AU761249B2 - Novel intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 REGULATION 3.2 Name of Applicant: Actual Inventor/s: G. D. SEARLE CO.

DAVID B. REITZ, LEN F. LEE, JINGLIN J. LI, HORNG-CHIH HUANG, SAMUEL J. TREMONT, RAYMOND E. MILLER and SHYAMAL C.

BANERJEE.

E.F. WELLINGTON CO., Patent and Trade Mark Attorneys, 312 St. Kilda Road, Melbourne, Southbank, Victoria, 3006.

Address for Service: Invention Title: "NOVEL INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF BENZOTHIEPINES HAVING ACTIVITY AS INHIBITORS OF ILEAL BILE ACID TRANSPORT AND TAUROCHOLATE UPTAKE" Details of Associated Provisional Applications Nos: The following statement is a full description of this invention including the best method of performing it known to us.

-1- NOVEL INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF BENZOTHIEPINES HAVING ACTIVITY AS INHIBITORS OF ILEAL BILE ACID TRANSPORT AND TAUROCHOLATE UPTAKE BACKGROUND OF THE INVENTION Field of the Invention The invention of the present application, which is a 'divisional' application "derived from Australian Patent Application No. 23266/97, relates to intermediates and processes for the preparation ofbenzothiepines, derivatives and analogs thereof, which 10 are useful in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.

Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total 15 cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the S...circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophvsica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.

Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenterolocv, 1982:83:804-11.

In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihn4r, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.

In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August pp. 18035-18046, 1993).

In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.

In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds" Selected benzothiepines are disclosed in world 15 patent application number WO93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.

Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, 20 especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.

The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.

Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89- 370688; U.S. 3,520,891 abstracted in Derwent 50701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.

2479DIV SUMMARY OF THE INVENTION In a first aspect, the present invention provides a compound of formula I-ID: RL

R'

R2

R

7 R0

R

8 H I-1D wherein: R' and R 2 are independently selected from the group consisting of hydrogen and alkyl;

R

7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and RL is hydroxy or methylsulfonato.

In preferred embodiments of the first aspect of the invention, the compound is S* characterized in that RL is hydroxy, more preferably: R and R 8 are hydrogen; or R' and R 2 are independently selected from the group consisting of hydrogen and Ci-6alkyl; or R and R 2 are independently selected from the group consisting of CI-6alkyl; or R' and R 2 are the same alkyl; or R' and R 2 are n-butyl; or one of R' and R 2 is ethyl and the other of R' and R 2 is n-butyl; or R' and R 2 are n-butyl, and R 7 and R 8 are hydrogen; or one ofR' and R 2 is ethyl and the other ofR 1 and R 2 is n-butyl, and R 7 and R 8 are hydrogen.

In other preferred embodiments of the first aspect of the invention, the compound is characterized in that RL is methylsulfonato, more preferably:

R

7 and R 8 are hydrogen; or R' and R 2 are independently selected from the group consisting of hydrogen and CI.

6 alkyl; or R' and R 2 are independently selected from the group consisting of Ci6alkyl; or R' and R 2 are the same alkyl; or 2479DIV R' and R 2 are each n-butyl; or one of R' and R 2 is ethyl and the other of R and R 2 is n-butyl; or R' and R 2 are n-butyl, and R 7 and R 8 are hydrogen; or one ofR 1 and R 2 is ethyl and the other ofR' and R 2 is n-butyl, and R 7 and R 8 are hydrogen.

In a second aspect, the present invention provides a compound having the structural formula XI-1: 0,0 S R 102 103

OH

N

R

1 0 8 XI-1 wherein R 1 02 and R 1 0 3 are independently alkyl, and R 1 0 8 is selected from the group consisting of meta-hydroxy, para-hydroxy, meta-protected hydroxy, para-protected hydroxy, meta-alkoxy and para-alkoxy.

-In preferred embodiments of the second aspect of the invention, the compound is characterized in that:

R'

08 is meta-hydroxy; or

R'

08 is meta-methoxy; or

R

1 0 8 is para-hydroxy; or

R'

08 is para-methoxy; or

R

1 02 and R' 0 3 are independently selected from the group consisting of Ci- 6 alkyl; or

R

1 02 and R 0 3 are n-butyl.

one of R 1 02 and R 1 03 is ethyl and the other of R' 0 2 and R 1 0 3 is n-butyl; or the compound has the structural formula XI-1A: 2479DIV

OCH

3 XI-1A

S.

S

S

the compound has the structural formula XI-1IB:

OH

XI-1B.

more preferably, the compound is the (4R,5R) enantiomers and diastereomers of the compound of formula XI-lB, or the (4S,5S) enantiomers and diastereomners of the compound of formula Xl-IB; or the compound has the structural formula XI-1IC: 2479DIV

OH

OCH

3 xI-1c

C

C

the compound has the structural formula XI-lID:

OH

OH

XI-1D.

In a third aspect, the present invention provides a compound having the structural formula XEI-i: 2479DIV 1 XII-1 wherein n is 0, 1 or 2, R' 0 2 and R 1 03 are independently alkyl, R 1 0 8 is selected from the group consisting ofmeta-hydroxy, para-hydroxy, meta-(protected hydroxy), para-(protected hydroxy), meta-alkoxy, and para-alkoxy, and R 109 is selected from the group consisting of nitro, amino, alkylamino and dialkylamino.

In preferred embodiments of the third aspect of the invention, the compound is characterized in that: R is meta-methoxy; or

R'

0 8 is para-methoxy; or n is 0; or n is 1; or n is 2; or

R

1 0 9 is selected from the group consisting of nitro and dimethylamino; or

R

102 and R 1 0 3 are independently selected from the group consisting of CI6alkyl; or

R

102 and R 03 are n-butyl; or one of R' 02 and R 103 is ethyl and the other of R' 02 and R 1 0 3 is n-butyl; or the compound has the structural formula XII-1A: 2479DIV 020 0 2

N

XII-A

OCH

3 004* the compound has the structural formula XII- 1 B: *for 066

S

0 2

N,,

OCH

3 X1IR the compound has the structural formula XIl- 1 C: 2479DIV 1 02o

N

OCH3 xII-1c the compound has the structural formula XI[I-1D: 02 0

N

OGH

3 XII-1D 2479DIV In a fourth aspect, the present invention provides a compound having the structural formula XI-1:

.R

l 1 0 2

N

XIII-1 wherein R" 0 is selected from the group consisting of halo and mercapto, and is selected from the group consisting of meta-hydroxy, para-hydroxy, meta-(protected hydroxy), para- (protected hydroxy), meta-alkoxy and para-alkoxy.

In preferred embodiments of the fourth aspect of the invention, the compound is characterized in that: is meta-methoxy; or

R

1 is para-methoxy; or

R'

1 0 is halo; or

R"

0 is chloro; or

R"

1 is mercapto; or the compound has the structural formula XIII-1A: SCl 0 .d AO XIII-1A 2479DIV the compound has the structural formula XII-1B: -/Cl

OCH

3

S.

XIII-1B In a fifth aspect, the present invention provides a compound having the structural formula Xfl-2: RllO 0 2

N

j il XIII-2 wherein R 110 is selected from the group consisting of halo and mercapto, R 111 is selected from the group consisting ofmeta-hydroxy, para-hydroxy, meta-(protected hydroxy), para- (protected hydroxy), meta-alkoxy and para-alkoxy.

In preferred embodiments of the fifth aspect of the invention, the compound is characterized in that: R' 1 is meta-methoxy; or

R"

11 is para-methoxy; or

R

11 is halo; or 2479DIV R 1 0 is chioro; or R1 0 is mercapto; or the compound has the structural formula Xm-2A: XIII-2A the compound has the structural formula XIII-2B: -0CH 3 XIII-2B the compound has the structural formula XIII-2C: 2479DIV XIII-2C *fl.

9*

S

the compound has the structural formnula XIII-2D: XIII-2D In a sixth aspect, the present invention provides a compound having the structural formula XIV- 1:

OH

MIV-i Nil 2 wherein R 12and R1 03 are independently alkyl.

2479DIV In preferred embodiments of the sixth aspect of the invention, the compound is characterized in that: the compound has the structural formula XIV-1A:

NH

2 a a* *aaa a.* a a ft 9 XIV-1A the compound has the structural formula XIV-1B: XIV-1B the compound has the structural formula XIV-1C:

OH

NH2 XIV-1C 2479DIV the compound has the structural formula XIV-1D:

OH

NH

2 XIV-1D 9 9 9 99 99 9 In a seventh aspect, the present invention provides a compound having the structural formula XVI-1:

R

103

OH

i O N

R

114 XVI-1 wherein R 10 2 and R 1 03 are independently alkyl, and R 11 4 is selected from the group consisting of halogen and -N+(CH 2

CH

3 3 In preferred embodiments of the seventh aspect of the invention, the compound is characterized in that: the compound has structural formula XVI-1A: 2479DIV

OH

XVI-1A.

the compound has the structural formula XVI-1B:

OH

N)-

XVI-1B.

the compound has the structural formula XVI- 1C: 2479DIV

OH

Wvi-ic 9~ a.

a a a the compound has the structural formula XVI-lD: XVI-1D.

the compound has the structural formula XVI-1E:

OH

0 N Br XVI-1E 2479DIV the compound has the structural formula XVI-1F:

OH

0 N Br XVI-1F

S

In an eighth aspect, the present invention provides a process for the preparation of a compound of Formula I-1C: I-1C wherein: R' and R 2 are independently selected from the group consisting of hydrogen and alkyl, and

R

7 and R 8 are independently selected from the group consisting of hydrogen and alkyl, the process comprising reacting a compound of Formula I-1A: I-1A 2479DIV with a compound of Formula I-1B:

R

7

R

8 wherein R 2

R

7 and R 8 are as defined above.

I-1B ess.

S

*5

S

In preferred embodiments of the eighth aspect of the invention, the process is characterized in that: R' and R 2 are independently selected from alkyl, and R 7 and R 8 are hydrogen; or R' and R 2 are n-butyl, and R 7 and R 8 are hydrogen; or the compound of Formula I-1A is reacted with the compound of Formula I-1B in the presence of an alkali metal hydroxide.

In a ninth aspect, the present invention provides a process for the preparation of a compound of Formula I-1D: 50 @0 0 00 0550

S

0050

S.

S

RL

I-1D wherein: R' and R 2 are independently selected from the group consisting of hydrogen and alkyl, R 7 and R are independently selected from the group consisting of hydrogen and alkyl, and RL is methylsulfonato, the process comprising reacting a compound of Formula I-1C: 2479DIV H I-1C with a methylsulfonylating agent, wherein R 2

R

7

R

8 and RL are as defined above.

In preferred embodiments of the ninth aspect of the invention, the process is characterized in that: S R' and R 2 are independently selected from alkyl, and R 7 and R 8 are hydrogen; or R' and R 2 are n-butyl, and R 7 and R 8 are hydrogen; or the compound of Formula I-1C is reacted with a methylsulfonyl halide to prepare a compound of Formula I-ID; or the compound of Formula I-1C is reacted with methanesulfonyl chloride to prepare a compound of Formula I-1D; or the reaction is carried out in the presence oftriethylamine.

In a tenth aspect, the present invention provides a process for the preparation of a compound having the structural formula II-1: C1 02N R101 II-1 wherein R' 1 0 is para-methoxy or meta-methoxy, the process comprising converting acid to 2-chloro-5-nitrobenzoyl chloride, and reacting the 2479DIV chloride with methoxybenzene to form the compound of Formula II-1.

In preferred embodiments of the tenth aspect, the process is characterized in that:

R'

1 0 is para-methoxy; or

R'

1 0 is meta-methoxy; or the 2-chloro-5-nitrobenzoic acid is contacted with phosphorus pentachloride to form the chloride; or the converting step is carried out in a chlorobenzene solvent; or the reacting step is carried out in the presence of a Lewis acid, more preferably, the Lewis acid is aluminum trichloride.

In an eleventh aspect, the present invention provides a process for the preparation of a compound having the structural Formula Efl-1: III-1 wherein R 1 01 is para-methoxy or meta-methoxy, the process comprising contacting a compound of Formula II-1: 2479DIV 24 C1

O

02 R101 II-1 with a reducing agent, wherein R 1 01 is as defined above.

In preferred embodiments of the eleventh aspect of the invention, the process is characterized in that: Ro 1 0 is para-methoxy; or

R

1 01 is meta-methoxy; or the reducing agent is triethyl silane; or the compound of Formula II-1 is contacted with triethyl silane in the presence of trifluoromethane sulfonic acid; or the compound of Formula II-1 is contacted with triethyl silane in the presence of trifluoromethane sulfonic acid in a methylene chloride solvent.

