Purification by trituration with Et 2 O afforded 24.9 g (96%) of the title compound. MS (ESI) nz 396 (M+l1)*. Example 126E 20 (S)-tert-butyl 2-(5-bromo- I H-imidazol-2-yl)pyrrolidine- I -carboxylate A mixture of Example 126D (12.5 g, 31.5 innol) in dioxane (400 mL) and H 2 0 (400 mL) had a solution of Na 2

SO

2 (43.7 g, 347 nmol) in H20 (400 mL) added and was heated to reflux for 21 hours. The mixture was concentrated to half volume and extracted with C1 2 Cl 2 (3 x 200 inL). The organic was then washed with brine, dried (MgSO 4 ), filtered and concentrated. Purification by 25 trituration (CH 2

CI

2 , tBuOMe, and Hlexanes) afforded 5.2 g (52%) of the title compound. MS (ESI) m/z 317 (M+1H)*. Example 126F (S)-5-bromo-2-(pyrrolidin-2-yl)- I H-imidazole hydrochloride 30 A mixture of Example 126E (5.0g, 15.8 nunol) in 4M HICI/Dioxane (40 mnL) was allowed to stir for one hour. The mixture was concentrated to afford 3.99g (100%) of the title compound. MS (ES1) m/z 217 (M+H)*. Example 126G 35 methyl (S)-1-((S)-2-(5-bromo- IH-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-I-oxobutan-2-ylcarhamatc 245 A mixture of Example 126F (3.

9 9g, 15.8 miol), Example 126A (2.77 g, 15.8 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.63 g, 19.0 mmol), 1-Hydroxy benzotriazole hydrate (2.90 g, 19.0 mmol) and N-melhylmorpholine (12.2 mL, 111.0 nunol) in DMF (150 nL) were allowed to stir overnight. Mixture was diluted with H120 and extracted with EtOAc (3 5 x 300 mL). The organic was washed with H 2 0 and Brine. The organic was then dried (MgSO 4 ), Filtered and concentrated. Purification by chromatography (silica gel, 75% EtOAc in lexanes) afforded 5.2 g (88%) of the title compound. 'H NMR (400 MHz, DMSO-d) 6 ppm 0.79 (dd, J=6.67, 3.63 H-z, 6 H), 1.84 - 1.96 (in, 3 H), 2.02 - 2.14 (m, 2 H), 3.51 (s, 3 H), 3.66 - 3.80 (m, 2 H), 3.96 4.03 (m, I -1), 4.91 - 4.99 (i, I H), 7.06 (d, J=1.52 -lz, I H), 7.26 (d, J=8.46 Hz, 1 H), 12.01 (s, I H). 10 MS (ESI) i/z 373 (M+H)*. Example 12611 (IS,4S)-1,4-bis(4-bronophenyl)butane-1,4-diol (IS,4S)-1,4-bis(4-bromophenyl)butane-1,4-diol was prepared using the method of Example 15 69A and (R)-alpha, alpha-diphenyl-2-pyrrolidinemethanol). F F1, F F' 'F Br Br Example 1261 (2R,5R)-2,5-bis(4-broimophenyl)-I-(4-sulfur pentafluoride phenyl)pyrrolidine 20 A solution of iethanesulfonic anhydride (2.95 mL, 23.02 imol) in 2-Me THF (15 ml-) was cooled in ice/salt bath to -U'C. To this cold solution a solution of Example 12611 (4.0524 g, 10.13 nmol) and N,N-diisopropylethylamine (5.5 mL, 31.8 mmol) in 2-Me TIF (40 mL) was added dropwise over 40 minutes. The reaction was slowly warmed to 20 *C. At this time 4 aminophenylsulfur pentafluoride (7.1238 g, 32.5 minol) was added and the mixture was warmed to 38 25 "C for 17 hours. [he reaction was cooled and partioned between EtOAc and water. lie organic fraction was washed with water (2 x) brine (I x) and concentrated. Purification by flash chromatography (silica gel, EtOAc/hexane) afforded the title compound (1.95 g, 33%). LC/MS Rt 2.38 m/z 584 (M+H)+. 30 Example 126J 246 (2R,5R)-1 -(4-sulFur pentafluoride phenyl)-2,5-bis(4-(4,4,5,5-tetraimethyl-l,3,2-dioxahorolan-2 yl)phenyl)pyrrolidine The product from Example 1261 was processed using the method described in Example 39E to afford the title compound (1.67 g, 74%). MS (ESI) m/ 678 (M+1-1)+. 5 Example 126K methyl [(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)aimino]-3 methylbut anoyl )pyrrolidin-2-ylI -I H-imidazol-5-yl phenyl)- I -[4-(pentafluoro-lambda-6sulfanyl)phenyllpyrrolidin-2-yl}phenyl)- IH-imidazol-2-yllpyrrolidin- I-yl}-3-methyl-I-oxobutan-2 10 yllcarbamate The product from Example 126J and Example 126G were processed using the method described in Example 39F to afford the title compound (0.75 g, 30%). 'H NMR (400 MHz, DMSO d6) 8 0.85 (dd, J = 6.7, 15.8, 12H), 2.26 - 1.66 (in, 14H), 3.53 (s, 6H), 3.87 - 3.63 (mn, 41-1), 4.14 3.91 (in, 21-1), 5.06 (dd, J = 3.0, 6.7, 2H-1), 5.34 (s, 2H), 6.34 (d, J = 9.1, 21-1), 7.17 (d, J = 8.2, 41-1), 7.26 15 (dd, J= 8.4, 17.3, 21-1), 7.75 - 7.34 (m, 81-1), 12.22 - 11.46 (in, 2H). MS (ESI) m/t 1010 (M+H)*, 1008 C~N (M-H)*. 0 0 \HN -. NH Example 127 20 methyl [(2S)-1-{(2S)-2-[5-(4-{ 1 -[4-(azepan-1-yl)phenyl]-5-(4-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)anino]-3-mnethylbutanoyl}pyrrolidin-2-yl]-I 1H-imidazol-5-yl}phenyl)-1H-I-pyrrol 2-yl phenyl)-1 H -imidazol-2-yllpyrrolidin-1-yl)-3-methyl-I-oxobutan-2-yllcarbamate Example 26E and 4-(1 -azepanyl)aniline were processed using the methods of Examples 76A, 39E, 39F, 55G, and 26J (reaction solvent = dichloromethane) to provide the title compound (6.1 mg). 25 MS (LSl) n/z 977 (M+l)+. 247 NNH 00 Example 128 methyl {(2S)-I-[(2S)-2-(5-{4-[(2R,5R)-1-(4-cyclohexylphenyl)-5-(4-{2-l(2S)-1-{(2S)-2 [(imethoxycarbonyl)amino]-3-methylbutanoyl)pyrroliclin-2-yl]- IH-iiidazol-5-ylpIphenyl)pyrrolidin 5 2-yllphenyl}-1H-iiidazol-2-yl)pyrrolidin-1-yI]-3-methyl-I-oxobutan-2-yl carbamate Example 126H and 4-cyclohexylaniline were processed using the methods of Examples 1261, 126J, and 126K to provide the title compound (0.14 g).'H NMR (400 Ml-lz, DMSO-D6) 6 0.85 (dd, J = 16.6, 6.9, 1211), 1.32 - 1.06 (in, 811), 1.65 (dd, 1= 19.1, 6.2, 711), 2.27 - 1.82 (m, 1311), 3.53 (s, 611), 3.78 (d, J= 6.8, 2H), 4.10 - 3.95 (in, 2H), 5.06 (dd, J = 6.9, 3.1, 2H), 5.19 (t, J= 6.7, 21), 6.21 (d, J = 10 8.7, 2FH), 6.76 (dd, J = 8.6, 3.7, 2H), 7.19 - 7.08 (in, 4H), 7.34 - 7.19 (i, 21-), 7.37 (d, J = 1.8, 1 1H), 7.50 (t, .1= 11.3, 1 H), 7.65 - 7.57 (i, 3H), 11.68 (s, I H), 12.10 - 11.93 (m, I H). MS (ESI) m/z 966 (M+H)+. HNJNH r 0 15 Example 129 methyl {(2S)- I-[(2S)-2-(4-chloro-5-{4-[(2R,5R)-5-(4-{4-chloro-2-[(2S)-I-{(2S)-2 [(methoxycarbonyl)anino]-3-methylbutanoyl}pyrrolidin-2-yl]-IH-iinidazol-5-yl)phenyl)-I-(4 cyclohexylphenyl)pyrrolidin-2-yl]phenyl)-1F-imidazol-2-yl)pyrrolidin-1-yli-3-iethyl-1-oxobutun-2 yl)carbaiate 20 N-Chlorosucciniiide (0.046 g, 0.342 minol) was added to a solution of the product from Example 128 (0.1435 g, 0.149 iniol) in dichloromethane (7 in.L) and stirred at ambient temperature for 17 hours. The reaction was diluted with dichloromethane and washed with sat aq Nal-C03 (2 x) and concentrated. The residue was purified by flash chromatography (silica gel, MeOH/dichloromethane) then by prep H1PI.C to afford the title compound (20.4 ing, 13%). 1H NMR 25 (free base) (400 MI-lz, DMSO-D6) 6 0.94 - 0.73 (im, 12H), 1.39 - 0.99 (in, 8H), 1.75 - 1.41 (in, 6H), 248 2.27 - 1.77 (im, 12H), 3.53 (s, 6H), 3.86 - 3.66 (in, 3H), 4.08 - 3.96 (in, 21H), 5.11 - 4.89 (in, 2H), 5.30 - 5.12 (in, I H), 5.55 - 5.33 (in, 1 H), 6.21 (d, J = 8.7, 11H1), 6.88 - 6.67 (in, 2H), 6.94 (dd, J = 4.3, 8.4, l-1), 7.42 - 7.02 (im, 611), 7.56 - 7.42 (in, 311), 7.61 (t, J = 8.5, 1H), 11.68 (d, J = 10.7, 11-), 12.49 12.26 (in, I H). MS (ESI) m/t 1034 (M+H)+. 5 N 0r Example 130 methyl [(2S)-I-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-((methoxycarbonyl)anino]-3 methylbutanoyl }pyrrolidin-2-yl] -11-i midazol-5-yl Iphenyl)- I -[4-(inorpholin-4-yl)phenyl]pyrrolidin 10 2-yl I phenyl)-I H -imidazol-2-yllpyrrolidin-1-yl -3-methyl-i-oxobutan-2-yflcarbamate Example 126H and 4-morpholinoaniline were processed using sequentially the methods of Examples 1261, 39E, 39F, 391, and 26J reactionn solvent = dichloromethane) to provide the title compound (0.16 g). 'H NMR (300 MHz, DMSO-D6) 6 0.86 (dd, 1= 12.2, 6.6, 12H), 1.77 - 1.55 (in, 211), 2.03 - 1.77 (in, 611), 2.21 - 2.03 (i, 411), 2.45 - 2.39 (in, 111), 2.58 - 2.54 (in, IH), 2.82 - 2.74 (in, 15 4H), 3.53 (s, 61H), 3.67 - 3.57 (in, 4H), 3.77 (d, J = 6.1, 311), 4.04 (t, J = 8.3, 2H), 5.06 (dd, J = 6.7, 3.0, 2H), 5.18 (1, J = 5.0, 2H), 6.22 (d, J = 9.0, 2H), 6.58 (dd, 1= 9.0, 1.9, 2H), 7.14 (d, J = 8.4, 4H), 7.32 - 7.17 (in, 3H), 7.37 (d, J = 1.8, 2H), 7.55 - 7.41 (i, I H), 7.63 (t, .1 = 10.0, 411), 11.68 (s, 1H), 12.15 - 11.90 (m, 1H). MS (ESI) m/z 969 (M+H)+. F NF F N, N N SNH 200 20 0b o Example 131 methyl [(2S)-I-((2S)-2-[4-chloro-5-(4-((2R,5R)-5-(4-[4-chloro-2-[(2S)-1-((2S)-2 [(methoxycarbonyl)aminol-3-methylbutanoyl pyrrolidin-2-yll-Il-l-iinidazol-5-yl phenyl)-1-[4 249 (pentafluoro-lambda-6--sulfanyl)phenyljpyrrolidin-2-yl Iphenyl)- 1 H-imidazol-2-ylpyrrolidin- I -yl} 3-methyl- I -oxobutan-2-yl]carhamate The product from Example 126K was processed using the method described in Example 129. The mixture of mnono and dichlorinated products was purified via reverse phase HPLC to afford the 5 title compound (90.9 mg, 19%). 'H NMR (free base) (500 MHz, DMSO-D6) 6 0.84 (dd, J = 6.8, 16.1, 1211), 2.23 - 1.70 (in, 1311), 3.53 (s, 611), 3.85 - 3.66 (in, 411), 4.02 (ddd, J = 4.8, 10.8, 16.1, 311), 5.05 - 4.91 (m, 21-), 5.43 (d, . = 5.8, 2H), 6.36 (d,./ = 9.1, 2H), 7.28 (d,./ = 8.4, 2H), 7.34 (d,. = 8.3, 4H), 7.46 (d, J = 9.4, 2H), 7.72 - 7.58 (in, 41-), 12.43 (s, 2H). MS(ESI) tz 1078 (M+H-)*. F FF cl No, N 10 < Example 132 methyl [(2S)-I -{ (2S)-2-[4-chloro-5-(4-{(2R,5 R)-5-(4-{2-[(2S)- I -I (2S)-2-[(methoxycarbonyl)amino] 3-imethylbuianoyl }pyrrolidin-2-yI]-l i i-midazol-5-ylphenyl)-1-[4-(pentafluoro-laimbda-6sulfanyl)phenyljpyrrolidin-2-ylIphenyl)- I --iiidazol-2-yl]pyrrolidin-i -yl}-3-methyl-I-oxobutan-2 15 ylicarbaiate The product from Example 126K was processed using the method described in Example 129. The mixture of mono and dichlorinated products was purified via reverse phase HPLC to afford the title compound (33.3 mg, 7%). 'H NMR (free base) (500 MHz, DMSO-D6) 80.94 - 0.76 (m, 12H), 2.24 - 1.63 (m, 13H), 3.53 (d, J = 1.2, 6H), 3.86 - 3.68 (m, 4H), 4.10 - 3.98 (m, 2H), 5.02 - 4.93 (m, 20 1 H), 5.06 (dd, J = 3.2, 7.1, 1 H), 5.48 - 5.30 (m, 2H), 6.35 (d, J= 9.1, 21-1), 7.21 -7.10 (m, 2H), 7.36 7.21 (i, 4H), 7.58 - 7.38 (in, 4H), 7.73 - 7.59 (m, 4H), 12.50 - 11.65 (in, 2H). MS (ESI) mL/z 1044 (M+H)*, 1042 (M-H). Q 0' 25 Example 133 250 methyl [(2S)- 1-1(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino j-3 niethylbutanoyl pyrrolidin-2-yl]-I H-imidazol-5-yl ) phenyl)-1-[6-(piperidin-l -yl)pyridin-3 yl]pyrrolidin-2-yl Iphenyl)- I H-imidazol-2-yl]pyrrolidin- 1 -yl }-3-methyl-I -oxobutan-2-yl]carbamate Example 12611 and 6-(piperidin- I -yl)pyridine-3-amine were processed using sequentially the 5 methods of Examples 1261, 39E, 39F, 391, and 26J (reaction solvent = dichloromethane) to provide the title compound (91.4 mg). 'H. NMR (400 MIH z, DMSO-D6) 8 0.85 (dt, J = 7.1, 14.3, 1211), 1.24 (s, 2H), 1.44 (s, 6H), 1.70 (d, J= 5.2, 2H), 2.04 - 1.82 (i, 6H), 2.23 - 2.04 (m, 4H), 3.21 - 3.03 (m, 4H), 3.53 (s, 61-), 3.87 - 3.67 (i, 4H), 4.12 - 3.96 (m, 2H), 5.06 (dd, J = 3.2, 7.0, 2FH), 5.20 (t, J = 6.8, 2 H), 6.49 (dd, J = 3.1, 9.1, 1-1), 6.60 (dd, J = 2.9, 9.2, I H), 7.20 - 7.10 (i, 4 H), 7.33 - 7.20 (in, 10 3H), 7.38 (d, J= 1.8, 2H), 7.51 (t, J= 10.4, IH), 7.64 (dd, J= 8.1, 15.7, 3H), 11.69 (s, I.4H), 12.06 (t, J= 32.1, 0.6H). N O Q HN DL O NH Example 134 15 methyl {(2S)-I -[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-((2S)-2-[(methoxycarbonyl)aminol-3 imethylbutanoyl} pyrrolidin-2-yl]-I H-benzimidazol-6-yli-I -[6-(piperidin-1-yl)pyridin-3-yllpyrrolidin 2-yl }-i i-benziiidar.ol-2-yl)pyrrolidin-I-yl]-3-mcthyl-l -oxobutan-2-yl }carbamate Example 109C and 6-(piperidin-I -yl)pyridine-3-aminc were processed using sequentially the methods of Examples II 3A, I 13B, 11 6F (Ra-Ni reduction conducted in an SS pressure bottle for 120 20 min at 30 psi at room temperature), 281 (reaction conducted at 50 "C for 4 hours), 391, and 26J (reaction solvent = dichloromethane) to provide the title compound (71 ing). 'H NMR (400 MHz, METI1ANOL-D4) 6 0.89 (ddd. J= 6.5, 20.7, 26.0, 1211), 1.62 - 1.43 (in, 611), 2.48 - 1.80 (in, l311), 2.72 - 2.60 (in, 2H), 3.10 - 2.97 (in, 4H), 3.64 (s, 6H), 3.93 - 3.78 (m, 2H), 4.09 - 3.94 (m, 21-1), 4.22 (d,. = 7.3, 2H), 5.21 (dd,. = 5.2, 7.6, 1 H), 5.44 - 5.30 (n, 2H), 6.50 (d,. = 9.1, 1 H), 6.83 - 6.71 (in, 25 1 H), 7.59 -7.15 (im, 7H). MS (ESI) rm/z 916 (M+1-), 914 (M-H)*. 251 F FN N 0 Example 135 methyl [(2S)-1-{(2S)-2-[5-(4- { -[6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]-5-(4-{2-[(2S)-I-((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yI]-I H -imidazol-5-ylphenyl)- IH-pyrrol 5 2-ylphenyl)-1H-iiidazol-2-yllpyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yllcarbamate Example 135A 2-(4,4-difluoropiperidin-1-yl)-5 -nitropyridine To a slurry of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and 4,4-difluoropiperidine 10 hydrochloride (4.97 g) in ethanol (40 muL) at ambient temperature was added N,N diisopropylethylamine (12.00 mL, 69.4 mmol) and the mixture heated to 70 *C for 18 hours. The reaction was concentrated, partitioned between CH2CI2 and 1M NaOH. The organic phase concentrated and purified by chromatography (elution with 2% MeOH-CH2CI2 then 3% MeOH CH2Cl2) to provide the title compound as a yellow oil. MS (DCI) tnz 261 (M+-1NH 4 )*. 15 Example 135B 6-(4,4-difluoropiperidin- I-yl)pyridin-3-amine The product from Example 135A (4.56 g, 18.75 mmol) and solvent THF (20 imL)/DMF were added to Ra-Ni 2800, water slurry (4.56 g, 78 minol) in a 250 iL SS pressure bottle and stirred for 2 20 hr at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and washed with MeOH. The filtrate was concentrated and dried under vacuum to afford the title compound (3.40 g, 85%). 'H NMR (400 MHz, DMSO-D6) 8 2.03 - 1.88 (in, 4H), 3.49 - 3.38 (in, 4H), 4.61 (s, 2H), 6.73 (d, J= 8.8, IH), 6.93 (dd, J= 2.9, 8.8, IH), 7.61 (d, J= 2.6, 1 H). MS (ESI) m/z 214 (M+H*). 25 Example 135C 5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)- lH-imidazol-5-yl)phenyl)-1HI-pyrrol-1-yl)- 2 -(4,4 difluoropiperidin-1-yl)pyridine TFA (0.046 mL, 0.596 mmol) was added to a mixture of the product from Example 138B (0.2114 g, 0.298 minol) and the product from Example 135B (0.095 g, 0.447 minol) in toluene (2.98 252 mL..). The mixture was heated at 110 "C for 18 hours. The reaction was cooled and additional TFA (0.023 nil.,, 0.298 inmol) was added and stirred for another hour. The solvent was removed under reduced pressure and azatroped with toluene to afford the title compound. 5 Example 135D methyl [(2S)-I-{(2S)-2-[5-(4-{ I -[6-(4,4-difluoropiperidin-1 -yl)pyridin-3-yl]-5-(4-{2-[(2S)-1-{(2S)-2 [(nethoxycarbonyl)aminoJ-3-methylbutanoyl}pyrrolidin-2-yl]-lH-imidazol-5-yl phenyl)-IH-pyrrol 2-yl phenyl)-I H -imidazol-2-yljpyrrolidin-1-yli-3-methyl- I-oxobutan-2-yljcarhamate The product from Example 135C was processed using the method described in Example 26J 10 to afford the title compound. '1 NMR (400 MHz, DMSO-D6) 6 0.94 - 0.73 (in, 12H), 2.03 - 1.82 (in, 10H), 2.20 - 2.04 (im, 4H-1), 3.53 (s, 6H), 3.64 (s, 4H), 3.86 - 3.69 (m, 4H), 4.04 (dd, 2H), 5.04 (dd, J = 3.0, 7.0, 211), 6.53 - 6.39 (m, 211), 6.93 - 6.79 (m, I1 [), 7.06 (d, J = 8.4, 311), 7.13 (dd, J = 10.9, 19.3, I1), 7.30 - 7.21 (in, 211), 7.39 - 7.30 (m, 11H), 7.42 (d, J = 1.7, IH), 7.48 - 7.43 (m, 111), 7.66 - 7.49 (i, 41H), 7.85 (dd, J =2.7, 9.7, 1 H), 12.16 - 11.64 (in, 2H). MS (ESI) m/ 1000 (M+H)+, 998 (M-H)+. 15 F 0 FNO ,0 Example 136 methyl {(2S)-I -[(2S)-2-(4-{ 4-[5-(4-{2-[(2S)-1-{(2S)-2-[(meilioxycarbonyl)aiino]-3 imethylbulanoyl ) pyrroliclin-2-yl]- H-iimidazol-4-yl ) phenyl)-1- { 4-[(trifluoroumethyl)sulfonyl]phcnyl} 20 lI-pyrrol-2-yllphenyl)- 1H-iiidazol-2-yl)pyrrolidin-1-yl]-3-imcthyl-1-oxobutan-2-yl carbamate Example 136A 2,5-bis(4-bromophenyl)- 1 -(4-(trifluoromnethylsulfonyl)phenyl)- I H-pyrrole To a slurry of the product from Example 26E (0.60 g, 1.52 nunol) and 4 25 (trifluoromethylsulfonyl)aniline (0.51 g, 2.27 minol) in toluene (12 niL) was added a IN solution of iilanium(IV) chloride (1.6 mL, 1.6 ininol) in ioluenc. The mixture was stirred overnight at room temperature and then heated to reflux for 3 hours. The cooled mixture was filtered and the solid residue was suspended in a mixture of water and diethyl ether. The solid was diluted with water and ether and stirred vigorously for 15 minutes. The mixture was filtered and then washed thoroughly 253 with diethyl ether to give the title compound as a crude mixture that was used in subsequent reactions without further purification (0.60g, 68% yield crude). Example 136B 5 methyl ((2S)-I-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 inethylbutanoyl)pyrrolidin-2-yl]-llH-imidazol-4-yl)phenyl)-1{4-[(trifluoromethyl)sulfonyl]phenyl} IH-pyrrol-2-ylJphenyl)-lI H-inidazol-2-yl)pyrrolidin-1-ylJ-3-methyl-I-oxobutan-2-yl carbamate Example 136A was processed using sequentially the methods of Examples 26G, 26H, 65B, and 65C to provide the title compound (90 mg). '-I NMR (400 MHz., DMSO-D6) S 12.20- 11.68 (in, 10 2H-1), 8.17 - 8.04 (in, 2H), 7.63 - 7.42 (in, 8H), 7.31 - 7.15 (i, 2H), 7.02 - 6.90 (i, 4H), 6.64 - 6.53 (in, 2H), 5.08 - 4.97 (in, 2H), 4.05 - 3.97 (in, 2H), 3.83 - 3.69 (in, 4H-1), 3.53 (s, 6H), 2.18 - 1.79 (in, 1011), 0.90 - 0.78 (in, 1211). MS (ESI; M+Hl) m/z = 1013. N H /NH ( N / 15 Example 137 methyl [(2S)-1-{(2S)-2-14-(4-{ 1-[4-(2-cyanopropan-2-yl)phenyl J-5-(4-{2-[(2S)-I -{(2S)-2 [(methoxycarbonyl)amino]-3-imethylbutanoyl} pyrrolidin-2-yl]-I H-iimidazol-4-yl iphenyl)- 1--pyrrol 2-yl)phenyl)-I H-imidazol-2-yl]pyrroliclin- 1-yl}-3-methyl-I-oxobutan-2-yl]carbamate Example 26E and 2-(4-aminophenyl)-2-mnethylpropanenitrile were processed using 20 sequentially the methods of Examples 26F, 26G, 2611, 6513, and 65C to provide the title compound (100 mg). 1H NMR (400 MHz, DMSO-D6) 8 12.15 - I 1.68 (in, OH), 7.58 - 7.44 (i, OH), 7.44 - 7.36 (in, O1-), 7.30 - 7.12 (m, OH), 7.07 - 6.91 (m, OH), 6.55 - 6.42 (m, OH), 5.06 - 4.96 (m, OH), 4.02 (t,.J = 8.3, 0-H), 3.81 - 3.67 (mi, OH), 3.52 (s, OH), 2.15 - 1.82 (in, OH), 1.65 (s, OH), 0.90 - 0.74 (m, I H). MS (ES; M+H) n/z = 948. 25 254 H /P Example 138 methyl {(2S)- I-[(2S)-2-(4-{4-[-(3-tert-butylphenyl)-5-(4-{2-[(2S)-i-{(2S)-2 [(methoxycarbonyl)amino]-3-incthylhutanoyl}pyrrolidin-2-yi]- 1--imidazol-4-yl }phenyl)-1-H-pyrrol 5 2-yl]phenyl)-IH-iiidazol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl)carbamate Example 138A I,4-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-l,4-dione To a solution of the product from Example 26E (2.00 g, 5.05 mmol), bis(pinacolato)diborane 10 (3.85 g, 15.15 nmnol), potassium acetate (1.982 g, 20.20 minmol) in dimethoxyethane (50 mL) at room temperature was added PdCl 2 (dppf)-CH2CI 2 adduct (0.412 g, 0.505 nmol) and the mixture degassed (purge with N 2 ). The mixture was heated to reflux for 1 hour. The cooled mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water, brine and dried (NaSO 4 ). After filtration and removal of solvent, the residue was purified by chromatography (80 g 15 column; gradient elution from 0% to 40% ethyl acetate-hexanes) to provide the title compound (2.22 g; 90%) as a white solid. 'FINMR (CDCl 3 ; 400 MHz): 6 8.02 (AA'XX', J=8.24 Hz, 4H), 7.91 (AA'XX', J=8. 13 Hz, 411), 3.47 (s, 4H), 1.36 (s, 24H). N N N /0 H -OO O NN 0 20 Example 138B di-tert-butyl (2S,2'S)-2,2'-[(1,4-dioxobulane-1,4-diyl)bis(benzene-4,1-diyl-IH-imidazole-5,2 diyl)Jdipyrrolidine- I -carboxylate A solution of the product from Example 138A (2.22 g, 4.53 nunol), PICl 2 (dppf)-CH 2 C]2 adduct (0.37 g, 0.45 nunol), I M sodium carbonate (18 mL, 18 niniol) and the product from Example 255 261) (4.30 g, 13.6 minol) in ethanol (23 mnl..)/toluene (23 ml..) was degassed (purge N 2 ) and heated in oil bath at 90 *C overnight. The cooled mixture was concentrated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated and the residue was purified by chromatography (gradient elution from 30% to 100% ethyl acetale-hexane) to provide the title 5 compound (1.90 g, 59%) as a light tan solid. 1INMR (DMSO-d 6 ; 400 MHz): 8 12.06 (m, 2H), 8.04 7.96 (in, 411), 7.89-7.78 (in, 411), 7.69 (in, 211), 4.85-4.75 (in, 211), 3.53 (i, 211), 3.35 (i, 411), 2.24 1.87 (m, 10-1), 1.39 (br s, 8H), 1.14 (br s, IOH). M S (ESI; M+H) m/z = 709. Example 138C 10 (S)-4,4'-(4,4'-(I-(3-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(2-((S)-pyrrolicdin-2 yl)-IH-inidazole) To a solution of the product from Example 138B (180 mug, 0.25 mmol) and 3-tert-butylaniline (57 mug, 0.38 mmol) in toluene (2.0 mL) was added trifluoroacetic acid (39 pL 0.50 mmnol). The mixture was heated to 110 *C overnight. To the cooled mixture was added trifluoroacetic acid (0.4 15 iL) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure. The residue was partitioned between 25% isopropyl alcohol in CIC1 3 and saturated sodium bicarbonate solution. The organic layer was separated and dried over Na 2

SO

4 , filtered and concentrated under reduced pressure to provide the title compound. 20 Example 138D methyl {(2S)-I-[(2S)-2-(4-{4-[l-(3-tert-butylphenyl)-5-(4-{2-[(2S)-I-{(2S)-2 [(me thoxycarbonyl)amino]-3-imethylbutanoyl }pyrrolidin-2-yl]- I -- imidazol-4-yl }phenyl)-I H-pyrrol 2-yll phenyl)-I I--imidazol-2-yl)pyrrolidin-1-yl1-3-methyl-1-oxobutan-2-yl }carbamate A solution consisting of NI -((ethylimino)nethylene)-N3,N3-dimethylpropane- 1 ,3-diani ne 25 hydrochloride (109 mug, 0.57 mmol), IH-benzo[d]I1,2,3]triazol-1-ol hydrate (87 mg, 0.57 mmol), (S) 2-(methoxycarbonylaino)-3-methylbutanoic acid (100 mng, 0.57 iniol) and 4-nmethylnmorpholinc (0.14 nL, 1.0 umnol) in DMF (2.6 niL) was cooled in an icebath. To this mixture was added the product from Example 138C (161 mg, 0.26 mmol). Additional 4-methylmorpholine was added to the mixture until the p-I was adjusted to 8. The reaction was stirred for 3.5 hours and then the icebath 30 was removed and the reaction was stirred for an additional 16 hours. Water was then added to the reaction mixture and the resulting precipitate was recovered by filtration. The residue was washed with copious amounts of water followed by diethyl ether. The crude product was purified by chromatography on silica gel eluted with a solvent gradient of 0-5% methanol in CH 2

CI

2 to provide the title compound (15 ing, 6% yield). 'l- NMR (400 MIz, DMSO-D6) 6 12.04 - 11.65 (m, 21-1), 7.57 35 - 7.45 (i, 41-1), 7.43 - 7.35 (i, 2H), 7.33 - 7.08 (in, 51H), 7.05 - 6.91 (i, 4H), 6.79 (t, J = 7.5, 1H), 256 6.53 - 6.40 (in, 2H), 5.05 - 4.99 (i, 21H), 4.02 (t, J = 8.3, 2H), 3.82 - 3.68 (in, 4H), 3.56 - 3.47 (in, 6 H), 2.18 - 1.79 (m, 10 H), 1.09 (s, 91-), 0.89 - 0.75 (m, 121-1). MS (ES1; M+ 1) nz = 937. HN- H NN o >~0 /P 5 Example 139 methyl {(2S)-1-[(2S)-2-(4-{4-[I-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-l-{(2S)-2 [(methoxycarboyl)amnino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H1-imilazol-4-yl )phcnyl)-IH-pyrrol 2-yl]phenyl}-i ll-imidazol-2-yl)pyrrolidin-I-yl]-3-niethyl-i-oxobutan-2-yl}carbamate 10 Example 139A (S)-4,4'-(4,4'-( I-(4-cyclopropylphenyl)- I H-pyrrole-2,5-diyl)bis(4,1 -phenylene))bis(2-((S)-pyrrolidin 2-yl)-I H-i midazolc) tetrakis(2,2,2-trifluoroacetate) To a solution of the product from Example 138B (0.30g 0.43 nimol) and 4-cyclopropylaniline (85 mug, 0.64 minol) in toluene (3.4 niL) was added iriluoroacetic acid (65 pL 0.85 nunol). The 15 mixture was heated to 110 *C overnight. To the cooled mixture was added trifluoroacetic acid (1.0 mL) and the mixture was stirred for I hour at room temperature. The mixture was concentrated under reduced pressure and then triturated with diethyl ether to provide the title compound (0.42g, 28% yield). 20 Example 139B methyl {(2S)-I-[(2S)-2-(4-{4-f l -(4-cyclopropylphenyl)-5-(4-(2-[(2S)-1-((2S)-2 [(methoxycarboiiyl)anino]-3-methylbutanoyl}pyrrolidin-2-yl]- Hl-iimidazol-4-yl }phenyl)- IH-pyrrol 2-yl]phenyl-1IH-iidazol-2-yl)pyrrolidin-1-yl]-3-imethyl-I-oxobulan-2-ylcarbamate The title compound was prepared using the methods from Example 1381) substituting the 25 product from Example 139A for the product from Example 138C to provide the title compound (150 ig, 40% yield). 'H NMR (400 MHz, DMSO-D6) 6 12.09 - 11.63 (m, 2H), 7.56 - 7.46 (in, 41-I), 7.44 - 7.35 (in, 2H), 7.30 - 7.11 (m, 2H), 7.07 - 6.88 (i, 8H), 6.54 - 6.39 (m, 21-1), 5.07 - 4.97 (in, 2H), 4.03 (t, J = 8.3, 2H), 3.83 - 3.66 (in, 4H), 3.52 (s, 6H), 2.18 - 1.79 (in, IOH), 1.26 - 1.19 (mn, 1 H), 0.98 - 0.90 (in, 2H), 0.90 - 0.74 (in, I 2H), 0.69 - 0.60 (in, 2H). MS (ESI; M+H) m/z = 921. 30 257 HN NH N N N '' o\/ N HN /P Example 140 methyl [(2S)-I -{(2S)-2-[5-bromo-4-(4-{ I -(4-cyclopropylphenyl)-5-[4-(2-{(2S)-I-[N (niethoxycarbonyl)-L-valyllpyrrolidin-2-yl}- IH-iiidazol-4-yl)phenyll-1H-pyrrol-2-ylphenyl)-l H 5 imidazol-2-yl Ipyrrolidin- I -yl } -3-methyl- I -oxobutan-2-ylJcarbamate To a suspension of the product from Example 139 (47 mg, 0.051 immol) in CH 2

CI

2 (0.5 mL) was added a mixture of 1-bromopyrrolidine-2,5-dione (9.1 ing, 0.051 minol) in CH 2

CI

2 (0.5 mL). The mixture was stirred overnight at rooi temperature then concentrated under reduced pressure and triturated with diethyl ether to provide a mixture of brominated compounds that was subjected to 10 reverse phase HPLC purification eluted with a gradient of 10-100% CH 3 CN in 0.1% aqueous trifluoroacetic acid to afford the title compound (8 mg, 13% yield). 'H NMR (TFA salt) (400 MHz, DMSO-D6) 6 14.32 (s, 11H), 12.44 (s, 11-1), 7.97 (s, IH), 7.62 - 7.48 (im, 41-I), 7.31 (d, . = 8.4, IH), 7.24 (d, J = 8.5, I H), 7.18 - 7.08 (in, 4H), 7.09 - 7.00 (m, 4H), 6.61 (d, J =3.7, 1 H), 6.57 (d, J= 3.7, 1 H), 5.07 (t, J = 7.0. 1 H), 4.98 - 4.91 (in, I H), 4.08 (t, J = 7.9, 1 H), 4.02 (I, J= 8.3, 111), 3.90 - 3.67 15 (i, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 2.18 - 1.83 (in, 10H), 1.22 (s, I H), 1.01 -0.93 (i, 2H), 0.89 0.72 (i, 121-), 0.70 - 0.62 (m, 21H1). MS (ESI; M+-1) nz = 1000. H & NH NN /h Example 141 20 methyl (C2S)-1-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-broino-2-[(2S)-1-((2S)-2 [(methoxycarhonyl)aminoj-3-methylbutanoyl)pyrrolidin-2-yl]-IH -iimidazol-4-yl phenyl)- I-(4 cyclopropylphenyl)- 1H-pyrrol-2-yl]phenyl)-I H-inida7.ol-2-yl)pyrrolidin-1-yl]-3-iethyl-I-oxobutan 2-y IIcarhamate 258 'lhe title compound was formed as an additional product in Example 140. The mixture of products was subjected to reverse phase H PLC purification eluted with a gradient of 10-100% CH 3 CN in 0.1% aqueous trinuoroacetic acid to afford the title compound (15 mg, 23% yield). 'H NMR (TFA salt) (400 MHz, DMSO-D6) 6 12.43 (s, 211), 7.54 (dd, 4H), 7.25 (d, J = 8.4, 2H), 7.15 - 7.08 (in, 4H), 5 7.08 - 7.00 (im, 4H), 6.55 (s, 21-), 4.99 - 4.89 (in, 21-1), 4.02 (t, J = 8.3, 21-1), 3.82 - 3.68 (in, 4H), 3.51 (s, 611), 2.22 - 2.03 (m, 411), 2.00 - 1.81 (m, 61-1), 1.27 - 1.19 (m, IH), 1.02 - 0.92 (m, 21-), 0.90 0.77 (m, 12H), 0.70 - 0.61 (in, 2H). MS (ESI; M+H) n/z = 1078. N - /NH N N N 'L 3;' NH 10 Example 142 methyl ((2S)-l-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-I-((2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl) pyrrolidin-2-yl]- I H-imidazol-4-yl Iphenyl)- I -(4-tritylphenyl)-I H-pyrrol-2 yl]phenyl)- I H-imidazol-2-yl)pyrrolidin-1-yl]-3-inethyl-1-oxobutan-2-yl carbamate 15 Example 142A (S)-4,4'-(4,4'-( I -(4-tritylphenyl)- I 1-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(2-((S)-pyrrolidin-2-yl) I H-inidazole) tetrakis(2,2,2-tri fluoroacet ate) The title compound was prepared using the methods from Example 139A substituting 4 tritylaniline for 4-cyclopropylaniline to provide the title compound. 20 Example 142B methyl {(2S)-I-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-bromo-2-[(2S)-l -((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-IF1-imidazol-4-yl phenyl)-1-(4 cyclopropylphenyl)- H1-1-pyrrol-2-yl]phenyl} -1-l -imidazol-2-yl)pyrrolidin- 1 -ylI-3-mnethyl- I -oxobutan 25 2 -ylIcarbamate The title compound was prepared using the methods from Example 138D substituting the product from Example 142A for the product from Example 138C to provide the title compound (71 mug, 43% yield). 'F H NMR (400 MHz, DMSO-D6) 6 12.15 - 11.69 (in, 21-1), 7.61 - 7.48 (in, 4H), 7.46 259 - 7.37 (in, 2H), 7.35 -7.15 (in, I 1H), 7.10- 6.91 (ni, 14H), 6.55 -6.44 (in, 21H), 5.11 -5.00 (m, 2H), 4.03 (1, J = 8.5, 2H), 3.86 - 3.70 (in. 4H), 3.52 (s, 6H), 2.21 - 1.83 (ni, IOH), 0.92 - 0.76 (, 12H). MS (ESI; M-H) m/tz = 1123. NH NN Br~ 5 / Example 143 methyl {(2S)-I-[(2S)-2-(5-bromo-4-{4-[4-bronmo-5-(4-{5-hromo-2-[(2S)-1-{(2S)-2 [(mcthoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]- I--iiidazol-4-yli phcnyl)-1-(4 cyclohexylphenyl)-I H-pyrrol-2-yl]phenyl} -I H-imidazol-2-yl)pyrrolidin- 1-yl] -3-methyl-i -oxobutan 10 2-yl)carbamate To a suspension of the product from Example 74 (100 mg, 0.10 imol) in CH 2 Cl 2 (1.0 iL) at -78 *C was added a mixture of 1-bromopyrrolidine-2,5-dione (59 ing, 0.33 mmol) in CH 2 Clz (1.0 mL). The mixture was stirred for 3 hours, warming to room temperature then concentrated under reduced pressure and triturated with diethyl ether to provide the title compound (103 mg, 83% yield). 15 'HA NMR (400 M H7., DMSO-D6)6 12.47 (s, I-), 11.02(s, IH),7.54(d,J=26.1,4H),7.29-6.98 (in, IOH), 6.71 (s, I H), 5.01 - 4.90 (i, 2H), 4.02 (t, J= 8.1, 211), 3.86 - 3.67 (in, 4H1), 3.52 (s, 6H), 2.18 1.58 (m, 161), 1.35 - 1.20 (im, 51-), 0.90 - 0.76 (in, 121-1). MS (ESI; M+1-) mi/z = 1200. Q NH H ~ NH \ NN N 20 Example 144 260 methyl [(2S)-1-1(2S)-2-[4-(4-{5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutaiioyl }pyrrolidin-2-yl]I H-i midazol-4-yl)phenyl)-I-[6-(piperidin-1-yl)pyridin-3-yl]-I H pyrrol-2-yl iphenyl)-I H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-l-oxobutan-2-yl]carbamnale 5 Example 144A 5-nitro-2-(piperidin-l-yl)pyridine To a slurry of 2-chloro-5-nitropyridine (100 g, 632 mmol) in ethanol (2000 iL) at room temperature was added piperidine (206 mL, 2.08 mol) and the mixture heated to 60 "C for 30 minutes. The cooled mixture was concentrated and the residue taken up in CH2Cl 2 then washed with saturated 10 NaHCO 3 and brine. The mixture was dried (Na 2

SO

4 ), filtered, and concentrated to provide the title compound as a yellow solid (130.4g, 99% yield). 'H NMR (400 MHz, DMSO-D6) 68.94 (d, J= 2.9, 111), 8.17 (dd, J = 9.6, 2.9, 11-), 6.93 (d, J = 9.6, 11-H), 3.79 - 3.73 (m, 411), 1.69 - 1.64 (m, 211), 1.61 1.51 (m, 411). 15 Example 144B tert-hutyl 6-(piperidii-1-yl)pyridin-3-ylcarbamate To a solution of the product from Example 144A (130.4g, 629 mmol) and di-tert-butyl dicarbonate (165g, 755 inmol) in ethanol (750 mL) was added PtO 2 (5.4g, 24 mmol). The mixture was pressurized at 40 psi with 112 and stirred overnight at room temperature. To ensure complete 20 reaction additional P102 (3.2g, 14 ninol) was added and the pressurized nixturc was heated to 50 *C for I hour. The mixture was then filtered, concentrated under reduced pressure and absorbed onto silicagel and placed on top of a 4 to 5" plug of silica in a 3000 mL sintered glass funnel. Material was eluted with 15% diethyl ether in CH 2

CI

2 and the filtrate was concentrated under reduced pressure and the residue triturated with boiling hexanes. Additional product was recovered upon concentration of 25 the filtrate, which was then chromatographed on silica gel etuled with 10% diethyl ether in CH 2

CI

2 . The appropriate fractions were collected and concentrated then triturated with boiling hexancs. The two lots of lavender solids were combined to provide the title compound (100g, 57% yield). 'H NMR (400 MHz, DMSO) 6 9.02 (bs, I H), 8.11 (s, I H), 7.63 - 7.54 (m, I H), 6.74 (d, J = 9.1, 1 H), 3.42 3.37 (m, 41-), 1.57 - 1.49 (in, 61H), 1.45 (9, 1H1). 30 Example 144C 6-(piperidii- I -yl)pyridin-3-amine dihydrochloride The product from Example 144B (1.00 g, 3.62 mimol) was added slowly to 4 M hydrochloric acid (10 mL, 40 nuniol) and stirred at room temperature. After stirring overnight, ether was added and 35 the solid filtered. Dried in vacuum oven to a white solid (0.817 g; 84%). 'H NMR (400 MHz, 261 methanol-d4) 6 1.77 (s, 6H-1), 3.65 (s, 41H), 7.41 (d, J-9.8 Hz, IH), 7.70 (d, J=2.6 lz, lI H), 7.79 (dd, J=2.7, 9.8 Hz, I H). Example 144D 5 5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)- lH-imida7ol-4-yl)phenyl)-IH-pyrrol-1-yl)-2-(piperidin-l yl)pyridine To a solution of the product from Example 138B (0.20 g, 0.28 mmol) and the product from Example 144C (0.11 g, 0.42 mmol) in toluene (2.8 ml.) was added TFA (22 pL, 0.28 mmol). The mixture was stirred at Il0 "C for 3 hours. To the cooled mixture was added TFA (0.5 imL) and the 10 mixture was stirred for I h at ri. The solvent was then removed under reduced pressure and triturated with diethyleiher and dried to provide 0.31 g of the desired compound as a TFA sally. 'HNMR (DMSO-d 6 ; 400 M H z): 6 9.78 (br s, 21), 7.84 (d, J=2.71 lz, 11H), 7.75 (s, 211), 7.67 (AA'XX', J=8.34 Slz, 41), 7.35 (dd, J=9.11, 2.71 Hz, 111), 7.18 (AA'XX', J=8.46 lz, 41H1), 6.79 (d, J=9.1 I lz, 111), 6.53 (s, 211), 4.79 (app t, J=7.81 Hz, 211), 3.4-3.2 (i, 411), 2.44-2.36 (m, 211), 2.25-1.98 (i, 611), 15 1.65-1.45 (m, 61-). Example 144E methyl [(2S)-1-((2S)-2-[4-(4-{5-(4-{2-[(2S)- 1-{(2S)-2-((methoxycarbonyl)amino]-3 methylbutanoyl pyrrolidin-2-yl]- 1H-imidazol-4-ylphenyl)--[6-(piperidin-1-yl)pyridin-3-yl]-Ill 20 pyrrol-2-yl phenyl)-IlH-imidazol-2-yl]pyrrolidin-l-yI)-3-methyl-1-oxobutan-2-yl]carbamate To a solution of NI-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-dianine hydrochloride (0.17 g, 0.89 mmol), liH-benzo[dl[1,2,3]triazol-l-ol hydrate (0.14 g, 0.89 nunol), (S)-2 (mnethoxycarbonylaimino)-3-mnethylbutanoic acid (0.16 g, 0.89 mmol) in DMF (1.0 nL) was added 4 methylmorpholine (0.3 il.., 2.7 inmol). ''his mixture was stirred at room temperature for 15 minutes 25 and then added to a solution of the product from Example 144D (0.31 g, 0.25 minol) and 4 methyliorpholine (0.2 niL, 1.8 mmol) in DMF (0.7 mL). After stirring 4 h, water was added to this mixture and the solid collected by filtration then washed with water and diethylether. The residue was purified on silica gel elated with 60% THF/IHexanes to provide 100 Ing of the title compound. 'Ii NMR (400 M-lz, DMSO) 8 12.17 - 11.70 (i, 211), 7.84 - 7.76 (m, 11H), 7.64 - 7.50 (i, 41), 7.49 30 7.40 (i, 21-1), 7.31 - 7.02 (i, 7H), 6.76 - 6.69 (i, 1H), 6.52 - 6.41 (in, 2H), 5.09 - 5.01 (i, 21-), 4.04 (t, J = 8.3, 2H), 3.83 - 3.71 (m, 41H), 3.53 (s, 6H), 3.50 - 3.44 (m, 41-I), 2.18 - 2.04 (in, 4H), 2.03 - 1.86 (m, 6H), 1.61 - 1.46 (mn, 6H), 0.90 - 0.79 (m, 121-1). MS (ESI; M+1H1) m/z= 965. 262 /F Example 145 methyl {(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-I-((2S)-2-[(inethoxycarbonyl)aminol-3 methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-4-yl phenyl)-1-{4-[(trifluoromethyl)sulfanyl]phenyl} 5 1H-pyrrol-2-yllphenyl)-IH-imidazol-2-yl)pyrrolidin-1-yIl-3-methyl-i-oxobutan-2-yl}carbamate Example 138B and 4-(trifluoromethylthio)aniline were processed using the methods of Examples 139A and 138D to provide the title compound (19 mg). H NMR (400 MHz, DMSO-D6) 6 12.18 - 11.65 (m, 21), 7.73 - 7.63 (in, 21-1), 7.60 - 7.48 (m, 41H), 7.45 - 7.39 (in, 21), 7.31 - 7.15 (in, 41H), 7.06 - 6.92 (in, 4H), 6.58 - 6.46 (m, 2H), 5.08 - 5.00 (m, 2H), 4.03 (t, J = 8.4, 2H), 3.85 - 3.69 10 (i, 4H), 3.53 (s, 61-I), 2.23 - 1.79 (m, 101-), 0.93 - 0.77 (in, 12H). MS (ESI; M+1) m./z= 981. 4H Example 146 methyl {(2S)-I-[(2S)-2-(4-(4-[5-(4-{2-[(2S)-1-((2S)-2-[(methoxycarbonyl)aminol-3 15 methylbutanoyl) pyrrolidin-2-yl I-l H-imidazol-4-yl Iphenyl)- 1 -(2-methyl- 1,3-benzothiazol-5-yl)- H pyrrol-2-yljphenylI-I H-iimidazol-2-yl)pyrrolidin-1-ylJ-3-methyl-I-oxobutan-2-yl)carbamate Example 138B and 2-methylbenzoldJthiazol-5-amine dihydrochloride were processed using the methods of Examples 139A and 138D to provide the title compound (19 mg). '-I NMR (400 MHz, DMSO-D6) 8 12.04 - 11.63 (in, 211), 8.02 - 6.85 (m1, 1511), 6.58 - 6.45 (m, 211), 5.07 - 4.96 20 (m, 2H), 4.02 (t, J = 8.4, 211), 3.86 - 3.67 (m, 411), 3.53 (s, 611), 2.75 (s, 311), 2.21 - 1.78 (m, 1011), 0.93 - 0.76 (m, 121-). MS (ESI; M+H) m/z = 952. 263 Example 147 diethyl (4-{2,5-bis[4-(2-((2S)-I-[N-(methoxycarbonyl)-..-valyl]pyrrolidin-2-yl}11 H-imidazol-4 yl)phcnyll-1 H-pyrrol- I-yl}benzyl)phosphonate 5 Example 138B and diethyl 4-aninobeizylphosphonate were processed using the methods of Examples 139A and 138D to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 8 12.19 11.63 (in, 211), 7.56 - 7.44 (m, 41), 7.42 - 7.34 (in, 211), 7.32 - 7.10 (in, 411), 7.10 - 6.91 (in, 611), 6.53 - 6.40 (m, 21H), 5.10 - 4.98 (m, 2H), 4.03 (t, J = 8.4, 2H), 3.91 - 3.67 (in, 8H), 3.53 (s, 6H), 3.23 (d, . = 21.8, 2H), 2.22 - 1.80 (in, 10H), 1.15 - 1.04 (m, 6H), 0.92 - 0.77 (i, 12H). MS (ESI; M+1) 10 m/z= 1031. /P Example 148 miethyl {(2S)-I -[(2S)-2-(4-(4-[1-(1 1-1indazol-6-yl)-5-(4-{2-[(2S)-l -{(2S)-2 15 [(iiethoxycarbonyl)aimino]-3-imethylbulanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl Iphenyl)-IH-pyrrol 2-yl]phenyl )- I l-iidazol-2-yl)pyrrolidin-1-yI-3-methyl- l -oxobutan-2-yI Icarbanate Example 13813 and I H -indazol-6-amine were processed using the methods of Examples 139A and 138D to provide the title compound (24 ing). 'H NMR (40) MHz, DMSO-D6) 6 13.08 - 12.99 (i, IH), 12.05 - 11.62 (in, 2H), 8.13 - 8.04 (m, I H), 7.74 - 7.66 (m, 1-1), 7.54 - 7.42 (m, 4H), 7.41 20 7.34 (in, 2H), 7.31 - 7.09 (m, 3H), 7.05 - 6.77 (m, 51H), 6.58 - 6.47 (in, 2H), 5.06 - 4.97 (m, 211), 4.02 (t, J = 8.4, 2H), 3.83 - 3.66 (in, 4H), 3.53 (s, 611), 2.20 - 1.78 (in, 1OH), 0.89 - 0.76 (in, 12H). MS (ESI; M+H) in/z = 921. 264 H Example 149 methyl [(2S)-I-{(2S)-2-[4-(4-{ I -[3-fluoro-4-(piperidin-1-yl)phenylJ-5-(4-{2-[(2S)- 1-((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-y]-11-iinidazol-4-yl phenyl)-Iil-pyrrol 5 2-yl }phenyl)- l i-imidazol-2-yl]pyrrolidin-1 -yl} -3-methyl-1-oxobutan-2-yl]carbamate Example 138B and 3-fluoro-4-(piperidin-1-yl)aniline were processed using the methods of Examples 139A and 138D to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 8 12.15 11.69 (in, 2H), 7.62 - 7.49 (i, 4H), 7.48 - 7.39 (in, 2H), 7.32 - 7.15 (in, 2H), 7.12 - 6.77 (im, 7H), 6.52 - 6.42 (in, 2H), 5.08 - 4.99 (im, 2H), 4.04 (t, J = 8.4, 2H), 3.84 - 3.70 (in, 4H), 3.53 (s, 6H), 3.01 10 - 2.89 (in, 4H), 2.19 - 1.82 (in, 10H), 1.68 - 1.43 (in, 6H), 0.92 - 0.75 (in, 12H). MS (ESI; M+H) in/z = 982. Example 150 15 methyl [(2S)-I-{(2S)-2-[4-(4-{ I -[4-(hexyloxy)phenyl]-5-(4-(2-[(2S)-I -{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-I H-imidazol-4-yl phenyl)- IH-pyrrol 2-yl phenyl)-I H-iiidazol-2-yllpyrrolidin-1-yl}-3-methyl-l-oxobutan-2-yl]carbamate Example 138B and 4-(hexyloxy)aniline were processed using the methods of Examples 139A and 1381) to provide the title compound (15 ing). 'I- NMR (400 MHz, DMSO-D6) 6 12.12 - 11.67 20 (im, 21-), 7.59 - 7.48 (in, 4H), 7.45 - 7.39 (n, 211), 7.30 - 7.13 (m, 2H), 7.08 - 6.96 (im, 6H), 6.90 6.83 (in, 2H), 6.52 - 6.42 (in, 2H), 5,07 - 5.01 (im, 21-I), 4.04 (t, J = 8.5, 2H), 3.92 (t, J = 6.4, 2H), 3.83 - 3.70 (m, 4H), 3.53 (s, 6H), 2.19 - 1.83 (in, 10H), 1.73 - 1.63 (in, 2H), 1.45 - 1.21 (m, 6H), 0.92 -0.77 (i, 1511). MS (ESI; M+HI) nVz = 981. 265 HH 'N N N NH NMNN Example 151 diethyl (4-{3-tert-butyl-2,5-bis[4-(2-{(2S)-I -[N-(methoxycarbonyl)-L-valyllpyrrolidin-2-yl} -I I imidazol-4-yl)phenyll-1 H -pyrrol- I -yl I benzyl)phosphonate 5 The title compound was formed as an additional product from Example 147. The mixture of products was purified by chromatography on silica gel eluted with a solvent gradient of 0-5% methanol in (H 2

C

2 to provide the title compound. 'H1 NMR (400 MHz, DMSO-D6) 6 11.68 (d, J= 13.5, 21H), 7.55 - 7.39 (tm, 51]), 7.37 - 7.23 (m, 3H), 7.21 - 6.90 (m, 8H), 6.43 (s, I H), 5.07 - 4.99 (im, 2H), 4.06 - 3.97 (im, 2H), 3.83 - 3.58 (m, 8H), 3.53 (s, 6H), 3.07 (d, J = 21.5, 2H), 2.20 - 1.81 (in, 10 101-), 1.15 (s, 91), 0.98 (t, J= 7.0, 611), 0.90 - 0.78 (m, 1211). MS (ESl; M+H) m/z = 1087. C1 00 Example 152 methyl [(2S)-1-{(2S)-2-[4-(4-{ I -[4-(2,2-dichloro-1-methylcyclopropyl)phenyll-5-(4-(2-[(2S)-1 15 {(2S)-2-[(methoxycarbonyl)aminol-3-methylbutanoyl pyrrolidin-2-yll-II-imidazol-4-yl phenyl) I H-pyrrol-2-yl i phenyl)-Il-I-i midazol-2-yljpyrrolidin-1 -yl}-3-methyl--oxobutan-2-ylJcarbamate Example 138B and 4-(2,2-dichloro-in-methylcyclopropyl)aniline were processed using the methods of Examples 139A and 1381) to provide the title compound (36 ig). '1H NMR (400 MHz, DMSO-D6) 8 12.18 - 11.68 (i, 211), 7.55 - 7.42 (m, 411), 7.41 - 7.22 (in, 611), 7.17 - 6.90 (in, 611), 20 6.57 - 6.44 (m, 211), 5.08 - 5.00 (i, 211), 4.03 (t, I = 8.3, 211), 3.86 - 3.69 (m, 411), 3.53 (s, 611), 2.22 (t, J = 8.5, 1 H), 2.18 - 1.81 (m, 10H), 1.79 - 1.72 (i, IH), 1.65 (s, 3H), 0.92 - 0.77 (m, 121-I). MS (ESI; M+H) nz = 1003. 266 F F N4 Example 153 methyl [(2S)-l -{(2S)-2-[4-(4-{ l -[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyll-5-(4-{2 [(2S)-1-{(2S)-2-[(nethoxycarbonyl)unbno]-3-nethylbutanoyl ) pyrrolidin-2-yl]- llH -i midazol-4 5 yl}phenyl)-IH-pyrrol-2-yl phenyl)-1lH-iinidazol-2-yl]pyrrolidin-l-yi}-3-methyl-I-oxobutan-2 yI]carbamate Example 138B and 2-(4-aininophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol were processed using the methods of Examples 139A and 138D to provide the title compound (45 mg). 'H NMR (400 MHz, DMSO-D6) 6 12.08 - 11.71 (m1, 2H), 8.80 (s, I H), 8.01 - 7.37 (m, 8H), 7.33 - 7.13 (mn, 10 4H), 7.06 - 6.89 (in, 4H), 6.57 - 6.47 (in, 2H), 5.03 (d, J = 6.8, 2H), 4.03 (, J = 8.4, 21-1), 3.77 (d, J= 6.2, 4H), 3.53 (s, 6H), 2.21 - 1.80 (m, 101-H), 0.92 - 0.76 (in, 12H). MS (ESI; M+H) m/z = 1047. Example 154 methyl [(2S)-1-{ (2S)-2-[4-(4-{5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 15 imethylbutanoyl pyrrolidin-2-yll-1lH-inidazol-4-yl)phenyl)-1-[6-(morpholin-4-yl)pyridin-3-yll-IH pyrrol-2-yl phenyl)- IH-imidazol-2-yllpyrrolidin-1 -yli-3-methyl-1-oxobutan-2-yllcarbanate Example 154A 4-(5-nitropyridin-2-yl)morpholine 20 The title compound was prepared using the methods from Example 144A substituting morpholine for piperidine to provide the title compound. Example 154B 6-morpholi nopyridiin-3-ami ne 25 To a solution of the product from Example 154A (12.5, 59.5 inmol) in THF (150 mL) was added to Ra-Ni 2800, water slurry (12.5 g, 212 nimol) in a 500 mL SS pressure bottle. The mixture 267 was pressurizied (H 2 , 30 psi) and stirred for 2 hours at room temperature. The mixture was filtered and then concentrated under reduced pressure to provide the title compound. Example 154C 5 methyl [(2S)-I-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-l -{(2S)-2-[(methoxycarbonyl)amino]-3 imethylbutanoyl lpyrrolidin-2-yi]- I i-imidazol-4-yl)phenyl)-I-[6-(morpholin-4-yl)pyridin-3-yl]-1-l pyrrol-2-yl phenyl)- IH-inidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yllcarbamate Example 138B and Example 154H were processed using the methods of Examples 139A and 1381) to provide the title compound. 1I- NMR (400 MHz, DMSO-D6) 8 12.16 - 11.69 (m, 2H), 7.89 10 - 7.80 (m, 1 H), 7.63 - 7.50 (m, 4 H), 7.50 - 7.40 (m, 21-I), 7.39 - 7.02 (in, 7H), 6.80 - 6.71 (in, I H), 6.52 - 6.41 (m, 2H), 5.10 - 5.00 (m, 2H), 4.04 (1, J = 8.7, 2H), 3.85 - 3.72 (in, 4H), 3.69 - 3.59 (m, 411), 3.53 (s, 611), 3.45 - 3.37 (i, 411), 2.20 - 1.82 (m, 101I), 0.94 - 0.77 (m, 1211). MS (ESI; M+1) m/z = 967. 15 Example 155 methyl {(2S)-I-[(2S)-2-(4-{4-[1-{6-[bis(2-methoxyethyl)aiinopyridint-3-yl}-5-(4-{2-[(2S)-1-((2S) 2-[(mitethoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-1H-iniidazol-4-yl )plcnyl)-l H pyrrol-2-yl]phenyl)-IH-iidazol-2-yl)pyrrolidin-I-yl]-3-mcthyl-1-oxobutan-2-yl carbamale 20 Example 155A N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine The title compound was prepared using the methods from Example 144A substituting bis(2 methoxyethyl)amine for piperidine to provide the title compound. 25 Example 155B N2,N2-bis(2-methoxyethyl)pyridine-2,5-diaiine Example 155A was processed using the methods of Example 154B to provide the title compound. 30 Example 155C 268 methyl 1(2S)-I -[(2S)-2-(4-{4-[I-{6-lbis(2-methoxyethyl)aininoJpyridin-3-yl}-5-(4-{2-[(2S)-1-1(2S) 2-[(imethoxycarbonyl)aminoJ-3-niethylbutanoyl pyrrolidin-2-yl]- IH-imidazol-4-yl Iphenyl)-IH pyrrol-2-yl]phenyl)-lH-imiidazol-2-yl)pyrrolidin-1-y1]-3-meihyl-I-oxobutan-2-ylcarbaimate Example 138B and Example 155B were processed using the methods of Examples 139A and 5 138D to provide the title compound. 'H NMR (400 MHz, DMSO-D6) 8 12.17 - 11.67 (in, 21-I), 7.86 - 7.77 (mi, 111), 7.63 - 7.49 (in, 411), 7.49 - 7.38 (ni, 211), 7.34 - 7.20 (i, 311), 7.20 - 7.03 (in, 4 11), 6.64 - 6.56 (m, I H), 6.52 - 6.40 (i, 2H), 5.09 - 5.00 (in, 2H), 4.04 (t, .1 = 8.2, 2H), 3.84 - 3.69 (in, 4H), 3.65 - 3.57 (in, 41H), 3.53 (s, 6H), 3.47 - 3.40 (in, 4H), 3.21 (s, 6H), 2.20 - 1.84 (in, 101H), 0.84 (in, 12H). MS (ES1; M+H) nz = 1013. 10 NH Example 156 methyl 1(2S)-I -[(2S)-2-(4- {4-[1-(2-tert-butylphenyl)-5-(4-{2-[(2S)- 1-( (2S)-2 [(inetioxycarbonyl)aiinoJ-3-mnethylbutanoyl) pyrrolidin-2-ylj- I H -imidazol-4-yIlphenyl)- I H-pyrrol 15 2-ylJphenyl -1 H -imidazol-2-yl)pyrrol idin- I -ylJ-3-methyl- I -oxobutan-2-yl }carhamate Example 138B and 2-tert-buylaniline were processed using the methods of Examples 139A and 138D to provide the title compound (10 ing). 'H NMR (400 MHz, DMSO-D6) 6 12.07 - 11.64 (in, 2H), 7.61 - 7.11 (in, 12H), 7.06 - 6.93 (in, 4H), 6.65 - 6.49 (m, 2H), 5.08 - 4.97 (m, 2H), 4.04 (1, J= 7.2, 211), 3.82 - 3.69 (m, 411), 3.53 (s, 611), 2.17 - 1.83 (m, 1011), 0.92 - 0.77 (m, 211-1). MS (ESI; 20 M+1) n/z= 937. Example 157 269 niethyl 1(2S)-1-( (2S)-2-[4-(4-{ 1 -[4-(l,4-dioxa-8-azaspirol4.5]dec-8-yl)phenylJ-5-(4-(2-[(2S)- I (2S)-2-[(methoxycarbonyl)aminoj-3-methylhutanoyl } pyrrolidin-2-ylJ-1 H-imidazol-4-yl }phenyl) I -1-pyrrol-2-yl}phenyl)- I H-iiidazol-2-yl]pyrrolidin- I -yl }-3-methyl-1 -oxobutan-2-yl]carbainae Example 138B and 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline were processed using the 5 methods of Examples 139A and 138D to provide the title compound (156 ng). 'H NMR (400 MHz, DMSO-D6) 8l 12.06 - 11.65 (in, 211), 7.59 - 7.46 (m, 411), 7.44 - 7.36 (m, 211), 7.30 - 7.13 (i, 211), 7.09 - 6.96 (m, 4H), 6.90 (p, 4H), 6.53 - 6.39 (in, 2H), 5.08 - 4.98 (in, 2H), 4.04 (t, . = 8.4, 211), 3.90 (s, 4H), 3.86 - 3.71 (in, 4H), 3.53 (s, 6H), 3.29 - 3.20 (in, 41H), 2.19 - 1.83 (in, 10H), 1.73 - 1.64 (in, 4H), 0.93 - 0.77 (in, 121-1). M S (ESL M+H) m/z = 1022. 10 0O H Example 158 dimethyl ([I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis ( benzene-4,1 liyliiictliaicdiylcarbaimoyl(2S)pyrrolidine-2,1-cliyl[(2S)-3-imclhyl-1-oxobutane-1,2 15 diyl]})biscarbamaie Example 158A 4,4'-( -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile A solution of Example 42C (2.0 g, 3.9 mmol) and copper(I) cyanide (1.047 g, 11.69 mimol) in 20 DMF (19 inL) was heated in a microwave for 7 hours at 160 C. Afterwards the mixture was poured in water (700 ml) and then concentrated ammonium hydroxide (40 mL) was added and the solution extracted with EtOAc. Ilie organic extract was dried, filtered, concentrated and the residue purified by flash chromatography (silica gel, EtOAc/hexanes) to afford 1.23 g (78%) of the title compound. MS (ESI) mn/z 406 (M+H-1)+. 25 Example 158B 4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene)diiethanamine To a solution of Example 158A (0.63 g, 1.554 inmol) in T'lHF (21 mL) was added lithium aluinunm hydride (0.236 g, 6.21 inniol) then stirred at room temperature for 20 minutes and at 70 "C 30 for I hour. The mixture was then cooled in an ice bath and a solution of saturated aqueous ainionium chloride was added followed by extraction with EtOAc and the organic layer extracted 270 with Rochelle's solution. The organic solution was then dried, filtered and concentrated to give the title compound. MS (ESI) nz 414 (M+H)+. Example 158C 5 dimethyl ([I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis ( benzene-4,1 diylmethanediylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2 diyl] ))biscarbamatc The product from Example 158B (45 mg, 0.109 mmol), the product from Example 37B (62.2 mg, 0.228 minol) and HATU (91 mng, 0.239 imol) in DMSO (3 mlL) was added Hunig's base (0.095 10 mL, 0.544 iniol), and the reaction mixture was stirred at room temperature for I hr. The reaction mixture was partitioned between water and dichloromefhane, and the organic layer was dried over MgSO., filtered and concentrated. Purification by flash chromatography (silica gel, 0-10% methanol/dichloromethane) afforded 55 mg (55%) of the title compound as a mixture of stereoisomers. 1 H- NMR (400 MHz, DMSO-D6) S ppm 8.11 (in, 2 H), 7.08 (s, 2 11), 6.95 (m, 8 11), 15 6.74 (d, 1=8.8 Hz, 2 H), 5.97 (d, J=8.7 Hz, 2 i), 5.01 (m, 2H), 4.15 (in, 4H), 4.05 (in, 4 H), 3.80 (in, 2 H-1), 3.31 (s, 6 H), 2.40 (in, 2 I), 1.90 (in, 2 H), 1.85 (in, 4 H), 1.80 (in, 4 H), 0.95 (s, 9 H), 0.70 (in, 2 H), 0.65 (in, 12 H); M S (FS1) m/z 923 (M+H)+. H N~ NH N)4 N =0I N I N K J O=<S HN0 o-a 20 Example 159 methyl {(2S)-I-[(2S)-2-(4-(4-[(3S,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-I -((2S)-2 [(imethoxycarbonyl)amninol-3-methylbutanoyl pyrrolidin-2-yil-IH-inidazol-4 yl iphenyl)thiomtorpholin-3-ylIpheniyl 1} -H-imidazol-2-yl)pyrrolidinI-1-y11-3-iethyl-I-oxobutan-2 yl carbamatee 25 Example 159A 2,2'-thiobis(1 -(4-bromophenyl)ethanone) A solution of 2-broino-1-(4-bromophenyl)ethanone (27.8 g, 100 mmol) was dissolved in acetone, the solution was cooled in an ice bath then sodium sulfide nonahydrate (12.01 g, 50 inmol) 30 dissolved in water (100 niL) was added dropwise over 45 minutes time. The resultant solution was stirred an additional 2 hours at room temperature, the solid formed in the reaction was collected and 271 then washed with water then ethanol and dried in a vacuum oven to provide 18.5 g (43%) of the title compound. Example 159B 2,2'-thiobis(I-(4-bromophenyl)ethanol) 5 To a solution of Example 159A (5.0 g, 11.68 mmol) in ethanol (78 mL) was added sodium borohydride (0.972 g, 25.7 mmol) portionwise and the mixture was stirred at room temperature for 20 minutes. Afterwards the solution was concentrated, then a solution of IN aqueous hydrochloric acid (100 mL.) was added and extracted with EtOAc. The organic extract was dried, filtered and concentrated to 5.05 g (100%) of a colorless solid as the title compound. 10 Example 159C N,N'-(2,2'-thiobis(1-(4-bromophenyl)ethane-2, I -diyl))bis(4-tert-butylaniline) To a solution of Example 159B (5.05 g, 11.68 nmol) in TIIF (145 ml.) and dichloromethane (145 mL) was added triethylamine (4.86 mL, 35.1 mmol) and the mixture cooled in an ice bath. To 15 this solution was added methanesulfonyl chloride (2.276 mL, 29.2 nmmol) dropwise followed by stirring at 0 "C for an additional 30 minutes followed by concentration at room temperature to a residue. The resultant residue was dissolved in DMF (39 inL) followed by the addition of 4-tert butylaniline (18.62 mL, 117 mmol) and the mixture heated at 50 "C for 5 hours. Afterwards IN aqueous hydrochloric acid was added followed by extraction with EtOAc. The organic extract was 20 dried, filtered and concentrated. Purification by flash chromatography (silica gel, 0-30% EtOAc/hexanes) afforded 2.67g (42%) of the title compound. Example 159D 3,5-his(4-bro mophenyl)-4-(4-tert-hutylphenyl)thiomorpholine 25 To a solution of Example 159C (350 ing, 0.504 nimol) in toluene (5 mL) was added silica gel (1.0 g) that had been dehydrated by heating at 180'C in a vacuum oven for 3 hours, and trifuoromethanesulfonic acid (0.045 mL, 0.504 imnol) and heated at 100*C for 3 hours. After cooling to ambient temperature, dichloromethane was added and the silica gel was removed by filtration and the solution extracted with half-saturated aqueous sodium bicarbonate solution. The 30 organic extract was dried, filtered and concentrated to afford 220 ing (80%) of the title compound as a mixture of isomers. MS (ESI) m/z 546 (M+H)+. Example 159E 4-(4-tert-butylpheiyl)-3,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 272 I'he product of Example 1591) (200 tmg, 0.367 mmol) was processed using the method described in Example 421) to provide 105 mg (45%) of the title compound as a mixture of isomers. MS (ESI) m/z 640 (M+H)+. 5 Example 159F (2S,2S)-tert-butyl 2,2'-(4,4'-(4,4'-(4-(4-tert-butylphenyl)thiomorpholine-3,5-diyl)bis(4,1 phenylene))bis(lH-i midazole-4,2-diyl))dipyrrolidine-l-carboxylate The product of Example 159E (190 mug, 0.297 mmol) and the product from Example 261) (282 mg, 0.891 mmol) were processed using the method described in Example 42E to provide 110 mng 10 (43%) of the title compound as a mixture of isomers. MS (ESI) m/z 859 (M+H)+. Example 159G 4-(4-tert-butylphenyl)-3,5-bis(4-(2-((S)-pyrrolidin-2-yl)- I H-imidazol-4-yl)phenyl)thiomorpholine To the product of Example 159F (110 mg, 0.128 mmol) was added dimethoxyethane (5 ml) 15 and a solution of 4N hydrochloric acid in dioxane (5 mL) and the resultant solution stirred at room temperature for 1 hr. The solvent was then removed under vacuum and the resultant residue was diluted with acetonitrile and water (0.1% TFA) and purified by reversed phase chromatography (C18), eluding with 10-100% acetonitrile in water (0.1% TPA) to afford 12 mg (14%) of the title compound as a mixture of stereoisoners. MS (ES[) m/z 658 (M+1)+. 20 Example 159I methyl ((2S)-I-[(2S)-2-(4-{4-((3S,5R)-4-(4-tert-butylphenyl)-5-(4-(2-[(2S)-1-((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-1H-inmidazol-4 yl Ipheiyl)thiomorpholin-3-yllphenlyl 1-1 H-imidazol-2-yl)pyrrolidin-1 -ylJ-3-methyl-I -oxobutan-2 25 y Icarbamate The product from Example 159G (10 ing, 0.015 nmnol), (S)-2-(mnethoxycarbonylamino)-3 methylbutanoic acid (5.86 mg, 0.033 nunol) and HATU (12.71 mg, 0.033 mmol) in DMSO (0.5 nL) was added Ilunig's base (0.013 mL, 0.076 mmol), and the reaction mixture was stirred at room temperature for 1.5 hr. The reaction mixture was partitioned between water and dichloromethane, and 30 the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was redissolved in methanol (5 ml.) then added potassium carbonate (50 mg) then stirred at room temperature for 20 minutes, the solids removed by filtration, the filtrate concentrated and purified by chromatography (silica gel, 0-10% methanol/dichloromnethane) to afford 7 tmg (47%) of the title compound. 1 H NMR (400 MHz, DMSO-D6) 8 ppm 11.65 (m, 2 H-), 7.47 (m, 2 H-), 7.32 (m, 4 H1), 35 7.23 (m, 411), 6.85 (m, 4 H-), 5.02 (m, 2 H-1), 4.38 (in, 211), 4.02 (m, 2 1-1), 3.75 (m, 4 11), 3.52 (s, 6 -1), 273 3.10 (in, 2 H), 2.66 (in, 2 H), 2.08 (in, 4 -1), 1.91 (m, 4 H), 0.97 (s, 9 -1), 0.82 (m, 12 H); M S (ES1) nz 973 (M+H)+. N ±N o NN S HN -o 5 Example 160 methyl {(2S)-I-[(2S)-2-(4-(4-[(3S,5S)-4-(4-tert-butylphenyl)-5-(4-(2-[(2S)-I-((2S)-2 [(methoxycarbonyl)amino]-3-nethylbutanoyl pyrrolidin-2-yl]- H-iiidazol-4 yl )phenyl)thiomorpholin-3-yl]phenyl )- H-imidazol-2-yl)pyrrolidin-I-yl]-3-mnethyl-1-oxobutan-2 yl}carbamnate 10 and methyl {(2S)-I-[(2S)-2-(4-{4-[(3R,5R)-4-(4-teri-butylphenyl)-5-(4-i2-[(2S)-l -{(2S)-2 [(mnethoxycarbonyl)amino] -3-methylbut anoyl} pyrrolidin-2-yl]-I H-imidazol-4 yl }phenyl)thioimorpholin-3-yl]phenyl }-1 H-imi dazol-2-yl)pyrrolidin-1-yl]-3-mnethyl-1 -oxobutan-2 yl Icarbanate 15 The product from Example 159E (100 mug, 0.156 mmol), the product from Example 1260 (146 mg, 0.391 miunol), and [1, l'-bis(diphenylphosphino)ferrocenieldichloropalladium(II) dichloromethane adduct (25.5 mg, 0.031 mmnol) in a mixture of toluene (3 mL), ethanol (3 mL.) and a IN aq. sodium bicarbonate solution (0.469 mL, 4.69 mmol) and bubbled nitrogen gas through the solution for 10 min, then heated at 80 *C for 18 h. Solution was cooled to room temperature and 20 water (20 iL) added then extracted with dichloromnethane (50 mL), then dried, concentrated and the residue purified by reversed phase chromatography (C18), eluling with 10-100% aceonitrile in water (0.1% TFA) to afford 8.5 mg (6%) of the title compound as a mixture of stereoisomers. IlH NMR (free base) (400 M H z, DMSO-D6) 8 ppm 11.70 (bs, 2 11), 7.64 (m, 4 H), 7.45 (m, 2 11), 7.37 (in, 411), 7.28 (m, 2 H), 7.01 (m, 2 H), 6.46 (d, J=8.7 Hz, 2 H), 5.38 (m, 2 H), 5.07 (n, 2H), 4.03 (m, 2 1-1), 3.52 25 (s, 6 H), 3.10 (m, 2 H), 2.12 (m, 4 H), 1.91 (m, 4 H), 1.12 (s, 9 H), 0.86 (m, 12 H); MS (ESf) mn/z 973 (M+H)+. 274 N N3 N NMHN .- -o Example 161 methyl {(2S)-I-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)I-{(2S)-2 [(imcthoxycarbonyl)aminol-3-methylbutanoyl}pyrrolidin-2-yl]- 1 H-imidazol-4-yl } phenyl)-1,1 5 dioxidothiomorpholin-3-ylIphenyl }-I H-iinidazol-2-yl)pyrrolidin-l-yll-3-methyl- I -oxobutan-2 yl Icarbamate Br / Br NN oA.e Example 161A 10 3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)thiomorpholine 1,1-dioxide (ACD v12) A solution of Example 159D (850 mg, 1.56 mmol) in mixture of acctone (15 mL), water (5 mL.) and THF (5 nL.) was added a solution of osmium tetroxide (2.5% in icrt-hutanol, 0.587 ml, 0.047 inmol) and the mixture was stirred at room temperature for 1.5 hr. The solution was then diluted with water and extracted with EtOAc, the organic extract dried, filtered and concentrated to 15 afford 900 ing (100%) of the title compound. MS (ESI) m/z 578 (M+H)+. Example 161B methyl {(2S)-!-[(2S)-2-(4-{4-14-(4-tert-butylphenyl)-5-(4-{2-[(2S)- I-{(2S)-2 I(methoxyc arbonyl)amino] -3-met hyl but anoyl I pyrroli din-2-yl]-I H -imidazol-4-yl I phenyl)- 1, 1 20 dioxidothiomorpholin-3-yl]phenyl)-lH-imiiidazol-2-yl)pyrrolidin-I-yl]-3-methyl-I-oxobulan-2 yl carbaimate Example 161A was processed using sequentially the methods of Examples 42D, 42E, 159G, and 1591H to provide the title compound as a mixture of trans stereoisomers. I-1 NMR (400 MHz, DMSO-D6) 8 ppm 11.73 (bs, 2 H), 7.64 (m, 4 1-1), 7.55 (m, 2 Hl), 7.44 (i, 4H), 7.24 (m, 2 H), 7.04 25 (m, 2 H), 6.60 (i, 2 H), 5.48 (m, 2 H), 5.06 (in, 2H), 4.04 (in, 2 H), 3.78 (m, 6 H), 3.52 (s, 6 H), 2.11 (m, 4 H), 1.92 (in, 6 H), 1.13 (s, 9 H), 0.92 (i, 12 H); MS (ESI) m/z 1005 (M+H)+. 275 H H Example 162 methyl {(2S)-1-[(2S)-2-(4-(4-[(2R,5R)-I-(4-cyclopropylphenyl)-5-(4-(2-[(2S)-I-((2S)-2 [(niethoxycarbonyl)amninol-3-imethylbutanoyl pyrrolidin-2-yl -1H-imidazol-4-yl phenyl)pyrrolidin 5 2-yllphenyl]-lH-iinidazol-2-yl)pyrrolidin-1-yll-3-methyl-1-oxobutan-2-yl carbaniate Tlie product from Example 95B was purified by chiral chromatography on a Chiralpak lB column eluting with a mixture of hexaneiTHF/methanol (85/10/5). The title compound was the first of the 2 diastercomers io elute. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.33 - 0.43 (in, 2 H) 0.65 0.72 (i, 2 H) 0.79 - 0.91 (i, 12 H) 1.56 - 1.64 (in, I H) 1.66 - 1.72 (m, 2 H) 1.84 - 2.03 (m, 6 H) 2.06 10 - 2.19 (i, 4 I-) 3.53 (s, 6 H-) 3.73 - 3.84 (in, 4 1-) 4.04 (t, J=8.35 Iz, 2 H-) 5.06 (dd, J=6.89, 3.09 iz, 2 11) 5.14 - 5.23 (in, 2 H-) 6.19 (d, J=8.67 Iz, 2 11) 6.60 - 6.67 (in, 2 11) 7.09 - 7.31 (i, 6 11) 7.34 - 7.68 (in, 6 H) 11.62 - 12.11 (in, 2 H); MS (ESI+) n/z 924.6 (M+H). 0 15 Example 163 methyl {(2S)-I-[(2S)-2-{5-[(2R,5R)-I-(4-cyclopropylphenyl)-5-{2-[(2S)-1-{(2S)-2 [(niethoxycarbonyl)ainino]-3-niethylbutanoyl pyrrolidin-2-yl]-1 H-benzimidazol-5-yl pyrrolidin-2 ylJ-l i-benzimidazol-2-yl pyrrolidin-I-ylJ-3-iethyl-I-oxobutan-2-ylcarbamate Example 109C and 4-cyclopropylaniline were processed using sequentially the methods of 20 Examples 113A (cyclization reaction conducted at room'temperature overnight), 11313, 113C, 281 (reaction conducted at 50 *C for 3 hours), 28J, and 66E to provide the title compound (122 ing) as a solid. III NMR (400 M Hz, DMSO-D6) 6 ppm 0.32 - 0.39 (m, 2 H) 0.63-0.69 (in, 2 H) 0.77 -0.90 (mn, 12 H) 1.53 - 1.61 (in, 1 11) 1.66 - 1.74 (i, 2 H-) 1.86 - 2.04 (in, 8 H) 2.14 - 2.23 (m, 4 11) 3.54 (s, 6 H-) 3.78 - 3.87 (m, 4 H) 4.00 - 4.07 (in, 2 1H) 5.10 - 5.18 (in, 2 H) 5.31 - 5.39 (in, 2 H) 6.22 (d, J=8.67 Hz, 25 2 1-1) 6.57 - 6.65 (in, 2 1-) 7.00 - 7.07 (i, 2 1-1) 7.16 - 7.32 (in, 4 H) 7.36 (d, J=8.13 Hz, I H) 7.44 (d, .1=8.24 Hz, 1 H) 11.97 - 12.27 (n, 2 H-1); MS (ESI+) n/z 872.5 (M+H)+. 276 Example 164 methyl {(2S)-I-[(2S)-2-(5-{(2R,5R)-5-(2-[(2S)-I-{(2S)-2-[(methoxycarbonyl)amino]-3 5 methylbulanoyl)pyrrolidin-2-yl]-lH -benziinidazol-5-yl}-1-[4-(imorpholin-4-yi)phenyl]pyrrolidin-2 yl}-1H-benziiidazol-2-yl)pyrrolidin-I-yl]-3-methyl-I-oxobutan-2-yl}carbamate Example 109C and 4-morpholinoaniline were processed using sequentially the methods of Examples I 13A (cyclization reaction conducted at room temperature overnight), I 13B, 1 13C, 281 (reaction conducted at 50 *C for 2 hours), 28J, and 28K to provide the title compound (100 10 mg) as a solid. IlH NMR (400 MHz, DMSO-D6) 5 ppm 0.76 - 0.91 (in, 12 H) 1.66 - 1.72 (i, 2 H) 1.87 - 2.03 (in, 8 H) 2.15 - 2.22 (m, 4 H) 2.72 - 2.78 (in, 4 H) 3.53 (s, 6 H-) 3.57 - 3.62 (i, 4 H) 3.78 3.86 (m, 4 H) 4.00 - 4.12 (in, 2 H) 5.09 - 5.18 (in, 2 H) 5.30 - 5.37 (in, 2 H) 6.25 (d, J=8.78 Hz, 2 H) 6.52 - 6.59 (m, 2 H) 7.05 (t, J=7.54 Hz, 2 11) 7.18 - 7.32 (m, 4 H) 7.36 (d, J=8.13 Hz, 1 H) 7.44 (d, J=8.24 Hz, I H) 11.91 - 12.28 (m, 2 1-); MS (ESI+) m/z 917.5 (M+H)+. 15 0N > NH Example 165 dimethyl ([(2R,5R)-I-(4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl} pyrrolidine-2,5-diyllbis{(2 aninobenzene-4, I -diyl)carbaitoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl- I -oxobutane- 1,2 20 diyl] })biscarbamate Example 165A (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-l -(4-iodophenyl)pyrrolidine 277 Example 109C (3.34 g, 6.0 mmol) and 4-iodoaniline (7.88 g, 36.0 mmol) were processed using the method of Example I13A with the reaction allowed to proceed for 4 days at room temperature to provide the title compound (2.01 g, 57%) as a yellow solid. 5 Example 165B 4-(5 -(4-((2R,5 R)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin- I -yl)phenyl)pyridin-2-yl)morpholine The product from 165A (1.869 g, 3.2 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)pyridin-2-yl)morpholine (0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 inmol), tris(dibenzyl ideneacetone)dipal ladiu m(0) (0.029 g, 0.032 mmol) and 1,3,5,7-tetramethyl-6-phenyl 10 2,4,8-trioxa-6-phosphaadaiante (0.028 g, 0.Y)6 nunol) were combined in THF (18 nL)/water (6 mL). The mixture was purged with nitrogen for 15 minutes and stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (20% to 40%) 15 to give the title compound (1.01 g, 51%) as a solid. Example 165C dimethyl (2S,2'S)-1, l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-I-(4-(6-norpholinopyridin-3 yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1 20 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-I-oxobutane-2,1 diyl)dicarbamate The product from Example 165B (683 mg, 1.10 mmol), the product from Example 1 16C (895 mg, 3.30 mmol), cesium carbonate (1004 mg, 3.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (60.4 mg, 0.066 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (115 mg, 25 0.198 nunol) were combined in dioxane (15 mL). The mixture was purged with nitrogen for 15 minutes and stirred at 100 'C for 3 hours. The mixiure was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with methanol/dichloromethane (1% to 3%) to give the title compound (631 mg, 53%) as a solid. 30 Example 165) dimethyl ([(2R,5R)-I-14-16-(morpholin-4-yl)pyridin-3-ylJphenyl }pyrrolidine-2,5-diylJhis{(2 aminobenzene-4,1 -diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-mnethyl-1-oxobutane-1,2 diyl]})biscarbaimate 35 The product from Example 165C (628 mg, 0.576 mmol) and Ra-Ni 2800 (628 mg) were combined in TI-IF (40 mL). The mixture was hydrogenated at 30psi for 4 hours. The mixture was 278 filtered and the filtrate was evaporated. The residue was purilfed by chromatography on silica gel eluting with methanol/dichloromethane (2% to 5%) to give the title compound (590 g, 99%) as a solid. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.88 (d, J=6.61 Hz, 6 H) 0.91 (d, J=6.72 Hz, 6 H) 1.62 - 1.69 (m, 2 H) 1.82 -2.04 (in, 8 H) 2.10 - 2.20 (in, 2 H) 2.52 - 2.56 (in, 2 H) 3.37 - 3.41 (in, 4 H) 3.52 5 (s, 6 H) 3.56 - 3.62 (in, 2 H) 3.65 - 3.70 (in, 4 H) 3.78 - 3.85 (m, 2 H) 3.98 - 4.07 (i, 2 H) 4.36 - 4.44 (in, 2 H-) 4.87 (s, 4 H) 5.06 (d, J=6.32 Iz, 2 H) 6.36 (d, J=8.78 Hz, 2 H) 6.42 (d, J=8.02 lz, 2 H1) 6.57 (d, J=1.19 Hz, 2 H) 6.78 (d, 1=8.89 Hz, 1 H) 6.96 (d, .1=8.02 Hz, 2 H) 7.23 (d, J=8.78 Hz, 2 H) 7.36 (d, J=8.24 Hz, 2 H) 7.68 (dd, J=8.78, 2.49 Hz, I H) 8.27 (d, J=2.49 H z, I H) 9.24 (s, 2 1-1); MS (FSl+) n/z 1030.6 (M+H)+. 10 N NHH Fxample 166 methyl {(2S)-1-[(2S)-2-(5-[(2R,5R)-5-{2-[(2S)-I-((2S)-2-[(methoxycarbonyl)anino]-3 nethylbutanoyl}pyrrolidin-2-yl]- 1H-benzinidazol-5-yl}-1-{4-[6-(morpholin-4-yl)pyridin-3 15 yl]phenyl}pyrrolidin-2-yl]-lHI--benzimidazol-2-yl pyrrolidin-1-yl]-3-methyl-1-oxobutan-2 yl )carbamate The product from Example 165D (520 g, 0.505 mnmol) and acetic acid (0.087 mL, 1.514 mmnol) were combined in toluene (10 mL). The mixture was stirred at 50 'C for 4 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with 20 methanol/dichloromethane (2% to 5%) to give the title compound (309 mug, 62%) as a solid. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.73 - 0.90 (im, 12 H) 1.70 - 1.76 (in, 2 H) 1.84 - 2.05 (Im, 8 H) 2.14 2.21 (in, 2 H) 2.55 - 2.60 (in, 2 H) 3.34 - 3.39 (in, 4 H) 3.53 (s, 6 H) 3.62 - 3.69 (i, 4 H) 3.75 - 3.87 (in 4 11) 4.02 - 4.08 (in, 2 1-) 5.06 - 5.17 (in, 2 11) 5.40 - 5.47 (in, 2 1-) 6.40 (d, J=8.67 Hz, 2 H1) 6.75 (d, .1=8.89 Hz, I H) 7.02 - 7.20 (in, 4 H) 7.25 (s, I H) 7.28 (d, .1=8.46 Hz, 2 H) 7.34 (s, 1 H) 7.39 (d, 25 J=8.13 Hz, I H) 7.47 (d, 1=8.24 Hz, I H) 7.60 (d, J=8.60 Hz,I 1-1) 8.21 (s, 1 H) 11.96 - 12.11 (i, 2 H); MS (ESI+) n/z 994.5 (M+H)+. 279 Example 167 methyl [(2S)-1-{(2S)-2-[5-(4-{5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl}pyrrolidin-2-yl]-I H-imidazol-5-yl phenyl)-1-[4-(piperidin-1-yl)phenyl]-ll-pyrrol-2 5 yl phenyl)- 1H-iiidazol-2-yl]pyrrolidin-1-yl)-3-methyl-I-oxobutan-2-yl]carbamate Example 26E and 4-piperidinoaniline (Maybridge) were processed using sequentially the methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the title compound (106 mg). 'H NMR (400 MHz, DMSO-D6) 6 0.83 (d, .1=6.73 Hz, 6 H) 0.87 (d, .=6.73 Hz, 6 H) 1.50 - 1.62 (in, 6 H) 1.90 - 2.15 (in, 10 H) 3.13 (in, 4 H) 3.53 (s, 6 H) 3.77 (in, 4 H) 4.04 (in, 2 H) 5.04 (i, 2 H) 6.47 10 (im, 2 H) 6.80 - 7.35 (in, 10 H) 7.42 (im, 2 H) 7.53 (in, 4 H) 11.73 (s, 2 H). Example 168 methyl [(2S)-I-{(2S)-2-[5-(4-{5-(4-{2-[(2S)-1-((2S)-2-[(methoxycarbonyl)amino]-3 15 methylbutanoyl}pyrrolidin-2-yl]1 -1-iiidazol-5-yl phenyl)-I-[4-(Iricyclo[3.3.1.1-3,7-]dec-1 yl)phenyl]-lII-pyrrol-2-yl)phenyl)-Il-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2 yl]carbanate Example 26E and 4-(1-adaiantanyl)aniline hydrochloride (Enaiine) were processed using sequentially the methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the title compound 20 (320 mg). 'l-l NMR (400 MHz, methanol-D4) 6 0.91 (in, 12 H) 1.75 - 2.35 (m, 25 H) 3.64 (s, 6 H) 3.84 (in, 2 H) 4.00 (in, 2 1-1) 4.20 (in, 2 H) 5.12 (in, 2 H) 6.48 (s, 2 H) 7.02 (m, 6 H) 7.31 (n, 4 H) 7.46 (in, 6 IH) 7.72 (d, J=8.13 Hz, I H) 7.82 (d, J=8.24 Hz, 1 1). 280 0 Example 169 methyl [(2S)-1-{(2S)-2-[5-(4-{5-(4-(2-[(2S)-1-((2S)-2-[(methoxycarbonyl)aminol-3 methylbut anoyl }pyrrolidin-2-yl]-1 H-i midazol-5-yl}phenyl)-1-[4-(morpholin-4-yl)phenyl]- IH-pyrrol 5 2-yl iiphenyl)- i H-imidazol-2-yl]pyrrolidiii-l-yl}-3-imethyl-i-oxobutan-2-yl]carbamate Example 26E and 4-morpholinoaniline (Aldrich) were processed using sequentially the methods of Examples 26F, 26G, 74C, 19D, and 74E to provide the title compound (133 mg). 'H NMR (400 MHz, DMSO-D6) 6 0.83 (d, J=6.83 Hz, 6 H) 0.87 (d, J=6.61 Hz, 6 H) 1.88 - 2.17 (i, 10 H) 3.11 (in, 4 H) 3.53 (s, 6 H) 3.70 - 3.80 (in, 8 H) 3.97 - 4.08 (in, 2 H) 5.04 (m, 2 H) 6.41 - 6.51 (i, 10 2 H) 6.84 - 7.35 (in, 10 H) 6.93 - 7.02 (m, 6 H) 11.71 - 12.03 (in, 2 H). N /0 Example 170 methyl {(2S)-I-[(2S)-2-(5-broimo-4-(4-[(2S,5S)-5-(4-{5-broio-2-[(2S)-I-{(2S)-2 15 (methoxycarbonyl)amino]-3-methylbutanoyI pyrrolidin-2-yl] -11-1H-imidazol-4-y I phenyl)- I -(4-tert butylphenyl)pyrrolidin-2-yl]phenyl}-IH-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2 yl Icarbainate To a solution of Example 44 (0.100 g, 0.106 ininol) in CH2Cl 2 (5 iL) at rt was added N hroiosuccinimnide (0.019 ml-, 0.223 ininol). After 15 min, the reaction was washed with saturated 20 NaHCO 3 and concentrated. Residue purified by chromatography (1% gradient elution from 0% to 4% MeOll-CH 2 Cl2; 12 g column) to provide 60 mg (51%) of the title compound as a light yellow solid. '11 NMR (400 MHz, DMSO-D6) 6 0.8 (d, J=6.61 Hz, 6 H) 0.87 (d, J=6.56 Hz, 6 H) 1.11 (s, 9 H) 1.72 - 1.75 (m, 2 -1) 1.87 - 1.98 (m, 7 H) 2.10 - 2.15 (i, 5 H) 3.53 (s, 6 H) 3.70 -3.75 (m, 4 H) 4.00 = 4.06 (m, 2 1-1) 4.96 - 5.00 (i, 2 H) 5.27 - 5.35 (in, 2 H) 6.24 (d, J=8.78 1-z, 2 H) 6.97 (d, J=8.78 Hz, 2 H) 25 7.24 - 7.35 (in, 6 H) 7.60 - 7.65 (m, 4 H) 12.41 (i, 2 H). 281 Example 171 methyl {(2S)-I-[(2S)-2-(5-(4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-l -{(2S)-2 [(methoxycarbonyl)anino]-3-methylbut anoyl)pyrrolidin-2-yl]-4H -1,2,4-iriazol-3 5 yl ) phenyl)pyrrolidin-2-yl]phenyl)-4H-1,2,4-triatol-3-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2 yl )carbanate and methyl ((2S)-I-[(2S)-2-(5-{4-[(2R,5R)-I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-2 i(methoxycarbonyl)aiinol-3-methylbutanoyl pyrrolidin-2-yll-4H -1,2,4-triazol-3 10 yllphenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]-3-methyl-I-oxohutan-2 yl }carbamate Example 171 A Dimethyl 4,4'-(1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzoale 15 A mixture of Example 42C (0.5 g, 0.974 nunol), Et 3 N (0.407 mL, 2.92 mmol) and [1,1' Bis(diphenylphosphino)ferrocene]dichloropalladium(H) (71.3 mg, 0.097 mmol) in methanol (20 mL) was subjected to an atmosphere of carbon monoxide gas (60 psi) for 24 hours at 100 *C. '[he mixture was filtered through celite and concentrated. Purification by chromatography (silica gel, 25% EtOAc in hexanes) afforded 396 mg (86%) of the title compound. MS (ESI) m/z 472 (M+H)*. 20 Example 171B 4,4'-(l -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzohydrazide A mixture of Example 171A (350 mg, 0.742 mmol) and Hydrazine (0.140 p L, 4.45 mmol) in methanol (10 mL) was refluxed for 72 hours. The mixture was concentrated to afford 350 mg of the 25 title compound as a mixture of stereoisomers. MS (ESI) nz 472 (M+H)*. Example 171 C (2S,2'S)-tert-hutyl 2,2'-(5,5'-(4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(4H-l I,2,4-triazole-5,3-diyl))dipyrrolidine-I -carboxylate 30 A mixture of Example 171B (105 mg, 0.223 mmol), (S)-l-N-Boc-2-cyano-pyrrolidine (175 mg, 0.891 mmol), and K2CO 3 (9.23 mug, 0.067 mmol) in n-butanol (0.5 mL) was heated to 150 *C for 282 90 minutes in a microwave. The mixture was diluted with EtOAc and then washed with 120 and Brine. The organic was then dried (MgSO 4 ), filtered and concentrated. Purification by chromatography (silica gel, 90% EtOAc in Hexanes) afforded 59 mg (32%) of the title compound as a mixture of stereoisomers. MS (ESI) m/z 829 (M+H)*. 5 Example 171D (S)-5,5'-(4,4'-(I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, I -phenylene))bis(3-((S)-pyrrolidin-2 yl)-4H-1,2,4-triazole) pentahydrochloride A mixture of Example 171C (59 mg, 0.071 mmol) in 4M HCI/Dioxane (2 mL) was allowed to 10 stir for one hour. The mixture was concentrated to afford 58 mg (100%) of the title compound as a mixture of stereoisomers. MS (ESI) mnz 628 (M+H)*. Example 171 E methyl {(2S)-I-[(2S)-2-(5-{4-[(2S,5S)- I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-2 15 {(methoxycarbonyl)amninol-3-methylbutanoyl pyrrolidin-2-yll-4H -1,2,4-triazol-3 yl iphenyl)pyrrolidin-2-yljphenyl -4H -1,2,4-triazol-3-yl)pyrrolidin-i-yl]-3-niethyl- I-oxobutan-2 yl carbamate and methyl {(2S)-I-[(2S)-2-(5-{4-[(2R,5R)-I-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-2 20 ((methoxycarbonyl)aninol-3-methylbutanoyllpyrrolidin-2-yll-41-l,2,4-triazol-3 yl (phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]-3-nethyl-1-oxobutan-2 yl carbamnate A mixture of Example 171D (58 mg, 0.071 mmol), (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid (25 mg, 0.142 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide 25 hydrochloride (30 mg, 0.157 nunol), l-Hydroxy-benzotriazolc hydrate (24 mg, 0.157 nunol) and N methylmorpholine (78 p L, 0.712 mniol) in DMF (I mL) were allowed to stir overnight. Mixture was diluted with EtOAc. The organic was then washed with H 2 0 and Brine. The organic was then dried (MgSO 4 ), filtered and concentrated. Compound subjected to IPLC purification on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to afford both the 30 title compounds of Example 171 (24 mg, 70%) which cluted first (trans isomers) and title compound of Example 172 which eluted second (Cis isomer). 'H NMR (free base) (400 MHz, DMSO-d(,) 8 ppm 0.27 (d, J=6.72 Hz, 2 H), 0.71 (dd, J=6.61, 2.49 Hz, 2 H), 0.78 - 0.95 (in, 9 H), 1.03 (d, 1=6.07 Hz, 12 -1), 1.09 (s, 9 H), 1.22 (s, 2 H), 1.65 - 1.77 (in, 3 H), 1.82 - 2.30 (in, 10 H), 3.52 (s, 6 -1), 3.57 - 3.66 (n, i 11), 3.71 - 3.92 (m, 3 1-1), 4.00 - 4.16 (m, 2 1I), 5.07 - 5.15 (m, I H1), 5.25 - 5.34 (i, 2 H1), 5.65 (d, 35 1=4.88 Hz, 1 H), 6.21 (dd, 1=8.73, 3.20 H z, 2 11), 6.94 (dd, 1=8.78, 2.82 Hz, 2 11), 7.16 - 7.46 (i, 6 I-), 7.83 - 7.92 (in, 4 I-), 14.01 (s, 1 11); MS (ESI) m/z 943 (M+H)*. 283 0 H Example 172 methyl {(2S)-1-I(2S)-2-(5-{4-[(2R,5S)-I-(4-tert-butylphenyl)-5-(4-{5-[(2S)- 1-((2S)-2 5 [(methoxycarbonyl)aminoJ-3-methylbutanoyl pyrrolidin-2-ylJ-4H-l,2,4-triazol-3 yl I phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyrrolidin-1-yl]-3-micthyl-l-oxobutan-2 yl)carbaiate The title compound, Example 172, was the second eluting compound described in the procedures for Example 171E. The procedure afforded 21 mg (61%) of the title compound (Cis 10 isomer). 'H1 NM R (free base) (400 MIHz, DMSO-d 6 ) 8 ppm 0.27 (d, 1=6.29 Iz, 2 H-), 0.71 (d, 1=6.61 Hz, 2 H), 0.81 - 0.96 (i, 9 H), 1.03 (d, J=6.07 1-z, 12 H), 1.12 (s, 9 H), 1.22 (s, 2 H), 1.82 - 2.30 (in, 12 H), 3.52 (s, 6 H), 3.72 - 3.91 (m, 4 H), 4.03 - 4.17 (i, 2 H), 4.33 (d, J=4.23 Hz, 1 1H), 4.73 - 4.83 (in, 2 H-1), 5.09 - 5.18 (i, 2 H), 6.33 (d, J=8.78 Hz, 2 H), 7.03 (dd, J=8.78, 3.04 Hz, 2 H), 7.29 (d, 1=7.70 Hz, I H), 7.57 - 7.69 (in, 4 H), 7.92 - 8.01 (m, 4 H), 13.84 (s, 2 H); MS (ESI) m/z 943 15 (M+H)*. Example 173 methyl {(2S)-I-[(2S)-2-(2-{4-l(2S,5S)-I-(4-tert-butylphenyl)-5-(4-{4-((2S)-1-{(2S)-2 20 [(methoxycarbonyl)amino]-3-methylbutaioyl}pyrrolidin-2-yl]-I H-i midazol-2-yl }phenyl)pyrrolidin 2-yl]phenyl }-1 H -iiidazol-4-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl }carbamate and methyl ((2S)-I-[(2S)-2-(2-{4-[(2R,5R)-I-(4-tert-butylphenyl)-5-(4-(4-[(2S)-I-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-1 H -imidazol-2-ylphenyl)pyrrolidin 25 2-yl]phenyl)-il-I-imidazol-4-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl carbamate 284 Example 173A 4,4'-(l -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile A mixture of Example 42C (1.0 g, 1.948 nunol) and CuCN (523 ing, 5.84 nunol) in Dimethylformamide (9.5 mL) was heated to 160 *C for 4.5 hours in a microwave. Mixture was 5 poured into a dimethylamine/H 2 0 mixture (1/10) and extracted with EtOAc (3 x 150 mL). The combined organics were washed with 1120 and Brine. The organic was then dried (MgSO 4 ), filtered and concentrated. Purification by chromatography (silica gel, 20% EtOAc in Hexanes) afforded 395 mg (50%) of the title compound. MS (ESI) m/z 406 (M+H)*. 10 Example 17313 dimet hyl 4,4'-(l -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzimidate A mixture of Example 173A (0.5 g, 1.233 mmol) in anhydrous MeOl- (12 mL) at 0 *C was bubbled an excess amount of -IC (g) for 45 minutes. Mixture was then stirred at ambient temperature for 24 hours and then concentrated to afford the title compound. 15 Example 173C 4,4'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzimidamide A mixture of Example 173B (0.579 g, 1.233 mmol) in anhydrous MeOH (12 muL) at 0 *C was bubbled an excess amount of NH 3 (g) for 45 minutes. Mixture was then stirred at ambient 20 temperature for 24 hours and then concentrated and subjected to purification via chromatography (C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA) to afford the title compound as a mixture of trans isomers; Cis isomer was discarded.. MS (ESI) m/z 440 (M+H)*. Example 173D 25 methyl (S)- 1 -((S)-2-(2-diazoacetyl)pyrrolidin- I -yl)-3-methyl- I -oxobutan-2-ylcarbamate A mixture of Example 37B (100 mg, 0.367 mmol) and Et 3 N (154 pL, 1.102 mmol) in tetrahydrofuran (4 mL) at 0 *C was added Isobutyl chloroformate (50 pL, 0.386 mmol). Mixture was then stirred at 0 *C for 30 minutes followed by addition of excess diazomethane in Et 2 0. Mixture was allowed to slowly conic to ambient temperature over 3 hours. Mixture was then concentrated and 30 diluted with EtOAc. Organic was then washed with saturated aqueous NaHCO 3 and brine. Organic was dried (MgSO 4 ), filtered and concentrated. Purification by chromatography (silica gel, 100% EtOAc) afforded 82 mg (75%) of the title compound. MS (ESI) m/z 297 (M+H)*. Example 173E 35 methyl (S)-I -((S)-2-(2-bromoacetyl)pyrrolidin- I -yl)-3-methyl- I -oxobutan-2-ylcarbamate 285 A mixture of Example 1731) (70 mg, 0.236 mmol) in HOAc (0.6 ml-) at ambient temperature was added 48%HIBr (80 pL, 0.709 mmol). Mixture was stirred at ambient temperature for I hour. Mixture was poured into ice/H 2 0 and extracted with CH 2 Cl 2 (3 x 75 mL). Organic was dried (Na 2