.9 In a twelfth aspect, the present invention provides a process for the preparation of a S* compound having the structural formula IV-1:

SH

0 2

N

l01 RioI R IV-1 2479DIV wherein R' i is para-methoxy or meta-methoxy, the process comprising reacting a compound of Formula I-1: *5 9 XIII-1 with a metal sulfide, wherein R 101 is as defined above.

In preferred embodiments of the twelfth aspect of the invention, the process is characterized in that: the metal sulfide is lithium sulfide; or the metal sulfide is dilithium sulfide; or

R

101 is para-methoxy; or

R'

10 is meta-methoxy; or the compound of Formula i-1 is reacted with dilithium sulfide to form the compound of Formula IV-1; or the compound of Formula rn-1 is reacted with dilithium sulfide in a dimethylsulfoxide solvent.

In a thirteenth aspect, the present invention provides a process for the preparation of a compound having the structural formula V-1: 2479DIV .V-1 wherein R1 0 1 is para-methoxy or meta-methoxy, and R' 02 and R' 03 are independently selected from the group consisting of hydrogen and alkyl, the process comprising reacting a compound of Formula JV-1: 'v-i with a compound of Formula M-E: R 10 2

RL,

H

M-E

wherein: R Lis methylsulfonato, and R10, R'0 and R'0 are as defined above.

2479DIV In preferred embodiments of the thirteenth aspect of the invention, the process is characterized in that:

R'

0 1 is para-methoxy; or R1 0 is meta-methoxy; or

R

1 0 2 and R 03 are independently selected from alkyl; or R'0 2 and R' 0 3 are n-butyl; or one of R 102 and R' 0 3 is ethyl and the other of R 1 0 2 and R' 0 3 is n-butyl; the compound of Formula IV-1 is reacted with dibutylmesylate in a dimethylsulfoxide solvent.

In a fourteenth aspect, the present invention provides a process for the preparation of a compound having the structural Formula VI-1: 0 2

N

R1 0 1

R

VI-1 wherein n is 1 or 2, R 1 01 is para-methoxy or meta-methoxy, and R 1 02 and R 103 are independently selected from the group consisting of hydrogen and alkyl, the process comprising contacting a compound of Formula V-l: 2479DIV 28 102 103 101 R V-1 with an oxidizing agent, wherein R 1 01

R

02 and R 1 0 3 are as defined above.

In preferred embodiments of the fourteenth aspect of the invention, the process is characterized in that:

R'

1 0 is para-methoxy; or

R'

10 is meta-methoxy; or

R

1 2 and R' 0 3 are independently selected from alkyl; or

R'

0 2 and R' 0 3 are n-butyl; or nis 1; or n is 2; or the oxidizing agent is 3-chloroperbenzoic acid; or S..the oxidation is carried out in a methylene chloride solvent.

In a fifteenth aspect, the present invention provides a process for the preparation of a compound having the structural formula VII-1: 2479DIV R1 0 R101 VII-1 wherein R 101 is para-methoxy or meta-methoxy, R 1 02 and R 1 03 are independently selected from the group consisting of hydrogen and alkyl, and R 104 and R 1 os are independently selected from the group consisting of hydrogen and alkyl, the process comprising reductively alkylating a compound of Formula VI-1B: n 9 R102 R103 VI-1B to form a compound of Formula VII-1, wherein R' 0 1

R

1 02 and R 1 03 are as defined above.

In preferred embodiments of the fifteenth aspect of the invention, the process is characterized in that:

R

1 01 is para-methoxy; or

R'

1 0 is meta-methoxy; or

R'

02 and R 1 03 are independently selected from alkyl; or 2479DIV

R'

02 and R' 03 are n-butyl; or

R'

04 and R 05 are independently selected from alkyl; or

R

104 and R 0 are methyl; or the compound of Formula VI-1B is contacted with formaldehyde in the presence of a palladium catalyst; or the reductive alkylation is carried out in an alcohol solvent, more preferably, the solvent is ethanol.

In a sixteenth aspect, the present invention provides a process for the preparation of a compound having the structural formula VII-1: 00 S R102

R

10 3 R N R105.1 N R 15OH f R 10 1 VIII-1 wherein R' 10 is para-methoxy or meta-methoxy, R 1 02 and R 103 are independently selected from the group consisting of hydrogen and alkyl, and R' 04 and R' 0 o are independently selected from the group consisting of hydrogen and alkyl, the process comprising contacting a compound of Formula VII-1: 2479DIV 31 O RI102 R103 S o R 104 R1 0 RlOl 101 R VII-1 with a ring cyclizing agent, wherein R' 01

R'

02

R'

03

R

1 04 and R 05 are as defined above.

i In preferred embodiments of the sixteenth aspect of the invention, the process is characterized in that:

R

1 01 is para-methoxy; or 0

R

1 01 is meta-methoxy; or

R'

02 and R 1

O

3 are independently selected from alkyl; or

R

102 and R 1 03 are n-butyl;

R'°

4 and R'° 5 are independently selected from alkyl; or

R

1 04 and R 1 05 are methyl; or the ring cyclizing reagent is a base; or the ring cyclizing reagent is an alkali metal alkoxide; or the compound of Formula VII-1 is contacted with potassium tert-butoxide in a tetrahydrofuran solvent.

In a seventeenth aspect, the present invention provides a process for the preparation of a compound having the structural formula DX-1: 2479DIV 32

OO

R 102 0R 103

R

105

OH

106

I-

wherein R I 02 and R 1 03 are independently selected from the group consisting of hydrogen and alkyl, and R 1 04 and R 1 05 are independently selected from the group consisting of hydrogen and alkyl, and R' 06 is para-hydroxy or meta-hydroxy, the process comprising demethylating a compound of Formula Vm-l: R102 SR105

OH

R

10 1 VIII-1 wherein R 1 01 is para-methoxy or meta-methoxy, and R 1 0 2

R

1 03

R

1 04 and R 0 5 are as defined above.

In preferred embodiments of the seventeenth aspect of the invention, the process is characterized in that:

R'

0 1 is para-methoxy and R 106 is para-hydroxy; or

R

1 0 1 is meta-methoxy and R 106 is meta-hydroxy; or

R'

0 2 and R' 0 3 are independently selected from alkyl; or

R'

0 2 and R' 1 3 are n-butyl; or

R'

04 and R 1 05 are independently selected from alkyl; or 2479DIV

R

10 4 and R' 0 5 are methyl; or the compound of Formula VII-1 is contacted with boron trifluoride to form the compound of Formula IX-1; or the compound of Formula VIII-1 is contacted with boron trifluoride in a chloroform solvent.

In an eighteenth aspect, the present invention provides a process for transforming a compound of Formula XV: S7 'S R8 x R 2 7

R

2

R

5 OH XV from a trans configuration to a cis configuration, the process comprising contacting a compound of Formula XV wherein the R 5 substituent and the 4-hydroxy substituent have a trans configuration with a base in the presence of a phase transfer catalyst to yield a compound of Formula XV wherein the R 5 substituent and the 4-hydroxy substituent have a cis configuration, wherein: q is an integer from 1 to 4; R' and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9

NR

9

R'

0

N+R

9 R'RA, SR 9

S+R

9 RoA-, P+R 9 ROR''A-, S(O)R 9 S0 2

R

9 SO3R 9

CO

2

R

9 CN, halogen, oxo, and CONR9R wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9

N+R

9 RA-, S, SO, SO 2 S+R9A, P R9Ri'A-, or phenylene, wherein R 9

R'

1 and R w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or 2479DIV R' and R2 taken together with the carbon to which they are attached form C 3

-CIO

cycloalkylidene; wherein R" and R' 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9 9 R'o, SR 9

S(O)R

9

SO

2

R

9 S0 3

R

9 C0 2

R

9 CN, halogen, oxo, and CONR 9

R'

0 wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or

R

1 and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

RS

5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9

SR

9

S(O)R

9 S0 2

R

9 and S0 3

R

9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quatemrnary heteroaryl, halogen, oxo, OR' 3

NR'

3 R'4, SR' 3 S(O)R13, SO 2 R13, SO 3 R1 3 NR1 3 0R1 4 NR13IIR 4 R5, NO2,

CO

2

R'

3 CN, OM, SO 2 0M, SO 2

N

13

R

4

C(O)NR'

3

R

14 C(O)OM, COR 3 P(O)R 3

R

4 p+R33R14R"A P(OR' 3 )OR1 4 S+R1 3 R14A-, and NR 9 RR ,2A-, wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable 4*SS cation, S.said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR', NRR, SR S(O)R 7 S0 2 R, S0 3 R, C0 2 R, CN, oxo, CONR 7

R

8

NRR

8

R

9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quatemrnary heterocycle, quaternary heteroaryl, P(O)R 7 PR 7R9A-, and P(O)(OR 7 and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR NR 7

R

8 S, SO, SO2, SR PR 7

P(O)R

7

P+R

7

R

8 A, or phenylene, and R' 3 R14, and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quatemrnary heteroaryl, and quaternary heteroarylalkyl, 2479DIV wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR 9

N+R

9

R'

0 K, S, SO, SO 2

S+R

9

PR

9

P+R

9

R,'

0

K,

P(O)R

9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R'

3 R' and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9

NR

9

R'

0 N+R9R"R 12A, SR 9

S(O)R

9 S0 2

R

9

SO

3

R

9 oxo, C0 2

R

9 CN, halogen, CONR 9

R'

0 S0 2 0M,

SO

2

NR

9

R'

0 PO(OR 1 6

)OR'

7

P+R

9 R R A, S +R 9

R'

0 K, and C(O)OM, wherein R'1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or R' and R' 5 together with the nitrogen atom to which they are attached, form a cyclic ring; RS R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more RX are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl-, OR 13 NR 3 R 1 4 SR 13

S(O)R

1 3

S(O)

2 R 1 3 S0 3 R 3, S R 13R K4A, p.a1 OR'1 4 N R 13 NR4 R15, NO 2 @0613, OM 00,S2R1 4 R4 )N13 14, N14C 13, COR ,CN, MSOMSON 3

R'

4 NR (O)R 1 3 R C(O)R C(O)OM, COR' 3 s(o)nNR18, NR1 R 1,N 8OR4 W 9 R12A, P R9R R 12Aamino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR', NR 9

R'

0

N+R

9 R 2 SR', SO 2 R, S0 3

R

9 oxo, 91 +7 11 12 C0 2

R

9 CN, halogen, CONR 9

R

10

SO

2 OM, SO 2 NR9R' 0

PO(OR'

6

)OR'

7 P R9R R K,

S+R

9

R

10 K, or C(O)OM, and wherein R1 8 is selected from the group consisting of acyl, arylalkboxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9

NR

9

R'

0 N R R R 1A- R, S(O)R9, S0 2

R

9 S0 3

R

9 oxo, C0 2

R

9 CN, halogen, CONR 9

R

10 S0 3

R

9

SO

2 OM, SO 2

NR

9

R'

0

PO(OR'

6

)OR'

7 and C(O)OM, 2479DIV wherein in Rx, one or more carbons are optionally replaced by O, NR 1 3

NR"

3

R'

4

A

S, SO, SO 2

S+R

3 A, PR 1 3

P(O)R

1 3

P+R

3

RI

4 A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9

N+R

9 S, SO, SO 2

S+R

9 A PR 9

P+R

9 RI'A- or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR' 3

NR'

3

R

14

SR

13

S(O)R

13

SO

2

R

13 S0 3

R

13

NRI

3 0R 14 NR13NR1 4 Rs 5

NO

2

CO

2

R

13 CN, OM,

SO

2 OM, SO 2 NR13R 4 C(O)NR1 3

R

14 C(O)OM, COR 1 3 P(O)R3R 14 P+R3R4R 1

A-,

P(OR'

3

)OR'

4 S R' 3

R'

4 A, and N R 9

R"R'

2

A'.

In preferred embodiments of the eighteenth aspect of the invention, the process is characterized in that: o the base is sodium hydroxide; or the transformation is carried out in methylene chloride; or the base is potassium tert-butoxide; or the transformation is carried out in tetrahydrofuran.