SO

4 ), filtered and concentrated afford 63 mg (76%) of the title compound. MS (ESI) m/z 350 5 (M+H)*. Example 173F methyl {(2S)-I-I(2S)-2-(2-{4-1(2S,5S)-I -(4-tert-butylphenyl)-5-(4-{4-l(2S)-1-{(2S)-2 |I(methoxycarbonyl)aminol-3-methylbutanoyl }pyrrolidin-2-yl]-I H -imidazol-2-yl }pheiyl)pyrrolidin 10 2-yl]phenyl}-I H -imidazol-4-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl icarbaimate and methyl {(2S)-I -[(2S)-2-(2-{4-[(2R,5R)- I-(4-tert-butylphenyl)-5-(4-{4-[(2S)-1-{(2S)-2 [i(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yI]- I-1imidazol-2-yl)phenyl)pyrrolidin 2-yl]phenyl } -I II -imidazol-4-yl)pyrrolidin- I -yl]-3-methyl- I -oxobutan-2-yl Icarbamate 15 A mixture of Example 173E (59.6 mg, 0.171 inmol), Example 173C (25 mg, 0.057 minmol) and K 2 COj (65 mg, 0.470 mmol) in tetrahydrofuran (I inL) was refluxed for 4 hours. Mixture was diluted with CH 2

CI

2 and washed with H1 2 0 and Brine. The organic was then dried (MgSO4), filtered and concentrated. Compound subjected to HPLC purification on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to afford 4.5 mg (6.7%) the title 20 compound Example 173 (Trans isomers). 'H NMR (free base) (400 M~lz, DMSO-d 6 ) S ppm 0.78 0.89 (m, 12 H), 1.09 (s, 9 H), 1.68 - 1.74 (in, 4 I), 1.88 - 2.04 (m, 8 H), 3.52 (s, 6 H), 3.70 - 3.78 (in, 4 H), 4.04 (t, J=8.19 Hz, 2 H), 5.07 (t, J=4.61 Hz, 2 1-1), 5.26 (s, 2 H), 6.21 (d, J=8.46 Hz, 2 H), 6.82 (s, 2 1-1), 6.93 (d, .1=8.67 Hz, 2 1-1), 7.22 (d, .=8.89H z, 2 H), 7.26 (d, 1=8.13 H-z, 4 Hl), 7.78 (d, .1=8.13 Hz, 4 H), 7.82 (d, 1=7.70 Hz, 2 H ), 12.11 - 12.20 (in, 2 H). MS (RSI) m/z 941 (M+H )*. 25 Example 174 methyl ((2S)-I -[(2S)-2-{6-[(2R,5R)-5-{2-((2S)-I -{(2S)-2-[(methoxycarbonyl)aminol-3 methylbutanoyl }pyrrolidin-2-yl]-I H-benziinidazol-6-yl } -1-(6-methoxypyridin-3-yl)pyrrolidin-2-yl] 30 I H-henzimidaol-2-yl )pyrrolidin-I-yl]-3-incthyl-I-oxobutan-2-yl }carbamate 286 Example 109C and 6-methoxypyridin-3-ainine were processed using sequentially the methods of Examples II 3A (dichloromethane used as solvent and cyclization conducted at room temperature overnight), 165C, 113C, and 166 to provide the title compound which was purified by HPLC on a semi-prep C18 reverse-phased column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to 5 afford 27 mg of the title compound. 'H NMR (free base) (400 MFz, DMSO-d 6 ) 8 ppm 0.76 - 0.86 (in, 12 11), 1.69 - 1.76 (in, 2 11), 1.84 - 2.04 (in, 4 11), 2.13 - 2.22 (m, 4 11), 2.52 - 2.60 (in, 2 H-), 3.52 (s, 6 H), 3.55 (s, 3 H), 3.76 - 3.85 (in, 4 1-1), 4.05 (t, J=8.40 lz, 2 H), 5.08 - 5.16 (m, 2 H), 5.31 - 5.41 (in, 2 H), 6.36 - 6.45 (m, 2 H), 6.74 (dd, J=9.00, 3.04 Hz, 2 H), 7.05 (t, J=8.57 Hz, 2 H), 7.15 - 7.24 (mn, J=17.02 Hz, 3 1-1), 7.28 (d, J=8.46 Hz, 2 -1), 7.31 (s, I I), 7.37 (d, J=8.13 Hz, 1 -1), 7.45 (d, J=8.13 10 Hz, I 1-), 12.03 (s, 2 H); MS (ES!) m/z 864 (M+-1)*. Example 175 methyl ((2S)-I-((2S)-2-{6-[(2R,5R)-1-[6-(dimethylamino)pyridin-3-ylj-5-{2-[(2S)-1-((2S)-2 15 t(methoxycarbonyl)aminoJ-3-methylbutanoyl pyrrolidin-2-yl]-1H-benzimidazol-6-yl pyrrolidin-2 yl]-l H-benziidazol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2-yl)carbamate Example 175A N,N-dimethyl-5-nitropyridin-2-amine 20 A mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 minol) and 40% solution of Dimethylamine (10.66 g, 95 nimol) in eihanol (40 mL) was heated to 75 *C for 1 hour. The mixture was cooled to ambient temperature, diluted with CH 2

CI

2 and washed with saturated aqueous NaHCO 3 (3 x 100 mL) and brine. The organic was dried (MgSO 4 ), filtered and concentrated to afford 5.27 g (100%) of the title compound. MS (ESI) m/z 168 (M+H)*. 25 Example 175B

N

2

,N

2 -diinethylpyridine-2,5-diamine A mixture of Example 175A (5.27 g, 31.5 mmol) and Raney Nickel (5.27 g, 90 inmnol) in tetrahydrofuran (60 mL) was subjected to an atmosphere (30 psi) of hydrogen gas for 2 hours at 287 ambient temperature. Mixture was filtered and concentrated to afford 4.3 g (100%) of the title compound. MS (ESI) nz 138 (M+-1)*. Example 175C 5 methyl {(2S)-I-[(2S)-2-{6-[(2R,5R)-1-[6-(dimethylamino)pyridin-3-yl]-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-11H-benzimidazol-6-yl)pyrrolidin-2 yl]-l-H-benzimidazol-2-ylipyrrolidin-l -ylJ-3-methyl-1-oxobutan-2-yl carbamate Example 175B was processed using the methods referred to or described in Example 174 to provide the title compound (8.5 mg). 'H NMR (free base) (400 MHz, DMSO-d) 6 ppm 0.75 - 0.86 10 (m, 12 H), 1.71 (d, J=4.99 Hz, 2 H), 1.86 - 2.05 (m, 6 H), 2.12 - 2.23 (m, 3 H), 2.55 (s, 2 H), 2.70 (s, 6 H), 3.16 (s, 2 H), 3.52 (s, 6 H-1), 3.81 (s, 3 H), 4.05 (t, J=8.35 Hz, 2 H), 5.09 - 5.18 (i, 2 H), 5.33 (d, J=5.53 Hz, 2 11), 6.33 (d, J=9.00 lz, 1 11), 6.63 (dd, J=9.05, 2.98 lz, I 1-), 7.04 (d, J=7.70 Hz, 2 H-), 7.19 - 7.31 (m, 4 H), 7.34 - 7.48 (m, 2 H1), 12.02 (s, 2 H-); MS (ESI) m/z 877 (M+H-1)*. 15 Example 176 methyl ((2S)-I-[(2S)-2-(6-[(2R,5R)-I-(6-tert-butylpyridin-3-yl)-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)aninol-3-methylbutanoyl pyrrolidin-2-yll-1H-benzimidazol-6-yl pyrrolidin-2 yl] -I--henzimidazol-2-yl pyrrolidin-I-ylJ-3-methyl-I-oxohutan-2-yl carbamate 20 6-tert-lButylpyridin-3-amine was processed using the methods referred to or described in Example 174 to provide the title compound (62.5 mg) of the title compound. 'H NMR (free base) (400 MHz, DMSO-d 6 ) 5 ppm 0.74 - 0.88 (m, 12 H), 1.08 (s, 9 H), 1.68 - 1.77 (in, 2 H-1), 1.83 - 2.04 (in, 7 H-), 2.12 - 2.23 (m, 4 11), 2.53 - 2.61 (m, 2 1-), 3.16 (d, J=5.20 l z, 2 H1), 3.52 (s, 6 H1), 3.76 - 3.85 (i, 4 H), 4.00 - 4.11 (m, 3 H), 5.08 - 5.16 (m, 2 H-), 5.37 - 5.46 (i, 2 H), 6.54 - 6.61 (m, I H), 6.88 - 6.96 25 (in, 2 H), 7.08 (t, J=9.00 Hz, 2 H), 7.20 (s, I H), 7.25 - 7.31 (i, 3 H), 7.39 (d, J=8.13 Hz, I H), 7.47 (d, J=8.24 Hz, I H), 7.60 (d, J=3.25 Hz, I H), 12.04 (d, J=27.76 Hz, 2 H); MS (E.SI) m/z 890 (M+H)*. 288 Example 177 methyl {(2S)-I-((2S)-2-(6-{(2S,5S)-5-(2-[(2S)-1-((2S)-2-[(inethoxycarbonyl)aminol-3 methylbutanoyl pyrrolidin-2-yl]-I H -benzimidazol-6-yl}-l-[6-(piperidiii-l-yl)pyridin-3-yljpyrrolidin 5 2-yl }-I H-benziinidazol-2-yl)pyrrolidin-1-ylJ-3-inethyl-l -oxohutan-2-yl carbamate Example 177A 5-((2S,5S)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-(piperidin-1-yl)pyridine (IR,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol (prepared using (S)-(+)-alpha,alpha 10 diphenyl-2-pyrrolidinemethanol and the method of Example 109C) (0.60 g, 1.5 mmol) was processed using the method described in Example 182A to give the title compound (0.41 g, 50%). Example 177B dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I -(6-(piperidin- I -yl)pyridin-3-yl)pyrrolidine-2,5 15 diyl)bis(2-nitro-4, I -phenylene))bis(azanediyl)bis(oxonethylene)bis(pyrrolidine-2, I -diyl))bis(3 methyl-I -oxobutane-2, I -diyl)dicarbamate The product from Example 177A (0.20 g, 0.369 mmol) was combined with the product from Example I 16C (0.30 g, 1.11 mmol), cesium carbonate (0.336 g, 1.03 mmol), Xantphos (38 mg, 0.066 mmnol) and tris(dihcnzylideneacetone)dipalladiumn (20.3 mg, 0.022 mmol). Anhydrous 1,4-dioxane 20 (3.7 ml) was added, and the mixture was bubbled with N 2 gas for 15 min. The resulting mixture was stirred in a scaled tube at 100 *C for 2 h. The mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. '[he organic extract was washed with brine, dried (NaSO 4 ), filtered and concentrated. Purification by flash chromatography twice (silica gel, 0-10% MeOI-/CH 2

CI

2 ) afforded the title compound (235 mug, 60%). 25 Example 177C dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)- I-(6-(piperidin-1-yl)pyridin-3-yl)pyrrolidine-2,5 diyl)bis(2-amnino-4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, I -diyl))bis(3 methyl-I -oxobutane-2,1-diyl)dicarbamate 289 To a solution of the product from Example 177B (237mg, 0.234 mmol) in ethanol (1.2 mL) and tetrahydrofuran (1.2 ml.,) was added platinum(IV) oxide (13.29 mg, 0.059 mmol). The mixture was placed under a hydrogen atmosphere for about 1 hour. The mixture was filtered over celite, washing with methanol and concentrated. Purification by flash chromatography (silica gel, 0-10% 5 MeOH/Ci 2

C

2 ) afforded the title compound (186 mg, 84%). Example 177D methyl {(2S)-I-[(2S)-2-(6-{(2S,5S)-5-12-1(2S)-1-l(2S)-2-[(methoxycarbonyl)aminoj-3 methylbutanoyl }pyrrolidin-2-ylI-IH -beizimidazol-6-yl )- -l6-(piperidin-1-yl)pyridin-3-yljpyrrolidin 10 2-yl}-I H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-mclihyl-1-oxobutan-2-yl}carbamnaic To a solution of the product from Example 177C (113 mg, 0.119 mnmol) in toluene (1.2 mL) was added acetic acid (34 pL, 0.593 mmiiol) and 3A molecular sieves. The mixture was heated to 60 C for 2 hours. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The organic phase was washed with saturated aqueous Nal-C0 3 , dried (Na 2

SO

4 ), filtered and 15 concentrated. The crude product was purified by reverse-phase HPLC (C18) using a solvent gradient of 10-90% CH3CN in water (0.1% TFA). Fractions containing the desired product were pooled and concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO 3 , and CH 2 CI2 The organic layer was dried (Na 2

SO

4 ), filtered and concentrated to afford the title compound (9 mg, 8%). 111 NMR (400 M Hz, DMSO-D6) 8 ppm 0.78 - 0.85 (m, 7 Hl), 0.87 (dd, J=6.7, 3.0 Hz, 6 H-1), 20 1.23 (s, I 1), 1.43 (s, 6 H-), 1.72 (s, 2 H1), 1.97 (s, 5 11), 2.18 (s, 3 H-), 3.09 (s, 4 H-), 3.30 (s, 2 H), 3.53 (d, J=1.5 Hz, 6 H), 3.81 (s, 4 1-1), 4.07 (s, 2 H), 5.13 (s, 2 H), 5.33 (s, 2 1-1), 6.48 (d, J=4.4 Hz, 1 H), 6.59 - 6.64 (m, I -1), 7.05 (s, 2 -1), 7.22 (s, I H), 7.25 - 7.34 (in, 4 H), 7.37 (s, 1 1-1), 7.44 (s, 1 H), 12.06 (s, 2 H); MS (ES[) m/z 916 (M+H)*. 25 Example 178 methyl {(2S)-I -[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl )pyrrolidin-2-yI]-I H-benzimidazol-6-yl}-1-[6-(trifluoromethyl)pyridin-3 yl]pyrrolidin-2-yl}-1 l-benzimidazol-2-yl)pyrrolidin-1 -yl]-3-methyl-1-oxobutan-2-yl carbamate 290 Example 109C and 5-ami no-2-(trifluoromethyl)pyridi ne were processed using sequentially the methods of Examples 182A, 177B, 177C, and 177D to provide the title compound. 1 H NMR (400 MHz, DMSO-D6) 6 ppm 0.79 - 0.89 (in, 15 H), 1.61 (s, 4 H), 1.97 (s, 6 H), 2.19 (s, 5 H), 3.50 - 3.58 (im, 7 H), 3.82 (s, 4 H), 3.99 - 4.10 (in, 2 H), 5.15 (s, 2 11), 6.89 - 6.98 (m, 2 1-), 7.19 (s, I H), 7.26 5 7.34 (m, 4 H), 7.36 (d, J=8.2 Hz, I H), 11.94 (d, J=12.9 Hz, 2 H). MS m/z 901 (M+H)*. HN Example 179 N-(methoxycarbonyl)-L,-valyl-N-{4-[(2S,5S)I-(4-tert-butylphenyl)-5-(2-{(2S)-l -lN 10 (methoxycarbonyl)-l.,-valylJpyrrolidin-2-yl}-I -l-benzinidazol-5-yl)pyrrolidin-2-yljphenyl 1-L prolinamide and N-(methoxvcarbonyl)-L-valyl-N-{4-[(2R,5R)-I -(4-tert-butylphenyl)-5-(2-{(2S)-1-[N (methoxycarbonyl)-L-valyl]pyrrolidin-2-yl I- I H-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L 15 prolinamide Example 179A 1-(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butanc-1,4-dione To a mixture of zinc chloride (39.1 g, 287 inmol) in benzene (215 mL) was added 20 diethylamine (22.24 inL, 215 nunol) and 2-methylpropan-2-ol (20.57 mL, 215 ninol). The resulting mixture was stirred at rt for 2h, and 2-bromo-I-(4-nitrophenyl)ethanone (35.0 g, 143 mmol) and 1-(4 chloro-3-nitrophenyl)ethanone (42.9 g, 215 minol) were added in one portion. The resulting mixture was stirred at rt overnight. Added 5% aq. 112S04 (50 inL) and stirred vigorously to induce precipitation. The resulting solid was collected by filtration and washed successively with benzene, 25 water, methanol, and C-1 2 C1 2 . The solid was dried in vacuo to give the title compound. Example 179B 1-(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butane- 1,4-diol To a solution of the product from Example 179A (10.0 g, 27.6 mmol) in EtOll (220 mL) was 30 added sodium borohydride (2.190 g, 57.9 mmiriol) in several portions over I h. The resulting mixture was stirred at rt for I h, filtered through elite, and concentrated in vacuo. The residue was dissolved 291 in EtOAc and washed by IN aq. ICL. The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo to give the title compound (9.29 g, 92%) Example 179C 5 I-(4-tert-butylphenyl)-2-(4-chloro-3-nitrophenyl)-5-(4-nitrophenyl)pyrrolidine To a solution of product from Example 179B (9.29 g, 25.3 mmol) in anhydrous CH 2 Cl2 (200 mL) at 0 *C was added triethylamine (10.53 mL, 76 mmol), followed by dropwise addition of methanesulfonyl chloride (4.93 mL, 63.3 mmol). The resulting mixture was stirred at 0 *C for 2 h, and then concentrated in vacuo. The resulting solid was dissolved in anhydrous DMF (70 miL), 4-tert 10 butylaniline (40.4 mL, 253 mmol) was added, and the resulting mixture was stirred at 50 *C for I h. The resulting mixture was cooled to rt and poured into ice cold IN aq. HCI (500 mL) to give a yellow precipitate. The precipitate was collected by filtration and dried to give the title compound (13.2 g). Example 179D 15 4-(I-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)-N-(4-methoxybenzy)-2-nitroaniline The product from Example 179C (13.2 g, 27.5 mmol) and 4-nethoxybenzylamine (18 mL, 139 nutnol) were combined and stirred at 145 *C for 1.5 h. The mixture was cooled to ri, and C1 2 Cl 2 was added. The resulting precipitate was filtered off, and the filtrate was washed successively with IN aq. HCI and saturated aq. NaHCO 3 . The organic layer was dried over Na 2

SO

4 , filtered and 20 concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (5.0 g, 31%). Example 179E 4-(5-(4-aminophenyl)- 1-(4-tert-butylphenyl)pyrrolidin-2-yl)-N 1 -(4-methoxybenzyl)benzene- 1,2 25 diamine To a solution of the product from Example 179D (2.74 g, 4.72 minol) in EtOH (25 mL) and T HF (25 mL) was added platinum(IV) oxide (0.5 g, 2.2 mmol). The resulting mixture was stirred at rt under I atm 1-12 overnight. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on 30 silica gel using a solvent gradient of 0-45% EtOAc in hexane to give the title compound (1.74 g, 71%). Example 179F (2S)-tert-butyl 2-(4-(5-(3-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxaniido)-4-(4 35 methoxybenzylanino)phenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbanoy)pyrrolidine-l carboxylate 292 To a mixture of the product from Example 179E (1.74 g, 3.33 mmol), (S)-l-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.793 g, 8.33 inmol) and HATU (3.17 g, 8.33 mmol) in DMSO (33 mL) was added Hunig's base (1.746 mL, 10.00 ininol). The resulting mixture was stirred at rt for I h and was partitioned between 120 and CH 2 C1 2 . The organic layer was dried over 5 Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (2.1 g, 69%). Example 179G 10 (2S)-teri-butyl 2-(4-(5-(4-amino-3-((S)-I-(tert-buioxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-1 (4-tert -butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-1-carboxylate To a solution of the product from Example 179F (1.06 g, 1.16 mmol) in CI1 2 Cl 2 (40 mL) and 1120 (2 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.316 g, 1.393 mmol) in several portions. The mixture was stirred at rt for 20 min and was washed with saturated.aq. NaIHCO 3 . 15 The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (0.53 g, 57%). Example 17911 20 (2S)-tert-butyl 2-(4-(5-(2-((S)- I -(tert-butoxycarbonyl)pyrrolidin-2-yl)- I 1-benzo[d]imidazol-5-yl)- I (4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine- I -carboxylate A solution of product from Example 179G (0.526 g, 0.662 mmol) in acetic acid (4.73 mL, 83 mmol) was stirred at 65 *C for I h. The resulting mixture was partitioned between CH 2 Cl 2 and saturated aq. NaICO 3 . The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. 25 The crude product was purified by column chromatography on silica gel using a solvent gradient of 0 2.5% MeOH in CH 2 Cl2 to give the title compound (0.23 g, 45%). Example 1791 (S)-N-(4-((2S,5S)-I-(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)-Ili-benzuod]imidazol-5 30 yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide and (S)-N-(4-((2R,5R)- I -(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)- IH-bcnzo[d]imidazol-5 yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide To a solution of the product from Example 179HI (0.302 g, 0.389 niunol) in CI- 2 C1 2 (3 moL) 35 was added TFA (2.5 mL), and the resulting mixture was stirred at rt for 1.5 h. The mixture was concentrated in vacuo, and the crude product was purified by reversed-phase HPLC (C18) using a 293 solvent gradient of 10-100% acetonitrile in H 2 0 (0.1% TFA). The trans-pyrrolidine isomer eluted before the cis-pyrrolidine isomer. Fractions containing the trans-isomer were concentrated in vacuo, and the residue was partitioned between CH 2

CI

2 and saturated aq. NaHCO 3 . The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo to give the title compound (83 mg, 37%). 5 Example 179J N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)I-(4-tert-butylphenyl)-5-(2-{(2S)-l-[N (methoxycarbonyl)-l.-valyllpyrrolidin-2-yl}- I H-benzi midazol-5-yl)pyrrolidin-2-ylJphenyl}-L prolinamide 10 and N-(melhoxycarbonyl)-L-valyl-N-(4-[(2R,5R)-I-(4-teri-butylphenyl)-5-(2-((2S)-1-[N (methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-IH-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L prolinamide To a mixture of the product from Example 1791 (83 mg, 0.144 mmol), (S)-2 15 (imethoxycarbonylamino)-3-methylbutanoic acid (63 mg, 0.361 mmol), and HATIJ (0.137 g, 0.361 mmol) in DMSO (1.5 ml-) was added Hunig's base (0.101 ml, 0.578 mmol), and the resulting mixture was stirred at rt for I h. The mixture was partitioned between CH 2

CI

2 and H 2 0. The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-3.5% MeOl- in CH 2 Cl 2 to give the 20 title compounds (80 mg, 60%). 111 NMR (400 MHz, DMSO-D6) 6 ppm 0.74 - 0.99 (in, 12 11), 1.09 (s, 9 H), 1.59 - 1.73 (m, 2 H), 1.81 - 2.05 (in, 6 H), 2.07 - 2.24 (in, 2 H), 3.50 - 3.56 (in, 6 H), 3.58 3.67 (in, I H), 3.76 - 3.85 (in, 2 H), 3.99 - 4.10 (in, 2 H), 4.43 (dd, J=8.0, 4.9 Hz, 1 1-1), 5.08 - 5.16 (m, I H), 5.16 - 5.25 (in, 1 -1), 5.26 - 5.37 (m, I H), 6.21 (d, .=8.8 Hz, 2 H), 6.88 - 6.97 (m, 2.5 H), 7.00 7.08 (in, I H), 7.11 - 7.20 (i, .1=5.7 Hz, 2.5 H), 7.21 - 7.34 (m, 2 H), 7.37 (dd, J=8.2, 2.0 H z, 0.5 H), 25 7.45 (d, J=8.3 Hz, 0.5 H), 7.50 (d, J=8.3 Hz, 2 H), 9.98 (s, I H), 12.01 (in, I H); MS mn/z 891.6 (M+H)*. H - H Example 180 294 methyl {(2S)-1-I(2S)-2-(4- 4-[(2R,5R)-l -(4-tert-butylphenyl)-5-(4-{5-chloro-2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-I H-inidazol-4-yI Iphenyl)pyrrolidin 2 -yl ]phenyl}-5-chloro-1 H-imidazol-2-yl)pyrrolidin- I-yl]-3-methyl-1-oxobutan-2-ylicarbamate To a solution of the product from Example 43 (114 mg, 0.121 mmol) in CH 2 Cl2 (1.2 mL) was 5 added N-chlorosuccinimide (54 mg, 0.41 mmol), and the resulting mixture was stirred at rt for 9 h. 'rhe mixture was diluted by CIH 2 C1 2 and washed with saturated aq NaHCO 3 . The organic layer was dried over Na 2 SO. filtered, and concentrated in vacuo. The crude product was subjected to reversed phase H PLC (C18) using a solvent gradient of 40%-100% acetonitrile in water (0.1% TFA). Fractions containing the desired product were pooled and concentrated in vacuo. lie residue was 10 purified on a preparative 'LC plate, cluting with 3% MeOH in C1 2

C

2 to give the title compound (3.5 tmg, 3%). IH NMR (400 MHz, DMSO-D6) 8 ppm 0.80 - 0.92 (m, 12 H), 1.11 (s, 9 H), 1.72 (d, J=5.0 Hz, 2 H), 1.87 - 2.04 (m, 6 H1), 2.05 - 2.23 (tn, 2 H-), 3.53 (s, 6 H-), 3.72 - 3.82 (n, 2 H-), 4.04 (t, J=8.4 Hz, 2 H), 4.98 (dd, 1=6.8, 3.5 Hz, 2 11), 5.29 (dd, J=3.5, 2.5 Hz, 2 H-1), 6.23 (d, J=8.8 Hz, 2 H1), 6.96 (d, J=8.8 H z, 2 H1), 7.27 (d, J=8.6 lz, 2 11), 7.32 (d, 1=8.2 H1z, 4 11), 7.61 (d, J=8.1 -1z, 4 H), 12.41 (s, 2 15 H); MS i/z 1009.1 (M+H)*. 0 A Example 181 iethyl I (2S)-I-[ (2S)-2-(4-{4-[(2R,5R)- I -(4-tert-butyl-2-chlorophenyl)-5-(4-{5-chloro-2-[(2S)- 1 20 {(2S)-2-[(imethoxycarboiyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]- IH-imidazol-4 yl}phenyl)pyrrolidin-2-yl]phenyl}-5-chloro-1HI-imidazol-2-yl)pyrrolidin-l-yl]-3-imethyl-1-oxobutan 2-yl)carbainate The product from Example 43 (114 ng, 0.121 mmol) was subjected to the procedure described in Example 180 to give the title compound (4.7 tmg, 4%). 1H NMR (TFA salt) (400 MHz, 25 DMSO-D6) 6 ppm 0.78 - 0.89 (in, 12 H), 1.05 (s, 9 H), 1.85 - 1.97 (in, 10 H), 2.04 - 2.18 (m, 4 H), 3.52 (s, 6 H), 3.69 - 3.81 (i, 4 H), 4.03 (t, J=8.3 Hz, 2 H), 4.95 (dd, 1=7.0, 4.0 Hz, 2 H), 5.53 (d, J=7.5 Hz, 2 H), 6.91 - 6.95 (in, I H), 6.96 - 7.02 (in, 2 H), 7.26 (d, J=8.5 H z, 2 H), 7.30 - 7.41 (in, 4 H), 7.49 (d, J=7.6 Hz, 4 H), 12.34 (s, 2 H); MS n/z 1045.1 (M+H)*. 295 Example 182 methyl [(2S)-I -{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-I -{(2S)-2 [(methoxycarbonyl)aminol-3-methylbutanoyl I pyrrolidin-2-ylJ- 1H -imidazol-4-yl I phenyl)- 1-[6 (piperidin-l -yl)pyridin-3-yl]pyrrolidin-2-yl I phenyl)- I H-1-imidazol-2-yl Ipyrrolidin-l-yl )-3-methyl- I 5 oxobutan-2-yl]carbainate Example 182A 5-((2S,5S)-2,5-bis(4-broinophenyl)pyrrolidin-1-yl)-2-(piperidin-1-yl)pyridine To a suspension of the product of Example 69A (0.50 g, 1.25 inmol) in anhydrous CH 2

C

2 (12 10 iL) at 0 *C was added E1 3 N (0.52 mL, 3.75 mmnol), followed by inethanesulfonyl chloride (0.243 nL, 3.12 minol). The resulting mixture was stirred and 0 *C for 90 min and then evaporated to dryness. The solid was dissolved in anhydrous DMF (10 mL), and Example 144C (1108 mg, 6.25 immol) was added. The resulting mixture was stirred at 40 *C overnight, and was partitioned between 0.2 N aq HCI and EtOAc. The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo. The 15 crude product was purified by column chromatography on silica gel using a solvent gradient of EtOAc and hexane to give the title compound (107 ing, 16%). Example 182B methyl [(2S)-I -{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)aminol-3 20 methylbutanoyl}pyrrolidin-2-yl]-l-l-imidazol-4-yl phenyl)-1-[6-(piperidin-1-yl)pyridin-3 yl]pyrrolidin-2-yl)phenyl)- IH-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-l-oxobutan-2-yl]carbaimate The product from Example 182A was subjected to the procedures described in Examples 42D, 42E, 42F, and 42G to give the title compound. 1H NMR (free base) (400 MHz, DMSO-D6) 8 ppm 0.80 - 0.94 (in, 12 1-1), 1.24 (s, 4 H), 1.44 (s, 6 H), 1.89 - 2.04 (in, 6 H), 2.07 - 2.20 (i, 4 H), 3.12 25 (s, 4 1), 3.53 (s, 6 H), 3.77 (d, 1=6.7 Hz, 2 H), 4.05 (t, J=8.4 Hz, 2 H), 5.06 (dd, 1=6.7, 3.0 Hz, 2 11), 5.19 (d, 1=6.4 lz, 2 H), 6.45 - 6.53 (in, I H), 6.56 - 6.63 (in, I H), 7.15 (d, 1=8.2 Hz, 4 H), 7.21 - 7.32 (n, 4 H1), 7.38 (d, J=1.8 lz, 2 1-), 7.62 (d, J=8.0 lz, 4 11), 11.69 (s, 2 11); MS im/z = 968.8 (M+H). 296 HN H Example 183 methyl [(2S)-I-((2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)anino]-3 mnethylbutanoyl}pyrrolidin-2-yI]-I H-i midazol-4-yl }phenyl)-l -[6-(rifluoromethyl)pyridin-3 5 yl]pyrrolidin-2-yl}phenyl)-lIH-inidazol-2-yl]pyrrolidin-I-yl}-3-methyl-i-oxobutan-2-yl]carbamate Example 183A 5-((2S,5S)-2,5-bis(4-hromophcnyl)pyrrolidin-I -yl)-2-(trifluoromcthyl)pyridine The product from Example 69A (1.0 g, 2.5 nunol) was subjected to the procedure described in 10 Example 182A, substituting 6-(trifluoromethyl)pyridin-3-amine for Example 144C, to give the title compound (0.13 g, 10%). Example 183B methyl [(2S)-1-{(2S)-2-(4-(4-{(2S,5S)-5-(4-(2-[(2S)-1-{(2S)-2-1i(methoxycarbonyl)aminol-3 15 methylbutanoyl } pyrrolidin-2-yl]-I H-imidazol-4-yl }phenyl)- I-[6-(tritluoromethyl)pyridin-3 yl]pyrrolidin-2-yl }phenyl)- IH-imiidazol-2-yl]pyrrolidin-I-yl)-3-methyl-I-oxobutan-2-yl]carbamate The product from Example 183A was subjected to the procedures described in Examples 42D, 42E, 42F, and 42G to give the title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) 6 ppm 0.75 - 0.91 (m, 12 11), 1.84 (d, 1=5.6 H z, 2 11), 1.96 - 2.10 (m, 6 11), 2.1 1 - 2.20 (m, J=10.8, 5.5 20 Hz, 2 H), 3.54 (s, 6 H), 3.76 - 3.91 (i, 4 H), 4.10 (t, J=7.9 Hz, 2 H), 5.11 (t, 1=6.8 Hz, 2 H), 5.56 (d, 1=5.1 Hz, 2 H), 6.74 (dd, 1=8.8, 2.5 Hz, 1 H), 7.32 (d, J=8.5 Hz, 2 H), 7.41 (d, J=7.8 Hz, 4 H), 7.44 7.48 (i, .1=8.8 Hz, 1 -1), 7.71 (d, 1=8.2 Hz, 4 H), 7.76 (d, 1=2.5 Hz, I H), 7.97 (s, 2 H-1), 14.50 (s, 2 H); MS n/z 953.6 (M+H)*. 25 Example 184 297 methyl {(2S)-I-l(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-((2S)-2-l(methoxycarbonyl)aminoj-3 methylbutanoyl pyrrolidin-2-ylIJ-I H-henziinidazol-6-yl}-1-[2-(piperidini-1-yl)pyriimidin-5 yl]pyrrolidin-2-yl-lI H-benzimdazol-2-yl)pyrrolidin-1 -yl]-3-mnethyl- I -oxobutan-2-yl}carbamate 5 Example 184A 2-(piperidin- I -yl)pyrimidin-5-amine To a suspension of 2-chloro-5-nitropyrimidine (1.5 g, 9.40 inmol) in EtOH (15 mL) was added piperidine (2.79 ml., 28.2 iniol), and the resulting mixture was refluxed for 2 h. The cooled mixture was concentrated in vacuo, and the residue was partitioned between CH 2

CI

2 and saturated aq. 10 NaHC 3 The organic layer was dried over Na 2

SO

4 , filtered and concentrated in vacuo to give a solid (1.65 g, 84%). The solid was placed in a 250 niL stainless steel pressure bottle and dissolved in TI-IF (20 mL). Raney-Ni 2800 in water slurry (1.650 g, 28.1 mmol) was added, and the mixture was stirred at rt for 2 h under 1-12 gas at a pressure of 30 psi. The mixture was filtered through a nylon membrane and concentrated in vacuo to give the title compound (1.4 g, 99%). 15 Example 184B 5-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-(piperidin-1-yl)pyrimidine The product from Example 109C (1.09 g, 2.72 nmol) was subjected to the conditions described in Example 182A, substituting Example 184A for Example 144C, to give the title 20 compound (0.59 g, 40%). Example 184C methyl {(2S)-I-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)aminol-3 methylbutanoyl Ipyrrolidin-2-yl J-I H -benziinidazol-6-yl} -l -[2-(piperidin- I -yl)pyri midin-5 25 ylipyrrolidin-2-yl I - I H-benzinidazol-2-yl)pyrrolidin-I-yl]-3-iehyl-I-oxobut an-2-yl carbamate The product from Example 184B was subjected to the procedures described in Examples 17713. 177C, and 177D to give the title compound. IH NMR (TFA salt) (400 MHz, DMSO-D6) 8 ppm 0.71 - 0.91 (in, 12 11), 1.24 (s, 2 11), 1.32 - 1.41 (in, 4 H-), 1.44 - 1.52 (in, 2 H-), 1.82 (d, 1=5.1 Hz, 2 H1), 1.92 - 2.26 (i, 12 H1), 3.86 (s, 6 11), 4.12 (t, 1=8.0 Hz, 2 H-), 5.20 (dd, J=8.0, 5.2 Iz, 2 11), 5.54 30 (d, J=6.2 Hz, 2 -1), 7.33 (d, .1=8.3 Hz, 2 H), 7.40 (d, 1=7.8 Hz, 2 H), 7.51 (s, 2 H), 7.57 - 7.61 (in, 2 H), 7.72 (d, 1=8.3 Hz, 2 1-1); MS m/z 917.5 (M+H)*. 298 Example 185 methyl {(2S)-I-[(2S)-2-(5-{4-[(2S,5S)-5-(4-(2-f(2S)- 1-{(2S)-2-[(methoxycarbonyl)aminol-3 methylbutanoyl} pyrrolidin-2-yl]- IH-imidazol-5-yl phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3 5 yl]phenyl }pyrrolidin-2-yl]phenyl}- I H-i midazol-2-yl)pyrrolidin-1 -yl]-3-mcthyl-I-oxobutan-2 yl )carbamnate and methyl {(2S)-l -I(2S)-2-(5-{4-[(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl pyrrolidin-2-yl]- I H-irnidazol-5-yl Iphenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3 10 yl]phenyl pyrrolidin-2-yl]phenyl}-IH-imidazol-2-yl)pyrrolidin-I-yl]-3-methyl-I-oxobutan-2 yl Icarbamate Example 185A 2,5-bis(4-bromophenyl)-I-(4-iodophenyl)pyrrolidine 15 The product from Example 42B (1.39 g, 2.499 mmol) in DMF (6.25 moL) was treated with 4 iodoaniline (Aldrich, 4.38 g, 19.99 nimol), heated at 40-50 *C for two hours, cooled and diluted into EtOAc. The EtOAc layer was washed 3 X 50 mL with I M id, with water, brine, dried (Na 2

SO

4 ), filtered and concentrated. Purification by flash chromatography on an ISCO 40 g silica cartridge eluting with 0-20% EtOAc in hexane afforded the title compound as a tan foam as a mixture of 20 stereoisomers (0.96 g, 66 %). MS (ES) n/z 584 (M+H)'. Example 185B 4-(5-(4-(2,5-bis(4-bromophenyl)pyrrolidin-i-yl)phenyl)pyridin-2-yl)morpholine The product from Example 185A (0.1 g, 0.171 nnol), 4-(5-(4,4,5,5-tetramethyl-1,3,2 25 dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.050 g, 0.171 mmol), potassium phosphate (0.028 mL, 0.343 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.570 mug, 1.715 pmol) and 1,3,5,7 tetrammethyl-6-pheyl-2,4,8-trioxa-6-phosphaadamante (1.504 mg, 5.14 pmol) were combined in THF (1.2 ml.) / water (0.4 ml..). The mixture was sparged with nitrogen for 15 minutes diluted into EtOAc, washed with IM sodium bicarbonate, brine, dried (Na 2

SO

4 ), filtered and concentrated. Purification 299 hy flash chromatography on an lsco 12 g silica cartridge eluting with 20-70 % EtOAc in hexane gave the title compound as a cream colored powder (91 mg, 86%). %). MS (ESI) n/z 620 (M+H)*. Example 185C 5 methyl {(2S)-I-I(2S)-2-(5-{4-[(2S,5S)-5-(4-{2-[(2S)-l -{(2S)-2-[(methoxycarbonyl)amnino]-3 methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-5-yl phenyl)-l-{4-[6-(niorpholin-4-yl)pyridin-3 ylJphenyl }pyrrolidin-2-ylJphenyl}-I H-inidazol-2-yl)pyrrolidin-1-yl]-3-methyl-I-oxobutan-2 yl carbainate and 10 methyl ((2S)-1-[(2S)-2-(5-{4-[(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)aminol-3 met lylbulanoyl ) pyrrolidin-2-yl]-l H-imidazol-5-ylIiphenyl)-I-{4-16-(morpholin-4-yl)pyridin-3 yl]phenyl )pyrrolidin-2-yl]phenyl}- IH-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2 yl carbamate The product from Example 185B was processed as described in Example 42D, 42E, 42F, and 15 42G to afford the title compounds. 'H NMR (free base) (400 MHz, DMSO-d 6 ) 8 0.77 - 0.94 (in, 12 H) 1.71 - 2.47 (in, 16 H) 3.36 - 3.42 (in, 4 H) 3.53 (s, 6 H) 3.63 - 3.71 (in, 4 H) 3.74 - 3.84 (in, 3 H) 4.00 - 4.08 (m, I H) 4.79 (d, J=4.23 Hz, I H) 5.02 - 5.11 (in, 2 H) 5.24 - 5.32 (m, 1 H) 6.37 (d, J=8.89 Hz, 1 -I) 6.49 (d, J=8.78 Hz, I H) 6.79 (dd, J=14.91, 8.95 Hz, 1 H) 7.12 - 7.78 (m, 15 H) 8.23 - 8.31 (m, I 11) 11.64 - 12.11 (m, 2 11). MS (ESI) m/z 1046 (M+l1)*. H N NH 20 Example 186 methyl {(2S)-l -[(2S)-2-(4-{4-[(2S,5S)- I-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(imethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1 H -iinidazol-4-ylphenyl)pyrrolidin 2-yljphenyl I-I H-iiidazol-2-yl)pyrrolidin-1-yll-3-methyl-I -oxobutan-2-yl Icarbamate 25 The product from Example 958 was purified by chiral chromatography on a Chiralpak IB column cluting wiih a mixture of hexancPHF/methanol (85/10/5). The title compound was the second of the 2 diastereoners to elute. IH NMR (400 MHz, DMSO-D6) 6 ppm 0.35 - 0.42 (m, 2 1-1) 0.65 - 0.73 (in, 2 H) 0.80 - 0.92 (in, 12 H) 1.58 - 1.65 (m, I H) 1.67 - 1.71 (m, 2 H) 1.87 - 2.02 (m, 6 H) 2.07 - 2.17 (m, 4 H) 3.53 (s, 6 H) 3.70 - 3.85 (in, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.06 (dd, J=6.72, 30 2.82 Hz, 2 H) 5.16 - 5.25 (in, 2 H) 6.19 (d, J=8.67 Hz,, 2 H) 6.64 (d, J=8.57 Hz, 2 H) 7.09 - 7.32 (in, 6 H) 7.36 - 7.69 (in, 6 H) 11.60 - 12.09 (in, 2 1-1); MS (ESI+) m/z 924.6 (M+H). 300 a NHN N N .110 Example 187 dimethyl ([(2R,5R)-1-{3-[6-(morpholin-4-yl)pyridin-3-yllphenyl}pyrrolidine-2,5-diyll bis{(2 5 aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-nethyl-1-oxobutane-1,2 diyl]})biscarbamate Example 187A (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-I -(3-iodophenyl)pyrrolidine 10 The mesylate of Example 109C (4.17 g, 7.48 mnol) in DMF (15 ml) was treated with 3 iodoaniline (Aldrich, 7.2 mL, 59.8 mmol), stirred at ambient temperature for 48 hours and diluted into EtOAc. The EtOAc layer was washed 3 X 50 mL with I M IICI, with water, brine, dried (Na 2

SO

4 ), filtered and concentrated. Purification by flash chromatography on an Isco 300 g silica cartridge eluting with 10-30% EtOAc in hexane afforded the title compound as a bright yellow foam (2.6 g, 60 15 %). MS (ESI) m/z 584 (M+H)*. Example 187B 4-(5-(3-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2 yl)morpholine 20 The product from Example 187A (1.4 g, 2.396 mnmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.695 g, 2.396 nnol), potassium phosphate (1.017 g, 4.79 mmol), tris(dibeni.ylideneacetone)dipalladium(0) (0.022 g, 0.024 mmol) and 1,3,5,7-tetramethyl 6-phenyl-2,4,8-irioxa-6-phosphaadamante (0.021 g, 0.072 iniol) were combined in THF (18 niL) / water (6 niL). The mixture was sparged with nitrogen for 15 minutes, stirred for 6 hours diluted into 25 EtOAc, washed with IM sodium bicarbonate, brine, dried (Na 2

SO

4 ), filtered and concentrated. Purification by flash chromatography on an Isco 120 g silica cartridge eluting with 20-60 % EtOAc in hexane gave the title compound as a yellow glass (1.1 g, 74%). MS (ESI) m/z 620 (M+H)*. Example 187C 301 dimethyl ([(2R,5R)-I-{3-[6-(morpholin-4-yl)pyridin-3-ylJphenyl}pyrrolidine-2,5-diylJbis{(2 ami nobenzene-4,1 -diyl)carhamoyl(2S)pyrrolidine-2, I -diyll(2S)-3-methyl-1 -oxohutane- 1,2 diyl]))biscarbanate The product from Example 187B (0.5 g, 0.806 minol), was processed using the methods in 5 Examples 165C and 165D to afford the title compound (400 mg, 45% two steps). 'H NMR (400 MHz, DMSO-d 6 ) 8 0.89 (dd, 1=11.82, 6.61 lHz, 12 11) 1.35 - 2.22 (m, 14 11) 3.36 - 3.46 (m, 8 11) 3.52 (s, 6 1-) 3.56 - 3.86 (in, 4 H) 3.97 - 4.43 (i, 4 H) 4.85 (s, 4 H) 5.09 (s, 2 H) 6.25 (d, .=7.26 Hz, I H) 6.42 6.51 (in, 3 H) 6.58 (s, 2 H) 6.66 (d, 1=7.59 Hz, I H) 6.81 (d, 1=8.78 I-7, 1 H) 6.95 - 7.02 (in, 3 H) 7.36 (d, J=8.35 Hz, 2 H) 7.51 (dd, 1=8.73, 2.33 Hz, I H) 8.12 (d, J=2.06 H-z, I H) 9.23 (s, 2 H). MS 10 (ESI) m/z 1031 (M-+H)*. Example 188 methyl ((2S)-I-[(2S)-2-{5-[(2R,5R)-5-{2-[(2S)-I-{(2S)-2-[(imethoxycarbonyl)aiino]-3 15 methylbutanoyl}pyrrolidin-2-yl]-I H-benziimidazol-5-yl}-l-{3-[6-(imorpholin-4-yl)pyridin-3 yl]phenyl pyrrolidin-2-yl]- IH-henzinidazol-2-ylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2 yl carbainate The product from Example 187C (0.4 g, 0.388 inmol) was treated with acetic acid (0.089 ml, 1.553 nmol) in toluene (7.77 nil) at 50 *C for 4 hours, cooled and concentrated. The residue was 20 dissolved in EtOAc, washed with 10% sodium bicarbonate, brine, dried (Na 2

SO

4 ), altered and concentrated. Purification by flash chromatography on an Isco Gold 12 g silica cartridge eluting with 1-6% McOI in dichloroineihane afforded the title compound (183 ng, 45%). 'H NMR (400 MHz, DMSO-d 6 ) 8 0.71 - 0.90 (m, 12 11) 1.62 - 2.28 (m, 14 11) 3.37 - 3.43 (m, 4 H1) 3.53 (s, 6 H-) 3.64 - 3.68 (m, 4 11) 3.80 (s, 4 11) 4.05 (t, J=8.35 Iz, 2 -1) 5.08 - 5.19 (in, 2 H-) 5.48 (s, 2 11) 6.29 (d, J=8.02 lz, 1 25 H) 6.54 - 6.64 (m, 2 H) 6.76 (d, J=8.89 Hz, I H) 6.93 (d, J=4.66 Hz, 1 H) 7.11 (d, J=8.13 Hz, 2 H) 7.23 - 7.30 (in, 3 H) 7.34 - 7.40 (in, 2 H) 7.46 (s, 2 H) 8.05 (s, 1 1H) 12.01 (s, 2 H). MS (ES!) nVz 995 (M+1)*. 302 H ,o Example 189 methyl [(2S,3R)- 1-{(2S)-2-[(4-((2S,5S)-I-(4-tert-butylphenyl)-5-[4-({[(2S)-1-((2S)-2 [(metlioxycarbonyl)amino]-3-methylbulanoyl)pyrrolidin-2-yl]carbonyl )amino)phenyl]pyrrolidin-2 5 yl phenyl)carbamoyl]pyrrolidin-1-yli-3-methoxy-1-oxobutan-2-yl]carbamate Example 189A (S)-tert-butyl 2-(4-((2S,5S)- I -(4-tert-butylphenyl)-5-(4-((S)- I -((S)-2-(methoxycarbonylanino)-3 methylbutanoyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine- I 10 carboxylate To a solution of the product from Example 213 (33 ig, 0.052 mmol) in anhydrous DMSO (0.5 niL) was added (S)-1-(teri-butoxycarbonyl)pyrrolidine-2-carboxylic acid (13.3 mug, 0.062 nunol), HATIJ (23.5 mg, 0.062 mnmol) and Hunig's base (18 pL, 0.10 inniol). The resulting mixture was stirred at rt for 90 min and then partitioned between 1120 and EtOAc. The organic layer was dried 15 over Na 2

SO

4 , Filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% MeOH in CH 2 Cl 2 to give the title compound (33 mg, 76%). Example 189B 20 methyl [(2S,3R)- 1-{(2S)-2-[(4-{(2S,5S)-I-(4-tert-hutylphcnyl)-5-[4-({[(2S)-I -((2S)-2 [(mctlhoxycarbonyl)aminol-3-methylbutanoyl pyrrolidin-2-yllcarbonylI amnino)phenyl]pyrrolidin-2 yl phenyl)carbamoyl]pyrrolidin-I -yl}-3-methoxy- I -oxobutan-2-yl]carbamate A solution of the product from Example 189A (30 ng, 0.036 mmol) in a 1:1 mixture of CH2Cl 2 :TFA (0.4 mL) was stirred at rt for 45 min. The mixture was concentrated in vacuo, and the 25 residue was partitioned between saturated aq. NaHCO 3 and EtOAc (2x). The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated in vacuo to give a solid. 'Ihe solid was subjected to the procedure described in Example 189A (27 tmg), substituting (2S,3R)-3-methoxy-2 (methoxycarbonylamino)butanoic acid for (S)-1-(tert-buloxycarbonyl)pyrrolidine-2-carboxylic acid, to give the title compound (17 tmg, 52%). 1 H NMR (400 MHz, DMSO-D6) S ppm 0.85 - 0.97 (i, 6 30 -1), 1.08 - 1.19 (i, 12 H), 1.60 - 1.66 (m, 2 -1), 1.80 - 2.05 (in, 8 H), 2.08 - 2.20 (m, 2 H), 3.25 (s, 3 H-), 3.42 - 3.50 (i, 2 H-), 3.52 (s, 3 H-), 3.53 (s, 3 H-), 3.58 - 3.72 (in, 2 H1), 3.76 - 3.87 (m, 2 H-1), 3.98 4.06 (in, 1 1-1), 4.26 (t, J=7.81 Hz, I H), 4.38 - 4.46 (m, 2 H), 5.15 (d, J=6.40 Hz, 2 H), 6.17 (d, .1=8.78 303 Hz, 2 H), 6.94 (d, J=8.89 Hz, 2 H), 7.13 (d, J=8.24 Hz, 4 H), 7.32 (t, 1=8.84 Hz, 2 H), 7.49 (dd, J=8.57, 2.06 Hz, 4 H), 9.96 (d, J=15.51 lIz, 2 H). MS (ESI) m/z 910.6 (M+H)*. Ao o 5 Example 190 dimethyl ([1l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis (benzene-4,lI -diylcarbonylhydrazine-2, 1 diylcarbonyl(2S)pyrrolidine-2, I -diyl[(2S)-3-methyl- 1-oxobutane-1I,2-diyl]}I)biscarbamate) T1o a solution of the product from Example 171 B (50 mg, 0.106 mmol) and the product from Example 37B (72 mg, 0.27 mmol) in anhydrous DMSO (1 mL) was added HATUJ (100 mg, 0.27 10 mmol) and H-unig's base (56 1.L, 0.32 mmnol). The resulting mixture was stirred at rt for 90 mini, and then partitioned between H 2 0 and EtOAc (2x). The combined organic layers were dried over Na 2

SO

4 , Filtered, and concentrated in vacuo. The crude product was purified by colum chromatography on silica gel using a solvent gradient of 0-10% MeOH in CH 2 Cl 2 to give the title compound (68 nmg, 65%) as a mixture of cis and trans stereoisomers. IH NMR (400 MI-z, DMSO-D6) 6 ppm 0.81 -0.98 15 (im, 1 2 H-), 1.08 - 1.17 (im, 9 H), 1.64 - 1.77 (in, 2 H), 1.78 -2.06 (in, 8 H), 2.07 - 2.22 (in, 2 H-), 3.50 3.55 (nm, 6 H), 3.58 - 3.69 (in, 2 H1), 3.70 - 3.83 (in, 2 H), 3.96 - 4.08 (mn, 2 H), 4.38 - 4.49 (in, .1=8.13 H z, 2 H ), 4.76 - 4.87 (mi, 0.7 H ), 5.28 - 5.40 (mn, 1.3 H), 6.14 - 6.33 (in, 2 H ), 6.92 - 7.08 (mn, 2 H ), 7.27 - 7.38 (mn, 1=8.02 H-Iz, 5 H-), 7.62 (d, 1=8.35 H z, I H), 7.79 - 7.96 (mn, 4 H ), 9.87 - 9.98 (in, 2 H-), 10.31 - 10.44 (in, 2 H~); MS (ESI) m/z981.I (M+H)*. 20 ONH H Example 191 methyl { (2S)- -. [(2S)-2-(5- { 4-[(2S,5S)- i -(4-tert-butylphenyl)-5-{( 2-[(2S)- I - { (2S)-2 [(mnethoxycarbonyl)amino]-3-mneihylbutanoyl Ipyrrolidin-2-yl]-l H-benzimnidazol-6-yl Ipyrrolidin-2 25 yl] phenyl}-IH-imidazol-2-y)pyrrolidin- I - yl]-3-methyl-eoxobutan-2-yl carbamate 304 and methyl {(2S)-l-[(2S)-2-(5-{4-[(2R,5R)-l-(4-tert-hutylphenyl)-5-{2-[(2S)-l-t(2S)-2 [(methoxycarbonyl)amino]-3-iethylbutanoyl pyrrolidin-2-yl]-l-H-benziimidazol-6-yl}pyrrolidin-2 yl]phenyl}-IH-imidazol-2-yl)pyrrolidin-1i -yl]-3-methyl-1-oxohutan-2-yl}carbamate 5 Example 191A 1-(4-bronophenyl)-4-(4-chloro-3-nitrophenyl)butane- 1,4-dione Zinc chloride ( 2.73 g, 20 mmole)was treated with anhydrous benzene (10 ml..) followed by diethylamine (1.55 ml-, 15 mmole) and tert-hutanol (1.4 mL, 15 mmole) and the resulting slurry was 10 stirred at room temperature for 1.75 hr until all solids had dissolved. To the cloudy suspension was added 4'-chloro-3'-nitroacetophenone followed by 2,4-dibromoacetophenone and the resulting light yellow slurry was stirred at room temperature for 68 hours. The resulting thick white slurry was treated with 25 mL. 5% aqueous sulfuric acid with stirring and the resulting slurry was filtered. The solid was washed with water (50 mL), MeOH (50 mL)and CI-1 2 C1 2 (50 nL), then dried in vacuo at 15 room temperature for 1 hr and at 55"C for 5 hr. giving the title compound as a white solid, 3.4 g, 86%. Example 1911B 1-(4-bromophenyl)-4-(4-chloro-3-niLTrophcnyl)hutanec- l,4-diol The product from Example 191A (4.62 g, 11.65 mole) was mixed with EtOH (100 mL) and 20 the resulting slurry was treated in portions over a five tninute period with solid NaBH 4 (0.97 g, 25.6 mmole). The resulting foaming slurry was stirred and heated at reflux for 1 hr. The reaction was deemed complete by LC-MS. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oily residue. The residue was dissolved in CH 2 C1 2 and applied to an 80 g silica gel column. The column was eluted with a gradient of hexane/acetone, 90/10 to 20/80 over 32 minutes. 25 The fractions containing product were pooled and concentrated in vacuo giving the title compound as a white solid, 3.14 g, 67%. Example 191C l-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane- 1,4-diyl dimethanesulfonate 30 The product from Example 191B (3.14 g, 7.84 mmole) was dissolved in 70 mL CH 2 Cl 2 and cooled in an ice-acetone bath to -10 C. Triethylamine (3.82 mL, 27.4 inmole) was added dropwise to the cold solution, followed by dropwise addition of methanesulfonyl chloride (1.53 mL, 19.59 mmole) in 20 n.. C1 2 Cl 2 over 10 minutes. The resulting clear solution was stirred in the cold for 90 min. The reaction was deemed complete by LC-MS analysis and the solvent was removed in vacuo leaving a 35 light yellow solid as the title compound, (4.36 g, 100%), that was used directly in the next reaction. 305 Example 1911) 2-(4-hromnophenyl)- I -(4-tert-butylphenyl)-5-(4-chloro-3-nitrophenyl)pyrrolidine The light yellow solid, obtained in Example 191C (4.36 g, 7.84 inole) was treated with DMF (15 mL) followed by dropwise addition of 4-tert-butylaniline (12.47 mL, 78 mmole), then 5 placed in an oil bath at 52 *C and stirred for a total of 12 hr. The reaction mixture was concentrated in vacuo to an oily residue. The mixture was diluted with 100 mL EtOAc and washed with 50 mL 0.5 M HCl. The aqueous layer was back extracted with 100 mL EtOAc. The combined organic extracts were washed with 10% NaHCO 3 , 10% NaCI, dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving a reddish oil. The oil was dissolved in CH 2 Cl 2 (10 mL) and applied to an 10 80 g silica gel column. The column was eluted with a gradient of hexane/Acetone, 90/10 to 30/70 over 32 minutes. The title compound was isolated as a 1:1 mixture of cis and trans-pyrrolidine isomers, 3.13 g, 75%. Example 191E 15 4-(5-(4-bromophenyl)- 1-(4-tert-butylphenyl )pyrrolidin-2-yl)-N-(2,4-dimnethoxybenzyl)-2-nitroani line The product from Example 1911) (1.1 g, 2.14 mole) was treated with 2,4 dimethoxybenzylamine (3.22 ml, 21.41 mmole) and the resulting slurry was heated at 140 "C (oil bath) for 1 hr. The resulting homogeneous red reaction mixture was concentrated in vacuo leaving a red oil. The oil was diluted with 30 mL CH 2

C

2 , filtered solid and applied the Filtrate to a 120 g silica 20 gel column. The column was eluted with CI-12C12 over a 25 min period. The fractions were pooled and concentrated in vacuo giving the title compound as an orange foamy solid as a mixture of stereoisomers (1.18 g). Example 191F 25 4-(5-(4-bromophcnyl)- 1-(4-tert-butylphenyl)pyrrolidin-2-yl)-N 1-(2,4-dinethoxybenzyl)benzenc- 1,2 diamnine The product from example 191E (1.18 g, 1.831 inmnole) was dissolved in a mixture ofITHF(10 mL):EtOll(10 mL):EtOAc (10 mL), treated with PtO 2 (42 mg)and evacuated 10 minutes, followed by introduction of 1-12 (g) via balloon. The reaction mixture was stirred overnight at room temperature. 30 The next day, the reaction mixture was filtered and the solvent removed in vacuo leaving a dark green foamy solid. The solid was dissolved in 10 mL CH 2

C

2 applied to a 40 g silica gel column and eluted with a gradient of hexane/EtOAc; 90/10 to 30/70 over 20 minutes. The title compound was isolated as a white foamy solid as a mixture of isomers 0.54 g, 48%. 35 Example 191G 306 methyl (2S)-I -((2S)-2-(5-(5-(4-bromophenyl)- I -(4-tert-butylphenyl)pyrrolidin-2-yl)-2-(2,4 dinethoxyhenzylanino)phenylcarhamoyl)pyrrolidin-1-yl)-3-methyl-I -oxobutan-2-ylcarhaniate (S)- I -((S)-2-(imethoxycarbonylaimino)-3-imetlylbutanoyl)pyrrolidine-2-carboxylic acid (0.33 9 g, 1.245 mmole) and HOBt (0.191 g, 1.245 nunole) were dissolved in DMF (4 mL) cooled in 5 an ice bath and treated with EDAC (0.245 g, 1.245 mmole) and N-Methylmorpholine (NMM) (0.55 nL, 4.98 mmole). The resulting solution was stirred 5 minutes in the ice bath, treated dropwise with the product from Example 191F in DMF (4 mL) and the resulting dark mixture was stirred in the ice bath for I hr then at room temperature for 18 hr. The next day, the reaction mixture was diluted with EtOAc (50 ml.) and the organic layer was washed with 10% NaHCO 3 and 10% NaCl, dried over 10 anhydrous Na2S0 4 (s), filtered and the solvent was removed in vacuo leaving an oily residue as the title compound as a mixture of isomers (0.65 g). ESI+ (nz): 868.2. Example 19111 methyl (2S)- I -((2S)-2-(2-amino-5-(5-(4-bromophenyl)- I -(4-tert-butylphenyl)pyrrolidin-2 15 yl)phenylcarbamoyl)pyrrolidin- 1 -yl)-3-methyl-1 -oxobutan-2-ylcarbanate The product from example 191G (0.65 g, 0.748 mmole) was dissolved in CH 2 Cl 2 (10 mL) then added concentrated trifluoroacetic acid (2 ml., 26 mmole)) and the reaction mixture was stirred 10 minutes. The solvent was removed in vacuo and the residue was re-evaporated twice from CH 2

CI

2 and once from toluene. The residue was dissolved in EtOAc (100 mL) washed with 10% NalHC0 3 , 20 dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving a brown foamy material as the title compound as a mixture of isomers (0.5 g). Example 1911 methyl (2S)-I-((2S)-2-(6-(5-(4-bromophenyl)-I-(4-tert-butylphenyl)pyrrolidin-2-yl)-I H 25 benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-iethyl-1-oxobuian-2-ylcarbamatc The product from Example 1911H (0.5 g, 0.696 ininole) was treated with acetic acid (5 mL, 87 nunole) and heated in an oil bath at 75 *C for 70 in. The reaction mixture was cooled to room temperature and concentrated in vacuo leaving an oily residue. The residue was dissolved in EtOAc (100 nL) washed with 10% NaIICO 3 (20 ml- ) and 10% NaCI (20 mL), dried over anhydrous 30 Na 2 SO.(s), filtered and solvent removed in vacuo leaving a brown fbamny solid. The residue was dissolved in 10 ml, CH 2

CI

2 and applied to a 12 g silica gel column. The column was eluted with a gradient ofCH2CI2/MeO-l, 99/1 to 95/5 over 15 minutes and the product was isolated as a tan solid as a mixture of isomers (0.31g). ESI(mi/z)+: 702.3. 35 Example 191J 307 methyl (2S)-1 -((2S)-2-(6-(1-(4-tert-butylphenyl)-5-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborol an-2 yl)phenyl)pyrrolidin-2-yl)- IIH -benzoldjiimidazol-2-yl)pyrrolidin- I -yl)-3-methyl- 1 -oxobutan-2 ylcarbanate The product from Example 1911 (0.31g, 0.442 innole), bis(pinacolato)diboron (0.34 g, 1.327 5 mmole) and potassium acetate (0.17 g, 1.77 minole) were combined and dissolved in toluene (5 mL), added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (32 ing, 0.044 mnole) and the reaction mixture was bubbled with N 2 for 5 minutes, sealed and placed in an oil bath at 95 0 C for 2 hr. The mixture was cooled to room temperature and diluted with EtOAc (100 ml.) washed with water (20 ml.) and 10% NaCl (20 tmL), dried over anhydrous Na 2

SO

4 (s), filtered and 10 solvent removed in vacuo leaving a brown oil. The oil was dissolved in CH 2

C

2 (10 nL), applied to a 12 g silica gel column and the column was eluted with a gradient of hexane:EtOAc, 50:50 to 0:100 over 18 minutes. The title compound was isolated as a white solid as a mixture of isomers (0.23 g). Example 191K 15 (2S)-tert-butyl 2-(5-(4-(I-(4-tert-butylphenyl)-5-(2-((S)-I-((S)-2-(mnethoxycarbonylanino)-3 methylbutanoyl)pyrrolidin-2-yl)-IH-benzo[djimidazol-6-yl)pyrrolidin-2-yl)pheiyl)-IlI-iindazol-2 yl)pyrrolidine- I -carboxylate. The product from example 191J (0.23g, 0.308 tnmole) and the product from Example 26D (0.1 9 5g, 0.615 Itmole) were combined in a 20 mL microwave tube and dissolved in toluene (1.5 20 nL)/ethanol(l.5 mL) . To this solution was added IM aqueous sodium carbonate 0.92 mL, 0.92 mnole) followed by 1, l'-bis(diphenylphosphino)ferrocenedichloro palladium(lI) dichloromethane complex (23 tmg, 0.036 inmole) and the resulting mixture was bubbled with N 2 for 10 minutes, sealed and heated at 100"C for 2 hr. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 ml..). The aqueous carbonate layer was separated and the organic layer was washed with 25 water (20 iL) and 10% NaCl (20 tmL), dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving a foamy solid. The solid was dissolved in 10 muL C1 2 C1 2 and applied to a 12 g silica gel colunmu. The column was eluted with a gradient of CH2CI2/MeOH, 99/1 to 95/5 over 20 minutes. The title compound was obtained as a tan solid as a mixture of isomers (0.1 Ig). 30 Example 191L (2S)-2-(5-(4-(I-(4-tert-butylphenyl)-5-(2-((S)-I -((S)-2-(nethoxycarbonylanino)-3 nethylbutanoyl)pyrroliditi-2-yl)-1 H -benzo[d jimidazol-6-yl)pyrrolidin-2-yl)phenyl)- I lI-imidazol-2 yl)pyrrolidinium chloride The product from example 191K (0. 11 g, 0.28 mmole) was dissolved in dioxane (2 mL), then 35 added 4N ICI/dioxane (I mL). The resulting solid mass is stirred 30 minutes at room temperature. 308 The solvent is removed in vacuo leaving a tan solid as the title compound as a mixture of isomers (0.092g) which stored under vacuum overnight. Example 191M 5 methyl {(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-I-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-1HII-benzimidazol-6-yl pyrrolidin-2 yl]phenyl }-lI -- imidazol-2-yl)pyrrolidin-l -yl]-3-methyl-1-oxobutan-2-yl carbamate and methyl {(2S)- I-[(2S)-2-(5-{4-((2R,5R)-I-(4-tert-butylphenyl)-5-{2-[(2S)- 1-{(2S)-2 10 [(imethoxycarbonyl)amino]-3-meihylbutanoyl pyrrolidin-2-yl]-IH-benzimilazol-6-yl pyrrolidin-2 yllphenyl}- IH-iimidazol-2-yl)pyrrolilin-1-yl]-3-ineihyl-1-oxobulan-2-yl carbainate The product from example 191L (0.092g, 0.116 mole) , (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid (0.020g, 0.116 inmole)and HIOBt (000.018g, 0.116 mmole) were combined in a 25 il., RB flask and dissolved in DMF (I mL). The reaction mixture was placed in an ice bath and 15 treated with EDAC (0.022g, 0.116 mmole) and N-methylnorpholine (0.12 mL, 1.091 nimole. The light yellow reaction mixture was stirred in the ice bath for I hr, then stirred at room temperature for 9 hr. The reaction mixture was diluted with EtOAc (100 mL) washed with water (20 ml.,) and 10% NaCl (20 mL), dried over anhydrous Na 2

SO

4 (s), filtered and solvent removed in vacuo leaving an oily residue. The residue was dissolved in 5 mL C12C2 and applied to a 12 g silica gel column. The 20 column was eluted with a gradient of C1 2 Cl 2 /MeOl, 99/1 to 95/5 over 22 minutes. The title compound was isolated from the first fraction eluted from the column as a white solid consisting of a mixture of trans-pyrrolidine isomers, 21 mg, 19%. 'H NMR (400 M Hz, DMSO-d 6 ) 8 ppm 0.71 - 0.95 (m, 12 H) 1. 1 (s, 9 H) 1.99 (m, 6 H) 2.13 (m, 4 H) 3.53 (s, 6 H) 3.81 (im, 4 H) 4.04 (m, 4 H) 5.06 (in, 2 H) 5.11 - 5.15 (in, I -1) 5.18 - 5.26 (m, I H) 5.32 (m, I I-) 6.25 (in, 2 H) 6.86 - 6.96 (in, I H) 7.05 25 (i, 2 H) 7.33 (in, 6 H) 7.61 (in, 2 H) 11.53 (s, I H) 11.68 (s, 1 H) 12.00 (in, 2 H); ESI+: 914.5. ANN Example 192 methyl {(2S)- I-[(2S)-2-(5-{4-[(2R,5S)-I-(4-tert-buiylphcnyl)-5-(2-[(2S)- 1-((2S)-2 30 [(mtethoxycarbonyl)aiiino]-3-mtethylbutanoyl pyrrolidin-2-yl]-IH-benzimidazol-6-ylipyrrolidin-2 yl]phenyl}-IH-inidazol-2-yl)pyrrolidin-l -yl]-3-methyl-I-oxobutan-2-ylIcarbatnate 309 and methyl {(2S)-I -[(2S)-2-(5- 4-t(2S,5R)- I-(4-leri-butylphenyl)-5-{2-1(2S)-1-{(2S)-2 [(iethoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]- IH-benzimiidazol-6-ylpyrrolidin-2 yl]phenyl )-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-ylIcarbamate 5 The title compound was isolated from the late fraction eluted from the column described in Example 191M as a white solid as a mixture of cis pyrrolidine isomers, 18 ing, 17%. 'H NMR (free base) (400 M1-1z, DMSO-d 6 ) Sppm 0.71 - 0.95 (i, 12 H) 1.11 (s, 9 H) 1.99 (n, 6 H) 2.13 (mn, 4 H) 3.53 (s, 6 1H) 3.81 (i 4 H) 4.04 (m, 4 H) 4.72 (m, I H), 4.83 (in, I H) 5.11 - 5.15 (mn, I H) 5.18 - 5.26 (m, I H) 5.32 (in, I H) 6.25 (i, 2 H) 6.86 - 6.96 (in, 1 H) 7.05 (in, 2 Hl) 7.33 (m, 6 H) 7.61 (in, 2 H) 10 11.53 (s, I H) 11.68 (s, 1 -I) 12.00 (in, 2 H); ESI+: 914.5. N Example 193 dimethyl ([(2S,5S)- 1-{ 4-[6-(imorpholin-4-yl)pyridin-3-yl]phenyl }pyrrolidine-2,5-diyl]bis{ benzene 15 4,1 -diyliimino[(2S)-3-imethyl-I-oxobutane-1,2-diyl]})biscarbaiate and dimnethyl ([(2R,5R)-l-{4-[6-(imorpholin-4-yl)pyridin-3-yllphenyl)pyrrolidine-2,5-diyllbis{ benzene 4,1-diyliimino[(2S)-3-iethyl-1-oxobutane-1,2-diyll})biscarbaiate Example 86A and 4-(5-(4,4,5,5-tetraimethyl-1,3,2-dioxaborolaii-2-yl)pyridin-2-yl)iorpholine 20 were processed using sequentially the methods of Examples 99A, 9911, and IF (substituting (S)-2 (miiethoxycarbonylainino)-3-methylbutanoic acid ( 38.2nig, 0.218inmnole) for (S)-1-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid). Reverse phase (Cis) HPLC provided the title compound, a white solid, as a 1:1 mixture of trans diastereomers (40.4mg, 50.6% yield). 1H NMR (free base) (400 MIlz, DMSO-D6) 6 ppm 0.89 (d, J=6.72 Hz, 12 1-1) 1.67 (d, 1=5.64 lz, 2 H-) 1.92 25 2.04 (in, 2 H) 3.37 - 3.41 (in, 4 -1) 3.53 (d, .1=2.06 -z, 6 H) 3.67 (d, .1=5.10 Hz, 4 1-1) 3.94 (t, 1=8.08 Hz, 2 H) 5.25 (s, 2 H) 6.33 (d, 1=8.67 Hz, 2 H) 6.78 (d, J=8.89 Hz, I H) 7.14 - 7.23 (in, 6 H) 7.32 (d, 1=8.67 H z, 2 H) 7.54 (d, J=7.92 Hz, 4 H) 7.66 (dd, 1=8.84, 2.55 Hz, 1 1-1) 8.26 (d, J=2.49 Hz, I H) 10.01 (s, 2 H). MS ESI(+) inz @ 806.5 (M+H)+. 310 0 OH Example 194 diieihyl ({(2S,5S)-I-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]pyrrolidine-2,5-diyl bis{benzene 4,1-diylcarbamoyl( 2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-I,2-diyl] ))biscarbamate) 5 Example 194A ethyl 2-inethyl-2-(4-nitrophenyl)propanoate Into a 500mI., Morton flask equipped for mechanical stirring was added at room temperature under nitrogen ethyl 2-(4-nitrophenyl)acetate (10.0g, 55.2nunole), anhydrous diiethylformamide 10 (200mL) 18-crown-6 (2.189g, 8.28mmiole) and methyl iodide (23.13mL, 370mmole). The flask was cooled in an ice bath and sodium hydride as a 60% mineral oil dispersion ( 7 .73g, 193mmole) was added in portions so as to maintain the internal temperature at or below +10*C. The addition required fifty three minutes. On completion of the addition the reaction mixture was allowed to slowly warm to room temperature and stirred overnight. Subsequent cooling in an ice bath was followed by the drop 15 wise addition of water (200mL) with vigorous stirring. The mixture was partitioned between water (1200mL) and ethyl ether (200mL). The aqueous phase was extracted with ethyl ether (3x200mL each) and the combined organics water washed (3xl5OmL), dried over MgSO 4 , Filtered and concentrated to provide the title compound in nearly quantitative yield sufficiently pure for use as isolated. 20 Example 194B 2-methyl-2-(4-nitrophenyl)propan-1-o To a solution of the product from Example 194A (12.32g, 55.2inole) in anhydrous THF (300m.) at room temperature under nitrogen was added dropwise via cannulae IM B13 in THF 25 (200mL.,) over ten and one half minutes. On completion of the addition the flask was equipped with a condenser and the mixture heated under nitrogen to reflux in an oil bath for ten hours before cooling to room temperature. The reaction was quenched by the cautious drop wise addition of methanol (60mL).The resulting mixture was concentrated to an oil which was then dissolved in ethyl acetate (150imL) and treated with IN HCI and allowed to stir at room temperature for one hour. The 30 resulting organic phase was washed with brine (4x50mL), dried over MgSO 4 , filtered and concentrated. The residue was taken up in toluene (25miL) and re-concentrated. The oily solid was suspended in hexane (50mL) and collected by vacuum filtration. The cake was washed with hexane 311 (50mi.) then dried under vacuum to provide the title compound (9.55g, 89% yield) as a light orange solid. MS (DCI+) m/z @ 213.1 (M+NI-14)+. Example 194C 5 2-(4-aminophenyl)-2-methylpropan- I -ol The product from Example 194B (0.321g, 1.644mmole) was dissolved in a mixture of THF (10mL) and ethanol (2mL). To this was added platinum(IV)oxide (0.030g, 0.131nnole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture stirred at room temperature. An additional 38.2mg ( 0.167mmole) of 10 catalyst was added in two aliquots before chromatographic analysis indicated thai the starting material was consumed. After stirring overnight under hydrogen the mixture was filtered through a sand / celite plug followed by an ethyl acetate rinse. The filtrate was concentrated to dryness and the residue purified by chromatography on amine modified silica gel eluting with ethyl acetate - hexane beginning at 8% and advancing to 66% ethyl acetate to provide the title compound (0.3645g, 68% 15 yield) as a clear oil. MS (DCI+) m/z @ 183.1 (M+NH 4 )+. Example 1941) 2-(4-((2S,5S)-2,5-bis(4-nitrophenyl)pyrrolidin- I -yl)phenyl)-2-methylpropan- I -ol The product from Example 194C (0.595g, 3.60nunole) was combined in DMF (3mL) with 20 (1 R,4R)-l ,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate (0.259g, 0.530mmole), prepared as described in Example 37C, then heated overnight under nitrogen in an oil bath at 50*C. The reaction mixture was partitioned between ethyl acetate (50mL) and water (50mL). The organic phase was water washed (3x25mL), dried over MgSO 4 , Filtered and concentrated to an oil. Chromatography on silica gel eluting with ethyl acetate - hexane provided the title compound (0.0835g, 34.1% yield) as 25 an orange semi-solid. Example 194E 2-(4-((2S,5S)-2,5-bis(4-aminophenyl)pyrrolidin-1-yl)phenyl)-2-methylpropan-I-ol The product from Example 194D ( 83.5mg, 0.181mmole) was reacted as described in 30 Example 99B to provide the title compound in quantitative yield as a light yellow solid. MS (DCI+) nz @ 402.3 (M+H)+. Example 194F dinethyl ({(2S,5S)- 1-[4-(1 -hydroxy-2-mnethylpropan-2-yl)phenyl]pyrrolidine-2,5-diyl bis {benzene 35 4,1-diylcarbamnoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl]})biscarbamate) 312 The product from Example 194E (73.0mg, 0.181 mmole) was reacted with the product from Example 371 ( 104.0ig, 0.380mmole) as described in Example 37F. The title compound was isolated after purification by reverse phase (C18) HPLC as an off white solid (97.4mg, 59% yield). 114 NMR (free base) (400 MHz, DMSO-D6) 6 ppm 0.79 - 0.96 (in, 12 H) 1.03 (s, 6 1H1) 1.61 (s, 2 H) 1.76 - 2.04 5 (mn, 8 H) 2.04 - 2.17 (in, 2 H) 3.20 (dd, 1=5.42, 1.84 1z, 2 H) 3.51 (s, 6 H) 3.60 (dd, 2 H) 3.78 (s, 2 1-1) 4.01 (t, J=8.46 lz, 2 11) 4.35 - 4.49 (in, 3 11) 5.14 (s, 2 11) 6.16 (d, 1=8.78 Hz, 2 11) 6.89 (d, 1=8.78 Hz, 2 H) 7.12 (d, J=8.57 Hz, 4 H) 7.29 (d, .1=8.35 Hz, 2 H) 7.48 (d, J=8.46 Hz, 4 H) 9.97 (s, 2 H). MS ESl(+), m/z @ 910.7 (M+H)+. N