0 In a ninteenth aspect, the present invention provides a process for the preparation of a Scompound having the formula: R1 R2 (RX)

XLI

comprising: treating a thiophenol with an abstracting agent; coupling the thiophenyl and a cyclic sulfate to form an intermediate comprising a sulfate group; and 2479DIV removing the sulfate group of the intermediate to form the compound of formula XLI; wherein: q is an integer from 1 to 4; R' and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9

NR

9

R

0

NR

9 R'oR"A-, SR 9

S+R

9 R'OA-, P R 9 R'OR"A, S(O)R 9 S0 2

R

9

SO

3

R

9

CO

2

R

9 CN, halogen, oxo, and

CONR

9 R'o 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 N R 9 R'A, S, SO, SO 2 S+R9A P R9R'OA, or phenylene, or R' and R 2 taken together with the carbon to which they are attached form C 3 -Co 0 cycloalkylidene; wherein R 9

R

0 and R' are independently selected from the group consisting of H, S. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, 0 .alkylammoniumalkyl, and arylalkyl; wherein R" and R' 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9

NR

9 R'o, SR 9

S(O)R

9

SO

2

R

9

SO

3

R

9

CO

2

R

9 CN, halogen, oxo, and CONR 9 Ro 10 wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

RS

5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9

SR

9

S(O)R

9

SO

2

R

9 and S0 3

R

9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR' 3

NR'

3

R'

4 SR", S(O)R 3 S0 2

R

3 S0 3 R 3 NR30R 4 NR13R1 4 R, NO 2 2479DIV

CO

2

R'

3 CN, OM, SO 2 OM, SO 2

NR

13

C(O)NR'

3 C(O)OM, COR' 3

P(O)R'

3

R'

P+R' 3 R1 4

R'

5 A P(OR1 3 )OR 1 4

SR

3 R 1 4 and N+R 9

R

1 R1 2

A-,

wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyallcyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR', SR', S(O)R S0 2 R S0 3 R C0 2

R

7 CN, oxo, CONR R 8 N+R R R K9A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 P+R 7

RR

9 and P(O)(0R and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 N+R 7

R

8 A, S, SO,

SO

2 S+R PR 7

P(O)R

7 P+R R 8 or phenylene, and R' 3

R'

4 and R' 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N+R 9

R'

0 S, SO, SO 2

S+R

9

PR

9

P+R

9

R'

0

K-,

P(O)R

9 phenylene, carbohydrate, am-ino acid, peptide, or polypeptide, and

R"

3

R'

4 and R' 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR9'R s, *N+R9R R 12A, SR 9

S(O)R

9 S0 2

R

9 S0 3

R

9 oxo, C0 2

R

9 CN, halogen, CONR9R 0, S0 2 0M, S0 2

NR

9 R1 0 PO(OR 1 6 )0R 1 7

P+R

9

R'

0 R"N'A, S+R 9

R'

0 K, and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the sub stituents constituting R 9 and M; or R* and R' together with the nitrogen atom to which they are attached, form a cyclic ring; R and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R' are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, 13 heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR NR1 3 R1 4 SR'1 3 S(O)R 1 3 S(O),R 1 3 S0 3 R 1 3 S+R1 3

R

4 NR1 3 OR 1 4 NqRl 3 NR1 4

R

5

NO

2 2479DIV

CO

2

R'

3 CN, OM, SO 2 OM, SO 2

NR'

3 R 4 NR. 4 C(O)R 1 3

C(O)NR'

3 R 4

NR'

4 C(O)R 1 3 C(O)OM, COR'1 3

OR"

8 s(o),NR 18, NR. 'R 1 8 NR. 1 8 OR 1 4

,NWR

9 R 'R1 2

PR

9 R IR1 2

A-,

amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9

NR

9

R'

0

N+R

9 R'R 1R 2

SR

9

S(O)R

9

SO

2 R, S0 3 oxo, C0 2

R

9 CN, halogen, CONR 9

R'

0

SO

2 OM, SO 2

NR

9

R'

0 PO(OR 1 6 )OR'1 7 P R9R1 R 12A,

S+R

9

R

0 or C(O)OM, and wherein R 1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, 9::.wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary ~.heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the gopconsisting of OR 9

NTR

9

N+R

9 R" 'R 2 A, SR 9

S(O)R

9 S0 2

R

9 S0 3

R

9 oxo, C0 2

R

9 CN, halogen, CONR 9

R'

0 S0 3

R

9

SO

2 OM, S0 2

NR

9

R'

0 PO(OR 1 6 )OR 1 7 and C(O)OM, wherein in RX, one or more carbons are optionally replaced by 0, NRP. N R R A-, S, SO, S02, S R 3

PR'

3

P(O)R'

3

P+R'

3 R'A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9

N+R

9

R'

0 A7, S, SO, S02, S+R9A-, PR9, P+R9R NA, or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR' 3 NR'R',SR~ S(O)R' 3 I SOR' 3 S0 3

R'

3

O\R'

3

R

4 NR'NR" NO 2 C0 2

R'

3 CN, GM, S0 2 0M, S0 2 NR1 3 R 1 4

C(O)NR

3 R 1 4 C(O)OM, COR 1 3 P(O)R1 3 R 1 4

PR'

3 R1 4 R 1 5

A,

P(OR1 3 )OR'1 4

S+R'

3 R'1 4 A, and N+R9RR R2 A-.

In preferred embodiments of the nineteenth aspect of the invention, the process is characterized in that: the cyclic sulfate has the formula: 2479DIV R1 R2

S

0 O XL and the thiophenol has the formula:

SH

SH

IIIA

wherein R2, R 5 R' and q are as defined above; or the sulfate group is removed by treating the intermediate with a hydrolyzing agent, more S (Rx)q preferably, the hydrolyzing agent is a mineral acid, or the hydrolyzing agent is selected from the group consisting of hydrochloric acid and sulfuric acid; or

XVIIIA

the abstracting agent is a base having a pH of at least about 10; or the abstracting agent is an alkali metal hydride; or the abstracting agent is sodium hydride; or R' and R 2 are alkyl; or *o R' and R2 are Selected fom the group consisting of ethyl, n-butyl, iso-butyl and pentyl;acid; or R e and R are alkyl; or

R

l and R 2 are selected from the group consisting of ethyl, n-butyl, iso-butyl and pentyl; R' and R 2 are n-butyl.

In a twentieth aspect, the present invention provides a process for the preparation of a compound having the formula I: 2479DIV 6 4

R

6

RR

comprising: reacting a cyclic sulfate with a thiophenol to form an alcohol; oxidizing said alcohol to form a sulfone-aldehyde; and cyclizing said sulfone-aldehyde to form the compound of formula I; wherein: n is an integer from 0 to 2; Sq is an integer from I to 4; R' and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalcyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, S wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR', NR 9

N

4

R

9 RORVA-, SR',

S+R

9

R

1 0 A, P+R 9

R'

0

S(O)R

9 S0 2

R

9 S0 3

R

9 C0 2 CN, halogen, oxo, and CONRR1 wherein alkyl, alkenyl, alkynyl., alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N+R 9

R

0 S, SO, SO 2 S+R 9

P+R

9

R

0 or phenylene, or R1 and R 2 taken together with the carbon to which they are attached form C 3 -C 10 cycloalkylidene; 2479DIV wherein R 9

R'

0 and R" are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; wherein R" and R' 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR 9 R'o, SR 9

S(O)R

9

SO

2

R

9 SO3R 9

CO

2

R

9 CN, halogen, oxo, and CONR 9

R'

0 wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or

R"

1 and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R

3 is hydroxy;

R

4 is hydrogen;

R

5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9

SR

9

S(O)R

9 S0 2

R

9 and SO 3 R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyallcyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR' 3

NR

1 3

R'

4

SR'

3

S(O)R'

3

SO

2

R'

3

SO

3

R

3

NR'

3 0R 4

NR

13 N1I 4 R15, NO 2

CO

2 R' 3 CN, OM, SO 2 OM, SO 2 N1 3

R

4 C(O)NRR 4 C(O)OM, COR 3 P(O)R' 3

R

4

P+R'

3

R'

4

R'

5

P(OR'

3

)R

14 S R1 3

R'

4 A, and NR 9 R"R12A-, wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7

NR

7

R

8

SR

7

S(O)R

7 S0 2 R, S0 3

R

7 C0 2 R, CN, oxo, CONR 7 R

NR

7

R

8

R

9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R, PR 7

RR

9 and P(O)(OR 7

)OR

8 and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR7, NR 7 RA-, S, SO,

SO

2 SR PR 7

P(O)R

7

PR

7

R

8 A, or phenylene, and R' 3

R

4 and R 1 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, 2479DIV arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR 9

N+R

9

R'

0 S, SO, SO 2

S+R

9

PR

9

P+R

9

R'

0

A-,

P(O)R

9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R"

3

R'

4 and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9

NIR

9

R'

0 N+R9R"R 12A, SR 9

S(O)R

9 S0 2

R

9 S0 3

R

9 oxo, C0 2

R

9 CN, halogen, CONR 9

R'

0 S0 2 0M,

SONR

9

R'

0 PO(OR 1 6

)OR'

7

P+R

9

R'

0

S+R

9 and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or R 1 4 and R 1 5 together with the nitrogen atom to which they are attached, formn a cyclic ring; *R 6is hydrogen; R7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more RX are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalcyl, cycloalkyl, 13 **heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR NR3 14, SR 13, S(O)R 13, S(O) 2 S0 3 R 13, S+R 13R"A-, INR' 3 OR 1 4 iNR'INIR R5 NO 2 C0 2

R'

3 CN, OM, S0 2 0M, S0 2

NR'

3

NR'

4

C(O)R'

3

C(O)NR'

3

NR

14

C(O)R'

3 C(O)OM, C0R 13

OR"

8 S(O)nNR 18 NR1 3 NqR' 8 0R 14

NWR

9 R"1R' 2 ,PtR 9

R"R'

2

A,

amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9

NIR

9

R'

0

N+R

9 R' 1R 2 NA, SR 9

S(O)R

9

SO

2 R, S0 3

R

9 oxo,

CO

2 R9, CN, halogen, COKR'R' 0

SO

2 OM, S0 2

NR

9

R

1

PO(OR'

6

)OR'

7 P R R R 12A,

S+R

9

R

10 K, or C(O)OM, and wherein R 1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9

NR

9

R'

0

N+R

9 R'R R'A, SR 9

S(O)R',

2479DIV S0 2

R

9 S0 3

R

9 oxo, C0 2

R

9 CN, halogen, CONTR 9

R'

0 S0 3

R

9

SO

2 OM, S0 2

NR

9

R'

0

PO(OR'

6

)OR'

7 and C(O)OM, wherein in one or more carbons are optionally replaced by 0, NRL13, N+R1 3 R1 4

A-,

S, SO, SO 2

S+R

3

PR'

3

P(O)R'

3 P'R RA, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9

N+R

9

R'

0 S, SO, SO 2

S+R

9

PR

9

P+R

9

R

0 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR' 3 NR1 3 R1 4 SR 1 3

S(O)R'

3 S0 2 R 1 3 S0 3 R 1 3 NiR 13 OR 1 4 iNR1 3

INR'

4

NO

2 C0 2 R 1 3 CN, OMv, 13 14 13 14 12

**P(OR'

3

)OR'

4 S+R' R' 4 A, and N+R 9 R' 'R' 2

A.

In preferred embodiments of the twentieth aspect of the invention, the process is characterized in that: the cyclic sulfate has the formula: 0 XL and the thiophenol has the formula:

SH

(RX)q

XVIIIA

wherein R 2

R

5 Rx and q are as defined above; or R' and R 2 are alkyl; or R1 and R 2 are selected from the group consisting of ethyl, n-butyl, iso-butyl and pentyl; or R' and R 2 are n-butyl; or the alcohol is oxidized with an oxidizing agent to form an aldehyde, more preferably, the aldehyde is oxidized with an oxidizing agent to form a sulfone-aldehyde; or the sulfone-aldehyde is cyclized with a cyclizing agent that is a base having a pH between about 8 to about 9; or the sulfone-aldehyde is cyclized with a cyclizing agent that is an alkali alkoxide base; or the sulfone-aldehyde is cyclized with potassium tert-butoxide; or the alcohol is oxidized with pyridinium chlorochromate to form an aldehyde; the aldehyde is oxidized with metachloroperbenzoic acid to form a sulfone-aldehyde; and the sulfone-aldehyde is cyclized with potassium tert-butoxide.

With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the description and/or in the claims, unless the context requires otherwise, those words are used on the basis and clear understanding that they are to Sbe interpreted inclusively, rather than exclusively, and that each of those words is to S* be so interpreted in construing the description and/or the claims.

m BA.4064a 2479DIV 46 DESCRIPTION OF THE INVENTION As indicated above, the present patent application is a 'divisional' application derived from Australian Patent Application No. 23266/97, which is the national phase in Australia of International Application No. PCT/US97/04076 as published under WO97/33882, claiming priority of United States Patent Application No. 60/013119 filed 11 March 1996.

As also indicated above, the parent Australian Patent Application No. 23266/97 relates to novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.

Objects and features of the invention of the present 'divisional' application will be in part apparent and in part pointed out hereinafter in referring to the description of the invention set out in the specification of the parent Australian Patent Application No.

23266/97, as follows: SRL 6045 "4 The present invention furthers such efforts by providing novel benzothiepines, pharmaceutical compositions, and methods of use therefor.

Accordingly, among its various apects, the present invention provides compounds of formula i R fi n 8 S R r i 0 2; .9 1 2 R' 8

(I)

S(R 3 4 R R o R 3

R

6

R

5

R

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; 2 R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, S. haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituent selected from the group consisting of OR 9 910 9 9 1011 9 9 NR R 1 0 NR'R SR P'RR RRA-, S(0)R S02R 9 9 9 10 SO3R 9 CO2R CN, halogen, oxo, and CONR R 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyl SRL 6045 optionally have one or more carbons replaced by O, NR 9 N+R R S, SO S02, S R P+R R or phenylene, 9 10 wherein R R 0 and R w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or

R

1 and R 2 taken together with the carbon to which they are attached form C 3

-C,

0 cycloalkylidene; R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, *o* acyloxy, aryl, heterocycle, OR NR 1 0 SR S(O)R 9 S02R and S03R 9 wherein R 9 and R" 1 are as defined above; or 1 1 4 R3 and R together form =NOR 1 1

=NNR

11

R

12

=NR

9 or =CRR 1 2 ween1 1 12 wherein R I and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, 20 cycloalkyl, cyanoalkyl, OR 9 NR R 0 SR S(O)R 9 S02R 9 S03R 9 C02R 9 CN, halogen, oxo, and CONR R 0 wherein R and R 1 are as defined above, provided that both R 3 and R 4 cannot be OH, NH2, and SH, or 11 12 R and R together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R

5 and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,

OR

9 9 9 9 9

SR

9 S(O)R S02R and SO3R, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, SRL 6045 heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13

NR

13

R

14

SR

13

S()R

13 S02R 13 S03R 13

NR

3

OR

4

NR

3

NRR

1 5, NO2, C02R 3

CN,

S02N 13

R

14 13 14 13 OM, S020M, S02NR3R4, C(O)NR R C(O)OM, COR 13 P(O)R13R 14 p+R13R14R5A-,

P(OR"

3 S'RR"A-, and

NR

9

R

11

R

12

A,

wherein: So A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 8 7 7 7 7 7

NR

7

R

8

SR

7

S(O)R

7 S02R 7 S03R 7 C02R 7 CN, oxo,

CONR

8 N RR R alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary 7 8 heterocycle, quaternary heteroaryl, P(O)R R, P R7R8R A and P(O)(OR7)OR and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O,

NR

7 N R7R S, SO, S02, S+R7A-, PR 7 P(O)R7, 7 8 13 14 15 P R R or phenylene, and R 1 3

R

1 and R 1 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heterocycle, SRL 6045 quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR', NR 9

R

10 S, SO, S02, S R A, PR PR R P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and 13 14 1 R13, R, and R are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary 9 9 10 +9 +1112 9 heteroaryl, OR 9 NR R 1 N R R1 R2A SR 9

S(O)R

9 9 9 9 10 SO2R SO3R oxo, CO2R CN, halogen, CONR R 1 0 S02OM, SO2NR R 10 PO(OR16)OR17, P+R 9 RA-, S+R and C(O)OM, 17 S: wherein R and R 7 are independently selected from the substituents constituting R 9 and M, and p is 0 or 1; or 14 15 R and R 1 together with the nitrogen atom to which they are attached, form a cyclic ring; 7 8 SR and R are independently selected from the 20 group consisting of hydrogen and alkyl; and one or more R x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle, polyether, quaternary heterocycle, quaternary 13 13 14 13 13 13 heteroaryl, OR 13 NR R SR 1 3

S()R

13 S(0)2R 3 SO3R 3 S R R 4

NR

13

R

14

NR

3

NR

4

R

1 5, NO2, CO2R 3 13 14 14 13 13 14 CN, OM, SO2OM, SO2NR3R 4 NRC(O)R", C(O)NRR 1 4 NR14C(O)R13, C(O)OM, COR 1 3 OR, S(O)nNR 1 8

NR

3

R

1 8 NR OR 1 4 NR R R 2 A, PR R 11

R

2 A amino acid, SRL 6045 peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9

NR

9

R

1 0 +9 11 12 9 9 9 9 9 N+RR RA, SR S(O)R SO2R SO3R oxo, CO2R 9 10 9 10 CN, halogen, CONR R 1 0 S020M, S02NR 9

R

1 0 PO (OR 16

)OR,

PR

9

R

1 1 R1 2 S'R'R or C(O)OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituent selected from the group consisting of OR, NRR 10 N+R R R2A ,SR, S(O)R 9 9 9 9 10 9 SO2R S3R oxo, C02R CN, halogen, CONR R S03R 9 1R 0 16 17 S020M, S02NRR 1 0 PO(OR6)OR and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by O, NR 1 3 N R3RA-, S SO, S02, S RA-, 13 +13 14

PR

1 P(O)R13, P R R phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR NR R A-, +9 9 9 10 S, SO, S02, S R PR PR R or P(0)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, 52 SRL 6045 haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3

NR

3 R, SR 1 3

S(O)R

1 3 S02R 1 3 S03R 1 3 13 14 13 14 15 13

NR

13

R

14

NR

13

NR

14

R

15 NO2, CO2R 3 CN, OM, S02NR 1 3

R

4 C(0)NR 3 R C(0)OM, COR 1 3

P(O)R

3

R

1 4 P R 1 3

R

4 R15A-, P(OR")OR 4

S'R"R

4 A and NR 9 R R 12

A,

provided that both R 5 and R 6 cannot be hydrogen, OH, or SH and when R 5 is OH, R 1

R

2

R

3

R

4

R

7 and R cannot be all hydrogen; provided that when R 5 or R 6 is phenyl, only one of R' or R 2 is H; provided that when q 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

5 6 Preferably, R and R can independently be selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, 20 wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups O: independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, 13 13 14 13 13 13 13 oxo, OR 1 3

NR

3 R SR 1 3

S(O)R

1 3 S02R, S03R 3

NR

3 OR4, NR 3

NR

4

R

1 5, N02, CO2R 13 CN, OM, S020M, 13 14 13 14 13 13 14 S02NR 3

R

4

C(O)NRR

1 4 C(O)OM, COR P(O)RR 1 4 p+R3R14R15A-, P(OR)OR 4 S+R RA-, and N+R 9

R

1

R

1 2

A,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle SRL 6045 can optionally have one or more carbons replaced by O, 7 7 8 7 7 NR N R7RA-, S, SO, S02, S R PR 7 P(O)R7, P R7R8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7 78 7 7 7 7 7 NR7R8, SR S(O)R SO2R 7 SO3R 7 C02R 7 CN, oxo, 7 8 7 8 9 CONR R NR7R RA-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary 78 +7 8 heterocycle, quaternary heteroaryl, P(O)R7R P RR A, and P(O) (OR')OR.

More preferably, R 5 or R 6 has the formula: -Ar- (R wherein: t is an integer from 0 to 20 Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more R y are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9

SR

9

S(O)R

9 S02R and S03R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, SRL. 6045 and heterocycle can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, 13 1 4 13 13 arylalkyl, halogen, oxo, OR 13 NR R 14 SR ,S(O)R.

13 13 13 14 13 14 15 13 S02R ,S03R ,NR OR ,NR NR R ,N02, C02R ,CN, OM, S020M, S02NR 13

R

1

C(Q)N

1 R R C(O)OM, C0R 13 13 14 13 1414 P(O)R R PR R R15A- P (OR" 3 SR2RA, and N +R9 R11R12 -j wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent S 7 groups selected from the group consisting of OR ~78 7 7 7 7 7 NR R SR S(O)R ,S2 ,SOR C02R CN, oxo, CONR R N R 7

R

8

R

9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, q-uaternary heteroaryl, P(O)R 7 R 8 P +R 7 R 8

A-,

Stand P OR', and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle S £can optionally have one or more carbons replaced by 0, 78 7 7 NR N R R S, SO, S02, S R PR P(O)R, P +R 7R 8A-, or phenylene.

Most preferably, R 5 or R.

6 has the formula (II): SRL 6045

(II)

(RY)t The invention is further selected from among: R" R21 directed to a compound (Formula DI) R20 R19 R21 R R -R (Formula DII), and

R

22

R

20

R

19

R

21 (Formula DIII)

I

R

2 3 wherein R" is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon SRL 6045 atoms replaced by O, NR7, N+R7R8, S, SO, S02, S+R7R8, PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, 13 13 14 13 13 arylalkyl, halogen, oxo, OR 13

NR

3

R

14

SR

13

S(O)R

1 13 13 13 14 13 1415 13 S02R 3 S03R 3 NR3 OR NR NR R 1 5 N02, C02R 3

CN,

13 14 13 14 13 OM, S020M, SO2NR R C(O)NR R 1 4 C(O)OM, COR 1 3 .P(O)R R 1 4 PR 1 3 4R15A-, P(OR")OR 1 S'R R"A and

N+R

9 R R1 2

A-;

wherein R" further comprises functional linkages by which R" is bonded to R 20

R

1 or R 22 in the compounds of Formulae DII and DIII, and R 23 in the compounds of Formula DIII. Each of R 2

R

2 or R 22 and R 23 comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R 2

R

2 R and R comprises a benzothiepine moiety corresponding to the Formula: 0

X

S 8 1 (Formula DIV) SRL 6045 or: (0 R 7

(R'

(Formula

DIVA)

wherein R R R 3

R

4

R

5

R

7 Re, Rx, q, and n are as defined in Formula I as described above, and R 5 5 is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of R 20

R

n and R 2 in Formulae DII 10 and DIII, and R 3 in Formula DIII, be bonded at its 7or 8-position to In compounds of Formula DIVA, it is particularly preferred that R 5 comprise a phenylene moiety bonded at a m- or p-carbon thereof to R 9 Examples of Formula DI include: 1 o*o**o* SRL 6045 R8~ R 7__k .0 l

(III)

(RX~kA R)r o R 4

A

3

A

2 A

(V

~R1

A

(RX)q and SRL 6045

(RY)

R

8

R

1 R2 R 4 A RT R3 R 3A S RBA(V) (R 0 R7A (RX)q F ~In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various S* combinations.

In any of the compounds of the present invention, 1* 2 R and R2 can be ethyl/butyl or butyl/butyl.

In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.

Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.

In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising SRL 6045 administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.

In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and ~scope of the invention will beomce apparent to those 15 skilled in the art from this detailed description.

.9 61 SRL 6045 DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.

The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.

15 Definitions In order to aid the reader in understanding the following detailed description, the following definitions are provided: "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and 25 ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.

"Aryl" means a fully unsaturated mono- or multiring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures: SRL 6045 Z'z wherein Z, Z" or is C, S, P, 0, or N, with the proviso that one of Z, Z" or is other than carbon, but is not 0 or S when attached to another Z atom by a double bond or when attached to another 0 or S atom. Furthermore, the optional substituents are 10 understood to be attached to Z, Z" or only when each is C.

SThe term "heteroaryl" means a fully unsaturated heterocycle.

In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds S. 20 that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.

The term "quaternary heteroaryl" means a heteroaryl in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.

The term "halogen" means a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" means alkyl substituted with one or more halogens.

63 SRL 6045 The term "cycloalkyl" means a mono- or multiringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds.

The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.

The term "oxo" means a doubly bonded oxygen.

The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the 15 polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "cycloaklylidene" means a mono- or multiringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not 25 within the ring structures.

The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.

The term "peptide" means polyamino acid containing up to about 100 amino acid units.

The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 SRL 6045 9 amino acid units.

The term "alkylammoniumalkyl" means a NH, group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.

The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.

The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

The term "active compound" means a compound of the present invention which inhibits transport of bile acids.

When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.

The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing

LDL

and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.

SRL 6045 Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.

Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.

The compounds of the present invention also 15 include tautomers.

The compounds of the present invention as discussed below include their salts, solvates and prodrugs.

Compound Syntheses The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.

Generally, the compounds of the present invention can be prepared by the procedures described below.

For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methansulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the 66 SRL 6045 reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two.

racemic steroisomers of benzothiepin-(5H)-4-one

VIII

when R 1 and R 2 are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydrobenzothiepine-1,l-dioxides XI when R' and R 2 are nonequivalent.

SOptically active compounds of the present 15 invention can be prepared by using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).

a*.

SRL 6045 Scheme I R'

R

2

HCOH

1 0 NaOH

H

MsCINEt 3 Ms&- (Ms methanesulfonyl group) SH O (RX)q R7.

V

VI Zn/TCI 3 NEt 3

SO

(Rx)q

VI

7 R R 8 S, R2 2

VIH

excess

MCPBA

(RX)q -I H 2 IPd-C

,R

R

(RX)q

I

R

5

OH

(RX)q Alternatively, keto-aldehyde VI where R' is H can be prepared by reaction of thiophenol V with a 2substituted acrolein.