CN

t~ o o s 10 Example 195 methyl [(1S,2R)-2-methoxy-l -({(2S)-2-[4-(4-{5-[4-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L threonyl]pyrrolidin-2-yl)-IH-iimidazol-4-yl)phenyl]-1-(6-piperidin-1-ylpyridin-3-yl)-IH-pyrrol-2 yl}phenyl)-IH-imidazol-2-yl]pyrrolidin-I-yl}carbonyl)propyl]carbamate 15 The title compound was prepared using the methods from Example 144E substituting (2S,3S)-3-methoxy-2-(imethoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3 methylbutanoic acid to provide the title compound (280 mg, 37% yield). '-I NMR (400 MHz, DMSO-D6) 6 12.12 - 11.70 (in, 2H), 7.85 - 7.76 (in, I H), 7.63 - 7.49 (m1, 4H), 7.49 - 7.39 (mn, 2H), 7.34 - 7.03 (m, 7H), 6.77 - 6.69 (in, I H), 6.54 - 6.41 (in, 2H), 5.08 - 4.99 (in, 2H), 4.27 (1, J = 7.6, 20 2H), 3.86 - 3.75 (m1, 4H), 3.54 (s, 6H), 3.50 - 3.43 (m, 4H), 3.17 (s, 6H), 2.19 - 1.88 (in, 10H), 1.61 1.44 (m, 611), 1.12 - 0.99 (m, 611). MS (ESI; M+1) m/z = 997. Example 196 313 N-(nethoxycarbonyl)-l..-valyl-N-{4-1(2S,5S)-5-(4-{ [N-(tiiethoxycarbonyl)-L..-valylJamino Iphenyl)- {4-[6-(morpholin-4-yl)pyridin-3-ylJphenyl }pyrrol idin-2-yljphenyl }-L-prolinamide and N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-5-(4- {[N-(methoxycarbonyl)-L-valyl]amino) phenyl)- I 5 {4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl} pyrrolidin-2-yl]phenyl}-L-prolinamide N N 0

HN

4 \

H

2 N HN H Example 196A methyl (2S)-I-(4-(5-(4-aininophenyl)-1-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidin-2 10 yl)phenylamino)-3-methyl- I -oxobutan-2-ylcarbamate In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved 4,4'-(1-(4-(6 morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianilinc (30 mg, 0.061 mmol; prepared from Example 86A and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)norpholine using the methods of Examples 99A and 99B), and (S)-2-(nethoxycarbonylanino)-3-methylbutanoic acid 15 (11.22 mg, 0.064 mmol) in anhydrous DMSO (I mL), added HATU (26.3 mug, 0.067 nmol) and diisopropylethylamine (0.021 mL, 0.122 mmol), and stirred yellow solution at 25 C for 30 min. Diluted the reaction with MeOH (I mL) and purified by RP-C 18 HPLC (Waters Prep LC, 40mm Module with Nova Pak HR Ca 6ptm 40x100mm Prep Pak cartridge) cluting with a 30 min gradient of 95:5 0.1% TFA in H2O/AcCN to 25:75 0.1% TFA in H 2 0/AcCN, then 10 min to 100% AcCN at 20 20 nf/imin. Pure fractions were concentrated by rotary evaporation (water bath 35") to a small volume, partitioned between 20% iPrOH/CHCl 3 (50 nL) and sat'd aq NaHCO 3 (15 mL), separated layers, dried the organic extract over anhydrous MgSO., filtered, and concentrated by rotary evaporation to afford the title compound as an off-white solid (14.6 mg, 37%) as a mixture of stereoisotners. MS (ESI+) m/z 649 (M+H)*, 707 (M+AcCN+NH 4 )*, 1297 (2M+H)*. 25 Example 196B N-(nethoxycarbonyl)-..-valyl-N-(4-[(2S,5S)-5-(4-([N-(mnethoxycarbonyl)-L-valyl] amino phenyl)- {4-[6-(morpholin-4-yl)pyridlin-3-ylphenyl)pyrrolidin-2-yl]phenyl}-L-proliiamide and 30 N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-5-(4-{[N-(methoxycarbonyl)-L-valyl]amino phenyl)-l {4-[6-(morpholin-4-yl)pyridin-3-yllphenyl pyrrolidin-2-yllphenyl}-L-prolinamide 314 In a nitrogen-purged 5-mi. round bottom flask, dissolved the product of Example 196A (14 ing, 0.022 mmol) in anhydrous DMSO (1 mL..), added the product of Example 37B (6.46 mg, 0.024 mmol), HATU (9.30 mug, 0.024 minol), and diisopropylethylamine (7.54 pL, 0.043 mmnol). Stirred at 25 C for I hr, diluted the reaction with MeOH (I mL) and purified by RP-C 18 HPLC (Waters Prep 5 LC, 40mm Module with Nova Pak HR C 1 8 6pm 40xIOOmm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H 2 0/AcCN to 25:75 0.1% TFA in 1 2 0/AcCN, then 10 min to 100% AcCN at 20 nL/min. Pure fractions were concentrated by rotary evaporation (water bath 35*C) to near-dryness, the residue taken up in 1:5 v/v CH 2 Cl 2 /hexanes and evaporated (3 times), and the residue dried in vacuo to give a yellow solid (I1mg). 'lhe TFA salt was dissolved in 20% 10 iPrOH/CHCIb (30 mL), washed thoroughly with sat'd aq NaHCO 3 (5 mL), extracted the aqueous phase with 20% iPrOHI/CHCI 3 (20 mL), dried the combined organic extracts over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to afford the title compounds as a white solid (7 mg, 35%). '11 NMR (400 M Ilz, DMSO-D6) 8 ppm 0.83 - 0.96 (m, 12 11), 1.60 - 1.71 (m, 2 H-), 1.81 - 2.21 (in, 7 11), 3.36 - 3.43 (m, 4 H-), 3.49 - 3.56 (m, 6 H-), 3.58 - 3.65 (m, 1 H1), 3.65 - 3.70 (in, 4 H-), 3.75 15 3.85 (i, I H), 3.94 (t, .=8.08 H z, l 1), 4.02 (t, .1=8.19 Hz, 1 H), 4.42 (dd, .=7.86, 4.93 H z, I H), 5.24 (d, 1=5.31 H-z, 2 H), 6.32 (d, 1=8.35 H z, 2 -1), 6.78 (d, 1=9.00 Hz, I H), 7.13 - 7.19 (m, 4 H), 7.21 (d, J=8.78 H z, 2 H), 7.26 - 7.35 (in, 2 H ), 7.48 - 7.56 (in, 4 H), 7.66 (dd, J=7.86, 1.14 Hz, I H), 8.25 (d, J=2.17 Hz, I H), 10.00 (d, 1=3.47 Hz, 2 H); MS (ES1+) m/z 903 (M+H)*. HN NH ("N, ' \ N \ 20 / 0 Example 197 methyl {(2S)-1-[(2S)-2-(4-(4-[(2S,5S)-I-(4-tert-butylphenyl)-5-(4-(2-[(2S)-I -((2S)-2 [(methoxycarbonyl)aininoJ-3,3-di methylbutanoyl jpyrrolidiin-2-ylJ-I H-imidazol-4 yl} phenyl)pyrrolidin-2-yl]phenyl)-1 H-imidazol-2-yl)pyrrolidin-1 -yl]-3,3-dimethyl- I-oxobutan-2 25 yl)carbamate and methyl {(2S)-I-[(2S)-2-(4-{ 4-I(2R,5R)-I-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)aino]-3,3-di methylbutanoyl )pyrrolidin-2-ylI-1 H-imidazol-4 yl }phenyl)pyrrolidin-2-ylJphenyl )-I H-imidazol-2-yl)pyrrolidin-l-ylJ-3,3-dimethyl-I-oxobutan-2 30 yl Icarbamnate The product from Example 42F (0.228 g, 0.364 mmol) was processed as in Example i H to give 0.035 g (10%) of the title compound as a solid as a mixture of trans isomers. IH NMR (free 315 base) (400 MIH z., DMSO-D6) 6 ppm 0.91 (d, J=7.59 H z, 18 H) 1.08 (s, 9 H) 1.63 - 1.73 (in, 2 H) 1.83 - 2.24 (m, 12 H) 3.54 (s, 6 H) 3.70 - 3.80 (in, 2 H) 4.21 (d, J=7.92 Hz, 2 H) 5.06 (dd, J=6.99, 3.52 H z, 2 H) 5.15 - 5.25 (in, 2 H) 6.21 (d, J=8.67 Hz, 2 H) 6.92 (dd, J=8.73, 2.44 Hz, 2 H) 7.05 (d, J=8.78 Hz, 2 H) 7.14 (dd, J=8.24, 3.47 Hz, 4 H) 7.37 (s, 2 H) 7.61 (d, J=8.02 Hz, 4 H) 11.69 (s, 2 H); MS ESI+ 5 m/z 968.8 (M+H)+. F F QN N N- N,. N ss Example 198 methyl [(2S)-1 -{ (2S)-2-[(4-{(2R,5R)-5-{4-[({ l -[(2S)-2-[(methoxycarbonyl)amino]-4 10 (iethylsulfanyl)butanoyl]pyrrolidin-2-yl}carbonyl)amino]phenyl}-l -[4 (trifluoronethyl)phenyl]pyrrolidin-2-yl}phenyl)carbanoyl]pyrrolidin-1-yl}-4-(nethylsulfanyl)-1 oxobutan-2-yl]carbamate Example 198A 15 (S)-2-(methoxycarbonylainino)-4-(iethyl thio)butanoic acid To a solution of (S)-2-anino-4-(imethylthio)butanoic acid (1.0 g, 6.7 mmol) in dioxane at 0 *C was added NaOH (11.06 g, 22.12 ininol) followed by dropwise addition of methyl chloroformate (1.04 mL, 13.4 ininol) and the solution was warmed to room temperature with stirring over 2 I. The solution was diluted with EtOAc, washed with 1 N HCI, brine, dried (Na 2

SO

4 ), filtered and solvent 20 removed in vacuo to give the title compound (1.3 g, 6.27 mmol, 94%). 'H NMR (400 MlHz, CDCl 3 ) 8 ppm 1.95-2.07 (m, Ill) 2.07-2.13 (in, 311) 2.14-2.28 (m, IH) 2.59 (t, J=7.4 Ilz, 211) 3.71 (s, 311) 4.52 (br s, 11-) 5.33 (br s, I H). Example 198B 25 (2S,2'S)-N,N'-(4,4'-((2R,5R)-I-(4-(trifluoromcthyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene)dipyrrolidine-2-carboxamide Example 38A and 4-trifluoromethylaniline were processed using the methods of Examples 34A, 34B, 34C, and 34D to provide the title compound. 30 Example 198C 316 methyl [(2S)-1-{(2S)-2-[(4-{(2R,5R)-5-14-1(11-[(2S)-2-[(methoxycarbonyl)aiinoJ-4 (methylsulfanyl)butanoylIpyrrol idin-2-yl carbonyl)aminoJphenyl) -1 -[4 (Iriluoroniethyl)phenyl]pyrrolidin-2-yl I phenyl)carbamoyl]pyrrolidin- I -yl I -4-(methylsulfanyl)- I oxobuian-2-yllcarbamate 5 Example 198B and Example 198A were processed using the method of Example 1H to provide the title compound which was purified by flash chromatography on silica gel eluting with 10 80% EiOAc/CH 2 Cl 2 (29 mg). 'H NMR (400 MHz, CDCb 3 ) 8 ppm 1.78 (d, J=6.1 Hz, 2H) 1.83-2.00 (in, 6H) 2.02 (s, 6H) 2.04-2.26 (in, 4H) 2.43-2.61 (in, 8H) 3.47-3.83 (m, 4H) 3.69 (s, 6H) 4.75 (dd, J=8.0, 2.0 Hz, 4H) 5.15 (d, J=6.7 Hz, 2H) 5.43 (d, 2H-1) 6.32 (d, J=8.7 Hz, 2H) 7.09 (d, J=8.5 Hz, 4H) 10 7.18 (d, J=8.8 Hz, 2H) 7.42 (d, J=8.6 Hz, 4H) 9.05 (s, 2H). MS (ESI) m/z 971 (M+H)*. F F F N0. - NH 0 H ,oNy 0 10 Example 199 methyl [(2S,3S)- l-{ (2S)-2-[(4-{ (2R,5R)-5-(4-{ [(1-{(2S,3S)-2-[(imethoxycarbonyl)ainino]-3 15 iethylpentanoyl pyrrolidin-2-yl)carbonyllanino phenyl)-1-[4-(trifluoroimethyl)phenyllpyrrolidin-2 yl phenyl)carbamoyllpyrrolidin-1-yl}-3-methyl-I-oxopentan-2-yllcarbamate Example 199A (2S,3S)-2-(iethoxycarbonylamino)-3-methylpentanoic acid 20 To a solution of (2S,3S)-2-ainino-3-imethylpentanoic acid (1.0 g, 7.62 nmol) in dioxane (10 il.) at 0 *C was added NaOH (12.58 g, 25.2 miol) followed by dropwise addition of methyl chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to room temperature with stirring over 2 h, diluted with EtOAc, washed with I N HClI, brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo to give the title compound (1.4 g, 7.4 mrnol, 97%). 'H NMR (400 MHz, CDC 3 ) 6 25 ppm 1.27-1.39 (m, IH) 1.38-1.53 (m, 2H) 1.58-1.72 (m, 3H) 1.82-1.94 (i, 2H) 2.04 (d, J=3.8 Hz, 2H) 3.70 (s, 3H) 4.94 (br s, I H). Example 199B methyl 1(2S,3S)- -{(2S)-2-[(4-{(2R,5R)-5-(4-{[(I-((2S,3S)-2-[(methoxycarbonyl)amino]-3 30 methylpentanoyl pyrrolidin-2-yl)carbonyl] amino phenyl)-I-[4-(trifluoromethyl)phenyllpyrrolidin-2 yl phenyl)carbamoyljpyrrolidin-1-yl}-3-methyl-I-oxopentan-2-yl]carbamate 317 To a solution of Example 198B (60 ing, 0.101 mmol) in DMSO (0.5 ml.) was added Example 199A (48 mg, 0.254 mmol), followed by HATU (96 mg, 0.254 mmol) and N,N diisopropylethylamine (0.089 mL, 0.507 nunol) and the solution was stirred at room temperature for I h. Diluted with EtOAc, washed with H 2 0, brine, dried (Na 2

SO

4 ), Filtered and removed solvent in 5 vacuo to give crude product which was purified by flash chromatography on silica gel eluting with 10-80% EtOAc/CH 2

C

2 to give the title compound (II mg, 0.012 minol, 12%). 'H NMR (400 Hz,

CDC

3 ) 8 ppm 0.78-1.00 (i, 12H) 1.69-1.81 (i, 4H) 1.81-1.94 (m, 2H) 1.99-2.10 (in, 2H) 2.09-2.24 (in, 2H) 2.50 (br s, 21H) 2.53-2.61 (m, 2H) 3.63 (hr s, 21-) 3.68 (s, 6H) 3.75-3.87 (i, 2H) 4.34 (t, J=8.5 Hz, 2H) 4.79 (d, J=6.3 Hz, 2H) 5.14 (d, J=6.6 Hz, 2H) 5.28 (d, J=9.3 H z, 2H) 6.32 (d, J=8.7 H z, 2H) 10 7.08 (d, J=8.4 Hz, 4H) 7.18 (d, J=8.8 H z, 2H) 7.41 (d, J=8.5 Hz, 4H) 9.23 (s, 2H). MS (ESI) m/z 935 (M+H)*. F F F ,OONN Example 200 15 methyl [(2S,3R)-3-methoxy-I -{(2S)-2-[(4-((2R,5R)-5-(4-{[(I-{(2S,3R)-3-imethoxy-2 [(met hoxycarbonyl)amino]bulanoyl )pyrrolidin-2-yl)carbonyl]aiino } phenyl)-1-[4 (trifluoromethyl)phenyl]pyrrolidin-2-yl} phenyl)carbamoyl]pyrrolidin-1-yl}-l -oxobutan-2 yl]carbamate 20 Example 200A (2S,3R)-3-Methoxy-2-(methoxycarbonylamino)hutanoic acid A solution of O-methyl-L-threonine (1.01 g, 7.59 inmol) in saturated bicarbonate solution (93 niL) was treated dropwise with methyl chlorofonnate (900 pL, 1.10 g, 11.61 mniol), followed by stirring at RT for 24 h. The mixture was extracted methyl t-butyl ether and cooled to 0 *C. The 25 mixture was adjusted to pH 1-2 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3 x) and the combined extracts were extracted with saturated sodium chloride solution and dried (Na 2

SO

4 ). The solution was concentrated in vacuo to afford the title compound (1.31 g, 90%) as a white solid. 'H- NMR (400 MI-z, CDCl 3 ) 6 5.44 (d, J = 8.7 Hz, I -I), 4.39 (dd, J = 8.7, 2.3 Hz, 1 H), 4.00 (dd, J = 6.2, 2.4 lz, 1 H), 3.71 (s, 3 H), 3.36 (s, 3 H), 1.21 (1, J = 30 7.2 H z, 3 H). MS (+ESI) m/z (rel abundance) 192 (60, M+H), 209 (100, M+NH4). 318 Example 200B methyl I(2S,3R)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3R)-3-methoxy-2 [(melhoxycarbonyl)amino]butanoyl pyrrolidin-2-yl)carbonylliamino phenyl)-1-[4 (trifluoromethyl)phenyl I pyrrolidin-2-yl } phenyl)carbamoyl]pyrrolidin-1 -yl )-1 -oxobutan-2 5 yllcarbamate Example 198B (60 mg, 0.101 nmol) and Example 200A (48.5 mg, 0.254 mmol) were processed in the same manner as Example 19913 to give the title compound (10.5 mg, 0.011 mmol, I 1%). 'H NMR (400 MHz, CI)C 3 ) 6 ppm 1.19 (s, 3H) 1.21 (s, 3H) 1.78 (d, J=6.1 Hz, 2H) 1.94-2.16 (in, 6H) 2.40-2.57 (in, 4H) 3.36 (s, 6H) 3.66-3.84 (in, 6H) 3.69 (s, 6H) 4.64-4.72 (in, 2H) 4.81 (d, 10 J=8.l Hz, 2H) 5.14 (d, J-6.7 Hz, 2H) 5.64 (d, J=7.9 Hz, 2H) 6.31 (d, J=8.8 Hz, 2H) 7.08 (d, J=8.6 Hlz, 4H) 7.18 (d, J=8.8 H z, 2H) 7.43(d, J=8.6 Hz, 4H) 8.85 (s, 2Hf). MS (ESI) m./z 939 (M+H)*. Example 201l I5 methyl [(2S,3S)-3-methoxy- I-{I(2S)-2-I (4-{ (2R,5R)-5-(4-{ [(I -{I(2S,3S)-3-methoxy-2 [(methoxycarbonyl)amuinojbutanoyl }pyrrolidin-2-yl)carbonyl amino Iphenyl)- 1-[4 (mrifluoromethyl)phennyl]pyrrolidin-2-yl Iphenyl)carbamnoyl]pyrrolidin- I-yl}1-1 -oxobutan-2 yl]carbamate 20 Example 201A (2S.3S)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mnmol) in saturated sodium bicarbonate solution (47.6 mnL) was treated dropwise with methyl chloroformate (453 p.L, 553 mg, 5.85 mmol) followed by stirring at RT for 18 h. The mixture was extracted with ether and the 25 aqueous phase was cooled to 0 *C and acidified to pH~ 2-3 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3 x). The combined organic layers were extracted with saturated sodium chloride solution anid dried (NaSO 4 ). Concentration in vacuo afforded the title compound (640 mg, 86%) as a colorless oil. 'H NMR (400 MHz, CDCl 3 ) 6 5.48 (d, J = 7.8 Hz, 11H), 4.52 (d, J = 4.7 lHz, I H1), 3.71 (s, 3 H), 3.39 (s, 31H), 1.25 (t, J = 7.6 H z, 3 HI). 30 Example 2011B 319 methyl [(2S,3S)-3-methoxy- I - (2S)-2-[(4-1(2R,5R)-5-(4-([(1-{ (2S,3S)-3-methoxy-2 I(methoxycarbonyl)aminoJbutanoyl } pyrrolidin-2-yl)carbonyl amino I phenyl)-l -[4 (irifluoroimethyl)phenyl]pyrrolidin-2-yl) phenyl)carbamoyl]pyrrolidin- 1-yl)- 1 -oxobutan-2 yl]carbamate 5 Example 198B (40 mug, 0.068 nnol) and Example 201A (32.3 mg, 0.169 minol) were processed in the same manner as Example 199B to give the title compound (22 mg, 0.023 mmol, 35%). 'H NMR (400 MHz, CDCla) 6 ppm 1.24 (s, 3H) 1.25 (s, 3H) 1.78 (d, J-6.2 Hz, 2H) 1.87-1.99 (m, 2H) 1.99-2.16 (m, 4H) 2.45-2.58 (m, 4H) 3.20 (s, 6H) 3.46-3.56 (in, 2H) 3.65-3.83 (m, 6H) 3.69 (s, 6H) 4.5 1-4.59 (im, 2H) 4.78 (d, J=6.7 Hz, 2H) 5.14 (d, J=6.7 Hz, 2H) 5.39 (d, J=9.3 Hz, 2H) 6.30 10 (d, J=8.7 Hz, 21-1) 7.08 (d, J=8.5 Hz, 4H) 7.16 (d, J=8.8 Hz, 2H) 7.40 (d, J=8.5 Hz, 4H) 8.94 (s, 2H). MS (ESI) m/z 939 (M+H)*. NOH 0 Example 202 15 methyl [(IS)-2-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S)-2-[(methoxycarboiyl)aimino]-2 phenylacetyl pyrrolidin-2-yl)carbonyl]amino} Iphenyl)- I-[4-(trifluoroimethyl)phenyl]pyrrolidin-2 yl }phenyl)carbaioyl]pyrrolidin-1-yI }-2-oxo-l -phenylethyl]carbamate Example 202A 20 (S)-2-(methoxycarbonylanimino)-2-phenylacetic acid To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g, 3.31 mmol) in dioxane at 0 *C was added NaOH (5.46 g, 10.92 mniol) followed by dropwise addition of methyl chloroformate (0.51 ml, 6.62 iunol) and the solution was warmed to room temperature with stirring over I h. Diluted with EiOAc, washed with I N HCI, brine, dried (Na 2

SO

4 ), filtered and removed solvent in vacuo to give 25 the title compound (0.35 g, 1.673 minol, 5 1%). Example 202B methyl 1(lS)-2-{(2S)-2-[(4-{(2R,5R)-5-(4-{ (1-{(2S)-2-|(methoxycarbonyl)aiminol-2 phenylacetylipyrrolidin-2-yl)carbonyljamino phenyl)-I-[4-(trifluoromethyl)phenyllpyrrolidin-2 30 yl)phenyl)carbamoyllpyrrolidin-1-yl}-2-oxo-I-phenylcihyllcarbamae Example 198B (40 mg, 0.068 inmol) and Example 202A (35 mg, 0.169 mmnol) were processed in the same manner as Example 199B to give the title compound (7.5 mg, 7.7 Lm]ol, I1%). 320 'H NM R (400 MHz, CI)Ch) 8 ppm 1.76-2.05 (in, 8H) 2.43-2.58 (i, 4H) 3.18-3.29 (in, 2H) 3.57-3.65 (im, 2H) 3.67 (s, 6H) 4.82-4.86 (in, 2H) 5.18 (d, J=6.9 Hz, 2H) 5.48 (d, J=7.7 Hz, 2H) 5.99 (d, J=7.7 Hz, 2H) 6.35 (d, J=8.8 H z, 2H) 7.11 (d, J=8.5 Hz, 4H) 7.21 (d, J=8.7 Hz, 2H) 7.27-7.32 (in, 4H) 7.32 7.43 (im, 10H-1) 8.92 (s, 2H). MS (ESI) m/z 975 (M+H)*. 5 F F F oi Example 203 methyl [(2S)-3-methoxy- 1- ((2S)-2-[(4- ((2R,5R)-5-(4-{([(1-{ (2S)-3-methoxy-2 [(methoxycarbonyl) amino]-3-methylbutanoyl ) pyrrolidin-2-yl)carbonyl]amnino Iphenyl)- 1-[4 10 (trifluoromethyl)phenyl]pyrrolidin-2-yl Iphenyl)carbamoyl]pyrrolidin- I-yl)I-3-methyl-1I-oxobutan-2 ylcarhamate Example 203A (S)-(teri-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid 15 A solution of the (S)-2-amino-3-hydroxy-3-methylbutanoic acid (252 rmg, 1.89 imnol) in saturated sodium bicarbonate solution (6.3 niL) and tetrahydrofuran (6.3 mL) was treated with di-tert butyl-dicarbonate (764 mg, 3.50 mmiol) followed by stirring at RT for 24 h. The mixture was concentrated in vacuo to remove tetrahydrofuran and the mixture was extracted with hexanes. The aqueous phase was cooled to 0 *C and was acidifed to pH 3 by addition of I M citric acid solution. 20 The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na 2

SO

4

)

Concentration in vacuo afforded a gununy solid, containing other impurities in addition to the desired product. This material was dissolved in ethyl acetate and the mixture filtered through a millipore filter to remove undissolved material. The filtrate was concentrated in vacuo and after setting at RT for a week, eventually solidified to give the title compound as a white solid. 'H1 NMR (400 MHz, 25 Methanol-d 4 ) 8 4.08 (s, 1 H), 1.45 (s, 9 H), 1.29 (s, 3 H), 1.25 (s, 3 H). MS (-ESI) m/'z (rel abundance) 232 (100, M-H). Example 203B (S)-2-(tcr-buioxycarbonylamino)-3-mnethoxy-3-iethylbutanoic acid 30 To a solution of Example 203A (363 mag, 1.56 mmol) in THF (7 mL) at 0 *C was added NaH (373 mg, 9.34 innol) and stirring was continued for 15 min. lodomnethane (0.78 mL, 12.45 nnol) 321 was added and the solution was allowed to warm to room temperature and stirred for 18 h. Solution was quenched with 1-120, diluted with EtOAc, washed with 1120, brine, dried (Na 2

SO

4 ), filtered and solvent removed to give the title compound (165 mg, 0.67 minmol, 43%). MS (ESI) n/z 248 (M+H)*. 5 Example 203C (S)-3-methoxy-2-(methoxycarbonylanino)-3-methylbutanoic acid To a solution of Example 203B (163 mg, 0.66 mol) in CH 2 Cl 2 (2 mL) was added trilluoroacetic acid (2 il) and the solution was stirred at room temperature for I h. Solvent was removed in vacuo and the residue was suspended in saturated NaHCO 3 , extracted with EtOAc, the 10 organic extracts combined, washed with brine, dried (Na2SO 4 ), filtered and solvent removed in vacuo. The residue was dissolved in dioxane (I iL) and I M NaOH (1.1 mL, 2.175 nunol) was added followed by the dropwise addition of methyl chloroformate (0.102 mL, 1.3 mmol). The solution was stirred at room temperature for 16 h, diluted with EtOAc, washed with I N Hld, brine, dried (Na 2

SO

4 ), filtered and solvent removed in vacuo to give the title compound (96 mug, 0.468 mmnol, 15 71%). Example 2031) methyl [(2S)-3-methoxy- I -((2S)-2-[(4- {(2R,5R)-5-(4-{ [(1-{(2S)-3-methoxy-2 [(methoxycarbonyl)amino]-3-methylbutanoyl)pyrrolidin-2-yl)carbonyl]amino}phenyl)-l-{4 20 (trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-I-yl}-3-methyl-I-oxobutan-2 yl]carbamnate Example 198B (80.7 mg, 0.136 mmol) and Example 203C (70 mg, 0.341 mmol) were processed in the same manner as Example 199B to give the title compound (62 mg, 0.064 mmol, 47%). 'H NMR (400 MIHz, CDCl) 8 ppm 1.25 (s, 3H) 1.33 (s, 3H) 1.39 (s, 2H) 1.74-1.82 (m,2H) 25 1.89 (s, 2H) 1.93-2.16 (n, 5H) 2.38-2.59 (mi, 4H) 3.16-3.27 (m, 21H) 3.24 (s, 31H) 3.43-3.56 (m, 2H) 3.69 (s, 31-I) 3.71-3.78 (i, 21-I) 3.80 (s, 3H) 3.84-3.94 (in, 11-1) 4.61 (s, I H) 4.70-4.81 (m, 21H) 5.15 (d, J=6.3 I-z, 2H) 5.58 (s, 11-) 6.32 (d, J=8.7 liz, 2H) 7.05-7.13 (m, 41-1) 7.19 (d, J=8.7 Hiz, 2H) 7.33-7.50 (m, 411) 8.7 l(s, I I) 8.92 (s, 1 11). MS (ES!) m/z 967 (M+ 1)'. 322 Example 204 dimethyl ([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis( benzene-3,1 diylcarbainoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3-methyl- I -oxobulane- 1,2-diyl] })biscarbamate 5 and dimethyl ([(2R,5R)-I-(4-fluorophenyl)pyrrolidine-2,5-diyllbis{benzene-3,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-mnethyl- I-oxobutane -1,2-diyl]})biscarbamate Example 204A 10 (2S,2'S)-tert-butyl 2,2'-(3,3'-((2S,5S)-I -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1 phenylene))bis(azanedi yl)bis(oxomethylene)dipyrrolidine-I -carboxylate and (2,2'S)-tert-butyl 2,2'-(3,3'-((2R,5R)- I-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3, I phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate 15 The ether fraction from the work up of Example 55F was concentrated and purified by flash chromatography (silica gel, dichloromethanelEtOAc) to afford the title compound as a mixture of trans diastereomers (0.20 g, 10%). MS (ESI) m/z 742 (M+H)+. Example 204B 20 dimethyl ([(2S,5S)-I-(4-fluorophcnyl)pyrrolidine-2,5-diyl]bis ( henzcne-3,1 diylcarbamoyl(2S)pyrrolidinc-2, I -diyl[(2S)-3-mcthyl- I -oxobutane- 1,2-diyl] })biscarbamate and di methyl ([(2R,5R)- I -(4-fluorophenyl)pyrrolidine-2,5-diyl]bis { benzene-3, I diylcarbamoyl(2S)pyrrolidine-2, 1 -diyl r(2S)-3-methyl- I -oxobuiane- 1,2-diyll)biscarbamnate 25 The product from Example 204A was processed using the method described in Examples 19D and 19E (used (S)-2-(nethoxycarbonylamino)-3-methylbutanoic acid) to afford the title compounds (60.5 tmg, 22%). 1 Hl NMR (free base) (400 MHz, DMSO-D6) 8 0.99 - 0.81 (in, 12H), 1.67 (dd, J = 3.4, 5.0, 3H), 2.06 - 1.79 (in, 81H), 2.20 - 2.06 (in, 51H), 3.52 (d, . = 2.3, 61-I), 3.63 (q, .[ = 7.1, 1 H), 3.88 - 3.75 (m, I H), 4.08 - 3.96 (m, 2H), 4.41 (dt, J = 12.8, 25.2, 21-1), 5.11 (d, J = 28.1, 2H), 6.24 (dd, J = 323 6.0, 10.9, 2H), 6.80 (td, J = 4.2, 8.9, 2H), 6.88 (dd, J = 5.5, 6.4, 2H), 7.22 (ddd, J = 5.3, 10.4, 20.8, 211), 7.32 (d, J = 8.3, 2H), 7.43 - 7.34 (n, 2H), 7.57 (d, J = 7.8, 2H), 10.00 (d, J = 7.8, 2H). MS (ESI) m/z 856 (M+H)+. $F HN N 5f 0 Example 205 diiethyl ({(2R,5R)-I-[4-(tri fluoromethyl)phenyl]pyrrolidine-2,5-diyl )bis (benzene-3,1 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-I-oxobutane-l,2-diyl]})biscarbamate 10 Example 205A (IS,4S)-1,4-bis(3-nitrophenyl)butane-I,4-diol The product from Example 55A was processed using the method described in Example 33 to afford the title compound (1.74 g, 84%). MS (DCI) m/z 350 (M+NH 4 )f. 15 Example 205B (2R,5R)-2,5-bis(3-nitrophenyl)-I-(4-(trifluoromethyl)phenyl)pyrrolidine The product from Example 205A and 4-aminobenzotrifluoride were processed using the method described in Examples 55C and 55D to afford the title compound (0.27 g, 19%). MS (ESI) mtlz 858 (M+HI)+. 20 Example 205C 3,3'-((2R,5R)-1 -(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianiline The product from Example 205B was processed using the method described in Example 55E. The title compound was isolated by flash chromatography (silica gel, methanol/dichloromethane). MS 25 (ESI) m/z 398 (M+H)+, 396 (M-H)+. Example 205D 324 (2S,2'S)-tert-butyl 2,2'-(3,3'-((2R,5R)-I-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(3, 1 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-I -carboxylate The product from Example 205C was processed using the method described in Example 19C replacing DMF with dichloromethane to afford the title compound (0.36 g, 77%). MS (ESI) n/z 792 5 (M+H+). Example 205E dimethyl ({(2R,5R)-1-[4-(trifluoroniethyl)phenyllpyrrolidine-2,5-diylIbis{ benzene-3,1 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyll))biscarbamate 10 The product from Example 205D was processed using the method described in Examples 19D and 191 (used (S)-2-(nethoxycarbonylamino)-3-mcthylbutanoic acid and replacing HATU with HOBt and EDC) to afford the title compound (13.5 mg, 3%). 'H NMR (TFA salt) (400 MHz, METHANOL-D4) 6 1.08 - 0.89 (m, 12H), 1.88 - 1.73 (mn, 2H), 2.32 - 1.93 (in, 101), 2.62 (t, J= 6.9, 2H), 3.64 (s, 61), 3.77 - 3.67 (i, 2H), 4.00 - 3.90 (m, 2H), 4.20 (d, J = 8.0, 21-), 4.56 - 4.45 (m, 211), 15 5.26 (d, J = 6.5, 2H), 6.42 (d, J = 8.8, 2H), 6.98 (d, J = 7.6, 2H), 7.17 (d, J= 7.4, 2H), 7.27 (t, J = 7.8, 2H-1), 7.52 - 7.37 (i, 4H). MS (ESI) m/z 906 (M+H)*, 904 (M-H)*. F F F HN NH ce bp Example 206 20 dimethyl ({ (2R,5S)- I -[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl }bis { benzene-3,1 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-iethyl-l-oxobutane-l,2-diyl]])biscarbamate The product for Example 206 was isolated from the purification of Example 205E (12.5 mg, 3%). '1H NMR (TFA salt) (400 MIHz, DMSO-D6) 6 0.90 (dt, J = 6.2, 10.3, 12H), 2.23 - 1.73 (im, 12H), 2.47 - 2.39 (m, 6H), 3.52 (d, J = 3.3, 4H), 3.89 - 3.73 (in, 2H), 4.03 (t, J = 8.4, 2H), 4.44 (dd, J 25 = 4.9, 7.8, 211), 4.83 (t, J = 5.5, 211), 6.50 (d, J = 8.7, 211), 7.36 - 7.15 (in, 611), 7.39 (d, J = 8.7, 211), 7.73 - 7.57 (m, 411), 10.04 (d, J = 10.0, 21). MS (ESI) m/z 906 (M+l)*, 904 (M-Hl)*. 325 Hl N~y OyNH Example 207 dimethyl (I(2S,5S)- I-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{ pyridine-5,2 diylcarbamoyl(2S)pyrrolidine-2, 1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate 5 and dirnethyl ([(2R,5R)-l -(4-tert-butylphenyl)pyrrolidine-2,5-diyl Ibis( pyridine-5,2 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-imethyl-1-oxobutane-1,2-diyl]})biscarbamate Example 207A 10 1,4-bis(6-chloropyridin-3-yl)butane-I,4-dione The zinc chloride (3.04 g, 22.82 mmol), tert-butyl alcohol (1.576 mL, 16.71 mmol) and diethylamine (1.731 inL, 16.71 inmol) were combined in benzene (12 miL). The resulting slurry was stirred at room temperature for 2 hours until all solid dissolved. To this slurry was added 1-(6 chloropyridin-3-yl)ethanone (2.60 g, 16.71 nmol; reference: Bioorganic & Medicinal Chemistry 15 Leters, 1998, 8, 3087-3092), followed by 2-bromo-l-(6-chloropyridin-3-yl)ethanone (2.61 g, 11.14 mmol, reference: Blioorganic & Medicinal Chemistry Letters, 1998, 8, 3087-30)2). The resulting clear yellow solution was stirred at room temperature for 88 hours. The thick reaction mixture was treated with 5% H 2