68 SRL 6045

RH

SH 0H NEt3S 0 S =0 (RX)q

R

3 v (RX)q Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-l,1-dioxide

XII

which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers aof X, Xa and Xb, having the OH group and R' on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R 5 on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.

SRL 6045 2 MCPBA NaBH 4 (Rx)q vmL

R

RXq R 5

OH

0 000 0 0 0*e0 0000

S

0 0 00 000* 0 0*00 0@ S 0 *09 S

S

*SSOOO

0 NaOH

PTC/CH

2 C1 2 (Rx)q MCPBA m-chloroperbenzoic acid PTC phase transfer catalyst when R 1= butyl, R 2=ethyl, R 5=phenyl, X=H, q 4 6a Xa 6b Xb 6c Xc 6d Xd SRL 6045 The compounds of the present invention where R 5 is OR, NRR' and S(O),R and R 4 is hydroxy can be prepared by reaction of epoxide IX where R 5 is H with thiol, alcohol, and amine in the presence of a base.

RH R7 R S R HOR, or HNRR', or S R' R H S O nR R2 (Rx)q 0 (RX)q 5

OH

R

IX, where R H

R

5 OR, NRR, S(O)nR Another route to Xc and Xd of the present invention is 0 10 shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid.

Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with 500. either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd.

o.:o Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.

The thiophenols XVIII and V used in the present 20 invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J.

Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 OC, and the rearranged product is hydrolyzed SRIA 6045 with sodium hydroxide to yield the thiophenol XVIII.

Similarly, Thiophenol V can also be prepared from 2acyiphenol XIX via the intermediate thiocarbanate XX.

Scheme 2 R 2 R R R 2 Rs)

R

2 RR 0 2 MCPBA_0 2 S 0 H Pd 0SH SO H -JI R 5 C-H 2 (Rx)q (Rx)q (Rx)q

VI

potassium t-butoxide 2* OU .19 (RX)q R 5

OH

R 5

OH

*XC Xd SRL 6045 Scheme 3 OH

OH

R

5 CHCl NaH ONy- R (RX)q tuee (Rx)q XV

XVI

S

OH ~0

AN(CH

3 2 1. heat

SH

CIC(S)N((CH)

3 2 2. NaOH (Rx)q (RX)q (Rx)q *Xvi xvii xvmI

YN(CH

3 2 OHO0 0 0 1. heat SHO0 bo.CIC(S)N((CH) 3 2 2. aO *ev (RXq R)q (Rx)q :::XiX XX

V

09 Scheme 4 shows another route to benzothiepine-l,l- *boo odioxides Xc and Xd starting from the thiophenol XVIII.

Compound XVIII can be reacted with mesylate IV to give boo the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.

SRL 6045 Scheme 4 (Rx)q

H

IV

xvm R 1

R

7

R

8 1 R 2 s H (RX)q

XXI

2 MCPBA 10-

R

7 R Ri 2 02S H

R

(RX)q Xrv (RX)q XXIc

R

Xd XXIId Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-4nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfonealdehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV SRL 6045 with di-t-butyldicarbonate gives the N,O-di-(tbutoxycarbonyl)hydroxylamino derivative XXVI.

Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

a a.

a.* o**o o* SRL 6045 Scheme Cl

N

I0 32 -l 0

NO

2 1. Li 2

S

2.

V

R

3 R2 IV

S

2 MCPBA xxm

XXIV

*999 9*9* *9 *4~ 99 9.

9 9 *9 9 9 9 *99* 9 9 99 9 *9*9 *9 9 9 4*9* 9 9***99 9 Pd/C I I R R2( O 2

N(BOC)O(BOC)

XXVI 1. potassium t4l 2. acid workup 0 utoxide

XXV

n

HOHNJ

2

I<

p bH XXVIHc Where R 3 is jPd/C-H 2 loo psi deg C 02

H

2 N H

XAXH

HOHN

H Ph

O

XXVI~d I0 psi 50 deg C 02

H

2

NJY<

PhH XXXIIId In Scheme 6, reduction of the sulfone-aldehyde XXV 76 SRL 6045 with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.

o

A.

ft A SRL 6045 Scheme 6 0

R

2 H R

H

2 -Pd/C

R

6 CHOH

I

XXIV

S

S.

S.

S

potassium t-butoxide,

THF

If' R6 N'

H

R6 N

H

XXIXc XXIXd Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII.

Hydrolysis of the carboxylate and derivatization of the resulting acid to acid derivatives are well known in the art.

SRL 6045 Scheme 7 Hg(OTf) 2 12, 25 deg C

XXX

*5

S

S

S 5*

S

t 0* Pd catalyst CO/R O 100 deg C

XXXI

(Rx)q-

XXXII

Abbreviations used in the foregoing description have the following meanings: THF- -tetrahydrofuran PTC phase transfer catalyst Aliquart 336 methyltricaprylylammonium chloride MCPBA m-chloroperbenzoic acid Celite a brand of diatomaceous earth filtering SRL 6045 aid DMF---dimethylformamide DME----ethylene glycol dimethyl ether BOC---t-butoxycarbonyl group R and R 2 can be selected from among substituted and unsubstituted

C

1 to C 10 alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C 1 to C 0 alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, .isopropyl, -CHC (=O)CHS, -CH, 2 OCH, and -CH,0O-(4picoline). Ethyl, n-propyl, n-butyl, and isobutyl are 15 preferred. In certain particularly preferred compounds of the present invention, substituents R' and R are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (Rx) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxycarbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino,

N,N-

dialkylamino, (N)-alkoxycarbamoyl, aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, -N-alkylamido,

-N,N-

dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkyl-amino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, SRL 6045 hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute RX are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, *ethylthio, amino, hydroxylamine, N-methylamino, N,Ndimethylamino, N,N-diethylamino, S 15 (N)-benzyloxycarbamoyl, trimethylammonium,

A-,

-NHC(=O)CH,, -NHC(=O)CHi, -NHC (=O)CH 1 3 carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, -N-methylazetidinium -pyrrolidinyl, pyrrolyl, -N-methylpyridinium -N-methylmorpholinium A-, and N-N'-methylpiperazinyl, (N)-bromomethylamido, N-hexylamino, thiophene, (CH ),COH I, -NCH 3

CH,

2

CO,

2 H, (N)-N'-dimethylpiperazinium butyloxycarbamoyl, (N)-methylsulfonamido, methylpyrrolidinium, and -(OCHCH) 3 where A- is a pharmaceutically acceptable anion. The benzo ring is can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate a 5 or 6 carbon monosaccharide), peptide, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, -(OCHCH,)x-N R'R 4

RA,

where x is 2 to 10. Exemplary compounds are those set SRJ 6045 forth below in Table 1.

a a a b a a.

a a a SRL 6045 Table 1: Alternative Compounds #3 (Family F1O1.xacx.yyy)

R

5

R

Prefix Cpd# R 1

=R

2 RS (R'x)q (FFF.xaac. yyy) F101.001 01 ethyl Ph- 4* 4*

S

*5 *5 *5*S

S

02 03 04 05 06 07 08 09 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7 -me thyl 7-ethyl 7-iso-propyl 7 -tert-butyl 7-OH 7-OCH3 7-0 (iso-propyl) 7-SCH3 7-SOCH3 7-SO2CH3 7 -SCH2CH 3 7-NH2 7 -NHOH 7 -NHCH 3 7-N(CH 3 2 7-N+(CH 3 3

I-

7-NHC CH3 7-N(CH2CH 3 2 7 -NMeCH 2

CO

2

H

7-N+ (Me) 2 CH2CO2H, I- 7-M()-morpholine 7- -azetidirie 7-M()-N-methylazetidinium,

I-

7-M()-pyrrolidine 7-M()-N-methyl-pyrrolidinium.

I-

7-M()-N-methyl-morpholiniun,

I-

7- -methylpiperazine 7-M()-N'-dimethylpiperaziiiun,

I-

83 SRL 6045 Prefix Cpd* R 1

=R

2 RS (RX)q (FFF. xac. yyy) 29 ethyl Ph- 7-NH-CBZ ethyl Ph- 7-NHC(O)C 5 Hll 31 ethyl Ph- 7-NHC(O)CH 2 Br 32 ethyl Ph- 7-NH-C(NH)NH 2 33 ethyl Ph- 7-(2)-thiophene 34 ethyl Ph- 8-methyl ethyl Ph- 8-ethyl 36 ethyl Ph- 8-iso-propyl 37 ethyl Ph- 8-tert-butyl 38 ethyl Ph- 8-OH 39 ethyl Ph- 8-OCH 3 ethyl Ph- 8-O(iso-propyl) S41 ethyl Ph- 8-SCH 3 *42 ethyl Ph- 8-SOCH3 43 ethyl Ph- 8-SO2CH 3 44 ethyl Ph- 8-SCH 2

CH

3 ethyl Ph- 8-NH 2 46 ethyl Ph- 8-NHOH 47 ethyl Ph- 8-NHCH3 48 ethyl Ph- 8-N(CH 3 2 S ~49 ethyl Ph- 8-N+CCH3) 3

I-

555550 ethyl Ph- 8-NHC(=O)CH 3 51 ethyl Ph- 8-N(CH 2

CH

3 2 52 ethyl Ph- 8-NMeCH2CO 2

H

*.53 ethyl Ph- 8-N+(Me) 2

CH

2

CO

2 H, I- 54 ethyl Ph- 8-(N)-rnorpholine ethyl Ph- 8-(N)-azetidine 56 ethyl Ph- 8-(N)-N-methylazetidinium,

I-

57 ethyl Ph- 8-(N)-pyrrolidine 58 ethyl Ph- 8-(N)-N-methyl-pyrrolidiniun,

I-

59 ethyl Ph- 8-(N-N-rnethyl-morpholiniun,

I-

ethyl Ph- 8-(N)-N'-methylpiperazine 61 ethyl Ph- 8-(N-N'-dimethylpiperaziniun,

I-

62 ethyl Ph- 8-NH-CBZ 63 ethyl Ph- 8-NHC(O)C 5

H

11 64 ethyl Ph- 8-NHC(O)CH 2 Br 84 SRL 6045 Pref ix Cpd# R 1

=R

2 Rs (RX)cZ (FFF. aac. yyy) ethyl Ph- 8-NH-C(NH)NH 2 66 ethyl Ph- 8-(2)-thiophene 67 ethyl Ph- 9-methyl 68 ethyl Ph- 9-ethyl 69 ethyl Ph- 9-iso-propyl ethyl Ph- 9-tert-butyl 71 ethyl Ph- 9-OH 72 ethyl Ph- 9-OCH3 73 ethyl Ph- 9-O(iso-propyl) 74 ethyl Ph- 9-SCH3 ethyl Ph- 9-SOCH3 76 ethyl Ph- 9-SO2CH 3 :77 ethyl Ph- 9-SCH2CH3 78 ethyl Ph- 9-NH2 79 ety h-aN 79 ethyl Ph- 9-NHOH3 ethyl Ph- 9-N(CH 3 82 ethyl Ph- 9-N+(CH 3 )3 I 82 ethyl Ph- 9 -NH(=H3) 3 ,i- 83 ethyl Ph- 9-N(H(0CH 3 ethyl Ph- 9-NMeCH 2

CO

2

H

86 ethyl Ph- 9-N+(Me) 2

CH

2

CO

2 H, I- :87 ethyl Ph- 9-(N)-morpholine 88 ethyl Ph- 9-(N)-azetidine a...89 ethyl Ph- 9-(N)-N-methylazetidinium,

I-

ethyl Ph- 9-(N)-pyrrolidine 91 ethyl Ph- 9-(N)-N-methyl-pyrrolidinium, I- 92 ethyl Ph- 9-(N)-N-methyl-morpholinium, I- 93 ethyl Ph- 9-(N)-N'-inethylpiperazine 93 ethyl Ph- 9-(N)-N'-dimethylpiperaziniun, Iethyl Ph- 9-NH-CBZ 96 ethyl Ph- 9-NHC(O)C 5 Hll 97 ethyl Ph- 9-NHC(O)CH 2 Br 98 ethyl Ph- 9-NH-C(NH)NH 2 99 ethyl Ph- 9-(2)-thiophene SRL 6045 Prefix Cpd* R 1

-R

2 Rs (Rx)q (FFF. xxa. yyy) 0b

S

.5 *5*S

S

5% 5*

S

S

100 101 102 103 F101. 002 01 02 03 04 06 07 08 09 10 11 12 13 14 16 17 18 19 20 21 22 23 24 26 27 28 29 31 32 ethyl ethyl ethyl ethyl n-p ropyl n-p ropyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl fl-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-pr opyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-OCR 3 8-OCH 3 7-SCH 3 8-OCH3 7-SCH 3 8-SCH3 6-OCH3, 7-OCR 3 8-OCH 3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OR 7-OCR3 7-0 (is 0-propyl) 7- SCR3 7-SOCR 3 7-SO2CH 3 7 -SCR 2 CR3 7-NH 2 7 -NROH 7 -NHCH 3 7-N(CH 3 2 7-N+(CH3)3,

I-

7-NHC(=O)CR 3 7-N(CR2CH3) 2 7 -NMeCR2CO 2

H

7-N+ (Me) 2 CR2CO 2 R, I- 7- -xorpholine 7- -azetidine 7- -N-methylazetidiniun, I- 7- -pyrrolidine 7- -N-methyl-pyrrolidinium, I- 7- -N-methyl-morpholiniun,

I-

7-M()-N'-methylpiperazine 7- -dimethylpiperazinium, I- 7 -NH-CBZ 7-NRC (0)C 5

R

11 7-NRC(0) CR2Br 7-NR-C (NR) N12 SRL 6045 Pref ix (FFF. ,aaC.

000 0 .0* 0S Cpd# my)- 33 34 36 37 38 39 41 42 43 44 45 46 47 48 49 50 51.

52 53 54 56 57 58 59 61 62 63 64 66 67 68 ri-propyl ri-propyl ri-propyl ri-propyl ri-propyl ri-p ropyl ri-p ropyl n-propyl ri-propyl ri-propyl ri-propyl ri-propyl n-propyl ri-propyl n-propyl n-propyl n-p ropyl n-propyl n-propyl n-p ropyl ri-propyl n-propyl ri-propyl ri-propyl n-propyl ri-propyl n-propyl n-propyl n-propyl ri-propyl ri-propyl n-propyl ri-propyl n-propyl ri-propyl n-pr opyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7- -thiophene 8 -methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8 -OH 8-OCH 3 8-0 (iso-propyl) 8- SCH3 8-SOCH 3 8-SO2CH 3 8-SCH2CH 3 8-NH 2 8-NHOH 8 -NHCH 3 8-N(CH 3 2 8-N 4

(CH

3 3

I-

S-NHC

CH

3 8-N(CH 2

CH

3 2 8-NMeCH 2

CO

2

H

8-N 4 (Me) 2 CH2CO 2 H, I- 8- -morpholine 8- -azetidine 8- -N-rnethylazetidiniun, I- 8- -pyrrolidine 8- -N-methyl-pyrrolidinium,

I-

8- -N-methyl-morpholiniun, I- 8- -methylpiperaziie 8- -dimethylpiperazinium,

I-

8 -NH-CBZ 8-NHC CHll 8-NHC (0)CH2Br 8-NH-C (NH) NH2 8- -thiopherie 9-methyl 9-ethyl Rl=R 2 RS (RX) SRL 6045 Prefix Cpd# R 1

=R

2 RS (RX)q (FFF. xxx. yyy) 73.

72 73 74 76 77 78 79 80 831 82

S

0O** S S 0O S *0 @5 C 0

S

0@ OS S C *5 @0 S 0*e S 5.5.

5

*OSS

0 5555

S@

S

0@

*SSO

5 e.g.

*5 S. S *0C5

C

0 83 84 85 86 87 88 89 9.0 91 92 93 93 96 97 98 99 100 101 102 103 F101.003 01 "-&Jropyl n-propyl n-propyl n-propyl n-propyl n-propyl n-p ropyl n-propyl n-propyl n-propyl n-pr opyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-pr opyl n-propyl n-propyl n-propyl n-propyl n-pr opyl n-butyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9- iso-propyl 9 -tert-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SCH 3 9-SOCH 3 9-SO 2

CH

3 9-SCH2CH 3 9-NH2 9-NHOH 9 -NHCH 3 9-N(CH 3 2 9-N+(CH 3 3

I-

9 -NHC CH3 9-N(CH 2

CH

3 2 9 -NMeCH 2

CO

2

H

9-N+(Me) 2

CH

2

CO

2 H, I- 9-M()-morpholine 9- -azetidine 9- -N-methylazetidiniun, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidinium, I- 9- -N-methyl-morpholinium, I- 9- -methylpiperazine 9- -dimethylpiperazinium, I- 9 -NH-CBZ 9-NHC 9-NHC (0)CH2Br 9-NH-C (NH) NH2 9- -thiophene 7-OCH3, 8-OCH3.

7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8-OCH3 7-methyl 88 SRL 6045 Prefix Cpd# R 1

=R

2 RS (RX)q (FFF.,gac. yyy) 02 n-butyl Ph- 7-ethyl 03 n-butyl Ph- 7 -iso-propyl 04 ri-butyl Ph- 7-tert-butyl n-butyl Ph- 7-OH 06 n-butyl Ph- 7-OCH3 07 n-butyl Ph- 7 -O(iso-propyl) 08 n-butyl Ph- 7-SCH3 09 n-butyl Ph- 7-SOCH 3 n-butyl Ph- 7-SO2CH 3 11 ri-butyl Ph- 7-SCH2CH 3 12 n-butyl Ph- 7-NH 2 13 n-butyll Ph- 7-NHOH 14 n-butyl Ph- 7-NHCH 3 n-butyl Ph- 7-N(CH 3 2 n-butyl Ph- 7-N-(CH 3 3

I-

17 n-butyl Ph- 7-NHC(=O)CH 3 18 n-butyl Ph- 7 -N (CH 2

CH

3 2 19 n-butyl Ph- 7-NMeCH 2

CO

2

H

n-butyl Ph- 7-N+(Me) 2

CH

2

CO

2 H, I- *21 n-butyl Ph- 7- -morpholine *22 n-butyl Ph- 7- -azetidine 23 n-butyl Ph- 7 -(N-N-methylazetidinium,

I-

:24 n-butyl Ph- 7 -pyrrolidine n-butyl Ph- 7-(N-N-methyl-pyrrolidiniun,

I-

26 n-butyl Ph- 7 -(N)-N-methyl-morpholinium,

I-

27 n-butyl Ph- -methylpiperazine 28 n-butyl Ph- 7 -(N)-N'-dimethylpiperaziniun,

I-

29 n-butyl Ph- 7-NH-CBZ n-butyl Ph- 7-NHC(O)C 5 Hll 31 n-butyl Ph- 7-NHC(O)CH 2 Br 32 n-butyl Ph- 7-NH-C(NH)NH 2 33 n-butyl Ph- 7 -(2)-thiophene 34 n-butyl Ph- 8-methyl n-butyl Ph- 8-ethyl 36 n-butyl Ph- 8 -iso-propyl 37 n-butyl Ph- 8-tert-butyl 89 SRL 6045 Pref ix Cpd R 1

=R

2 RS (R 1

C

(FFF. aac. yyy) 38 n-butyl Ph- 8-OH 39 n-butyl Ph- 8-OCH 3 n-butyl Ph- 8-O(iso-propyl) 41 n-butyl Ph- 8-SCH 3 42 n-butyl Ph- 8-SOCH 3 43 n-butyl Ph- 8-SO 2

CH

3 44 n-butyl Ph- 8-SCH2CH 3 n-butyl Ph- 8-NH 2 46 n-butyl Ph- 8-NHOH 47 n-butyl Ph- 8-NHCH 3 *48 n-butyl Ph- 8-N(CH 3 2 *49 n-butyl Ph- 8-N+(CH 3 3

I-

n-butyl Ph- 8-NHC(=O)CH3 n-butyl Ph- 8 -N (CH2 CH3) 2 52 n-butyl Ph- 8-NMeCH 2

CO

2

H

53 n-butyl Ph- 8-N+(Me) 2

CH

2

CO

2 H, I- 54 n-butyl Ph- 8-(N)-morpholine n-butyl Ph- 8-(N)-azetidine 56 n-butyl Ph- 8-(N)-N-inethylazetidiiium,

I-

57 n-butyl Ph- 8-(N)-pyrrolidine 58 n-butyl Ph- -N-methyl-pyrrolidiiium,

I-

59 n-butyl Ph- 8-(N)-N-methyl-norpholiniun,

I-

n-butyl Ph- 8-(N)-N'-methylpiperazine 61 ri-butyl Ph- 8-(N)-N'-dirnethylpiperazinium,

I-

62 n-butyl Ph- 8-NH-CBZ 63 n-butyl Ph- 8-NHC(O)C 5

H

11 64 n-butyl Ph- 8-NHC(O)CH 2 Br n-butyl Ph- 8-NH-C(NH)NH 2 66 n-butyl Ph- 8-(2)-thiophene 67 n-butyl Ph- 9-methyl 68 n-butyl Ph- 9-ethyl 69 n-butyl Ph- 9-iso-propyl n-butyl Ph- 9-tert-butyl 71 n-butyl Ph- 9-OH 72 n-butyl Ph- 9-OCH3 73 n-butyl Ph- 9-O(iso-propyl) SRL 6045 Prefix Cpd# R 1

=R

2 RS (Rx)q (FFF. xxx. yyy) 74 76 77 78 79 81 82

S.

83 84 85 86 87 88 89 90 91 92 93 93 95 96 97 98 99 100 101 102 103 F101. 004 01 02 03 04 06 n-butyl n-butyl n-butyl n-butyl n-buty1 n-butyl n-buiyl n- butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl ri-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-pentyl n-pentyl n-pentyl n-perxtyl n-pentyl n-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph-- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-SCH 3 9 -SOCH3 9-SO2CH 3 9 -SCE2CH 3 9-NE 2 9-NHOH 9 -NHCH3 9-N(CE3) 2 9-N+(CH 3 3

I-

9-NEC

CE

3 9-N(CH 2

CH

3 )2 9 -NMeCE 2

CO

2

H

9-N+ (Me) 2 CE2CO2H, I- 9- -morpholine 9- -azetidine 9- -N-rethylazetidiniun, I- 9- -pyrrolidine 9- -N-rnethyl-pyrrolidinium, I- 9- -N-methyl-morpholinium, I- 9- -methylpiperazine 9- -dimethylpiperazinium, I- 9 -NE-CBZ 9-NEC 9-NEC(0) CE2Br 9-NE-C (NH)NH 2 9- -thiophene 7-OCE3, 8-OCH3 7-SCE 3 8-aCE 3 7-SCE3, 8-SCE 3 6-OCE3, 7-OCE 3 8-OCE3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OE 7-OCE3 91 SRL. 6045 Pre f ix Cpd# R 1

=R

2 RS MY-) q (FFF. xaaC. YY)Ph -ispryl 07 n-pefltylPh 7-is-rP) 08 n-pentyl Ph- 7-SCH3 09 n-pentyl Ph- 7-SOCH3 n-penty. Ph- 7-SO 2 CH3 12. n-pentyl Ph- 7-SCH2CH3 12 n-pentyl Ph-

-H

13 n-pentyl Ph- '7-NI{OH 14 n-pentyl Ph- 7-NHCH3 n-pefltyl Ph- 7-N(CH3)2 *9*16 n-pefltyl Ph- 7-N+(CH3)3, 17 n-pefltyl Ph- 7-NHC(0O)CH3 *18 n-pefltyl Ph- 7-N(CH2CH3)2 .19 n-pefltyl Ph- 7-NmeCH2CO2H n-pefltyl Ph- 7-N-(Me)2 CH2CO2H,

I

21 n-pefltyl Ph- -7-(N)-mIforpholine 22 n-pentyl Ph- 7-(N)-azetdilaetiiim 23' n-pefltYl

P

oo.24 n-pefltyl Ph- 7 -pyrroidine n-pefltyl Ph- 7 -(N)-N-methYl-pyrroljdinium, *2 6 n p ef l t y l P h 7 N e h l o p o i m I 27 n-pentYl Ph- 7 -(N)-N'-methylpiperazine 28 n-pentyl Ph- 7-N-'diehlierznu 1 .0029 n-pentyl Ph- 7-NH-CBZ 0:30 n-pentyl Ph- 7-NHC(O)C5H11 31 n-pentyl Ph- 7-NHiC(O)CH2Br 32 n-pefltyl Ph- 7 -NH- C(NH) NH2 33 n-penty). Ph- 7 -(2)-thiophene 34 n-pentyl Ph- 8-methyl n-pentyl Ph- 8-ethyl 36 n-pefltyl Ph- 8-iso-PrOPyl 37 n-perityl Ph- 8-te 'rt-butyl 38 n-perityl Ph- 8-OH 39 n-pentyl Ph- 8-OCH3 n-pentyl Ph- 8-O(iso-Propyl) 41 n-pentyl Ph- 8-SCH3 42 n-pentyl Ph- 8-SOCH3 SRL 6045 Prefix Cpd# R 1