SO

4 (10 mL), stirred for 30 minutes, filtered and dried to give the title compound (2.9 1g, 85%) as a solid. 20 Example 207B I,4-bis(6-chloropyridin-3-yl)butane- 1,4-diol The product from Example 207A (2.90 g, 9.38 imol) and sodium borohydride (0.745g, 19.70 mol) were combined in ethanol (94 ml..) at 0 'C. The mixture was warmed to room temperature and 25 stirred for 6 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and I M -C. The organic layer was washed with water, brine, dried with sodium sulfate, filtered and evaporated to give the title compound (2.62 g, 89%). Example 207C 30 1,4-bis(6-chloropyridin-3-yl)butane-1,4-diyl dimethanesulfonate 326 The product from Example 207B (2.23 g, 7.12 mmol) and triethylamine (2.98 ml.., 21.36 mmol) were combined in dichloromethane (50 ml..). The mixture was cooled to -20 C and melhanesulfonyl chloride (1.383 nL, 17.80 nunol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated to give the title product (approx 3.34 g) which 5 was directly used for the next reaction. Example 207D 5,5'-(I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)his(2-chloropyridine) The product from Example 207C (3.34 g, 7.12 nmol) and 4-tert-butylaniline (6.38 g, 42.7 10 nunol) were combined in DMF (20 mL). The mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and IM H-CL. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (5% to 30%) to give the title compound (2.95 g, 97%) as a yellow solid as a mixture of stereoisomers. 15 Example 207F dimethyl ([(2S,5S)- I-(4-ieri-butylplienyl)pyrrolidine-2,5-diylJhis{pyridine-5,2 diylcarbamoyl(2S)pyrrolidine-2,1-diyl((2S)-3-methyl-l -oxobulane-1,2-diylJ })biscarbamate and 20 dimethyl ([(2R,5R)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis { pyridine-5,2 diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-I,2-diyl]))biscarbamate The product from Example 207D (0.171 g, 0.40 nunol), the product from Example 116C (0.326 g, 1.200 mmol), cesium carbonate (0.365 g, 1.120 mniol), tris(dihenzylideneacetone)dipalladiuni(0) (0.022 g, 0.024 mmol) and (9,9-dimethyl-9H-xaithene-4,5 25 diyl)bis(diphenylphosphine) (0.042 g, 0.072 unol) were combined in dioxane (4 mL). The mixture was purged with nitrogen for 15 minutes and stirred at 100 'C for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with methanol/dichloroniethane (1% to 4%) to give the title 30 compound (5 mg, I%) as a mixture of trans diastereomers. 1H NMR (500 MIlz, DMSO-D6) 6 ppm 0.88 (t, J=6.41 Hz, 6 H) 0.92 (t, J=7.32 lz, 6 H) 1. 12 (s, 9 H) 1.68 - 1.75 (in, 2 H) 1.81 - 1.99 (mn, 8 H) 2.07 - 2.18 (in, 2 H) 2.50 - 2.53 (in, 2 H) 3.52 (s, 6 H) 3.57 - 3.64 (m, 2 -I) 3.78 - 3.86 (mn, 2 1-1) 3.98 - 4.03 (m, 2 11) 4.55 - 4.63 (m, 2 H) 5.27 (d, J=6.26 Hz, 2 H) 6.18 - 6.27 (m, 2 H-) 6.99 (dd, J=8.77, 1.60 Hz, 2 H) 7.28 - 7.37 (m, 2 H1) 7.59 (dd, J=8.62, 2.06 Hz, 2 H) 7.96 (d, J=8.39 Hz, 2 H) 35 8.12 - 8.20 (i, 2 H-) 10.53 (s, 2 H1); MS (ESI+) m/z 896.6 (M+H1)+. 327 0 NN Example 208 dimethyl ([(2S,5S)- I -phenylpyrrolidine-2,5-diyllbis {benzene-4, 1 -diylcarbamoyl(2S)pyrrolidine-2, I diyl [(2S)-3-methyl- I -oxobutane- I,2-diyl]))hiscarhamate 5 and dimethyl ([(2R,5R)-l -phenylpyrrolidine-2,5-diyl]bis benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,I diyl[(2S)-3-methyl-I-oxobutane-1,2-diyl]})biscarbamate The title compound was isolated from Example 85C as an additional product. Ill NMR (TFA salt) (400 MHz, DMSO-D6) 6 ppm 0.83 - 0.88 (n, 6 H), 0.88 - 0.94 (m, 6 H), 1.60 - 1.65 (m, 2 H), 10 1.79 - 2.02 (in, 8 H), 2.06 - 2.18 (m, 2 H), 3.51 (s, 6 11), 3.55 - 3.64 (in, 2 H), 3.75 - 3.83 (n, 2 H), 4.01 (t, .1=8.3 Hz, 2 1-1), 4.38 - 4.43 (in, 2 H), 5.16 (d, .=6.4 Hz, 2 H), 6.23 (d, .=8.3 H z, 2 11), 6.39 (t, J=7.3 Hz, I H), 6.90 (t, J=7.9 Hz, 2 H), 7.09 - 7.14 (in, 4 H), 7.25 - 7.31 (i, 2 H), 7.45 - 7.50 (in, 4 H), 9.97 (s, 2 11); MS in/z 838.4 (M+H)*. F F F NNN 15 f Example 209 dimiethyl (((2S,5S)-I -[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl }bis henzene-4,1 diylcarbamoyl(2S)pyrrolidiie-2, I -diyl[(2S)-3,3-dimethyl-1-oxobutanc- l,2-diyl]})biscarbaimate The product from Example 23C was separated by chiral chromatography on a Chiralpak AD 20 H- semi-prep column eluting with 40% 2-PrOI:EtOH (1:1) / 60% hexunes. The title compound was the first of 2 components to elute. 11 NMR (400 MHz, DMSO-D6) 6 ppm 0.97 (s, 18 H-), 1.61 - 1.73 (m, 2 H), 1.75 - 1.93 (i, 4 H), 1.94 - 2.06 (in, 2 H), 2.08 - 2.21 (m, 2 H), 3.54 (s, 6 H), 3.57 - 3.70 (in, 2 H), 3.70 - 3.83 (m, 2 H), 4.21 (d, 1=8.89 Hz, 2 H), 4.38 - 4.48 (m, 2 H), 5.27 (d, .1=6.51 Hz, 2 H), 6.37 (d, 1=8.78 Hz, 2 H), 7.08 (d, J=8.89 Hz, 2 H), 7.15 (d, 1=8.57 Hz, 4 H), 7.25 (d, 1=8.89 Hz, 2 H), 25 7.52 (d, 1=8.57 Hz, 4 H), 10.02 (s, 2 H); MS (ESI) m/z 951.6 (M+H)*. 328 F FF ... o Ho,... NQY 6 ~ -c--f Example 210 dimethyl ({(2R,5R)-I-[4-(trifluoromethyl)phenyllpyrrolidine-2,5-diyl} bis{ benzene-4,1 diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S)-3,3-dimcthyl- I -oxobutanc- 1,2-diyl] } )hiscarhamate 5 The product from Example 23C was separated by chiral chromatography on a Chiralpak AD -1 semi-prep column eluting with 40% 2-PrOH:EtOH (1:1) / 60% hexanes. The title compound was the second of 2 components to elute. 1-1 NMR (400 MHz, DMSO-D6) 6 ppm 0.96 (s, 18 H), 1.64 1.75 (i, 2 11), 1.76 - 1.93 (i, 4 11), 1.94 - 2.06 (n, 2 H), 2.07 - 2.21 (n, 2 11), 3.54 (s, 6 H1), 3.58 3.70 (i, 2 H), 3.70 - 3.86 (m, 2 H), 4.20 (d, J=8.89 Hz, 2 H), 4.38 - 4.47 (m, 2 H), 5.28 (d, J=6.18 Hz, 10 2 H), 6.36 (d, ./=8.89 Hz, 2 H), 7.07 (d, 1=8.89 Hz, 2 H), 7.14 (d, .=8.57 Hz, 4 H), 7.25 (d, .1=8.78 Hz, 2 H), 7.52 (d, .=8.57 H z, 4 H), 10.03 (s, 2 H); MS (ESI) m/z 951.4 (M+H)*. F 0 0 Example 211 15 dimnethyl ([(2R,5R)- 1-(4-fluorophenyl)pyrrolidine-2,5-diyl Ibis I benzene-4, I diylcarbamoyl(2S)pyrrolidine-2,1-diyl{(2S,3R)-3-methyl-I-oxopentane-1,2-diyll})biscarbamate The product from Example 25 was separated by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with 50% 2-PrOH:FtOH (1:1) / 50% hexanes. The title compound was the second of 2 components to elute. I H NMR (400 M Hz, DMSO-D6) 8 ppm 0.76 - 0.92 (m, 12 H), 1.05 20 - 1.19 (n, 2 H), 1.37 - 1.54 (i, 2 H), 1.57 - 1.70 (mi, 2 H), 1.69 - 1.96 (m, 6 H), 1.94 - 2.07 (ni, 2 H), 2.07 - 2.22 (in, 2 H), 3.53 (s, 6 H), 3.55 - 3.64 (m, 2 H), 3.69 - 3.83 (in, 2 H), 4.17 - 4.28 (in, 2 H), 4.42 (dd, J=7.81, 5.20 Hz, 2 H1), 5.16 (d, J=6.29 Hz, 2 H), 6.20 (dd, J=9.22, 4.45 Hz, 2 H), 6.77 (t, J=8.95 Hz, 2 H), 7.13 (d, J=8.46 Hz, 4 H), 7.49 (d, J=8.46 Hz, 2 H), 9.97 (s, 2 11); MS (ESI) m/z 884.4 (M+H)*. 25 329 H o- oN 0 0 0 Example 212 dimethyl ([(2R,5R)- I -(4-fluorophenyl)pyrrolidine-2,5-diylbis{ benzene-4, I diylcarbamoyl(2S)pyrrolidine-2,1 -diyl[(2S,3S)-3-methyl- I -oxopentane-l,2-diyll })biscarbamate 5 The product from Example 24 was separated by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with 50% 2-PrOH:EtOH (1:1) / 50% hexanes. The title compound was the second of 2 components to elutc. I H NMR (400 MHz, DMSO-D6) 6 ppm 0.80 (t, J=7.37 Hz, 6 H), 0.88 (d, J=6.72 Hz, 6 H), 1.02 - 1.18 (in, 2 H), 1.41 - 1.59 (m, 2 H), 1.59 - 1.75 (in, 4 H), 1.80 - 1.95 (in, 4 H), 1.95 - 2.06 (m, 2 H), 2.08 - 2.23 (in, 2 H), 3.52 (s, 6 H), 3.56 - 3.67 (in, 2 H-1), 3.74 - 3.89 (in, 10 2 11), 4.07 (t, 1=8.95 Hz, 2 11), 4.39 - 4.47 (in, 2 H1), 5.16 (d, 1=6.18 Hz, 2 11), 6.20 (dd, 1=9.22, 4.45 H z, 2 H), 6.78 (I, J=8.95 lz, 2 H), 7.13 (d, 1=8.46 Hz, 4 H), 7.35 (d, 1=8.46 Hz, 2 1-1), 7.50 (d, 1=8.57 Hz, 4 H), 9.99 (s, 2 H); MS (ESI) m/z 884.4 (M+H)*. o N NH, 15 Example 213 N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)-5-(4-aminophenyl)-I -(4-tert-butylphenyl)pyrrolidin-2 ylJphenyl}-L-prolinamide To a solution of the product from Example 37B (17.7 mg, 0.065 minol) and the product from Example 37E (50 mg, 0.130 minmol) in anhydrous DMSO (1.3 ml.) was added HATU (27.1 ing, 0.071 20 inmol) and Hunig'sBase (0.015 ml, 0.084 mmol). 'Tlie resulting mixture was stirred at ri for 30 min, and was then partitioned between 1120 (5 mL) and EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SO 4 . The drying agent was filtered off, and solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH 2

CI

2 to give the title compound (20 ig, 24%). 1 H NMR (400 M Hz, DMSO-D6) 6 ppm 25 0.88 (d, J=6.72 H., 3 H), 0.93 (d, 1=6.72 Hz, 3 H), 1. 11 (s, 9 H), 1.52 - 1.66 (in, 2 H-), 1.79 - 2.06 (im, 4 H), 2.06 - 2.20 (im, I H), 2.34 - 2.47 (in, 2 H), 3.52 (s, 3 H), 3.56 - 3.67 (mn, 1 H), 3.74 - 3.87 (im, 1 1-1), 4.02 (t, 1=8.51 lz, 1 H), 4.42 (dd, 1=8.08, 4.83 Hz, I H), 4.83 - 4.94 (in, 2 H), 5.02 (d, 1=7.16 Hz, 330 0.5 H), 5.08 (d, J=7.59 Hz, 0.5 H), 6.18 (d, J=8.78 Hz, 2 H), 6.48 (d, J=8.35 Hz, 2 H), 6.84 (d, J=8.35 Hz, 2 H), 6.93 (d, 1=8.89 H z, 2 H), 7.11 (d, J=8.57 -7, 2 H), 7.31 (d, 1=8.35 Hz, I H), 7.48 (d, 1=8.57 Hz, 2 H), 9.97 (s, 1 H); MS (ESI) m/z 640.3 (M+H)*. OH N H Example 214 dimethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2,1 -diyl))bis(3-inethyl- I oxohutanc-2, I -diyl)dicarbamate 10 and dimuethyl (2S,2'S)-1,1 '-((2S,2'S)-2,2'-(4,4'-((2S,5S)-I-(4-tert-bulylphenyl)pyrrolidine-2,5 diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxonethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-nethyl- I oxobutane-2,1 -diyl)dicarbamate 15 Example 214A diethyl 1- (4-tert-butylphenyl)pyrrolidinc-2,5-dicarboxylatc A solution of diethyl mcso-2,5-dibroioadipale (2.0 g, 5.55 mmol) and 4-icr-butylaniline (3.32 g, 22.22 mnmol) in dimethoxyethane (12 mL) was stirred at reflux for 10 h. The cooled mixture was partitioned between EcOAc (100 mL) and IN aq HCI (2x100 mL), and the organic layer was 20 dried over Na 2

SO

4 . The drying agent was filtered off, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes to give the title compound as an oil (1.95 g, quant.). IH NMR indicated a 3:2 mixture of cis:trans pyrrolidine isomers. 25 Example 214B I -(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid To a solution of the product from Example 214A (1.95 g, 5.61 mmol) in MeOlH (50 mL) was added a solution of NaOH (0.95 g, 23.8 mmol) in 1-120 (10 mL). The resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo to ca. 10 mL and was poured into IN HCI (50 30 mL). The mixture was extracted with CH 2

C

2 (3 x 50 mL), and the combined organic layers were dried over Na 2

SO

4 . The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as a light orange solid (1.42 g, 87%) as a mixture of stercoisomers. 331 Example 214C trais-l -(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid The product from Example 214B was subjected to column chromatography on C18 silica gel using a solvent gradient of 10-60% acetonitrile in H 2 0 (0.1% TFA). The title compound was the first 5 of 2 major components to elute. Example 2141) 1, l'-(trais-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-diazoethanone) To a solution of the product from Example 214C (0.963 g, 3.31 mmol) in dry CH 2

CI

2 (20 ml.,) 10 at 0 *C was added oxalyl chloride (1.157 mL, 13.22 inmol), followed by 2-3 drops of DMF, and the resulting ixturc was stirred at rt for 30 min until no further bubbling was observed. The cooled mixture was cone by evaporation with dry N 2 , and the residue was dissolved in dry CH 2 Cl 2 (10 mL). To the 0 *C solution was added a solution of diazomethane in E 2 O (-0.6 M, 20 mL) and the resulting mixture was stirred at 0 'C for ih. The mixture was concentrated in vacuo, and the crude product was 15 purified by colunin chromatography on silica gel using a solvent gradient of 0-100% EtOAc in hexanes to give the title compound (0.54 g, 48%). Example 214E 4,4'-(trans-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dithiazol-2-amine 20 A solution of the product from Example 214D (0.50 g, 1.47 nunol) in E 2 O (10 muL) was treated dropwise with 48% aq. hydrogen bromide (0.500 mL, 4.42 mmol). The resulting mixture was stirred at rt for 30 min. Water (I mL) was added, and the mixture was extracted with Et 2 O (3 x 10 mL). The combined organic layers were dried over Na 2

SO

4 , filtered, and concentrated in vacuo. The residue was dissolved in EtOl (15 mL). To the resulting solution was added thiourca (0.45 g, 5.89 25 miuol), and the resulting mixture was stirred at rt for I h and then concentrated to ca. I mL. Water (10 mL) was added, and the p-I was neutralized using saturated aq. Nal-C0 3 . The resulting solid was collected by filtration and dried in vacuo to give the title compound (0.455 g, 77%). Example 214F 30 (2S,2'S)-tert-butyl 2,2'-(4,4'-(trans-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(thiazole-4,2 diyl)bis(azanediyl)bis(oxomethylene))dipyrrolidine- I -carboxylate A mixture of the product from Example 214E (0.2 g, 0.501 mmol), (S)-l-(tert butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.431 g, 2.002 nnol), and NI ((ethylimnino)methylene)-N3,N3-dimethylpropane- I,3-diamine hydrochloride (1.151 g, 6.01 mmol) in 35 DMF (4 mil,) and pyridine (4 mil.) was stirred at rt overnight. The mixture was partitioned between IN aq. HCI and EtOAc (3x), and the combined organic layers were dried over Na 2 SO4. The drying 332 agent was filtered off, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-100% EtOAc in hexanes to give the title compound (0.28 g, 71%) as a mixture of trans diastereoiers. 5 Example 214G dimethyl (2S,2'S)- 1, '-((2S,2'S)-2,2'-(4,4'-((2R,5R)- I-(4-tert-butylphenyl)pyrrolidine-2,5 diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxoimethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-inethyl- oxobutane-2, 1 -diyl)dicarbamate and 10 dimethyl (2S,2'S)- 1, l'-((2S,2'S)-2,2'-(4,4'-((2S,5S)- 1 -(4-tert-but ylpheny1)pyrrolidine-2,5 diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxoimethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-iethyl- I oxobutane-2, I -diyl)dicarbamate A solution of the product from Example 214F was stirred in 2N ICI in dioxane (0.4 mL) for I h and then concentrated in vacuo. The residue was subjected to the procedure described in Example 15 10 to give the title compound as mixture of trans diastereomers. IH NMR (free base) (400 MHz, DMSO-D6) 6 ppm 0.80 - 0.97 (in, 14 H1), 1.12 - 1.16 (in, 9 H), 1.69 - 2.06 (m, 8 H1), 2.08 - 2.22 (in, 2 H), 3.51 - 3.57 (i, 6 H), 3.57 - 3.68 (m, 2 11), 3.77 - 3.91 (in, 2 H), 3.95 - 4.06 (in, 2 H1), 4.47 - 4.59 (in, J=7.16 1-z, I H), 5.08 - 5.17 (in, 2 H), 6.31 (t, 1=8.24 Hz, 2 H), 6.70 (d, J=21.04 Hz, 2 H), 7.02 (dd, J=8.67, 6.40 Hz, 2 11), 7.35 (d, 1=8.35 lz, 2 H), 12.24 (s, 2 H-). 20 F 0 N B, 0, 0 "r" doy 0 Example 215 dimethyl ([3-brono-I-(4-fluorophenyl)-IH-pyrrole-2,5-diyl]bis{ benzei-4,I diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-nethyl-1-oxobutane-1,2-diyl]})biscarbamate 25 To a suspension of the product from Example 51 (455 mg, 0.534 mmol) in CH 2 Cl 2 (2.7 inL) was added a mixture of 1-bromopyrrolidine-2,5-dione (95 mg, 0.534 mmol) in CH 2 C1 2 (2.7 mL). The mixture was stirred overnight at room temperature then concentrated under reduced pressure and triturated with diethyl ether to provide a mixture of compounds that was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH in 10mM ammonium acetate to afford 30 the title compound (84 ing, 17% yield). 'H NMR (free base) (400 MHz, DMSO-D6) 8 10.06 (s, IH), 10.02 (s, 11H), 7.46 (d, J = 8.7, 211), 7.41 (d, J = 8.7, 211), 7.30 (d, J = 7.7, 211), 7.15 - 7.03 (in, 611), 6.98 (d, J = 8.7, 21-), 6.53 (s, 11H), 4.45 - 4.33 (m, 211), 4.01 (t, J = 7.7, 211), 3.85 - 3.73 (in, 21-I), 3.66 333 - 3.54 (n, 2H), 3.51 (s, 6H), 2.20 - 2.05 (in, 2H), 2.03 - 1.77 (in, 8H-1), 0.97 - 0.79 (in, 121-). MS (FSI; M+H) nz= 933. F N N I N H .oBr Br O 5 Example 216 dimethyl ([3,4-dibromo-1-(4-fluorophenyl)- IH-pyrrole-2,5-diyl]bis{ benzene-4,1 diylcarbaimoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-imethyl-I-oxobutane-1,2-diyl]} )biscarbamate The title compound was formed as an additional product in Example 215. The mixture of products was subjected to reverse phase H PLC purification eluted with a gradient of 60-100% MeOH 10 in 1OmM ammonium acetate to afford the title compound (125 mng, 23% yield). 'H NMR (free base) (400 MIHz, DMSO-D6) 8 10.08 (bs, 211), 7.47 (d, J = 8.7, 411), 7.33 - 7.27 (m, 211), 7.13 - 7.01 (m, 8 1), 4.43 - 4.35 (m, 211), 4.01 (t, J = 8.4, 21-1), 3.84 - 3.74 (m, 211), 3.65 - 3.55 (in, 21-), 3.51 (s, 611), 2.21 - 2.05 (in, 211), 2.05 - 1.78 (m, 811), 0.91 (d, J = 6.7, 611), 0.86 (d, J = 6.6, 611). MS (ES!; M+1) i/z= 10ll. 15 F [ H ,oIN -,: \N/\IgQ Bi Example 217 The title compound was formed as a by-product in Example 215. The mixture of products was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH in 10mM 20 ammonium acetate to afford the title compound (61 ing, 12% yield). 'H NMR (free base) (400 MI-z, DMSO-D6) 8 10.00 (s, 2H), 7.41 (d, J = 8.7, 2H), 7.38 (d,.1 = 8.9, 21H), 7.29 (d, J = 6.6, 21-I), 7.14 (d, J = 7.3, 1 H), 7.11 - 7.05 (m, 3H), 7.01 - 6.93 (m, 2H), 6.89 (t, .1 = 8.7, 2H), 4.37 (dd, J = 4.9, 7.4, 21-), 4.00 (t, J = 8.4, 21-1), 3.84 - 3.74 (in, 2H), 3.64 - 3.55 (in, 2H), 3.51 (s, 611), 2.19 - 2.05 (in, 21-1), 2.03 - 1.78 (i, 8H), 1.23 (s, 9H), 0.91 (dd, J = 2.1, 6.6, 61-1), 0.86 (d, J = 6.4, 6H). MS (ESI; M+H) 25 m/z = 989. 334 HN o N-N / N HN \ Example 218 methyl {(2S)-I-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-(2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl]-IH-imidazol-4-ylIphenyl)-4H-1,2,4 5 triazol-3-yllphenyl}-IH-imidazol-2-yl)pyrrolidin-1-yI]-3-methyl-1-oxobutan-2-yl}carbamate Example 218A 4-bromo-N'-(4-broinobenzoyl)benzoylhydrazide Dissolved equimolar amounts of 4-hromobenzohydrazide (1.097 g, 5 mmol) and 4 10 bromobenzoyl chloride (1.120 g, 5 mmol) in anhydrous pyridine (25 mL) under nitrogen and heated at reflux (oil bath 135 *C) for 6 hr. Cooled reaction to room temperature, poured the mixture into absolute EtOH (100 mL), and cooled in a freezer overnight to give white crystals. Collected solids by vacuum filtration, washed solids with absolute EtOli (2 x 5 mL), and dried in vacuo to afford the title compound as a white solid (953 tmg, 48%). 'H NMR (400 MHz, DMSO-D6) 8 ppm 7.75 (d, .1=8.57 15 1z, 4 H), 7.86 (d, J=8.46 H-z, 4 H), 10.63 (s, 2 -1); MS (ESI-) m/z 395/397/399 (M-H)~ with two bromines. Example 218B 3,5-bis(4-bromophenyl)-4-(4-iert-butylphenyl)-4H- 1,2,4-triazole 20 In an oven-dried 10-mL round bottom flask, equipped with a septum and purged with nitrogen, 4-tert-butylaniline (450 mg, 3.01 mmol) was dissolved in anhydrous 1,2-dichlorobenzene (1.5 mL) and the solution cooled to 0 C. A solution of phosphorus oxychloride (0.047 mL, 0.502 mmol) in anhydrous 1,2-dichlorobenzene (0.5 mL) was added slowly in dropwise manner from a gas tight syringe. Upon completion of addition, removed the cooling bath and stirred at room temperature 25 for I hr to form the phosphoryl trianide in situ (reaction became progressively cloudy). Then added the product of Example 2 18A (200 ing, 0.502 nunol), replaced septum with a reflux condenser, and heated reaction in an oil bath at 200 *C for 4 hr. Cooled light brown colored solution to room temperature, then placed in a freezer for 3 days and collected an off-white solid (20 mg, 4-bromo-N (4-tert-butylphenyl)benzamide by-product) by vacuum filtration. The filtrate was treated with 30 hexanes (-50 mL) and the cloudy solution cooled in a freezer for 30 min. Collected an off-white solid (73 mg) by vacuum filtration and concentrated the filtrate by rotary evaporation to a solution of 335 product in I,2-dichlorobenzene. The latter was purified by flash chromatography (silica gel, 3.8 cm x 15 cm bed, gradient of CH 2 Cl 2 , 20% EtOAc/CH 2

CI

2 , and 30% EtOAc/CH 2

CI

2 ) to afford the title compound as a fluffy white solid (154 mg, 60%). 'H NMR (400 MHz, CDCl 3 ) 6 ppm 1.36 (s, 9 H), 7.06 (d, J=8.46 Hz, 2 H), 7.29 (d, J=8.57 Hz, 4 H), 7.43 (d, J=8.57 Hz, 4 H), 7.46 (d, J=8.57 Hz, 2 H); 5 MS (ESI+) m/z 510/512/514 (M+H)* with two bromines. Example 218C 4-(4-tert-butylphenyl)-3,5-his((4(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-4H- 1,2,4 triazole 10 Charged an oven-dried 25-mL round bottom flask, purged with nitrogen, with the product of Example 218B (144.2 mg, 0.282 mmol), bis(pinacalato)diboron (215 mg, 0.846 mnmuol), potassium acetate (90 mg, 0.917 minol), and anhydrous dioxane (1.5 nL). Sparged the mixture with nitrogen for 30 min, added 1, '-bis(diphenylphosphino)ferrocene-palladium(IH)dichloride dichloromethane complex (23.03 mug, 0.028 nmol), re-sparged with nitrogen for 5 min, replaced rubber septum with a 15 glass stopper, and heated in an oil bath (85 C) for 2 hr. Cooled reaction to room temperature, vacuum filtered through a small bed of Celite 545, washed catalyst thoroughly with CH 2 Cl 2 , and concentrated the filtrate by rotary evaporation to a dark brown oil. Purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 1:1 EtOAc/CH 2

CI

2 ) to afford a dark beige solid (230 tug). Repurified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, 3% 20 MeOll/CH 2 Cl 2 ) eluting with to afford the title compound as a beige solid (171 mg, 100%). '11 NMR (400 MHz, CDCl 3 ) 8 ppm 1.27 (s, 9 H), 1.33 (s, 24 H), 7.06 (d, J=8.46 Hz, 2 H), 7.38 - 7.47 (m, 6 H), 7.71 (d, J=7.92 Hz, 4 H); MS (ESI+) m/z 606 (M+H)*, 1211 (2M+H)*. Example 2181) 25 (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-(4-(4-tert-butylphenyl)-4H-1,2,4-triazole-3,5-diyl)bis(4,1 phenylene))bis( I H-i nidazole-4,2-diyl))dipyrrolidine- I -carboxylate Charged a nitrogen-purged microwave tube (size M, 5 miL) with the product of Example 218C (171 mg, 0.282 mmol), the product of Example 26D (223 mg, 0.706 mmol), and a mixture of absolute EtOl (1.5 mL) and toluene (1.5 mL), then added IM aq sodium carbonate (0.706 m.L, 0.706 30 mnmol) and sparged the mixture with nitrogen for 20 min. Added 1,1' his(diphenylphosphino)ferrocene-palladium(lI )dichloride dichloromethane complex (23.07 mg, 0.028 mmol), sparged again with nitrogen for 5 min, sealed the tube with an aluminum crimp cap, and heated in a microwave reactor (Personal Chemistry Emrys Creator) with stirring at 100 C for 1 hr. Cooled the reaction to room temperature, diluted reaction in EtOAc (75 mL), washed with 1120 (2 x 35 25 mL) and brine (25 mL), dried organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a yellow solid (330 tug). Purified by flash chromatography (silica gel, 3.8 cm x 336 15 cm, gradient of 4%, 6%, 8%, and 10% MeOH/CH 2

CI

2 ) to afford the title compound as a light yellow solid (135 mg, 58%). MS (ESI+) m/z 824 (M+H)*. Example 218E 5 4-(4-tert-butylphenyl)-3,5-bis(4-(2-((S)-pyrrolidin-2-yl)-IH-inidazol-4-yl)phenyl)-4H-1,2,4-triazole Dissolved the product of Example 2181) (131.5 mg, 0.160 mmol) in anhydrous CIzCl 2 (2 mL) under nitrogen, added trifluoroacetic acid (I mL, 12.85 mmol), and stirred at 25 *C for 30 min. Removed the solvent by rotary evaporation, took up the residue in 20% iPrOH/CHCl, (50 ml.), washed with sat'd aq NaHCO 3 (10 ml), extracted the aqueous phase with 20% iPrOH/CHCl 3 (2 x 25 10 iL), dried the combined organic extracts over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation. Took up residue in 1:5 v/v C12Cl2/hexancs and concentrated in vacuo to afford the title compound as a light tan solid (114 mg). 'I I NMR (400 MH z, DMSO-D6) 8 ppm 1.30 (s, 9 11), 1.66 1.94 (m, 6 1), 1.98 - 2.12 (m, 2 11), 2.80 - 3.07 (m, 4 11), 3.70 - 3.86 (m, 1 11), 4.12 - 4.22 (in, 2 H-), 4.34 (d, J=4.01 lz, I 11), 7.34 (t, 1=8.08 liz, 6 1-1), 7.47 - 7.57 (m, 4 11), 7.68 (d, 1=8.35 lIz, 4 11), 15 11.90 (s, 2 1-); MS (ESI+) 624 (M+H)'; (ESI-) m/z 622 (M-H)~. Example 218F (tmethyl {(2S)-I-[(2S)-2-(4-{4-[4-(4-teri-butylphenyl)-5-(4-{2-[(2S)-1-((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-yl)- A H-imidazol-4-yl) phenyl)-4H- 1,2,4 20 triazol-3-yl]phenyl}-IH-imidazol-2-yl)pyrrolidin-1-yl]-3-niethyl-I-oxobutan-2-yl}carbaiate In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 218E (50 tng, 0.080 minol) in anhydrous DMF (I mL), and cooled to 0 *C. Added sequentially (S)-2-(iethoxycarbonylamino)-3-methylbutanoic acid (29.5 mg, 0.168 mmol), HOBt hydrate (27.6 ing, 0.180 tmol), EDAC (35.3 mg, 0.180 mmol), and N-methylmorpholine (0.035 mL, 25 0.321 tnnol). Stirred the solution at 25 OC for 15 hr. Diluted the reaction in EtOAc (50 mL), washed with sat'd aq NaHCO 3 (25 mL), 1-120 (3 x 25 mL), and brine (25 mL), dried the organic phase over anhydrous MgSO, filtered, and concentrated by rotary evaporation to an off-white solid (72 mg). Purified by flash chromatography (silica gel, Alltech Extract-Clean lOg column, gradient of 6% to 8% MeOll/C1 2 Cl 2 ) to afford the title compound as an off-white solid (49 ing, 65%). 'H NMR (400 MHz, 30 DMSO-D6) 6 ppm 0.82 (d, .1=6.72 Hz, 6 H), 0.86 (d, .1=6.72 lz, 6 H), 1.29 (s, 9 H), 1.79 - 2.0l (in, 5 -1), 2.03 - 2.22 (i, 4 H1), 3.53 (s, 6 H), 3.70 - 3.86 (in, 4 H), 4.04 (t, J=8.35 Hz, 2 H), 5.04 (dd, 1=6.67, 3.20 Hz, 2 H), 7.23 - 7.43 (m, 8 H), 7.48 - 7.60 (m, 4 H), 7.61 - 7.73 (m, 4 H), I 1.77 - 12.21 (m1, 2 H); MS (ESl+) mn/z 939 (M+H)*. 337 NN NN ~ N-N /Z NH HN\ 0- 0 _ Example 219 methyl {(2S)-I-[(2S)-2-(4-{4-[4-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-((2S)-2 5 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-IH-imidazol-4-yl } phenyl)-4H-1,2,4 triazol-3-ylJphenyl -1 H-i midazol-2-yl)pyrrolidin-l-ylJ-3-methyl-1-oxohutan-2-yl carbamate Example 219A 3,5-bis(4-bromophenyl)-4-(4-cyclohexylphenyl)-4H-l ,2,4-triazole 10 In an oven-dried 10-mL round bottom flask, equipped with a septum and purged with nitrogen, 4-cyclohexylaniline (545 mg, 3.01 mmol) was dissolved in anhydrous 1,2-dichlorobenzene (1.5 inL) and the solution cooled to 0 "C. A solution of phosphorus oxychloride (78 mg, 0.502 minol) in anhydrous 1,2-dichlorobenzene (0.5 ml..) was added slowly in a dropwise manner from a gas-tight syringe. The reaction became an unstirrable solid gel; removed the cooling bath, added additional 15 I,2-clichlorobenzene (0.5 mL), sonicated the mixture, and stirred the thick suspension at room temperature for I hr to form the phosphoryl triamide in situ. Added the product of Example 218A (200 mg, 0.502 mmol), replaced the septum with a reflux condenser, and heated the reaction in an oil bath at 200 C for 4 hr under nitrogen. The reaction quickly became a homogeneous gold colored solution upon refluxing. Cooled the solution to room temperature and purified by flash 20 chromatography (silica gel, 3.8 cm x 15 cm, gradient of CF 2 Cl 2 to 20% EtOAc/CH 2

CI

2 to 40% EtOAc/CH 2

C

2 ) to afford the title compound as a fluffy white solid (201 mg, 74%). 'H NMR (400 MHz, CDCi3) 6 ppm 1.19 - 1.33 (in, I H) 1.35 - 1.50 (i, 4 H) 1.78 (d, 1=14.42 Hz, I H) 1.84 - 1.98 (m, 4 H) 2.51 - 2.65 (in, I H) 7.04 (d, J=8.35 Hz, 2 H) 7.28 (d, J=8.57 Hz, 6 H) 7.43 (d, J=8.57 Hz, 4 HI); MS (ESI+) m/z 536/538540 (M+1)*, 1072/1074/1076 (2M+1) with two bromines. 25 Example 219B 4-(4-cyclohexylphenyl)-3,5-bis(4(4,4,5,5-tetranmethyl-1,3,2-dioxaboralan-2-yl)phenyl)-4H-1,2,4 triazole Charged an oven-dried 10-ml., round bottom lask, purged with nitrogen, with the product of 30 Example 219A (100 mng, 0.186 inmol), bis(pinacalato)diboron (142 mg, 0.558 mmol), potassium 338 acetate (59.4 mg, 0.605 mmol), and anhydrous dioxane (3 ml.,). Sparged the thick white mixture with nitrogen for 30 min, added 1,l '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloronethane complex (15.20 tmg, 0.019 nunol), re-sparged with nitrogen for 5 min, replaced rubber septum with a glass stopper, and heated in an oil bath (85 *C). Reaction became homogeneous 5 upon heating and darkened with time to a reddish-brown color. TLC (SiO2, 50% EtOAc/CH 2

CI

2 ). After 2 hr, cooled reaction to room temperature, added additional bis(pinacalato)diboron (7 1 mg, -1.5 equiv) and potassium acetate (30 mg, -1.75 equiv), and heated for 1 hr at 85 'C. Cooled the brown colored reaction to room temperature, vacuum filtered through a small bed of Celite 545, washed the collected solids thoroughly with CH 2

CI

2 , and concentrated the filtrate by rotary evaporation to a 10 brown foam. Purified by silica gel flash chroimatography (Alltech Extract-Clean column, lOg bed) eluting with 30% EIOAc/CH 2 Cl 2 to afford the product as a light brown oil (190 tmg). Repurified by silica gel flash chromatography (Alltech Extract-Clean column, lOg bed) eluting with 3% MeOH/C-1 2 Cl 2 to afford the title compound as a light beige foam (122 mg, 100%), MS (ESI+) n/z 632 (M+I)*, 1263 (2M+1)*. 15 Example 219C methyl {(2S)-I-[(2S)-2-(4-{4-[4-(4-cyclohexylplienyil)-5-(4-{2-[(2S)-1-((2S)-2 [(methoxycarbonyl)amino]-3-methylbutanoyl } pyrrolidi n-2-yl}- H-imidazol-4-yl I phenyl)-4H- 1,2,4 triazol-3-ylIjphenyl }-I H-imuidazol-2-yl)pyrrolidin- I -yl1-3-methyl-I -oxobutan-2-yl carbamatee 20 Charged a nitrogen-purged microwave tube (size M, 5 mL) with the product of Example 219B (118 mg, 0.187 mmol), the product of Example 126G (174 tmg, 0.467 mmol), and a mixture of absolute EtOH (I miL) and toluene (I mL), then added IM aq sodium carbonate (0.467 mL, 0.467 mmol) and sparged the mixture with nitrogen for 20 min. Added 1,l' bis(diphenylphosphiio)ferroceie-palladiumii(ll)dichloride dichloromethane complex (15.26 mg, 0.019 25 minol). sparged again with nitrogen for 5 muin, sealed the tube with an aluminum crimp cap, and heated in a microwave reactor (Personal Chenistry Emrys Creator) with stirring al 100 C for 1 hr. Cooled reaction to room temperature, diluted reaction in EtOAc (50 mL), washed with H 2 0 (2 x 25 mL) and brine (25 nL), dried the organic phase over anhydrous MgSO 4 , filtered, and concentrated by rotary evaporation to a solid. Purified by flash chromatography (silica gel, step gradient 5% to 8% to 30 10% MeOH-/CH 2