=R

2

R

5 (RX)q (FFF. aac. yyy) 43 44 46 47 48 49 n-pentyl n-pentyl n-pen tyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-penty.

n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-SO 2

CH

3 8-SCH2CH 3 8-NH 2 8 -NHOH 8-NHCH 3 8-N(CH 3 2 8-N+(CH3) 3

I-

8-NHC CH3 8-N (CH2CH 3 2 8 -NMeCH 2

CO

2

H

8-N+ (Me) 2

CH

2

CO

2 H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidinium,

I-

8- -pyrrolidine 8- -N-methyl-pyrrolidiniun,

I-

8- -N-methyl-morpholinium,

I-

8-M()-N'-methylpiperazine 8-M()-N'-dimethylpiperazinium,

I-

8 -NH-CBZ 8-NHC C5H 1 8 -NHC CH2 Br 8-NH-C (NH)NH 2 8- -thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SCH3 9-SOCH 3 9-SO 2

CH

3 9- SCH2CH 3 9-NH 2 a.

a.

a a.

a a SRL 6045 Pref ix Cpd# R 1

=R

2 RS (RX) q (FFF.200c. yyy) 79 81 82

S

S

S 83 84 86 87 88 89 90 91 92 93 93 95 96 97 98 99 100 101 102 103 F101. 005 01 02 03 04 06 07 08 09 11 n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-perityl n-pentyl n-perityl n-pentyl n-pentyl n-pentyl n-perityl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n- hexyl n-hexyl n-hexyl n-hexyl n-hexyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9 -NHOH 9 -NHCH 3 9 -N (CH3) 2 9-N+(CH 3 3

I-

9-NHC (=O)CH 3 9-N CCH 2

CH

3 2 9 -NMeCH 2

CO

2

H

9-N*(Me) 2

CH

2

CO

2 H, I- 9-M()-morpholine 9- -azetidine 9- -N-methylazetidinium,

I-

9- -pyrrolidine 9- -N-methyl-pyrrolidinium,

I-

9- -N-rnethyl-morpholinium,

I-

9- -N'-methylpiperazine 9- -N'-dimethylpiperaziniun,

I-

9-NH-CBZ 9-NHC 9-NHC (0)CH 2 Br 9-NH-C (NH)NH 2 9-(2)-thiophene 7-OCH3, 8-OCH 3 7-SCH 3 8-OCH 3 7-SCH 3 8-SCH 3 6-OCH3, 7-OCH 3 8-OCH3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH3 7-0 (iso-propyl) 7-SCH3 7-SOCH 3 7-SO2CH 3 7 -SCH 2

CH

3 SRL 6045 Prefix Cpd# R 1

=R

2 RS (Rx)q (FFF.xxoc. yyy) 12 n-hexyl Ph- 7-NH2 13 n-hexyl Ph- 7-NHOH 14 n-hexyl Ph- 7-NHCH 3 n-hexyl Ph- 7-N(CH 3 2 16 n-hexyl Ph- 7-N+(CH 3 3

I-

17 n-hexyl Ph- 7-NHC(=O)CH 3 18 ri-hexyl Ph- 7-N(CH2CH 3 2 19 n-hexyl Ph- 7-NMeCH 2

CO

2

H

ri-hexyl Ph- 7-N+(Me) 2

CH

2 C0 2 H, I- 21 ri-hexyl Ph- 7-(N)-morpholine 22 n-hexyl Ph- 7- -azetidine 23 ri-hexyl Ph- 7 -(N-N-methylazetidinium,

I-

24 n-hexyl Ph- 7-(N)-pyrrolidine n-hexyl Ph- 7 -(N-N-methyl-pyrrolidiniut,

I-

n-hexyl Ph- 7 -(N-N-methyl-morpholinium,

I-

27 n-hexyl Ph- 7 -(N-N'-methylpiperazine *28 n-hexyl Ph- 7 -(N)-N'-dimethylpiperazinium,

I-

*29 n-hexyl Ph- 7-NH-CBZ n-hexyl Ph- 7-NHC(O)C 5 Hll *31 n-hexyl Ph- 7-NHC(O)CH 2 Br 32 n-hexyl Ph- 7-NH-C(NH)NH 2 33 n-hexyl Ph- 7-(2)-thiophene .:34 n-hexyl Ph- 8-methyl n-hexyl Ph- 8-ethyl 36 n-hexyl Ph- 8-iso-propyl 37 n-hexyl Ph- 8-tert-butyl 38 n-hexyl Ph- 8-OH 39 n-hexyl Ph- 8-OCH 3 n-hexyl Ph- 8-O(iso-propyl) 41 n-hexyl Ph- 8-SCH3 42 n-hexyl Ph- 8-SOCH 3 43 n-hexyl Ph- 8-SO2CH 3 44 n-hexyl Ph- 8-SCH2CH 3 n-hexyl Ph- 8-NH 2 46 -n-hexyl Ph- 8-NHOH 47 n-hexyl Ph- 8-NHCH 3 SRIL 6045 Pref ix Cpd# R 1

=R

2 RS (R')qc (FFF. aac. yyy) 48 n-hexy. Ph- 8-N(CH 3 2 49 n-hexyl Ph- 8-N+(CH 3 3

I-

n-hexyl Ph- 8-NHC(=O)CH 3 51 ri-hexyl Ph- 8-N(CH 2

CH

3 2 52 n-hexyl Ph- 8-NMeCH 2

CO

2

H

53 n-hexyl Ph- 8-N+(Me) 2

CH

2

CO

2 H, I- 54 n-hexyl Ph- 8-(N)-morpholine n-hexy. Ph- 8-(N)-azetidine 56 n-hexyl Ph- 8-(N)-N-methylazetidinium,

I-

57 n-hexyl Ph- 8-(N)-pyrrolidine 58 ey Ph .N--ehlproiiim 58 n-hexyl Ph- 8-(N)-N-methyl-pyrrholinium,

I-

n-hexyl Ph- 8-(N-N-methylpiperazine n-hexyl Ph- 8-(N)-N'-dimethlpiperaziniun,

I-

62 n-hexyl Ph- 8-NH-CBZ 63 n-hexy2. Ph- 64 n-hexyl Ph- 8-NHC(O)CH 2 Br n-hexyl Ph- 8-NH-C(NH)NH 2 66 n-hexyl Ph- 8-(2)-thiophene 67 n-hexy2. Ph- 9-methyl 68 n-hexyl Ph- 9-ethyl 69 n-hexyl Ph- 9-iso-propyl n-hexyl Ph- 9-tert-butyl 71 n-hexyl Ph- 9-OH 72 n-hexyl Ph- 9-OCH3 73 n-hexyl Ph- 9-O(iso-propyl) 74 n-hexyl Ph- 9-SCH 3 n-hexyl Ph- 9-S0CH 3 76 n-hexyl Ph- 9-SO2CHi3 77 n-hexyl Ph- 9-SCH 2

CH

3 78 n-hexyl Ph- 9-NH2 79 n-hexyl Ph- 9-NHOH n-hexyl Ph- 9-NHCH 3 81 n-hexyl Ph- .9-N(CH 3 2 82 n-hexyl Ph- 9-N+(CH 3 3

I-

83 n-hexyl Ph- 9-NHC(=O)CH 3 SRL 6045 Prefix Cpd# Rl=R 2

R

5 (RX)q (FFF. aac. yyy) 84 86 87 88 89 91 92 93 93 95 96 97 98 99 100 101 102 103 F101. 006 01 02 03 04 05 06 07 08 09 11 12 13 14 16 n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl n-hexyl iso-propyl iso -propyl iso-propyl iso-propyl iso-propyl i so-propyl iso-propyl i so-propyl iso-propyl iso-propyl iso-propyl i so-propyl iso-propyl iso-propyl iso-propyl iso-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-N(CH2CH 3 2 9 -NMeCH2C0 2

H

9-Nt (Me) 2

CH

2

CO

2 H, I- 9- -morpholine 9- -azetidirie 9- -N-methylazetidiiiu,

I-

9- -pyrrolidine 9- -N-methyl-pyrrolidinium,

I-

9- -N-methyl-rnorpholinium,

I-

9- -methylpiperazine 9- -dimethylpiperazinium,

I-

9 -NH-CBZ 9-NHC (0)C5Hl 1 9-NHC (0)CH2Br 9-NH-C (NH) NH 2 9 thiophene 7-OCH 3 8-OCH3 7-SCH 3 8-OCH3 7-SCH 3 8-SCH 3 6-OCH3, 7-OCH 3 8-OCH3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 (iso-propyl) 7-SCH 3 7 -SOCH 3 7-SO2CH 3 7-SCH2CH 3 7-NH2 7-NHOH 7-NIICH 3 7-N(CH 3 2 7-N+(CH 3 3

I-

SRI. 6045 Pref ix (FFF. xxx.

Cpd# 17 18 19 21 22 23 24 26 27 28 29 30 31 32 33 34 36 37 38 39 40 41 42 43 44 46 47 48 49 51 52 iso-propyl iso-propyl iso-propyl is 0-p ropyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl i so-propyl i so-propyl iso -propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl is 0-propyl iso-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7 -NBC

CH

3 7-N(CH 2

CH

3 2 7 -NMeCH 2

CO

2

H

7-N+(Me) 2

CH

2

CO

2 H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidinium,

I-

7- -pyrrolidine 7- -N-methyl-pyrrolidinium,

I-

7- -N-rnethyl-rnorpholinium,

I-

7-M()-N'-methylpiperazine 7- -dirnethylpiperazinium,

I-

7-NH-CBZ 7-NHC(O)C 5 Hll 7-NHC(O)CH 2 Br 7-NB-C (NH)NH 2 7- -thiophene 8 -methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8- OH 8-OCH3 8-0 (iso-propyl) 8-SCH 3 8-SOCH 3 8-SO2CH 3 8- SCH 2

CH

3 8-NH 2 8 -NHOH 8-NIICH 3 8-N(CH 3 )2 8-N+(CH 3 3

I-

8-NBC CH3 8-N(CH 2

CH

3 2 8-NMeCH 2

CO

2

H

R

1

-R

2 RS (RX')q SRL 6045 Prefix Cpd# RL.R 2 RS (Rx)q (FFF. acx. yyy) 53 iso-propyl 0*0@ @000 0000 C SO @0 0 00 *b 00 0 00 00 0 0 6 @0 0 0 0 iso-propyl is 0-propyl iso-propyl is 0-pr opyl iso-propyl iso-propyl iso-propyl iso-propyl is 0-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propy.

i so-propyl iso-propyl iso -propyl iso-propyl iso -propyl iso-propyl i so-propyl iso-propyl iso-propyl iso-propyl iso-propyl i so-propyl iso-propyl i so-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl Ph- 8-N-(Me) 2

CH

2

CO

2 H, I- Ph- 8- -morpholiie Ph- 8- -azetidine Ph- 8 -N-methylazetidinjum

I

Ph- 8- -pyrrolidine Ph- 8- -N-methyl-pyrrolidinium,

I-

Ph- 8- -N-methyl-morpholinium,

I-

Ph- 8-M()-N'-methylpiperazine Ph- 8- -dixethylpiperazinium,

I-

Ph- 8-NH-CBZ Ph- 8-NHC(O)C 5 Hll Ph- 8-NHC(O)CH 2 Br Ph- 8-NH-C(NH)NH 2 Ph- 8-(2)-thiophene Ph- 9-methyl Ph- 9-ethyl Ph- 9-iso-propyl Ph- 9-tert-butyl Ph- 9-OH Ph- 9-OCH 3 Ph- 9-0 (iso-propyl) Ph- 9-SCH3 Ph- 9-SOCH 3 Ph- 9-SO2CH 3 Ph- 9-SCH 2

CH

3 Ph- 9-NH2 Ph- 9-NHOH Ph- 9-NHCH 3 Ph- 9-N(CH 3 2 Ph- 9-N+(CH 3 3

I-

Ph- 9-NHC(=O)CH 3 Ph- 9-N(CH 2

CH

3 2 Ph- 9-NMeCH 2

CO

2

H

Ph- 9-N'(Me) 2

CH

2

CO

2 H, I- Ph- 9- -morpholine Ph- 9- -azetidine *0 5 0 *0 0000 0 0000 0 00 S S OnS 5*0050 5 SRL 6045 S. S. *5*S

S

*SS*

S

S**

SS

S

S.

**50 Prefix Cpd* (FFF. xxx. yyy) 89 91 92_ 93 93 96 97 98 99 100 101 102 103 F101.007 01 02 03 04 05 06 07 08 09 11 12 13 14 16 17 18 19 is0-pr opyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl is 0-propyl iso -propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl i so-butyl i so-butyl iso-butyl Ph- 9-(N)-N-xnethylazetidinium,

I-

Ph- 9- -pyrrolidine Ph- 9- -N-methyl-pyrrolidinium,

I-

Ph- 9 -(N)-N-methyl-morpholinium,

I-

Ph- 9-M()-N'-methylpiperazine Ph- 9-M()-N'-dimethylpiperaziniwn,

I-

Ph- 9-NH-CBZ Ph- 9-NHC(O)C 5 Hl 1 Ph- 9-NHC(O)CH 2 Br Ph- 9-NH-C(NH)NH 2 Ph- 9- -thiophene Ph- 7-OCH3, 8-OCH 3 Ph- 7-SCH3, 8-OCH 3 Ph- 7-SCH3, 8-SCH 3 Ph- 6-OCH 3 7-OCH3, 8-OCH3 Ph- 7-methyl Ph- 7-ethyl Ph- 7-iso-propyl Ph- 7-tert-butyl Ph- 7-OH Ph- 7-OCH3 Ph- 7-O(iso-propyl) Ph- 7-SCH 3 Ph- 7-SOCH 3 Ph- 7-SO 2

CH

3 Ph- 7-SCH 2

CH

3 Ph- 7-NH 2 Ph- 7-NHOH Ph- 7-NHCH 3 Ph- 7-N(CH3) 2 Ph- 7-N+(CH3)3,

I-

Ph- 7-NHC(=O)CH3 Ph- 7-N(CH 2

CH

3 2 Ph- 7-NMeCH2CO2H Ph- 7-N+(Me) 2

CH

2

CO

2 H, I- Ph- 7- -morpholine R'=R2R 5 q 21 iso-butyl SRL 6045 Pre fix (FFF. xxoc.

S

*5 Cpd# yyy) 22 23 24 26 27 28 29 31 32 33 34 35 36 37 38 39 41 42 43 44 45 46 47 48 49 51 52 53 54 56 57 iso-butyl iso-butyl iso-butyl iso-butyl -iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl i so-butyl iso-butyl iso -butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso -bu tyl iso-butyl iso-butyl iso -bu tyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso -butyl iso-butyl iso-butyl iso-butyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7- -azetidine 7- -N-methylazetidinium

I

7- -pyrrolidine 7- -N-rnethyl-pyrrolidinium,

I-

7- -N-methyl-morpholinium,

I-

7-M()-N'-methylpiperazine 7- -dimethylpiperazinium,

I-

7 -NH-CBZ 7-NHC 7-NHC (0)CH2Br 7-NH-C (NH) NH 2 7- -thiophene 8 -methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH 3 8-SOCH 3 8-SO 2

CH

3 8-SCH 2

CH

3 8-NH 2 8-NHOH 8-NECH 3 8-N(CH 3 2 8-N+(CH 3 3

I-

8-NHC (=O)CH3 8-N(CH 2

CH

3 2 8 -NMeCH 2

CO

2

H

8-N+ (Me) 2 CH2CO 2 H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidinium,

I-

8- -pyrrolidine

R

1

=R

2 RS (RX)q SRIL 6045 Pref ix (FFF. xxx.

*e *9 9 9* 9 9

S

9'9* 9*

S

9.* 9* 9*S*

S

.5* 9 Cpd# yyy) 58 59 61 62 63 64 66 67 68 69 70 71 72 73 74 76 77 78 79 80 81 82 83 84 86 87 88 89 91 92 93 iso-butyl iso-butyl i so-butyl i so-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso -butyl iso-butyl iso -butyl iso-butyl iso-butyl i so-butyl iso-butyl iso-butyl iso-butyl is o-butyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8- -N-methyl-pyrrolidinium, I- 8- -N-methyl-morpholiiium, I- 8- -methylpiperaziie 8- -dimethylpiperazinium, I- 8-NH-CBZ 8-NHC 8-NEC (0)CH2Br 8-NE-C (NH) NE 2 8- -thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SCH 3 9-SOCH3 9-SO2CH3 9-SCH2CH 3 9-NE2 9-NEOH 9-NECH 3 9-N(CH 3 2 9-N+(CH 3 3

I-

9-NHC(=O)CH 3 9-N(CH2CH 3 2 9 -NMeCH 2

CO

2

H

9-N 4 (Me) 2 CH2CO 2 H, I- 9- -morpholine 9- -azetidine 9- -N-methylazetidinium, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidinium, I- 9- -N-methyl-morpholinium, I- 9- -methylpiperazine

R

1

=R

2 RS (Rx)q 102 SRL 6045 a.

S

a Prefix Cpd* (FFF. xx. yyy) 93 96 97 98 99 100 101 102 103 F101.008 01 02 03 04 06 07 08 09 10 11 12 13 14 16 17 18 19 21 22 23 24 26 iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso -butyl iso-butyl iso-butyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-perityl iso-pentyl iso-pentyl iso-pentyl iso-pentyl 9-M()-N'-dirnethylpiperaziniun, I- 9-NH-CBZ 9-NBC 9-NBC (0)CH2Br 9-NB-C(NB)

NH

2 9- -thiophene 7-OCH 3 8-OCH 3 7-SCH 3 8-OCH 3 7-SCH3, 8-SCH 3 6-OCH3, 7-OCH3, 8-OCH 3 7-methyl 7-ethyl 7- iso-propyl 7-tert-butyl 7-OH 7-OCH3 7-0 (iso-propyl) 7- SCH3 7-SOCH3 7-SO2CH3 7-SCH2CH 3 7-NH2 7-NHOH 7 -NBCH3 7-N(CH 3 2 7-N+(CH 3 3

I-

7-NBC CH3 7-N (CH2CH 3 2 7-NMeCH 2

CO

2

H

2 CH2CO 2 H, I- 7- -morpholiie 7- -azetidirie 7- -N-methylazetidinium, I- 7- -pyrrolidine 7- -N-methy-pyrroidiiuml I- 7- -N-methyl-norpholiniuml I- R'=R2 R 5 (Rx) q Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- SRL 6045 Prefix Cpd# Rl=R 2 Rs (Rx)q (FFF. aac. yyy) 9* 27 28 29 31 32 33 34 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 56 57 58 59 61 62 iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso -pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-M()-N'-methylpiperazine 7-M()-N'-dimethylpiperaziniut,1 '7-NH-CBZ 7-NEC C5H 1 1 7-NEC (0)CH2Br 7-NE-C (NH)NH 2 7- -thiophene 8 -methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH 3 8- SCH2CH 3 8 -NE2 8-NEHOH 8-NECH3 8-N (CH 3 2 8-N+ (CH 3 3 1- 8-NHC(=O)CH 3 8-N(CH2CH 3 2 8 -NMeCH2CO 2

H

8-N+ (Me) 2 CH2CO2H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidinium, I- 8- -pyrrolidine 8- -N-methyl-pyrrolidiniun,

I-

8- -N-rnethyl-morpholinium, I- 8- -methylpiperazine 8-M()-N'-dixnethylpiperazinium,

I-

8 -NH-CBZ b*

I

104 SRL 6045 Pref ix (FFF. xac.

*4 9.

9

A

9 Cpd# my) 63 64 66 67 68 69 71 72 73 74 75 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 93 96 97 98 iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-penty.

iso-pentyl iso-pentyl iso-perityl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl i so-pentyl iso-pentyl i so-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NHC 8-NHC (0)CH 2 Br 8-NH-C (NH) NH 2 8- -thiophene 9-methyl 9-ethyl 9- iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SCH3 9-SOCH3 9-SO2CH 3 9-SCH 2

CH

3 9-NH2 9 -NHOH 9 -NHCH 3 9-N(CH 3 2 9-N 4

(CH

3 3

I-

9-NHC CH3 9-N (CH 2

CH

3 2 9 -NI~eCH 2

CO

2

H

9-N 4 (Me) 2 CH2CO 2 H, I- 9- -morpholine 9- -azetidine 9- -N-methylazetidiniun, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidiniui, I- 9- -N-methyl-morpholinium, I- 9- -methylpiperazine 9- -dimethylpiperazinium, I- 9 -NH-CBZ 9-NHC 9-NHC (0)CH 2 Br 9-NH-C (NH)NH 2

R

1

-R

2 RS (Rx) q SRL 6045 C U. U.

U

U.

U

U

S

U

'U.

Prefix Cpd# (FPF.xxx. yyy) 99 100 101 102 103 F101.009 01 02 03 04 06 07 08 09 11 12 13 14 15 16 17 18 19 21 22 23 24 26 27 28 29 iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2 Hs

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C (=0)C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9- -thiophene 7-OCH3, 8-OCH3 7-SCH 3 8-OCH3 7-SCH 3 8-SCH3 6-OCH 3 7-OCH3, 8-OCH 3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH3 7-0 (iso-propyl) 7-SCH3 7-SOCH 3 7-SO2CH 3 7-SCH2CH 3 7-NH 2 7-NHOH 7 -NHCH 3 7-N(CH 3 2 7-N+(CH 3 3

I-

7-NHC(=0)

CH

3 7 -N (CH 2

CH

3 2 7-NMeCH 2

CO

2

H

7-N(Me) 2 CH2CO 2 H, I- 7- -morpholine 7- -azetidine

R

5 (RX2 7- -N-methylazetidiniun,

I-

7- -pyrrolidine 7- -N-methyl-pyrrolidinium,

I-

7- -N-methyl-morpholiniun,

I-

7- -iethylpiperazine 7- -dimethylpiperaziniun,

I-

7-NH-CBZ 7-NiC 106 SRL 6045 Pref ix (FFF. -x

I..

StaSes 4 Cpd# my) 31.

32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 50 51 52 53 54 56 57 58 59 61 62 63 64

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2 H5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-NHC (0)CH2Br 7-NH-C (NH)NH 2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8 -OH 8-OCH 3 8-0 (iso-propyl) 8- SCH3 8-SOCH 3 8-SO2CH 3 8-SCH 2 CHi 8 -NHl 2 8 -NHOH 8 -NHCH 3 8-N(CH 3 2 8-N+(CH 3 3

I-

8-NEC

CH

3 8-N(CH 2

CH

3 2 8 -NMeCH2CO 2

H

8-N'(Me) 2

CH

2

CO

2 H, I- 8- -morpholine 8- -azetidine 8- -N-methylazetidinium,

I-

8- -pyrrolidine 8- -N-methyl-pyrrolidiniun,

I-

8- -N-methyl-morpholinium,

I-

8- -methylpiperazine 8- -direthylpiperazinium,

I-

8 -NH-CBZ 8-NEC 8-NHC CH2Br

R

1

=R

2 RS (Rx) q SRI, 6045 Prefix Cpd# Rl= 2 RS (Rx)q (FFF. gac. yyy) a 60 0.0.

p* 0.0.

66 67 68 69 71 72 73 74 76 77 78 79 80 81 82 83 84 86

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

HS

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

HS

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2 H5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2 H5

CH

2 C C 2

HS

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C (=0)C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NH-C (NH) NH 2 8- -thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9- SCH 3 9-SOCH 3 9-SO2CH 3 9-SCH 2

CH

3 9-NH 2 9-NHOH 9-N'HCH3 9-N(CH 3 )2 9-N+(CH 3 3

I-

9-NHC CH3 9-N(CH2CH 3 2 9 -NMeCH 2

CO

2

H

9-N+ (Me) 2

CH

2

CO

2

H,

9- -morpholine 9- -azetidine 9- -N-methylazetidiniun,

I-

9- -pyrrolidine 9- -N-methyl-pyrrolidinium,

I-

9- -N-methyl-morpholiniumn,

I-

9-M()-N'-methylpiperazine 9-M()-N'-dimethylpiperaziniun,

I-

9-NH-CBZ 9-NHC (0)C5H 11

L

9-NHC CH2Br 9-NH-C

(NH)NH

2 108 SRL 6045 Prefix Cpd# Rl=R 2 RS (RX)q (FFF. xxo. yyy) 99 100 101 102 103 a a. a.

a a a.

a a a a.

a a.

a.

a F1O1.010 01 02 03 04 05 06 07 08 09 11 12 13 14 15 16 17 18 19 21 22 23 24 26 27 28 29

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 C C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2 1H 5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9- -thiophene 7-OCH3, 8-OCH3 7-SCH 3 8-OCH 3 7-SCH3, 8-SCH3 6-OCH 3 7-OCH3, 8-OCH3 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7 -OCH3 7-0 (iso-propyl) 7- SCH 3 7-SOCH 3 7-SO2CH 3 7-SCH2CH3 7-NH 2 7 -NHOH 7-NHCH 3 7-N(CH 3 2 7-N+(CH 3 3

I-

7-NHC

CH

3 7-N (CH 2

CH

3 2 7-NMeCH 2

CO

2

H

7-N 4 