CI

2 ) to allord the product as a tan solid (72 mg) which was -85% pure (2 main impurities). Dissolved impure product in 1.5 ml.. 1:1 v/v MeCOH/DMSO and purified by RP-CI8 HPI..C (Waters Prep L-C, 40mm Module with Nova Pak HR Cis 6pm 40xOOnn Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H20/AcCN to 25:75 0.1% TFA in H 2 O/AcCN, then 10 min to 100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation 35 (water bath 354C) to a small volume, partitioned between 20% iPrOll/CHC 3 (50 mL) and sat'd aq NalHC0 3 (15 mL), separated layers, dried the organic extract over anhydrous MgSO 4 , filtered, and 339 concentrated by rotary evaporation to afford the title compound as a white solid (34.5 ing, 19%). 'H NMR (400 MI-z, DMSO-D6) 8 ppm 0.83 (d, J=6.72 Hz, 6 H) 0.86 (d, 1=6.72 Hz, 6 H) 1.29 - 1.47 (mn, 5 H) 1.65 - 2.01 (in, 12 H) 2.04 - 2.21 (in, 4 H) 3.53 (s, 6 H) 3.72 - 3.84 (in, 4 H) 4.04 (t, J=8.40 Hz, 2 H) 5.04 (dd, J=6.89, 3.20 Hz, 2 H) 7.23 - 7.40 (m, 10 H) 7.51 - 7.72 (m, 6 H) 11.84 (s, 2 H); MS 5 (ESI+) m/z 965 (M+-1)*. Examples 220-308 were prepared in analogous fashion according to the methods and conditions illustrated in the foregoing schemes and examples. NH HN I \ Example 220 10 methyl ((2S)-I-[(2S)-2-(5-[(2R,5R)-I-(4-tert-butylphenyl)-5-{2-[(2S)-I-((2S)-2 [(iethoxycarbonyl)aminol-3,3-dimethylbutanoyl pyrrolidin-2-yl]-lH-benzimidazol-5-yl pyrrolidin 2-yl|-I H-benziimidazol-2-yl )pyrrolidin-1-yll-3,3-diimethyl-i-oxobutan-2-yiIcarbamnate 'H NMR (400 MHz, DMSO-d6) 8 ppm 0.88 (d, 1=13.55 Hz, 18 H), 1.07 (s, 9 H), 1.62 - 1.78 (in, 2 H), 1.91 - 2.09 (in, 4 H), 2.10 - 2.26 (in, 4 H), 2.54 - 2.62 (in, 2 H), 3.55 (s, 6 H), 3.74 - 3.90 (in, 4 H), 15 4.23 (dd, 1=8.78, 4.55 Hz, 2 H), 5.09 - 5.23 (in, 2 H), 5.31 - 5.43 (m, 2 H), 6.26 (d, 1=8.89 Hz, 2 H), 6.84 -6.97 (im, 2 H), 7.06 (dd, J=8.29, 2.55 Hz, 2 1-1), 7.12 (t, J=9.43 Hz, 2 H), 7.20 (s, I H), 7.30 (s, I H-), 7.38 (d, 1=8.24 Hz, I H) 7.45 (d, 1=8.24 Hz, 1 H1), 12.02 (s, 2 H); MS (ESI+) n/z 916 (M+H)*. O Example 221 20 dimethyl ([(2R,5 R)-i -(4-tert-hutylphenyl)pyrrolidinc-2,5-diyl]his{ I H-bcnzimidazole-5,2 diyl(2S)pyrrolidinc-2, 1-diyl[(2R)-1 -oxo-2-phenylpropane-1,2-diyl]})biscarbaimate 'H NMR (400 MHz, DMSO-d6) 8 ppm 1.03 - 1.10 (m, 9 H), 1.49 - 1.58 (m, 2 H), 1.67 (d, J=16.70 Slz, 6 1-1), 1.70 - 1.95 (i, 4 H-), 2.04 (s, 3 1H1), 2.35 - 2.43 (m, 1 11), 2.97 - 3.11 (in, 2 H-), 3.22 - 3.29 (in, 1 H-), 3.50 (s, 6 11), 3.61 - 3.91 (i, 1 1-), 5.08 - 5.22 (m, 2 H1), 5.29 - 5.49 (m, 2 HI), 6.21 - 6.39 (im, 2 340 H), 6.84 - 6.99 (i, 2 H), 7.07 - 7.50 (in, 17 H), 7.53 (d, J=8.24 Hz, I H), 7.61 (s, 2 H), 12.10 (two s, 2 -); MS (ES1+) m/z 984 (M+H)*. N 5 N+ NExample 222 (2R,2'R)-1,1'-{ [(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyllbis[ I H-benzimidazole-5,2 diyl(2S)pyrrolidine-2, I -diyl1}bis(2-aimino-2-phenylpropan- 1-one) 'H NMR (400 MFiz, DMSO-d6) 6 ppm 1.10 (s, 9 H), 1.55 - 1.66 (n, 3 H), 1.68 - 1.82 (i, 4 H), 1.83 2.02 (in, 5 H), 1.93 (s, 6 H), 2.12 - 2.31 (m, 3 H), 2.57 (d, 1=3.90 Hz, 2 H), 5.26 - 5.36 (im, 2 H1), 5.41 10 - 5.57 (in, 2 H), 6.30 (d, J=8.78 Hz, 2 H), 6.93 (d, J=8.78 Hz, 2 H), 7.17 - 7.31 (in, 2 H), 7.38 (s, 2 H), 7.47 - 7.66 (i, 13 1-1), 8.43 (s, 6 H); MS (ESI+) n/z 868 (M+H)*. HO NN $ ',NH -O NNK r' OH 0 0- -o Example 223 methyl ((2S,3R)- I-[(2S,4S)-2-(5-[(2R,5R)-I-(4-tert-butylphenyl)-5-(2-((2S,4S)-4-hydroxy-1-[N 15 (miethoxycarbonyl)-O-iethyl-L-ihrconyllpyrrolidin-2-yI}-lH-benziiiiidazol-5-yl)pyrrolidin-2-yl]-IH benziimidazol-2-yl )-4-hydroxypyrrolidin-1-yll-3-iethoxy-I-oxobutan-2-yl)carbamate 'I H NMR (400 MI1z, DMSO-d6) 6 ppm 0.96 (d, 1=5.96 I1z, 6 H-), 1.09 (s, 9 11), 1.74 (d, 1=5.64 H z, 2 H), 2.06 -2.15 (i, 3 H), 2.96 - 3.03 (n, 1 H), 3.10 (s, 6 H), 3.55 (s, 6 H), 3.72 (dd, .1=9.65, 2.39 Hz, 3 H), 3.94 (dd, .1=10.25, 4.72 Hz, 2 H), 4.23 - 4.33 (in, 2 H), 4.38 (t, J=7.10 Hz, I H), 4.44 - 4.53 (i, 2 20 H), 5.26 (dd, J=8.46, 4.23 Hz, 2 H), 5.49 (d, 1=5.53 Hz, 2 1-1), 6.25 (d, 1=8.78 Hz, 2 H), 6.94 (d, J=8.78 Hz, 2 H), 7.22 (d, J=8.46 Hz, 2 H), 7.37 (d, 1=7.59 Hz, 2 H), 7.46 (s, 2 Fl), 7.69 (d, J=7.92 Hz, 2 H); MS (ESI+) nz 952 (M+H)*. 341 N-C)H HN-- = sNH 0 Example 224 methyl {(2S)-I-[(2S)-2-(6-((2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3 methylbutanoyl}pyrrolidin-2-yll-1 H-benzimidazol-5-yl}-1-[4-(1-methoxy-2-nethylpropan-2 yl)phenyllpyrrolidin-2-yl }- I H-benzimidazol-2-yl)pyrrolidin-I-yl]-3-methyl-I-oxobutaii-2 5 y I carbamate 1-1 NMR (400 MHz, DMSO-D6) 6 ppm 0.74 - 0.93 (in, 12 H) 1.04 (s, 6 H) 1.69 (d, J=4.34 Hz, 2 H) 1.85 - 1.94 (in, 2 H) 1.95 - 2.03 (in, 6 H) 2.13 - 2.25 (in, 2 H) 2.53 - 2.63 (In, 4 H) 3.11 (s, 3 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 4.05 - 4.15 (i, 2 H) 5.09 - 5.19 (in, 2 11) 5.32 - 5.41 (in, 2 H) 6.25 (d, J=8.78 Hz, 2 H-) 6.87 (ddd, J=8.89, 4.77, 4.55 H z, 2 H-) 7.07 (t, J=7.37 Iz, 2 H1) 7.20 (s, 1 H-) 7.25 - 7.33 (in, 3 11) 10 7.38 (d, J=8.24 l z, 1 H1) 7.46 (d, J=8.46 Iz, 1 11) 12.00 - 12.09 (i, 2 1I); MS ESI+ 918. OH HNN \Exaiple 225 methyl {(2S)-1-[(2S)-2-{6-I(2R,5R)-I-[4-(I-hydroxy-2-methylpropan-2-yl)phenyl]-5-{2-[(2S)-I {(2S)-2-[(methoxycarbonyl)aiino]-3-eicthylbutanoyl}pyrrolidin-2-yl]-lH-benziimidazol-5 15 yl}pyrrolidin-2-yl]-IH-benziiidazol-2-yl)pyrrolidin-1-yl]-3-imethyl-1-oxobutan-2-yl carbaimate 1H NMR (400 MHz, DMSO-D6) d ppm 0.76 - 0.91 (in, 12 H) 1.01 (d, J=2.60 1z, 6 H) 1.64 - 1.72 (in, 2 IH) 1.91 (dd, .1=14.42, 6.83 Iz, 2 1-1) 1.95 - 2.05 (in, 4 11) 2.14 - 2.23 (m, 4 1-1) 2.54 - 2.60 (in, 2 1-1) 3.53 (s, 6 H) 3.76 - 3.87 (m, 4 H) 4.11 (q, J=4.77 Hz, 4 H) 4.42 (s, 1 1-1) 5.09 - 5.17 (m, 2 H) 5.31 5.40 (m, 2 H) 6.25 (d, J=8.78 l z, 2 H) 6.83 - 6.92 (i, 2 H) 7.07 (t, J=7.21 Hz, 2 H) 7.20 (s, I H) 7.26 20 - 7.32 (in, 3 H) 7.38 (d, J=8.13 Hz, I I) 7.46 (d, J=8.35 Hz, I H) 11.99 - 12.06 (mn, 2 H); MS ESI+ i/z 904.5 (M+i)+. 342 F F F -- N S? HNN H NH oo 'Example 226 methyl {(2S)-I-[(2S)-2-{6-1(2R,5 R)-5-{2-1(2S)--f{(2S)-2-[(methoxycarbonyl)aimino-3 imihylbutaiioyl }pyrrolidin-2-yI]-I H-bcnzinidazol-5-yl}-I-{2-[4-(trifluoroimethyl)phenyl]-1,3 thiazol-5-ylIpyrrolidin-2-yi]- IH-benziimidazol-2-yl)pyrrolidin-1-yl]-3-imeihyl-l -oxobulan-2 5 yl carbamiate I II NMR (400 MIlz, DMSO-D6) d ppm 0.73 - 0.91 (i, 12 H1) 1.79 - 1.95 (in, 4 11) 1.96 - 2.06 (in, 4 H-) 2.15 - 2.27 (in, 2 H) 2.69 - 2.76 (m, 2 H) 3.43 - 3.50 (m, 2 11) 3.53 (s, 6 HI) 3.78 - 3.88 (in, 4 H) 4.01 - 4.10 (i, 2 H) 5.11 - 5.18 (m, 2 H-) 5.32 - 5.41 (m, 2 H) 6.43 (s, I H) 7.09 - 7.18 (i, 2 H) 7.27 (dd, J=8.24, 2.39 Hz, 2 11) 7.35 (s, 1 H-) 7.41 - 7.46 (m, 2 1) 7.51 (d, J=8.35 Hz, 1 H) 7.57 - 7.62 (m, 2 10 H) 7.64 - 7.70 (in, 2 H) 12.12 (s, 2 H); MS FSI+ i/i. 983.4 (M+H)+. HN Q NH Example 227 methyl {(2S)-I-I(2S)-2-{6-[(2R,5R)-I-(4-tert-butyl-2,6-diniethylphenyl)-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)aminol-3-iethylbutanoyl pyrrolidin-2-yll-1 H-benzimidazol-5-yl pyrrolidin-2 15 ylJ-I H -henziiidazol-2-yl pyrrolidin-I-ylJ-3-inethyl-I-oxobutan-2-yl carbainate Ii NMR (400 MIHz, DMSO-D6) d ppm 0.77 -0.89 (m, 121-1) 1.02(s, 9 H) 1.84-2.05 (im, 101-H)2.13 - 2.19 (in, 4 11) 2.24 - 2.30 (i, 6 H-) 3.53 (s, 6 1-) 3.80 (s, 4 11) 4.04 (t, J=8.08 Iz, 2 1) 5.07 - 5.14 (in, 2 H-1) 5.25 (s, 2 H1) 6.61 (dd, J=5.10, 2.71 Iz, 2 II) 7.06 (dd, J= 11.87, 8.51 Iz, 2 II) 7.20 - 7.37 (in, 6 H) 11.89 (s, 1 H) 11.99 (s, I H); MS ESI+ n/z 916.6 (M+11)+. 20 343 H / 0Example 228 methyl {(2S)-I -[(2S)-2-{6-[(2R,5R)-5-(2-[(2S)-I-((2S)-2-[(methoxycarbonyl)aninol-3 imethylbutanoyl)pyrrolidin-2-yll-l H-benzimidazol-5-yl)- I-(4-phenylcyclohexyl)pyrrolidin-2-yll-l H henzimidazol-2-yl}pyrrolidin-1-ylJ-3-methyl-I-oxobutan-2-yl}carbamate 5 IH NMR (400 MHz, DMSO-D6) d ppm 0.78 -0.93 (in, 12 H) 1.15 - 1.44 (111, 4 H-1) 1.46 - 1.59 (m, 2 H) 1.67 - 1.78 (in, 2 H) 1.84 - 1.96 (m, 4 H) 1.98 - 2.10 (m, 4 H) 2.14 - 2.27 (in, 4 H) 2.67 - 2.75 (m, 2 H) 3.07 - 3.21 (in, I H) 3.45 - 3.52 (in, I H) 3.54 (s, 6 H) 3.78 - 3.91 (in, 4 H) 4.03 - 4.13 (mn, 2 H) 4.64 - 4.73 (in, 2 H) 5.17 (d, J=4.88 H z, 2 H) 7.00 - 7.06 (i, 2 1-1) 7.09 (t, J=7.32 Hz, 2 H) 7.14 - 7.24 (in, 3 11) 7.30 (d, J=8.46 Hlz, 2 H) 7.38 (d, J=8.02 lz, I H) 7.43 - 7.50 (m, 3 H-) 12.00 (s, 2 H1); MS 10 ESLD+ m/z 914. HNN H O ONH 0 \Example 229 methyl {(2S)-I -[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-((2S)-2-[(imethoxycarbonyl)amino]-3 methylbutanoyl }pyrrolidin-2-yl]- H-henzinidazol-5-yl }- -[4-(tctrahydro-2H -pyran-4 15 yl)phenyl]pyrrolidin-2-yl}-IH-benziimidazol-2-yI)pyrrolidin-1-yl]-3-imethyl-1-oxobutan-2 yl)carbainate I- NMR (400 MHz, DMSO-D6) d ppm 0.73 - 0.94 (m, 12 H) 1.41 - 1.60 (m, 6 H) 1.65 - 1.75 (in, 2 H) 1.86 - 1.94 (m, 2 H) 1.95 - 2.05 (m, 4 H) 2.14 - 2.24 (in, 4 H) 2.37 - 2.46 (in, 2 H) 3.53 (s, 6 H) 3.77 - 3.86 (in, 7 H) 4.02 - 4.10 (in, 2 H) 5.09 - 5.17 (in, 2 H) 5.32 - 5.39 (in, 2 H) 6.26 (d, J=8.67 Hz, 20 2 H) 6.72 - 6.81 (i, 2 H) 7.06 (t, J=7.64 Hz, 2 H) 7.20 (s, I I-I) 7.26 - 7.31 (in, 3 H) 7.37 (d, J=8.13 Hz, I 11) 7.45 (d, J=8.13 Hz, I H) 12.00 - 12.05 (in, 2 H); MS ESLD+ i/z 917 (M+H)+. 344 HNN 0 Example 230 methyl 1(2S)-I -[(2S,4S)-2-{6-[(2R,5R)-l -(4-tert-butylphenyl)-5-{2-[(2S,4S)-4-hydroxy-1-{(2S)-2 [(icthoxycarbonyl)amino]-3-mcthylhutanoyl pyrrolidin-2-yl]-l H-hcnzimidazol-5-yl}pyrrolidin-2 yl]-l H-hcnziimidazol-2-yl}-4-hydroxypyrrolidin-1-yl]-3-mcthyl-l-oxohutan-2-yl}carbaniate 5 1 H NMR (500 MHz, DMSO-D6) d ppm 0.67 - 0.91 (m, 12 H) 1.07 (s, 9 H) 1.69 (d, J=3.97 Hz, 2 H-) 1.78 - 1.89 (m, 2 H) 2.01 (d, J=13.12 Hz, 2 H) 2.37 - 2.44 (in, 2 H) 3.53 (s, 6 H-1) 3.67 (d, J=10.07 Hz, 2 H-) 3.95 - 4.07 (m. 4 H-) 4.38 (s, 2 11) 5.12 (s, 2 If) 5.37 (s, 2 H) 6.25 (d, J=8.54 Iz, 2 H) 6.34 (s, 2 H) 6.86 - 6.94 (i, 2 H) 7.09 (d, J=7.93 Hz, 2 H) 7.22 - 7.33 (i, 4 H) 7.39 - 7.51 (m, 2 H) 12.27 (d, J=21.05 Hz, 2 H); MS ESLD+ m/z 920. 10 0--\ H _NH o Example 231 methyl {(2S)-I-[(2S)-2-{6-[(2R,5R)-1-(1,3-benzodioxol-5-yl)-5-{2-[(2S)-1-((2S)-2 [(methoxycarbonyl)anino]-3-methylbutanoyl }pyrrolidin-2-yl]- H -benzimidazol-5-ylpyrrolidin-2 yll-I H-benzinidazol-2-yl} pyrrolidin-I -yll-3-methyl-I -oxobutan-2-yl }carbamate 15 1l1 NM R (400 MHz, DMSO-D6) d ppm 0.78 - 0.91 (m, 12 H) 1.64 - 1.72 (m, 2 H) 1.86 - 2.04 (in, 6 H) 2.14 - 2.24 (in, 4 H) 3.29 (s, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.05 - 4.11 (m, 2 H) 5.10 - 5.18 (In, 2 H) 5.29 - 5.36 (m, 2 1-) 5.66 (d, J=2.93 -l7, 1 H) 5.70 - 5.75 (m, 2 H) 5.99 (d, J=2.28 lHlz, I H) 6.45 6.51 (m, I H) 7.02 - 7.09 (m, 2 H) 7.21 (s, 1 11) 7.28 (s, 1 H) 7.31 (d, J=6.40 Iz, 2 H) 7.37 (d, J=8.13 i z, I H) 7.45 (d, J=8.24 H z, 1 11) 12.03 (s, 2 11); MS TFA+ m/z 876.8 (M+H)+. 20 345 0 >NH H N /-'o - Examplc 232 methyl {(2S)-I -[(2S)-2-(6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-t(methoxycarbonyl)unino]-3 methylbutanoyl pyrrolidin-2-yl]-11 -benzimidazol-5-yl}-1-(4-{[(4S)-2-oxo-I,3-oxazolidin-4 yl]methyl}phenyl)pyrrolidin-2-yl]-1i H-benziinidazol-2-yl pyrrolidin-I-yl]-3-inethyl-1-oxobutan-2 5 yl carbamate 11- NM R (400 MHz, DMSO-D6) d ppm 0.77 - 0.92 (im, 12 H) 1.63 - 1.74 (m, 2 H) 1.86 - 2.04 (m, 6 H) 2.13 - 2.26 (in, 4 H) 2.55 - 2.65 (i, 2 H) 3.25 - 3.33 (in, 2 H) 3.54 (s, 6 H-) 3.75 - 3.87 (in, 6 F) 4.05 - 4.17 (m, 3 H) 5.09 - 5.19 (im, 2 H) 5.36 (d, J=5.10 Hiz, 2 H) 6.27 (d, J=8.57 Hz, 2 1-1) 6.71 - 6.79 (in, 2 1-) 7.05 (I, J=9.60 Hz, 2 1-1) 7.20 (s, I H) 7.27 - 7.33 (m, 3 H) 7.37 (d, J=8.24 Hz, 1 -1) 7.45 (d, 10 J=8.13 Hz, I H) 7.63 (s, 1 1-1) 12.03 (s, 2 H); MS ESI+ in/z 931.5 (M+H)+. HN N 0 Example 233 methyl 1(2S)-I-[(2S)-2-(6-{(2R,5R)-5-12-1(2S)-I-{(2S)-2-[(methoxycarhonyl)amhino]-3 iiethylbutanoyl} pyrrolidin-2-yI]--1 H-benzimicazol-5-yI}-1-[4-(propan-2-yloxy)phenyl]pyrrolidin-2 15 yI)- IH-beizimidazol-2-yl)pyrrolidin- I-yl]-3-imehyl-i-oxobutan-2-yIlcarbaimate IlH NMR (400 MlHz, DMSO-D6)dppm0.76 -0.89 (in, 12 H) 1.07 (t, J=5.42 Hz,6H) 1.68 (d, J=3.47 H z, 2 H) 1.85 - 2.05 (in, 6 H) 2.14 - 2.25 (in, 4 H) 2.58 (d, J=4.77 H z, 2 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 4.05 (t, J=8.40 Hz, 2 H) 4.13 - 4.25 (m, 1 H) 5.08 - 5.20 (in, 2 1-1) 5.32 (d, J=5.31 Hz, 2 H) 6.23 (d, 1=9.00 Hz, 2 H) 6.45 - 6.55 (m1, 2 H) 7.05 (t, J=8.19 Hz, 2 H) 7.20 (s, I H) 7.26 - 7.33 (m, 3 H) 7.37 20 (d, J=8.24 Iz, I H) 7.44 (d, J=8.35 Hz, 1 -1) 12.02 (d, J=4.55 Hz, 2 H); MS ESI+ nz 890.4 (M+H)+. 346 HNNH 0 Example 234 methyl 1(2S)-I-[(2S)-2-{5-[(2R,5R)-I-[2-(4-fluorophenyl)-1,3-thiazol-5-yl]-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)aininol-3-imethylbutanoyl } pyrrolidin-2-yIl-I H-benzimidazol-5-ylpyrrolidiii-2 yIl-I H-benziimidazol-2-yl Ipyrrolidin-1-yIl-3-iethyl-I -oxobutan-2-yllcarbamate 5 1-I NM R (400 MI-z, DMSO-D6) d ppm 0.75 - 0.85 (i, 12 H) 1.77 - 1.83 (m, 2 H) 1.87 - 1.93 (in, 2 H) 1.95 - 2.06 (in, 4 H) 2.14 - 2.25 (i, 6 H) 3.53 (s, 6 H) 3.77 - 3.86 (i, 4 1) 4.03 - 4.10 (im, 2 H) 5.12 - 5.18 (m, 2 H) 5.28 - 5.35 (i, 2 H) 7.06 - 7.16 (m, 5 H) 7.28 (dd, J=8.29, 2.01 Hz, 2 H) 7.33 (s, I H) 7.40 - 7.45 (in, 2 H) 7.47 -7.55 (m, 3 H) 12.10 (s, 2 H); MS ESI+ imz 933.4 (M+H)+. F HN NH 10 0 Fxample 235 methyl {(2S)-I-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-I-{(2S)-2-[(imethoxycarbonyl)amino]-3 nethyIbutanoyl}pyrrolidin-2-yl]-I H-benzinidazol-5-yi}-1-[4-(trifluoromethoxy)phenyllpyrrolidin-2 yI}-I H-benziiidazol-2-yl)pyrrolidin-1-yl]-3-imethyl-I-oxobutan-2-yl)carbanate I II NM R (400 MI1z, DMSO-D6) d ppm 0.74 - 0.87 (in, 12 H-) 1.67 - 1.76 (in, 2 11) 1.86 - 1.92 (in, 2 15 H) 1.96 - 2.06 (in, 4 H) 2.15 - 2.23 (in, 6 H) 3.53 (s, 6 11) 3.77 - 3.88 (m, 4 H) 4.05 (t, J=8.84 Hz, 2 H) 5.12 (t, J=7.05 Hz, 2 H) 5.37 - 5.46 (m, 2 H) 6.34 (d, J=9.11 H z, 2 H) 6.89 (q, J=7.30 H z, 2 H) 7.02 7.11 (m, 2 H) 7.21 (s, I H) 7.26 - 7.33 (i, 3 H) 7.39 (d, J=8.35 Hz, I H) 7.47 (d, J=8.13 Hz, I H) 12.06 (d, J=17.02 H z, 2 H); MS ESI+ n/z 916.4 (M+H)+. 347 HNJ - 0 NH 0 Example 236 methyl {(2S)-I -[(2S,4S)-2-(5-[(2R,5R)- I-(4-tert-butylphenyl)-5-{2-[(2S,4S)-4-methoxy-1-{ (2S)-2 [(nethoxycarbonyl)aninol-3-methylbutanoyl} pyrrolidin-2-yll- 1 H-benzimidazol-5-yl pyrrolidin-2 yll-I H-benzimidazol-2-yl }-4-methoxypyrrolidin-1 -ylJ-3-methyl-I-oxobutan-2-yl carbamate 5 11H NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.88 (m1, 12 H) 1.07 (s, 9 H) 1.67 - 1.76 (m, 2 H) 1.88 - 2.00 (i, 4 H) 2.06 - 2.16.(i, 2 H1) 3.12 - 3.21 (m, 2 H) 3.25 (d, J=4.23 Hz, 6 H) 3.54 (s, 6 H) 3.59 3.69 (m, 2 H) 4.02 - 4.13 (i, 4 1-1) 4.16 - 4.28 (m11, 2 1-) 5.11 (id, J=9.38, 6.51 Hz, 2 H) 5.35 (t, J=5.37 Hz, 2 H) 6.23 - 6.28 (in, 2 H) 6.90 (d, J=8.89 Hz, 2 H) 7.06 (d, J=10. 19 Hz, 2 H) 7.22 (d, J=3.25 Hz, I Hl) 7.25 - 7.32 (m, 3 H) 7.38 (d, J=8.35 lz, I 1-i) 7.45 (d, J=8.24 lz, 1 1-) 11.79 (d, J=18.32 lz, 2 Ii); 10 MS ESI+ m/z 948.5 (M+H)+. F F F F F N N HN ±/ 0 Example 237 methyl [(2S)-I-[(2S)-2-{5-[(2R,5R)-I-[2,5-difluoro-4-(trifluoronethyl)phenyll-5-{2-[(2S)-I-((2S)-2 15 [(imethoxycarbonyl)aninol-3-methylhutanoyl pyrrolidin-2-yl]-I H-benzimidazol-5-yl } pyrrolidin-2 yl]-l i-benziimidazol-2-yl pyrrolidin- I -ylJ-3-methyl-l -oxohutan-2-ylIcarbamate 1H-1 NMR (400 MHz, DMSO-D6) d ppm 0.74 - 0.90 (m, 12 H) 1.74 - 1.83 (m, 2 H) 1.86 - 1.93 (in, 2 11) 1.94 - 2.05 (m, 4 11) 2.13 - 2.25 (im, 4 H-) 3.44 - 3.48 (i, 2 H-) 3.53 (s, 6 1I) 3.77 - 3.88 (mn, 4 1-1) 4.06 (t, J=4.23 Hz, 2 H) 5.10 - 5.16 (m, 2 H) 5.63 - 5.74 (i, 2 11) 6.60 - 6.73 (m, I H) 7.04 - 7.20 (i, 20 4 H) 7.24 - 7.31 (in, 3 1-1) 7.38 (d, J=8.46 Hz, I H) 7.46 (d, J=8.13 Hz, I H) 12.08 (d, J=27.11 I Hz, 2 H); MS ESI+ m/z 936.4 (M+H)+. 348 FF F H"H NN HN NH 0 Example 238 methyl {(2S)-I-[(2S)-2-16-[(2R,5R)-1-f3-fluoro-4-(trifluoromethyl)phenyll-5-{2-((2S)-I-{(2S)-2 |(nethoxycarbonyl)aiminol-3-nethylbutanoylipyrrolidin-2-yll-1 H-henzinidazol-5-ylpyrrolidin-2 yl]-l -- hcnzimidazol-2-yl)pyrrolidin-1-yl]-3-imethyl-1-oxohutan-2-yl)carbamate 5 IH NM R (400 MHz, DMSO-D6) d ppm 0.75 - 0.90 (in, 12 H) 1.71 - 1.79 (in, 2 H) 1.87 - 1.95 (in, 2 H) 1.97 - 2.04 (m, 4 H) 2.13 - 2.25 (in, 6 H) 3.53 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.04 - 4.11 (in, 2 H) 5.11 - 5.18 (m, 2 H) 5.46 - 5.56 (in, 2 H) 6.24 (dd, J=8.24, 2.39 iz, 2 H) 7.04 - 7.11 (in, 2 H) 7.19 7.25 (m, 2 II) 7.28 (dd, J=8.46, 3.69 Iz, 2 H-) 7.32 (s, 1 H-) 7.41 (d, J=8.13 iz, 1 11) 7.49 (d, J=8.24 Hz, I H) 12.09 (dd, J=15.72, 2.17 Hz, 2 H); MS ESI+ nz 918.4 (M+H)+. 10 N H O- O NH example 239 methyl 1(2S)-I -[(2S)-2-{6-[(2R,5R)-I-(4-cyanophenyl)-5-{2-[(2S)I-t(2S)-2 [(methoxycarbonyl)ainiio]-3-methylbutaiioyl}pyrrolidin-2-yl]-1 --benzinidazol-5-ylpyrrolidin-2 15 yI]-I1 -benzinidazol-2-ylpyrrolidin- I-ylj-3-nethyl-1-oxobutan-2-ylIcarbaimate III NMR (400 MHz, DMSO-D6) d ppm 0.76- 0.90(m, 12 H-) 1.70- 1.79 (m, 2 II) 1.90 (dd, J=12.25, 6.40 -Iz, 2 H1) 1.95 - 2.02 (in, 4 H) 2.15 - 2.24 (in, 6 H) 3.54 (s, 6 H) 3.78 - 3.85 (in, 4 H) 4.06 (t, J=8.29 Hz, 2 H) 5.10 - 5.16 (i, 2 H) 5.46 - 5.55 (m, 2 H) 6.42 (d, J=8.67 Hz, 2 H) 7.05 (dd, J=12.90, 8.57 Hz, 2 1-1) 7.22 (s, I H) 7.25 - 7.34 (in, 5 H) 7.40 (d, J=8.24 Hz, 1 H) 7.47 (d, J=8.24 H-z, 1 H) 20 12.09 (s, 2 1-1); MS ESI+ m/z 857.4 (M+H)+. 349 N /N N H N~ H" oNH o Example 240 methyl ((2S)-I-[(2S)-2-{6-[(2R,5R)-I-[4-(2-cyanopropan-2-yl)phenyll-5-(2-[(2S)-I-{(2S)-2 ((methoxycarbonyl)aninol-3-methylbutanoyl pyrrolidin-2-yl]-1 H -benzimnidazol-5-yl}pyrrolidin-2 yl]-I H-benzi imidazol-2-yl }pyrrolidin- I -yl]-3-methyl- l -oxohutan-2-ylIcarbanate 5 I- NM R (400 MHz, DMSO-D6) d ppm 0.75 - 0.91 (in, 12 H) 1.47 (s, 6 H) 1.67 - 1.76 (m11, 2 H) 1.85 - 1.95 (in, 2 H) 1.96 - 2.03 (m, 4 H) 2.15 - 2.24 (in, 6 H) 3.53 (s, 6 H) 3.77 - 3.85 (in, 4 H) 4.05 (t, J=8.46 I-z, 2 H) 5.10 - 5.17 (n, 2 H) 5.37 - 5.45 (m, 2 H) 6.34 (d, J=8.89 Hz, 2 H) 6.97 - 7.04 (i, 2 H) 7.07 (t, J=8.35 Hz, 2 H4) 7.21 (s, I H) 7.28 (d, J=10.52 Hz, 3 H) 7.39 (d, J=8.13 Hz, I H) 7.47 (d, J=8.24 Hz, I H) 12.05 (d, J=13.01 Hz, 2 H); MS ESI+ m/z 899.4 (M+H)+. 10 F 1"O "o Example 241 meihyl ((2S)-I-[(2S)-2-{6-[(2R,5R)-I-(4-cyano-3-fluorophenyl)-5-{2-[(2S)-I -{(2S)-2 [(methoxycarbonyl)amino]-3-iethylbutanoyl I pyrrolidin-2-yl] -11H-benzimidazol-5 -y I }pyrrolidin-2 yl]-lH 1-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl carbamate 15 111 NMR (400 M Hz, DMSO-D6) d ppm 0.74 -0.92 (m, 12 11) 1.74 (i, J=9.00 Iz, 2 11) 1.87 - 1.94 (in, 2 H) 1.96 - 2.06 (m, 4 H) 2.15 - 2.25 (in, 4 H) 2.55 - 2.63 (in, 2 H) 3.54 (s, 6 1-1) 3.82 (s, 4 H) 4.06 (t, J=8.40 Hz, 2 H) 5.14 (d, J=2.28 Hz, 2 H) 5.55 (dd, J=16.26, 6.07 Hz, 2 H) 6.18 - 6.33 (in, 2 H) 7.01 7.15 (in, 2 H) 7.23 (s, 1 1-1) 7.25 - 7.35 (in, 4 H) 7.42 (d, J=7.70 Hz, I 1-1) 7.49 (d, J=8.46 -Iz, I H) 12.10 (s, 2 11); MS ESI+ i/z 875.4 (M+H-)+. 20 350 o F 0 Example 242 methyl { (2S)- I-[(2S)-2- {6-[(2R,5R)- I-(2,2-difluoro-1I,3-benzodioxol-5-yl)-5-{2-[(2S)-I- { (2S)-2 [(miethoxycarbonyl)amninol-3-methylbutanoyl ) pyrrolidin-2-yll -1 H -benzimnidazol-5-yl ) pyrrolidin-2 yll1-l H -benzimnidazol-2-yIlIpyrrolidin- I -yll -3-methyl-i1-oxobutan-2-yl ]carbamate 5 IH NM R (400 M Hz, DMSO-D6) d ppm 0.75 -0.91 (mi, 12 HI) 1.69 - 1.77 (in, 2 H) 1.91 (dd, J=14.26, 6.67 H z, 2 H ) 1.96 - 2.07 (mn, 4 H) 2.14 -2.24 (mn, 4 H- ) 2.54 - 2.60 (in, 2 H ) 3.53 (s, 6 H ) 3.78 - 3.86 (mn, 4 H ) 4.06 (i, J=8.40 H-lz, 2 [) 5.10 -5.1l7 (mn, 2 H ) 5.36 -5.44 (mn, 2 H ) 6.05 (dd, J=9.1 I, 2.17 H z, I H) 6.29 (d, J=2.60 Hz, I H) 6.89 - 6.95 (im, 1 H) 7.06 (t, J=8.51 H z, 2 H) 7.22 (s, I H) 7.26 - 7.33 (im, 3 H-) 7.39 (d, J=8.35 Hiz, I H) 7.47 (d, J=7.59 H-z, I H-) 12.03 - 12.09 (im, 2 HI); MS ESL+ nVz 10 912.8 (M+I1)+

SNH

2 HN H NH 0 Example 243 methyl {(2S)-I-[(2S)-2-{6-[(2R,5R)-I-[4-(I-aiino-2-methylpropan-2-y)phenyl]-5-2-[(2S)--{(2S) 2-[(iethoxycarbonyl)amino]-3-miiethylbutanoyl pyrrolidin-2-yl]-IH-benzimidazol-5-ylIpyrrolidin-2 15 yl]-IH-benziimidazol-2-yl pyrrolidin i-yl]-3-methyl-I-oxobutan-2-ylcarbamate I IH NMR (400 MHz, DMSO-D6) d ppm 0.74 - 0.92 (m, 12 H) 1.01 (d, =5.20 Hz, 6 H ) 1.65 - 1.76 (m6, 2 ) 1.86 - 1.93 (m, 2 H) 1.98 (d, .J=4.01 Hz, 4 H) 2.13 -2.25 (in, 4 H) 2.4 (s, 2 H) 2.53 - 2.61 (in, 2 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 4.05 (t, J=8.35 H z, 2 H) 5.08 -5.17 (mn, 2 H) 5.32 - 5.41 (m, 2 J1H) 6.27 (d, J=8.89 Hz, 2 H) 6.81 - 6.92 (in, 2 H) 7.07 (t, J=7.97 Hz, 2 H) 7.20 (s, 1 H) 7.25 - 7.32 (m, 3 20 H) 7.38 (d, J=8.13 I z, 1 H) 7.46 (d, J=8.13 Hz, I H) 12.02 (d, J=19.63 1z, 2 H); MS ESI+ nVz 903.4 (M+H)+. 35 0 N N 0 Example 244 methyl (2-(4-[(2R,5R)-2-{2-[(2S)-1 -{(2S)-2-1(methoxycarbonyl)aminoJ-3 methylbutanoyl }pyrrolidin-2-yi]-I H -henzi midazol-5-yi}-5-12-[(2S)-I-((2S)-2 [(methoxycarbonyl)aimino]-3-imethylbutanoyl )pyrrolidin-2-yI]-1 H-benzimidazol-6-ylpyrrolidin-1 5 yl]phcnyl }-2-mechylpropyl)carbamnate I II NMR (400 MHz, DMSO-D6) d ppm 0.75 - 0.91 (m, 12 H) 1.00 (d, J=6.07 Hz, 6 H1) 1.64 - 1.75 (m, 2 H) 1.83 - 1.94 (m, 2 H-) 1.96 - 2.05 (m, 4 H1) 2.14 - 2.23 (i, 4 Hl) 2.89 - 3.00 (m, 2 1-1) 3.17 (d, J=5.20 Hz, 2 H-) 3.42 (s, 3 H) 3.53 (s, 6 H) 3.77 - 3.87 (m1, 4 H) 3.99 - 4.07 (m, 2 H) 5.08 - 5.20 (mn, 2 H) 5.32 - 5.42 (m, 2 I) 6.27 (d, J=8.46 H z, 2 H) 6.72 - 6.80 (m, I H) 6.83 - 6.93 (i, 2 H) 7.07 (t, 10 J=8.62 Hz, 2 H) 7.20 (s, 1 H) 7.26 - 7.33 (in, 3 H) 7.38 (d, J=8.13 Hz, I H) 7.45 (d, J=8.57 Hz, 1 H) 12.03 (d, J=12.36 Hz., 2 H ) MS ESI+ nz 961.4 (M+H)+ F -K 15 " Example 245 methyl ((2S)-I-[(2S)-2-(5-[(2R,5R)-I-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-{2-[(2S)-1-{(2S)-2 [(methoxycarbonyl)aminol-3-methylbutanoyl )pyrrolidin-2-yl]-I H -benzimidazol-5-yl}pyrrolidin-2 yl]- I H-benzimidazol-2-yl }pyrrolidin-1-yl]-3-methyl-i-oxobutan-2-yl}carbamate MS (ESI) n/z 934 (M+H-1)* 20 352 0=<~ O>~ f "\ Example 246 methyl { (2S)-I -[(2S)-2-[f5-I(2R,5R)- I-[4-( 1,1-dioxidothiomiorpholin-4-yl)-3-fluorophenyl]-5- 12 I (2S)-I - ((2S)-2-[(miethoxycarbonyl)amiinol-3-methylbutanoyl Ipyrrolidin-2-yl]- IH-benzimiidazol-5 yI Ipyrroiidin.-2-yl]. -I-hcnzinlidazol.2.yl Ipyrrolidini-1I-ylI-3-micthyl- I-oxohutani-2-yI Icarbarnatc 5 MS (ESI) nih 994 (M+A)* 6 F IN- H N N N 0= H HN 0\ Example 247 methyl I (2S)- I-[(2S)-2- {5-[(2R,5R)- I-[3-fluoro-4-(4-nmethylpiperidiin-1I-yl)pheniyll-5-{ 2-[(2S)-lI ((2S)-2-[(Onethoxycarbonyl)amiiinol-3-miethylbutanioyl Ipyrrolidin-2-yI] - 1-I -benzirnidazol-5 10 yl pyrrolidiin-2-yIj-l I I-benzimiidazol-2-yl Ipyrrolidin-1I-ylJ-3-rnethyl-lI-oxobutan-2-yl Icarbainiatc MS (E.S!) nlz 948 (M+H)+ 353 HN N N 0 N 0'r NH NA~ 0 Example 248 methyl I (2S)-1I-I(2S)-2-(6-{ (5R)-5-{ 2-1(2S)-1I-{ (2S)-2-j(imethioxycarhonlyl)ainioj-3 iihylhutanioyl }pyrrolidini-2-yl]- IH-bcnziidazol.5.yl I-I-[4-QIricyclo[3.3. 1.1 -3,7-]dec- 1 yl)pie nylIjpyrro lid in-2-yl I)-I H-benziini dazol -2-yl) pyrrolidin- I -yl]j-3 -neieylI- I -oxobutan-2 5 yiI Icarbamate +ESI m/~z (rel abundance) 967 (100, M+1l1) 0 H 0 0 N Example 249 methyl { (2S)- I-[(2S)-2- (6-[(2R,5R)- I-[4-(azepan- I-yl)-3-fluorophenyll-5-1{2-[(2S)-lI-t (2S)-2 [(niethoxycarbonyl)aminio]-3-miethylbutanoyl Ipyrrol idini-2-yl] -1 H-benzimiidazol-5-yl Ipyrrolidin-2 10 yl] - I l-benziidazol-2-yl Ipyrrolidin-1I-yl]-3-mieihyl i -oxobutani-2-yl Icarbainiale +ESI mlz (rel abundance) 948 (100, M+H) HN /P0 Example 250 354 rncliyl 1(2S,3R)-1I-1(2S)-2- 6-I(2R,5R)- I-(4-teri-butylplieiiyi).5-(2-i (2S)-lI-[N-(metlioxycarhoinyl)-O ietiyl-l..-tiireoniylJpyrroiidini-2-y ) - IH-heinzinlidazol-6.yI)pyrrolidiin-2-y I-I -bI-hczimidazol-2 yI Ipyrrolidin- 1-yI]-3-imehoxy- I-oxobuian-2-yI Icarhamale NIS (EST) mA/ 920 (M+11)+. 5 HN 0 Exunmple 251 methyl ((2S)- I-[(2S)-2- {6-[(2R,5R)- I (4-cyclopropyl.2-fluoropheinyl)-5-1{2-[(2S)- 1- {(2S)-2 [(methoxycarbonyl)arnino]-3-.methylbutainoyl (pyrrolidin-2-yl]- IH-benzinlidazol-6-yl }pyrrolidin-2 10 yI]-Il1i-bcnziiidazol-2-yl Jpyrrolidin-1I-yl] -3-methyl-i -oxobutan-2-yI carbamatee Ims W's]) mr/z 990 (M+li). 00 0 Example 252 methyl [(2S)-1-I (2S)-2-[4-(3- (5-(3-1{2-[(2S)-1I- {(2S)-2-[(nieihoxycarbonyl)aniino]-3 I5 iniethylbutanioyl Ipyrrolidini-2-yI].-Ii-iimidazol-4-yl Ipheiiyl)- I -6-(piperidini- I-yI)pyridiin-3.yIJ- IH pyrrol-2-yl I phenyl)- IH-irnidazol-2-yllpyrrolidin. I-yl } 3-mieihyl- I oxobulan-2-yl]carbamtaie NIS (ESI; MAdl) m/z = 964.5. 355 00 /P : ;-cExamnple 253 methyl { (2S) I -[(2S)-2-1{6-[(2S,5S)-5 ( 2-[(2S)- I -((2S)-2-[(rnethoxycurboniy)anino]-3 nicihylbutanoyl Ipyrrolidini-2-yl] -I H-benizinidazol-6-yl)--14-[(2 methoxyethyl)(methyl)arniino]pheiiyl Ipyrrolidin-2-yI].l H-benizimidazol-2-yl }pyrrolidin-1I-yl]-3 5 mnethyl- I -oxobutaii-2-yl Icarbarnate M S (ES!I M +H-) nilz =919.4 ~~cN 00 HNI-- H \ -c? Examp 25 mehy methyl )I[(2S)-12- (-[(2,5)-5[-( 1-( (2Sylhny)-2-S)2-[(methoxycarbonylbomino]-3 10 nithyl--ttmeoyluaopyrrolidin-2-yI)- IH-benzimidazol-5-yroiJi--I - ti iid - 2 ylpyrliin1yl-3netox--oobtn--356ramt yI)elioxylpheny I pyrrolidiin-2-yl]- I H-benzimidazol-2-y I Ipyrrolidin- I -yi)-3.mnethyl- I -oxohutan-2 ylJcarhaniate MS (ESI; M+H) m/z = 959.6 Q, NH Exmpe 5 ielhyl ((2S)-I-I (2S)-2- {5-[(2R,5R)- I-[3.chloro-4-(piperidin-1I-yI)phenyfl-5- {2-[(2S)- 1- {(2S)-2 [(nmethoxycarboiiyl)amino]-3-niethylbutainoyl pyrrolidin-2-yl] -lIIL-benziidazol-5-yl Ipyrrolidin-2 yl]-llII-benziidazol-2-yI Ipyrrolidini- -yl] -3-mnethyl-lI-oxobutain-2-yI (carbamiate (ES 1+) nih 949.5 (M+H)+ 10 NHN / Example 257 mclhyl ((2S)- I -[2S)-2-(5- ((2R,5R)-5- {2-[(2S)- I- {(2S)-2-[(imncihoxycarbonyl)ainio]-3 inieihylbulanoyl }pyrrolidin-2-yl]- IH-benziinidazol-5-yI 1-1-[4-(piperidin- l-yl)-3 (trifluoronlethyl)phenyllpyrrolidin-2-yI - II-I-bcnizinidazol-2-yl)pyrrolidin-lI-yl]-3-rnethyl- I 15 oxobutan-2-yl Icarbaniate (12S1+) n/z 983.5 (M+H)+ 357 AN /I Example 258 methyl I (2S)-1I-I (2S).2-{ 5-I(2R,5R)- I-[3.cyanio-4-(piperidin-1I-yl)phenyl] -5- (2-[(2S)- 1- {(2S)-2 [(miethoxycarbonyl)aniino]-3-rnethylbutanoyl }pyrrolidini-2.yI] - III-benzimidazol-5-yl Ipyrrolidiin-2 yl]-Il-l-bcnziimidazol-2-yl }pyrroliditn- -yI] -3-miethyl-I -oxobutani-2-yl icarbamniate 5 ES 1+) m/z 940.4 (M+li)+ /N N N H H N / N Example 259 methyl { (2S)- I -(2S)-2- I6-j(2R,5R)- I-(6-ethioxypyridimi-3-yl)-5- I2-[(2S)- I - (2S)-2 [(methioxycarhoinyl)ainio-3-mcithylutaiioyl )pyrrolidini-2-yli. I H -heizimniidaz.ol-6-yl Ipyrrolidin-2 10 yI]-l lH-hcinzij idazol-2-yl )pyrrolidin- I -yl]-3-rncthyl- I -oxobutaii-2-yI }carhamniatc ESI+m/z 878 (M+H)+ N N NH HN /P 0\ Example 260 358 methyl 1(2S)- -t(2S)-2- (6-[(2R,5 R)-5- 2-[(2S)- I-I(2S)-2-I(mnethloxycarhoniyl)ainio]-3 iiiethiylhutanioyl } pyrrolidiin-2-yJ- I H-heinzinidazol-6-yl 1-1t6 [iniethyl(imethiylsulfoniyl)arninolpyridin-3-y }pyrrolidin-2-yl] -I H-beinziiidazol-2-yl }pyrrolidin- -yl] 3-miethyl- I -oxobutan-2-yi Icarbamate 5 ESIi-iuz 940 (M+H)+ 0 N 'N N H > NH HN 0 0 / \ Example 261 2-iiethylpropyl { 5-[(2R,5R)-2,5-bis(2- (2S)- I-[N-(miethoxycarboinyl)-L-valyllpyrrolidiin-2-yl - 11 beilzimidazol-6-yI)pyrrolidini- -yllpyridiin-2-yI I methylcarbainate 10 EST+ml~z 963 (M+H)s N F N 6 / \ Example 262 methyl { (2S)- I-[(2S)-2- (6-[(2R,5R)- I [4-(3,5-dimiethylpiperidin- I-yl)-3-fluoropheniyl]-5-{ 2-[(2S)- 1 I (2S)-2-[(miethoxycarhonyl)aiinio]-3-niethylbutanoyl Ipyrrolidin-2-yI] - I 1-bcnziidazol-6 15 yl I pyrrol idi11-2 -yl] -IH I-benzi nidazol -2-yl Ipyrrol idin- I -yl ]-3-mcthyl- I -oxobutan-2-yl I carba mate ESI+m/~z 962 (M+H)+ 359 N N NN N H ND 0 0

--

O.K NH HN /P\ Example 263 methyl ((2S)- I-[(2S)-2-1I6-1(2R,5 R)- I-[4-(diethylami no)-3.fluorophenyl]-5-{ 2-[(2S)- I-{ (2S)-2 [(miethoxycarhonyl)amino] -3-niethylbutanoyl Ipyrrolidin-2-yl I-I H-beinzimidazo1-6-yl pyrrolidin-2 yl]-l H-benziiinidazol-2-yl Ipyrrolidin- I-yl] -3-miethyl- I-oxohutani-2-yl Icarbamiate 5 ESI+rn/z 922 (M+H)+ ExNl 6 N NHN 0= / \ Example 26 metyl (2S-l-(2)-216-(2R5R)I 60coeyprdi--l--2[2)I(2)2 methyl 1(2S)- I-[(2S)-2- {6-[(2R,5 H)- I-[3-fluoro-4-(pyrrolidin. I -yl)phienylj-5- I2-[(2S)- 1-I (2S)-2 [(ielhoxycarhoinyl)ainio]-3.miethlylbutanioyl }pyrrolidiin-2-y11- I H-henzimidazol-6-yi lpyrrolidinl-2 yl] - H-benziidazol-2-yl I pyrrolidin. I .yI]-3-iinediyl-l1-oxobuiaii-2-yI Icarbaimale ESI+ (ni/z): 919.4 (rn-tH) 5 , joH H O$- O, 6 '\6 Example 266 methyl { (2S)- I-[(2S)-2- I6-I (2R,5R)- I-(4-tert-butylpheniyl)-5- {2-[(2S )- I-I(2S)-2. (miethoxycarhoniyl)aiiiio]-3-methylhutanioyl }pyrrolidini-2-yiJ- iH-inldol-6-yl }pyrrolidini-2-yl]- IH 10 inldoi-2-yI jpyrrolidini-1 -ylJ-3.miethyl- I-oxobutani-2-yI }carhamiate ni/z= 886.5 (LC/MS) HN-N 0-o Examrple 267 methyl { (2S)- I-[(2S)-2- {6-[(2R,5R)- I-(4-teri-buioxy-3-fluoropheiiyl)-5-{ 2-[(2S). -{ (2S)-2 15 [(inethoxycarboniyl)amiino]-3-.methylbutanioyl }pyrrolidin-2-yI]-I H-benizirnidazol-6-yl Ipyrrolidiin-2 yl] -11 -benzinmidazol-2-yI Ipyrrolidini- I-yI].3-m-ethyl-lI-oxobutani-2.yI Icarbamnate (ESI; M-sd1) m/z = 922.4 - N ~c~N N H H

H

00 20 1 -[3-tluoro-4-(propan.-2.yloxy)phicnyl] -5-I 2-[(2S)- 1-I (2S)-2-[(iniethoxycarhoniyl)ainio]-3 iiiethylhutanoyl I pyrrolidiin.2-yIJ- IH-benzimiidaz.ol-6-yl Ipyrrolidin.-2-yl]. I H-heninmidazol-2 yl Ipyrrolidin. I-yIJ-3-ictehyl-l -oxobulan-2-yI Icarbamalc 361 (E.S!, M+H) n/z = 908.5 '0o -1 Example 269 methyl { (2S)- 1-[(2S)-2- j6-[(2R,5R) I -(3-fluoro-4-hydroxyphcnyl)-5.{2.[(2S)-1 -{(2S)-2 5 [(methoxycarbonyl)amino]-3-mechylbutanuyl Ipyrrolidin-2-yI]- I H-benzimiidazol-6-yl Ipyrrolidin-2 yI] - IH-benziimidazol-2-yI Ipyrrolidini-1I-ylI-3-miethyl-lI-oxobutan-2-ylicarbamate (ES 1; MA 1) mnlz = 866.3 I Example 270 10 methyl 1(2S)-I -[(2S)-2- i6-[(2R,5R)- I-(3-tluoro-4-niechoxyphenlyl)-5-j 2-[(2S)-I - t(2S)-2 [(mcmhiloxycarhoiiy)aiinio]-3-miciiylbulainoyl pyrrolidini-2-yl] - IH-bcnzimiidaizol-6-yl Ipyrrolidiii-2 yl]-I H-benii-clazol-2-yl Ipyrrolidini- i-yl]-3-amieihyl- I-oxobutaan-2-vl Icarbamniale (ES I; M+I1I) rnlz = 880 Q NH 15 ? Example 271 mnethyl { (2S)- 1-r(2S)-2- {5-I (2R,5 R)- I-[3,5-difluoro-4-(piperidini- -yI)phcnyll-5- 12-1(2S)-I - f(2S)-2 [(thtloxycarhoinyl)aminlo]-3-nmctlylhutanoyl Ipyrrolidini-2-yl]- IH-hcnizimnidaz.ol-5-yl Ipyrrolidin.-2 yiI-lII--hcnzimniiclazol-2-yI Ipyrrolidini- I-yI].3-inctihyl-lI-oxobuwan-2-yI Icarbamiaic Ili NMR (400 MHz, DMSO-D6) 8 ppm 0.73 - 0.90(in, 12 I-1) 1.32 -2.28 (in, 20 H) 2.76 (s, 41-1) 3.54 20 (s, 6 H) 3.82 (s, 4 1-1) 3.99 -4.12 (iii, 2 H) 5.10 -5.20 (in, 2 H) 5.36 (d, J=7.59 I-lz, 2 I-1) 5.83 -5.95 (in, 362 2 H) 7.01 - 7.14 (mi, 2 H) 7.20 (s, I H) 7.26 -7.33 (mn, 3 H) 7.41 (d, J=8.24 Hz, I H) 7.49 (d, J=8.24 Hz, I H) 12.01 - 12.31 (mi, 2 H); MS (1151; M+H) in~z =951.5. Example 272 5 diinethyl ([(2S,5S)-I -(4-tert-butylplienyl)pyrrolidine-2,5-diyllbis I 1,3-thiazole-4,2 diylcarhamioyl(2S)pyrrolidince-2,1I-diyl[(2S)-3-incthyl- I-oxohutane- 1 ,2-diyl] )hbiscarhainatc FST min/ 909.4 (M4H) H Q Example 273 10 dimethyl ([(2R,5R)- I-(4-tert-buzylphenyl)pyrrolidine-2,5-diyl]bis {I 1,3-thiazole-4,2 diylcarbarnoyl(2S)pyrrolidince-2, I -diyl (2S)-3-iniethyl -lI-oxobutane- 1,2-diyll )biscarbaniate ESI ml?. 908.4 (M+Hf) 0 N --7\ Examiple 274 15 diinethyl ([(2S,5S)-I -(4.tert-butylphenyl)pyrrolidine-2,5-diyljbis I I,3-rhiazole-4,2 diylcarbamnloyl(2S)pyrrolidine-2, I -diyl [(2S)-3,3-dimethyl -1-oxobutane-1I,2-diyl] I )biscarhamate ESI nlz 936.5 (M+H) HQ<N~QHD Example 275 20 dimethyl ([(2S,5S)-I -(4-tert- but ylphnyl)pyrrolidine-2,5 -di yllIbis ( 1,3-thiazole-4,2 diylcarbaiiioyl(2S)pyrrolidinie-2, I -diyll (2S,3R)-3-mnethoxy- 1 -oxohutane- 1,2-diyll I)biscarbaimate ES! n~z 940.5 (M+H) 363 0- 0 Example 276 ditnehyl ([(2R,5R)- I -(4-ceri-bulylphenyl)pyrrolidinc.2,5-diyllhis{ 1 ,3-thiazole-4,2 diylcarbamioyl(2S)pyrrolidinie-2,1I diyl[(2S,3R)-3-rnethoxy. I-oxobutane-1I,2-diyl])I)biscarbamiate ES I rn/z 940.5 (M+H1-) 5 o N Examiple 277 dimiethyl ([(2S,5S)-1I-(4-tert-butylphenyl)pyrrolidine-2,5-diyljbisI ji,3-thiazole-4,2 diylcarbaiinoyl(2S)pyrrolidine-2, I -diyl [(2S,3S)-3-iinethyl- I -oxopenitane-1I,2-diyl] I )biscarbaiinate USI m/z 936.5 (M+H) 10 H H ExEaple 278 dlimethyl ([(2R,5R)- I -(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{I 1,3-ihiazole-4,2 diylcarbamioylh2S)pyrrolidine-2, I -diyi [(2S,3S)-3-incethyl-lI-oxopenitane- I,2-diyl] I)biscarbaiinate ESI nlz 936.5 (M+H) 15 Th XoH NN ( N N'~9Example 279 methyl { (2S)-]I-[(2S)-2- {6- i -(4-tert-butylpheinyl).5-{ 2-[(2S)-1I- {(2S)-2-[(nethoxycarhoniyl)aii in]i 3-miethlyihutainoyl }pyrrolidini-2-yl]-31--im-idain[4,5-h]pyridiin-6-yI Ipyrrol idin.-2-yl]-3H--imiidazo[4,5 blpyriclin-2-yI Ipyrrolidin- I -yI]-3-inelhiyl-l I oxobutan-2-yl Icarbaiaic 20 LCMS m/z 890 (M-s.I-) 364 Example 280 methyl ((2S)- I-[(2S)-2. (6-[(2R,5R). 1-(4-tcnt-butylphcniyl)-5- {2-[(2S)-1I-{ (2S)-2 [(mcthioxycarhoniyl)amiino]-3-mczehylbutanioyl Jpyrrolidini-2-yI]-1I,3-henizoxa7zol-6-yl Ipyrrolidin-2-yIJ I ,3-hcnizoxazol-2-yl Ipy'rmlidini- i-yl]-3-mrmtlhyl- I-oxobutanl-2-yl Icarharnatc 5 ESI+:(M+-1): 890.5 H H NO~Eapl8 /0~~O Example 282 m-iethoy { 2S)-i -[()--l{6--[(,RI -(4-tertbutyl-2uphenyl)-5-(2{ 2)--[(2S)-i- { (2Sron).2. Ivmthycroniiyl In- -beihlbuaoyl }pyrrolidin-2-y] -I-benzimpidaolyI prrolidn2 10 ESI+:(M+H-): 906.4 36 H <~ ~ OH a p~ 8 N H Example 28 4 (S4RI S4R-11-[[(2R)- I -(4-tert-buiylphenyl)pyrrolidine-2,5-diyl]bis[ I 1--benzinidazole-6,2-dy(Sproine diy(2~prroidne2, -diylcarbonyl] bis(7,7-diinczylbnicyclo[22.]hetn2oe MS (ES!) positive ion 902 (M+H)'. 010 Example 28 (I14,'S4R1F- [ [(2 R)- I -(4-tert-butylpheiyl)pyrrolidine-2,5-diyllbis[ I --benzirnidazole-6,2 diyl(2S)pyrrolidine-2, I -diynl] bis(,-diphentylpryco22 han-2-one) 15 ~ ~MS (APC[) positive ion 90 (M+H) oseve N 366 , N _& Example 286 (2S,2'S)- 1, 1'-( [(2R,5 R)- I -(4-tcrt-hutylpheniyi)pyrrolidiinc-2,5-diyI his[!I H-heiizimidazolc-6,2 cliyl(2S)pyrrolidinc-2, 1-dIiyl])bis(3,3,3-Lrifluoro-2-.mctlioxy-2-pheinylpropan.- I-one) MS (ESI) positive ion 1000 (M+H)*. 5 N~4 ?N--VNH N K7~ ~Example 287 [(2R,5 R)- I -(4-terl-butylpheniyl)pyrrolidine-2,5-diyllbis[ I H-benzinmidazole-6,2-diyl(2S)pyrrolidinc 2, 1 -diyl] }bis[( 1-plhcnylcyclopentyl)inielhanonc] MIS (ESI) positive ion 918.6 (M+H)*. 10 J1 xaple28 1,' (R5R-I-4Lrihillcylproiie-,-ilbs[I1lbniNiaoc62 iy(2S,)pyr(-tr-tlidi2,I-iyl])pyrbis( 2,-oeiyl2-phIIeniazoe 62 15 MS (ESI) positive ion 946 (M+11)+. 367 (N ± Example 289 1, 1 '-{ [(2R,5R)- I -(4-tcrt-butylphenyl)pyrrolidinc-2,5-diyllbis[ I H1-benzijnidazole-6,2 diyl(2S)pyrrolidine-2, 1 -diyll lbis(2-cyclohexyl -2-phenylethanione) MIS (ES!) positive ion 974 (M+H)*. 5 2 ~NH Examuple 290 (2R,2'R)-I, V- [(2R,5R)- 1(4-tert-butylphcniyl)pyrrolidiine-2,5-diyljbis[ ll-l-benziinidazole-6,2 diyl(2S)pyffolidline-2, I -diyl] )bis(3,3,3-trifluoro-2-iinethoxy-2-phenylpropan- I -one) 10 MIS (ESI) positive ioll 1006 (M-.-I[)*. o Example 291 ([(2R,5R)- I -(4-Icr-buiylphcenyl)pyrrolidinc-2,5-diyl]bis[ I H-bcnzinmidazolc-6,2-diyl(2S)pyrrolidince 2,1 -diyl] )bis[(2,2,3,3.ceiranmethylcyclopropyl)nmelhanone] 15 MIS (ESI) positive ion 822 (M41)*. 368 Example 292 1, 1'-f[(2R,5R)- I -(4-tert-butylphcniyl)pyrrolidinie-2,5-diyljbis[ I H-benziiinidazole-6,2 diyl(2S)pyrrolidine-2, I -diyl] ) bis(3-mcithyl-2-pheinylbutan- 1 -one) MS (ESI) positive ion 893 (M+Ni- 4

-

2 Of.

5 NH N <>Example 293 [(2R,5R)- I -(4-iert-butylphenyl)pyrrolidinie-2,5-diyl]bis[ I1-1-benzimlidazole-6,2-diyl(2S)pyrrolidinc 2,1 -diyl] }bis { [(1 R,3R)-2,2-diniethyl-3-(2-mniethylprop- 1-eni-i-yl)cyclopropyl] miethanoneI MS (ES!) positive ion 974 (M+H)*. 10 NHH Example 294 [(2R,5 R)- I -(4-;ert-hutylpheniyl)pyrrolidinie-2,5-diyiJhis[ I 1--benzinlida7DIe-6,2-diyl(2S)pyrrolidince 2, 1 -diyl] I his[(2,2-diclhloro- I -mihitylcyclopropyl)nlethanloneI MS (ES!) positive ion 874 (M+1-1lY. 15 N NH N Example 295 369 (2R,2'R)-1, ,I'-I [(2R,5R)- I -(4-teri-huiylplhcnyl)pyrrolidince-2,5-diyljbisj I H-henzimidazole-6,2 cdiyl(2S)pyrrolidine-2,1 -diyl] lbis(2-hydroxy-2-pheniylhutan- I -one) MS (ESD) positive ion (M+H)'. 5 Example 296 [(2R,5 R)- I -(4-ter-butylphenyl)pyrrolidinie-2,5-diyljbis[ 11-1-beinzirnidazole-6,2-diyl(2S)pyrrolidiioe 2, I -diyll Ibhis( [ I -(trifluoroiinethyl)cyclopropyl] niethanoie I MS (ESI) positive ion 846 (M+f-IY. Examnple 297 I[2,) 1-(4-tert-butylphenyl)pyrrolidinie-2,5-diyllbis[ 1 H-benzirnidazole-6,2-diyl(2S)pyrrolidinc 2, 1-diyll I isl(lI-phenylcyclopropyl)iniethanoneI MS (ES I) positive ion 862.5 (M+I-)+. 15 NHHN7NH Example 298 methyl ((2S)-I -[(2S)-2-I 5-[(2R,5R)- I-[4-(difluoroinethoxy)phcnyl] -5-I 2-[(2S)- I -{(2S)-2 [(niethoxycarboniyl)anmino]-3-methylbutanoyl pyrrolidin-2-yI] -ll-l-benzimiidazol-5-yl }pyrrol idin-2 20 yI] -I H-beniziidazol-2-yli pyrrolidini-1I-yI] -3-miethyl-I -oxobutan-2-yi }carbaniate (ESI+) rn/z 898.4 (M+H)+ 370 NN Example 299 methyl { (2S)-I -[(2S)-2-(f5-[(2R,5 R)- I-(3,5.ditluoro-4-.mcthioxyphleiyl)-5- I2-[(2S). -I (2S)-2 5 [(mielhoxycarbony!)amiino]-3-iniethiylbutanoyl }pyrrolidiii-2-yl]- I H-benziiidaz/ol-5-yI Ipyrrolidiin-2 yl]-1l H-hcnziiidazol-2-yl }pyrrolidin- I -yI]-3-iiethyl. I -oxobutan-2-yI }carbaniate (ESI+) m/z 898.4 (M+11)+ H N 10 Example 300 methyl { (2S)-1 -I(2S)-2- {5-[(2R,5R)- 1 [4.(4,4-diiihiylpiperidini-1I yI)-3-fluoroplicnyl]-5- (2-[(2S). 1 f(2S)-2-1iiiethoxycarbonyl)ainino]-3-iniethylbutanoyl )pyrrolidini-2-yI]- IH-benziiidazol-6 y ) pyrrolidini-2-yI]- III -benzinmidazol1-2-yI }pyrrolidini-1I yl]-3-iniethyl I -oxobutan-2-yI Icarbainuate MS +ESI nlz (rel abundance) 962 (100, M+H); 11 NMR (400 MHz, DMSO-d 6 ) 867.52 (d, J = 8.2, 1 I5 H), 7.44 (d, .1 = 8. 1, 1 H), 7.35 (d, I1 = RI, 3 H), 7.26 (s, 1I-1), 7.14 (in, 2 H), 6.75 (s, I H), 6.12 (in, 2 1-I), 5.40 (s, 2 H), 5.19 (s, 2 1-1), 4.12 (t, J = R.4. 2 1-I), 3.98 (s, 4 H), 3.60 (s, 6 H4), 2.70 (in, 5 H). 2.24 (,4 H1), 1.99) (in, 7 H), 1.75 (s, 2 H), 1.46 (s, 3 H), 1.39 (s., 8 H), 0.89 (in, 20 H). 371 Example 301 methyl 1(2S)- I-[(2S)-2- (6-[ I-(4-tert-butylpheilyl)-5-{ 4-fluoro-2-[(2S)-I - {(2S)-2 [(nmethoxycarbonyl)aiiiino]-3-niethylbutanoyl )pyrrolidin-2-yl] -I H-benzinmidazol-6-yI }pyrrolidin-2 5 yfl-4-fluoro- I H-benzimidazol-2-yl }pyrrolidin- 1-yil-3-inethyl- I-oxobutain-2-yl Icarbaniate MS (ES I) mlz7 924 (M+H)* o==K F E--xamiple 302 methyl { (2S)- I-[(2S)-2-{ 5-[(2R,5R)- I (4-cyclopropyl-3-fluorophcniyl)-5- (2-[(2S)- I 10 { (2S)-2-[(mniethoxycarbonyl)amniinoj-3-miethylbutanoyl pyrrolidiin.2-yl]-lI -I-benziimidamzol-5 yl I pyrrolidiin-2-yl]- 1 H-benizinidamzol-2-yl pyrrolidin- 1 .yl]-3-inethiyl- 1-oxobutaan-2-yl )carbamate MS (ESI) ,n/z 891 (M+-1)* I5 Example 303 methyl I (2S)-I -1(2S)-2- 6-[(2R,5R)-5- 12-[(2S)- I-I(2S)-2-[(methoxycarboniyl)aino]-3 thtlylbutanoyl Ipyrrolidin-2-yl]- I H-beiizimidazol-6-yl)[--4[-2 372 inethoxyelhoxy)eihoxy Iphenyl } pyrrolidin-2-ylJ- I H-benzimidazol-2-yl I pyrrolidiii- I -yl]-3-mcthyl- 1 oxobutan-2-yl }carbamate MS (ESI) m/z 950 (M+H), 948 (M-H)*. O O NH HN 5 \o Example 304 methyl {(2S)-I -[(2S)-2-{6-[(2R,5R)-I-[3-fluoro-4-(3-methylpyrrolidin-i-yl)phenyl]-5-{2-[(2S)-I {(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl pyrrolidin-2-y]-l -benzimidazol-6 ylpyrrolidin-2-yl]-1-I -benzimidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-ylcarbaimate 10 11-1 NMR (400 M1Hz, DMSO-D6) 6 ppm 0.76 - 0.89 (m, 12 H) 0.95 (d, J=6.72 Hz, 3 H) 1.62 - 1.72 (in, 2 H1) 1.83 - 2.06 (in, 9 H) 2.09 - 2.24 (in, 6 H) 2.52 - 2.61 (in, 2 -1) 2.91 - 3.15 (in, 4 H) 3.52 (s, 6 H) 3.74 - 3.86 (in, 4 H) 4.05 (t, J=8.35 Hz, 2 H) 5.08 - 5.17 (m, 2 H) 5.26 - 5.38 (in, 2 H) 5.97 - 6.10 (in, 2 H) 6.35 - 6.45 (m, 1 H) 7.01 - 7.08 (in, 2 H) 7.19 (s, I H) 7.25 - 7.32 (in, 3 11) 7.36 (d, J=8.24 Siz, I 11) 7.44 (d, J=7.92 iz, 1 H-) 12.01 (s, 2 11). 15 N N HH= Example 305 methyl {(2S)-I -[(2.S-2-(5-[(2R,5R)-I-[2,3-difluoro-4-(piperidin-1-yl)phcnyl]-5-{2-[(2S)-I-((2S)-2 [(ietlhoxycarbonyl)aminol-3-methylbutanoyl }pyrrolidin-2-yl j- IH-benziiidazol-5-y }pyrrolidin-2 20 yl]-I H-benziiidazol-2-yl } pyrrolidin-I-yl]-3-imeihyl-l-oxobutan-2-ylcarbaimate ESI+ (in/z): 951.5; 1 H NMR (400 M Hz, DMSO-D6) 6 ppm 0.74 - 0.90 (in, 12 H) 1.35 - 1.41 (in, 2 H) 1.44 - 1.51 (im, 4 H) 1.73 - 1.83 (in, 2 H) 1.86 - 2.02 (in, 6 H) 2.14 - 2.23 (m, 4 H) 2.59 - 2.72 (in, 6 H) 373 3.53 (s, 6 H) 3.77 - 3.84 (in, 4 H) 3.97 - 4.10 (in, 2 H) 5.06 - 5.18 (i, 2 H) 5.46 - 5.56 (mn, 2 H) 6.36 6.47 (i, 2 H) 7.03 - 7.11 (in, 2 -1) 7.23 - 7.45 (in, 6 H) 11.95 - 12.10 (m, 2 H) F H H N 0 NH HN 0=( )=o 5 Example 306 methyl ((2S)-I-[(2S)-2-{6-[(2R,5R)-I-(4-ethoxy-3-fluorophenyl)-5-(2-[(2S)-1-((2S)-2 f(methoxycarbonyl)aininol-3-nmethylbutanoyl)pyrrolidin-2-yll-1 H-benziiidazol-6-yl pyrrolidin-2 yI]-IH-heiiziinidazol-2-ylpyrrolidin-I-yl]-3-icthyl-I-oxohutan-2-ylcarhaiatc ESI+ (n/z): 894.4 10 HNk F 6NN NN H H H NH 00 Example 307 inethyl {(2S)- I -[(2S)-2-{6-[(2R,5R)-I-[4-(tert-butylainino)-3-fluorophenyll-5-{2-[(2S)-1-((2S)-2 15 [(nethoxycarbonyl)aninol-3-methylbutanoyl pyrrolidin-2-yll-1H-benziimidazol-6-yl pyrrolidin-2 yl]- IH-benzi midazol-2-yl Ipyrrolidin-1-yll-3-methyl- I-oxobut an-2-yl)carbaniate ESI+ (m/uz): 922; IlH NMR (400 MHz, DMSO-D6) 8 ppm 0.75 - 0.90 (in, 12 H) 0.97 (s, 9 H) 1.61 1.71 (in, 2 1-1) 1.83 - 2.04 (in, 6 H) 2.12 - 2.23 (m, 4 H-) 3.52 (s, 6 H) 3.76 - 3.86 (mn, 4 H) 4.01 - 4.08 (im, 2 H) 5.09 - 5.17 (in, 2 H) 5.27 - 5.37 (i, 2 11) 5.98 - 6.07 (m, 2 H) 6.56 - 6.66 (in, 1 H) 7.06 (I, 20 J=7.92 Iz, 2 H-) 7.19 (s, I H1) 7.27 (d, J=9.00 Iz, 3 H-) 7.38 (d, J=8.24 iz, 1 11) 7.46 (d, J=8.13 Hz, I H) 12.00 (s, I 1l) 12.08 (s, I 1H1) 374 -Q;o N N Example 308 ethyl 5-{(2R,5R)- I -(4-tert-butylphenyl)-5-[ I -(ethoxycarbonyl)-2-{(2S)- I -[N-(methoxycarbonyl)-L valyl]pyrrolidin-2-yl }-1 H-benzimidazol-5-yljpyrrolidin-2-yl} -2-{l -[N-(methoxycarbonyl)-L 5 valyl]pyrrolidin-2-yl }-I H-benzimidazole- I -carboxylate and ethyl 5-((2R,5R)-I-(4-tert-butylphcnyl)-5-[ I -(eihoxycarbonyl)-2-((2S)-1-[N-(iethoxycarbonyl)-L valylJpyrrolidin-2-yl}-1H-benzimidazol-6-yl]pyrrolidin-2-yl}-2-{(2S)-I-[N-(methoxycarbonyl)-L valyl]pyrrolidin-2-yl}-I H-benzimidazole-l-carboxylate 10 ESI+ (m/z): 1032.5; 1H NMR (400 MHz, DMSO-D6) 8 ppm 0.70 - 1.04 (in, 12 1-1) 1.08 (s, 9 -I) 1.33 - 1.46 (in, 6 H) 1.65 - 1.77 (i, 2 H) 1.8 1 - 2.13 (in, 8 H) 2.20 - 2.28 (in, 2 H) 2.55 - 2.62 (m, 2 H) 3.53 (d, J=4.23 Hz, 6 1-1) 3.80 - 3.92 (in, 4 1-1) 4.04 - 4.13 (in, 2 H) 4.41 - 4.59 (in, 4 H) 5.38 - 5.49 (in, 2 H) 5.66 -5.76 (in, 2 H) 6.17 - 6.33 (in, 2 H) 6.82 - 7.00 (in, 3 H) 7.18 - 7.56 (in, 5 H) 7.75 - 7.91 (in, 2 H) The iltle compounds of Examples 52, 53, 54, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 74, 15 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 93, 94, 95, 96, 97, 99, 101, 102, 103, 109, 110, 111, 112, 113, 117, 121, 122, 123, 125, 126, 127, 128, 129, 130, 131, 132, 135, 136, 137, 138, 139, 140, 141, 144, 145, 146, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 173, 176, 178, 179, 180, 181, 183, 184, 185, 186, 188, 189, 191, 192, 194, 195, 197, 198, 199, 200, 201, 202, 203, 205, 207, 208, 209, 210, 211, 212, 214, 215, 216, 20 217, 218, 219, 220, 221, 224, 226, 227, 228, 229, 230, 231, 233, 234, 235, 236, 237, 238, 240, 241, 242, 245, 247, 248, 250, 251, 252, 254, 256, 257, 258, 262, 263, 264, 266, 267, 268, 270, 271, 272, 273, 274, 275, 276, 277, 278, 282, 294, 295, 296, 297, 298, 299, 300, 301, 302, 305, and 306 showed an EC 50 value of less than about 0.1 nM in HCV Ib-Con i replicon assays in the presence of 5% FBS. The title compounds of Examples 51, 55, 56, 57, 70, 71, 72, 73, 78, 98, 100, 108, 114, 115, 116, 119, 25 120, 133, 134, 142, 143, 147, 164, 172, 174, 182, 196, 204, 206, 222, 223, 225, 239, 244, 249, 253, 259, 261, 265, 281, 287, 288, 292, 303, 304, 307, and 308 showed an EC 50 value of from about 0.1 to about I nM in HCV lb-ConI replicon assays in the presence of 5% F3S. The title compounds of Examples 92, 105, 106, 107, 118, 124, 158, 165, 175, 177, 187, 190, 193, 213, 232, 243, 246, 255, 260, 269, 279, 280, 283, 284, 285, 286, 289, 290, 291, and 293 showed an EC 50 value of from about I 30 to about 100 nM in HCV lb-Con I replicon assays in the presence of 5% FBS. 375 'lie present invention also contemplates pharmaceutically acceptable salts of each compound in Examples 1-308, as well as pharmaceutically acceptable salts of each compound described hereinbelow. The following compounds were similarly prepared according to the procedures described 5 above: F H H'.0 F F 1 0 N ,' N 0. 00 0 F N N H GFH H HOHNN N -NH 0 0 /0 0 F -0)~ \~ 4 N Y-0.. o4 0 0 10 F 0N 0? 00 N 0 N NH oi 0 0 376 F H H 0 N, N. N NN HNT",r -? 0 H N 0 H _ N 0 N N N0=/( N >=o N0 Y377 F Fj~ 0 N N N 0, 0 N: N -N F F F N tN 0 d 10 378 N \ N FN NO 0- 0 N N N \I N I0 00 00 I 0/ N d o379 N ~ N /0 0 N N 00

SN-/

0 0 0 0 N ~ N NN 0 -0 I00 38 HN NH N N HN -O NH

P-

4 0 rN NN (9" ~ N ~/ N 4 N-> N / o When tested using IICV lb-Coni replicon assays in the presence of 5% FBS, each of the 5 above compounds showed an EC 5 o value of less than I nM. In addition, the following mixtures of stereoisomers were prepared according to procedures similar to those described above, where each compound in each stereoisomer mixture can be readily isolated using chiral chromatography or other suitable methods as appreciated by those skilled in the art and, therefore, the present invention also features each compound in these stereoisomer mixtures: F HNO OH y 0 Q NH -~ tIN 0 100* 0N - m~ ~ M 0 ' ~0 10 0 mixture I 381 NH 0 0~NH OY NH FIN 0 mixture 2 0 5 mixture 3 ol 00 10 mixture 4 382 O~~TVOi~~ c NlYN H " 0 0 -'( N ., a 0 4 5 0 mirxture 6 1N mi0ture 7 o 0 383 0ll N N 0 0 j 2 N N NN -N . o N 0 N oc 04N'I 0I 0 N N N 00 > N / 0 0\ 0 N 10 ixture 10 _O _. jy N-CN 384 N N~ 00 mixture I I OH H OH 0~i 'C.. N 0 o0 ~~0 c0 10~~~ 0 mxtre1 5 x85 F N N (N 0 0$ 00 5 0 mixture 15 -N N O 'NN N~ ~ 10 mixureC1 N--/'-0 386 HO F NN N0 H NN N 0H N ')".. No NN mixture 17 387 -oH~H\~ H H NN N 0 0-~( o 0 " _o 01 11 0 0 00 0N0 d 0 N0 m~ixture 10 38 N N -o H H H N~ N P N N 0_ 50 0 m0tre2 N8 -oN oz *s=0 N c N N\, N/ mixture 23 -o oH H N N ~ Q N H H0 - N ."a / r 00 -o osoN )r 5 mixture 24 When tested using HCV lb-Coni replicon assays in the presence of 5% FBS, each of the above mixtures (except mixture 12) showed an EC5o value of less than I nM. Mixture 12 showed an ECsc value of from about 1 to 10 nM in HCV l b-Con I replicon assays in the presence of 5% FBS. 10 Likewise, the following compounds of Formula I or pharmaceutically acceptable salts thereof can be similarly prepared according to the schemes and procedures described above, D

L

3 A-L,-X-L2-B.Z 390 wherein A is selected from Table I a, B is selected from Table I b, ) is selected from Table 2, Y and Z

L

3 are each independently selected from Table 3, and L--X-L 2 is selected from Table 4, and A, B, D and X are each independently optionally substituted with one or more RA, and wherein LI, L 2 , L 3 and RA are as described above. Preferably, 1 1, 1,2 and L-3 are bond. 391 Table I a. A H - - / / N/ N / N - N N N= N/--N / HN \ < N\ -N-NN 0: j - o - 392 Tahle lb. B N OINNN I \\- N- N N N N~ N N N= I \ \ C NH \S) \No / \ / - N/ N\N= I o-j< I- ii >-I I NN I \/~~\/ N I/-Q- 9SI~I

~

N / N1 HN N F i\/S I\N \N -NQ -N I_(/I I\/ H-/ N9 Table 2. 1) F NN N N N QO NH=N O NH NH -N 1_Ki I-K _C _< 1---F -0CF 1- < -- c F\H F NF 394 TIable 3. Y and Z H N H ~ / O N ' 0 0 0 0 ~~ HO N 'N H H 0 0H Y Oyt 0N 0 o 0 O 0 H N 0.< 0 0 0~$O N 4~ HHH NK N 0 0 y : o 0 Oy 0-395 Table 3. Y and Z (continued) 1 N H1 0NO 0 a aN'N N/1 r~OH N aC "'O N o~ H 0 06 OH HOF HH N/ HNH/ N .

N ON O1 0 0~f 0: 0o~ 00 0 N a a/ H H HN ', o 2 0 N 0 NO N 0 0 0 S 'N 0 396 Table 3. Y and Z (continued) N N HN O 0 HO 0 N NHN#0 NH O0 0 O N/ 0 00 NH 0 / NI 00 H 0 O NH /N Ny Nk N O NH )O .N HHH O N O NN 0 NH 0 N 00 N- H N /N0N y 0N ON 0 /110 y N 00 0 0 0 ~ H CN "o -0 N N y 110 0 ' 0 Z~ 397,

L

3 TIable 4.

L

3 L ,L L, L L 3 N3 L3L L3 1.3 I I II L3 L3~~L L, N L L2 L NN N HH H 1.,

L

3 L.3L

L

1 N L , 1

L

2 L, 1.2 L2 H Nl N-0 N-S L3.3 L.3 . L 2 L L , . N 2 1 N L 2 N.6.r N16r -- N

L

3 L ,L L'.., L2 L,,,z L 2 L N L12 I 1 N . N IN , N &D 1.3 3 1.3 1.3 O N 0 ,N N 398 Other examples of the compounds of Formula I are provided in Table 5. 'Fable 5 F H H O N 00 'n N O 0 HN O OyN F N N N H H N'N N 1HN O O NH F H HO ,, OH N N

HN

5 399 HIZ (YIN N -O'AN $K m/ C~(~O 0-)N HN . ~ Q 0-) / 0 H SNH orI NIKN ,0 H0 400 N -NH N -N $, HN /00 N-NH NN-N HNN N0 N0 0 04 ~0 N~ N 00 N401 N-N H HNN ( 0 0 /0 N-NH HN-N NN HN- oN 04 N-NH HNN "O N0 0 N HN N / - NH N , 0 C 4 rNd 0 NN HN-N /0 NH 0 N 0 440 O KNH HNN N H HN- 'O -N /00 NH HN / 0 Each compound's anti-H-CV activity can be determined by measuring the activity of the luciferase reporter gene in the replicon in the presence of 5% FBS. Tlhe luciferase reporter gene is 5 placed under the translational control of the poliovirus IRES instead of the HICV IR ES, and HuH-7 cells are used to support the replication of the replicon. The inhibitory activities of the compounds of the present invention can be evaluated using a variety of assays known in the art. For instance, two stable subgenomic replicon cell lines cun he used for compound characterization in cell culture: one derived from genotype la-H-77 and the other 10 derived from genotype I b-Conti, obtained from University of Texas Medical Branch, Galv'eston, TX or Apath, LLC, St. Louis, MO, respectively. TLhe replicon constructs can be bicistronic subgenomic replicons. Tlhe genotype l a replicon construct contains NS3-NS5B coding region derived from the H77 strain of H-CV (la-H77). T'he replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. 'These two coding regions, separated by the FMDV 2a 15 protease, comprise the first cistron of the bicistronic replicon construct, with the second cistron containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S22041. T'he l b-Conl replicon construct is identical to the la-H-77 replicon, except that the IHCV 5' UTR, 3' UTR, and NS3-NS5B coding region are derived from the lb-Con I strain, and the adaptive mutations are K1609E, K1846T and Y3005C. In addition, the tb-Conl replicon 20 construct contains a poliovirus IRES between the H-CV IRES and the luciferase gene. Replicon cell lines can be maintained in D~ulbecco's modified Eagles medium (D)MEM) containing 10% (v/v) fetal 403 HN- '1 bovine serum (FBS), 100 U/mIl penicillin, 100 ing/ml streptomycin (Invitrogen), and 200 mg/mIl G418 (Invitrogen). The inhibitory effects of the compounds of the invention on HCV replication can be determined by measuring activity of the luciferase reporter gene. For example, replicon-containing 5 cells can be seeded into 96 well plates at a density of 5000 cells per well in 100 tl DMEM containing 5% FBS. The following day compounds can be diluted in dimethyl sulfoxide (DMSO) to generate a 200x stock in a series of eight half-log dilutions. The dilution series can then be further diluted 100-fold in the medium containing 5% FBS. Medium with the inhibitor is added to the overnight cell culture plates already containing 100 VI of DMEM with 5% HBS. In assays measuring inhibitory 10 activity in the presence of human plasma, the medium from the overnight cell culture plates can be replaced with DMEM containing 40% human plasma and 5% FBS. The cells can be incubated for three days in the tissue culture incubators after which time 30 pl of Passive Lysis buffer (Promega) can be added to each well, and then the plates are incubated for 15 minutes with rocking to lyse the cells. Luciferin solution (100 pl, Promega) can be added to each well, and luciferase activity can be 15 measured with a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA replication can be calculated for each compound concentration and the EC ., value can be calculated using nionlinear regression curve fitting to the 4-parameter logistic equation and Graphl'ad Prism 4 software. Using the above-described assays or similar cell-based replicon assays. representative compounds of ihc present invention showed significantly inhibitory activities against HCV 20 replication. The present invention also features pharmaceutical compositions comprising the compounds of the invention. A pharmaceutical composition of the present invention can comprise one or more compounds of the invention, each of which has Formula I (or IA, Is, IC or I1)). In addition, the present invention features pharmaceutical compositions comprising 25 pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of the invention. Without limitation, pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation, or allergic response, has a reasonable benefit/risk ratio, is effective for the intended use, and is not 30 biologically or otherwise undesirable. The present invention further features pharmaceutical compositions comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. By way of illustration not limilation, these other therapeutic agents can be selected from antiviral agents (e.g., anti-IIV agents, anti-1113V agents, or other anti-l-CV agents such as HCV protease inhibitors, HCV 35 polymerase inhibitors, IICV helicase inhibitors, IRES inhibitors or NS5A inhibitors), anti-bacterial agents, anti-fungal agents, iminunomodulators, anti-cancer or chemotherapeutic agents, anti 404 inflammation agents, antisense RNA, siRNA, antibodies, or agents for treating cirrhosis or inflammation of the liver. Specific examples of these other therapeutic agents include, but are not limited to, ribavirin, a-interferon, P-interferon, pegylated interferon-a, pegylated interferon-lambda, ribavirin, virantidine, R-5158, nitazoxanide, amantadine, Debio-025, NIM-811, R7128, R1626, 5 R4048, T-1106, PSI-7851 (Pharmasset) (nucleoside polymerase inhibitor), PSI-938 (Pharmasset) (nucleoside polymerase inhibitor), PF-00868554, ANA-598, IDX184 (nucleoside polymerase inhibitor), IDX102, LDX375 (non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside polymerase inhibitor), VCH-759, VCH-916, MK-3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052 (NS5A inhibitor), BMS-791325 (protease Inhibitor), BMS 10 650032, BMS-824393, GS-9132, ACH-1095 (protease inhibitor), AP-H005, A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics) (NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibitor), AZD2836, telaprevir (protease Inhibitor), boceprevir (protease Inhibitor), ITMN-191 (Intermune/Roche), BI-201335 (protease Inhibitor), VBY-376, VX-500 (Vertex) (protease Inhibitor), PHX-B3, ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease Inhibitor), SCH 900518 15 (Schering-Plough), TMC-435 (Tibotec) (protease Inhibitor), ITMN-191 (Intermune, Roche) (protease Inhibitor), MK-7009 (Merck) (protease Inhibitor), IDX-PI (Novartis), BI-201335 (Boehringer Ingeiheim), R7128 (Roche) (nucleoside polymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck) (nucleoside polymerase inhibitor), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF 4878691 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmnasset), PPI-461 (Presidio) (NS5A inhibitor), 20 BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis), ABT-450 (Abbott/Enanta) (protease Inhibitor), ABT-333 (Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott) (non-nucleoside polymerase inhibitor), ritonavir, another cytochrome P450 monooxygenase inhibitor, or any combination thereof. In one embodiment, a pharmaceutical composition of the present invention comprises one or 25 more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents. In another embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other anti-IICV agents. For example, a pharmaceutical composition of the present invention can 30 comprise a compound(s) of the present invention having Formula 1, IA, 1s, Ic, or ID (or a salt, solvate or prodrug thereof), and an agent selected from HCV polymerase inhibitors (including nucleoside or non-nucleoside type of polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors, CDXI inhibitors, cyclophilin inhibitors, IRES inhibitors, or NS5A inhibitors. In yet another embodiment, a pharmaceutical composition of the present invention comprises 35 one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents, such as anti-HBV, anti-HIV agents, or anti-hepatitis A, anti-hepatitis D, 405 anti-hepatitis E or anti-hepatitis G agents. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, alazanavir, tipranavir, TMc-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, 5 efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or other HIV protease, reverse transcriptase, integrase or fusion inhibitors. Any other desirable antiviral agents can also be included in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art. In a preferred embodiment, a pharmaceutical composition of the invention comprises a 10 compound of the invention (e.g.., a compound of Formula I, 1A, IB, 1 c, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof), and a HCV protease inhibitor. In another preferred embodiment, a pharmaceutical composition of the invention comprises a compound of the invention (e.g.., a compound of Formula I, IA, Ia, Ic, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof), and a ICV polymerase inhibitor (e.g., a 15 non-nucleoside polymerase inhibitor, or preferably a nucleoside polymerase inhibitor). In yet another preferred embodiment, a pharmaceutical composition of the present invention comprises (1) a compound of the invention (e.g.., a compound of Formula I, lA, Ii, Ic, or I 1 ), or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof), (2) a HCV protease inhibitor, and (3) a I-ICV polymerase inhibitor (e.g., a non-nucleoside polymerase inhibitor, or preferably a 20 nucleoside polymerase inhibitor). Non-limiting examples of protease and polymerase inhibitors are described above. A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers/excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or 25 potato starch), cellulose or its derivatives (e.g., sodium carboxymcihyl cellulose, ethyl cellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g., propylene glycol), buffering agents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or phosphate buffer solutions. 30 Lubricants, coloring agents, releasing agents, coating agents, sweetening, flavoring or perfuming agents, preservatives, or antioxidants can also be included in a pharmaceutical composition of the present invention. The pharmaceutical compositions of the present invention can be formulated based on their routes of administration using methods well known in the art. For example, a sterile injectable 35 preparation can be prepared as a sterile injectable aqueous or oleagenous suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be 406 prepared by mixing drugs with a suitable nonirritating excipient such as cocoa butter or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drugs. Solid dosage fonns for oral administration can be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be admixed 5 with at least one inert diluent such as sucrose lactose or starch. Solid dosage forms may also comprise other substances in addition to inert diluents, such as lubricating agents. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing 10 inert diluents conunonly used in the art. Liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in U.S. Patent No. 6,703,403. Formulation of drugs that are applicable to the present invention is generally discussed in, for example, Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES 15 (Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FoRMs (Marcel Decker, New York, N.Y., 1980). Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to prepared pharmaceutical compositions of the present invention. In a preferred embodiment, a compound of the invention (e.g., a compound of Formula I, IA, 20 In, Ic, or lo, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof) is formulated in a solid dispersion, where the compound of the invention can be molecularly dispersed in an amorphous matrix which comprises a pharmaceutically acceptable, hydrophilic polymer. The matrix may also contain a phannaceutically acceptable surfactant. Suitable solid dispersion technology for formulating a compound of the invention includes, but is not limited to, 25 meh-extrusion, spray-drying, co-precipitation, freeze drying, or other solvent evaporation techniques, with mel-extrusion and spray-drying being preferred. In one example, a compound of the invention is formulated in a solid dispersion comprising copovidone and vitamin E TPGS. In another example, a compound of the invention is formulated in a solid dispersion comprising copovidone and Span 20. A solid dispersion described herein may contain at least 30% by weight of a phannaceutically 30 acceptable hydrophilic polymer or a combination of such hydrophilic polymers. Preferably, the solid dispersion contains at least 40% by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such hydrophilic polymers. More preferably, the solid dispersion contains at least 50% (including, e.g., at least 60%, 70%, 80% or 90%) by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such polymers. A solid dispersion described herein may 35 also contain at least 1% by weight of a pharmaceutically acceptable surfactant or a combination of such surfactants. Preferably, the solid dispersion contains at least 2% by weight of a pharmaceutically 407 acceptable surfactant or a combination of such surfactants. More preferably, the solid dispersion contains from 4% to 20% by weight of the surfactant(s), such as from 5% to 10% by weight of the surfactant(s). In addition, a solid dispersion described herein may contain at least 1% by weight of a compound of the invention, preferably at least 5%, including, e.g., at least 10%. In one example, the 5 solid dispersion comprises 5% of a compound of the invention (e.g., a compound of Formula I, IA, II, Ic, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof), which is molecularly dispersed in a an amorphous matrix comprising 7% Vitamin E-'TP;S and 88% copovidone; the solid dispersion can also be mixed with other excipients such as mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over the other excipients can range 10 from 5:1 to 1:5 with 1:1 being preferred. hi another example, the solid dispersion comprises 5% of a compound of the invention (e.g., a compound of Formula I, IA, lB, Ic, or ID, or preferably a compound selected from Examples 1-308, or a salt, solvate or prodrug thereof), which is molecularly dispersed in a an amorphous matrix comprising 5% Span 20 and 90% copovidone; the solid dispersion can also be mixed with other excipients such as mannitol/aerosil (99:1), the solid dispersion can also be mixed 15 with other excipients such as mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over the other excipients can range from 5:1 to 1:5 with 1:1 being preferred. Various additives can also be included in or mixed with the solid dispersion. For instance, at least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, plasticizers, colorants, or stabilizers may be used in compressing the solid dispersion to tablets. These additives 20 can be mixed with ground or milled solid dispersion before compacting. Disintegrants promote a rapid disintegration of the compact in the stomach and keeps the liberated granules separate from one another. Non-limiting examples of suitable disintegrants are cross-linked polymers such as cross linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose or sodium croscarmellose. Non-limiting examples of suitable fillers (also referred to as hulking agents) are lactose monohydrate, 25 calcium hydrogenphosphate, microcrystalline cellulose (e.g., Avicell), silicates, in particular siliciumn dioxide, magnesium oxide, tale, potato or corn starch, isomall, or polyvinyl alcohol. Non-limiting examples of suitable flow regulators include highly dispersed silica (e.g., colloidal silica such as Aerosil), and animal or vegetable fats or waxes. Non-limiting examples of suitable lubricants include polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium and calcium 30 stearates, sodium stearyl fumarate, and the like. Non-limiting examples of stabilizers include antioxidants, light stabilizers, radical scavengers, or stabilizers against microbial attack. The present invention further features methods of using the compounds of the present invention (or salis, solvames or prodrugs thereof) to inhibit HCV replication. The methods comprise contacting cells infected with IICV virus with an effective amount of a compound of the present 35 invention (or a salt, solvate or prodrug thereof), thereby inhibiting the replication of HCV virus in the cells. As used herein, "inhibiting" means significantly reducing, or abolishing, the activity being 408 inhibited (e.g., viral replication). In many cases, representative compounds of the present invention can reduce the replication of HCV virus (e.g., in an HCV replicon assay as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more. The compounds of the present invention may inhibit one or inure HCV subtypes. Examples 5 of HCV subtypes that are amenable to the present invention include, but are not be limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including ICV genotypes Ia, 1b, 2a, 2b, 2c, 3a or 4a. In one embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype Ia. In another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the 10 replication of HCV genotype lb. In still another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both IHICV genotypes I a and I b. The present invention also features methods of using the compounds of the present invention (or salts, solvates or prodrugs thereof) to treat HCV infection. The methods typically comprise 15 administering a therapeutic effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), or a pharmaceutical composition comprising the same, to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient. As used herein, the term "treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition, or one or more symptoms of such disorder or condition to which such term applies. The 20 term "treatment" refers to the act of treating. In one embodiment, the methods comprise administering a therapeutic effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof), or a pharmaceutical composition comprising the same, to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient. A compound of the present invention (or a salt, solvate or prodrug thereof) can be 25 administered as the sole active pharmaceutical agent, or in combination with another desired drug, such as other anti-HCV agents, anti-HIV agents, anti-HBV agents, anti-hepalitis A agents, anti hepatitis D agents, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be employed in the methods of the present invention. In one embodiment, the present invention features methods of 30 treating HCV infection, wherein said methods comprise administering a compound of the invention (e.g., a compound of Formula I, IA, [i, 1e, or 11), or preferably a compound selected from Examples I 308, or a salt, solvate or prodrug thereof), interferon and ribavirin to an HCV patient. The interferon preferably is a-interferon, and more preferably, pegylated interferon-a such as PEGASYS (peginierferon alfa-2a). 35 A compound of the present invention (or a salt, solvent or prodrug thereof) can be administered to a patient in a single dose or divided doses. A typical daily dosage can range, without 409 limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose. Preferably, each dosage contains a sufficient amount of a compound of the present invention that is effective in reducing the HCV viral load in the blood or liver of the patient. The amount of the active 5 ingredient, or the active ingredients that are combined, to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the 10 particular disease undergoing therapy. The present invention further features methods of using the pharmaceutical compositions of the present invention to treat I-ICV infection. The methods typically comprise administering a pharmaceutical composition of the present invention to an IICV patient, thereby reducing the IICV viral level in the blood or liver of the patient. Any pharmaceutical composition described herein can 15 be used in the methods of the present invention. In addition, the present invention features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to make medicaments of the present invention. 20 The compounds of the present invention can also be isotopically substituted. Preferred isotopic substitution include substitutions with stable or nonradioactive isotopes such as deuterium, "C, "N or "O. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at least 5 mol % (e.g., at least 10 mol %) of hydrogen in a compound of the present invention is 25 substituted with deuierium. In another example, at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium. In a further example, at least 50, 60,70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium. The natural abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with 30 enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions. The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the 35 invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents. 410

Claims (6)

1. A compound of Formula IB, or a pharmaceutically acceptable salt thereof, D 5R 2 R9 I RD'-T" Nt A-L 1 -X-L 2 -B-/N'T-RD' Rc, Rc' IB 5 wherein: X is , wherein X 3 is N and is directly linked to -L 3 -D; L 1 , L 2 and L 3 are bond; N A is H and is unsubstituted or is substituted with one or more halogen; N 10 B is H and is unsubstituted or is substituted with one or more halogen; J RN RN RN RN D is ,and each RN is independently selected from hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is unsubstituted or substituted with another C 3 -C 6 carbocycle or 3- to 6-membered 15 heterocycle which is unsubstituted or substituted with one or more halogen; Rc' is hydrogen; R 2 and R 5 , taken together with the atoms to which they are attached, form ; and 412 R 9 and R 1 2 , taken together with the atoms to which they are attached, form -T-RD' is each independently-C(O)-Ly'-N(RB)C(O)O-RD', and wherein Ly' is each independently C 1 -C 6 alkylene which is unsubstituted or substituted with -0 5 C 1 -C 6 alkyl; RD' is each independently C1-C 6 alkyl; RB is hydrogen.

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof. 10

3. A pharmaceutical composition comprising (1) dimethyl (2S,2'S)-1,1'-((2S,2'S) 2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1 C H~ Q oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV protease inhibitor. 15

4. A pharmaceutical composition comprising (1) dimethyl (2S,2'S)-1,1'-((2S,2'S) 2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1 H H N), o- . - -0 0 0 0 N oxobutane-2,1-diyl)dicarbamate ( \ ) and (2) an HCV polymerase inhibitor. 413

5. A pharmaceutical composition comprising (1) a pharmaceutically acceptable salt of dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine 2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 diyl))bis(3 -methyl-1 -oxobutane-2, 1 -diyl)dicarbamate C H H 0 H NANY /ry~ -oo 0 5 ( \ ) and (2) an HCV protease inhibitor.

6. A pharmaceutical composition comprising (1) a pharmaceutically acceptable salt of dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine 2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 diyl))bis(3 -methyl-1 -oxobutane-2, 1 -diyl)dicarbamate H H F 0 N)' N N ,o 10 ( ) and (2) an HCV polymerase inhibitor. AbbVie Bahamas Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON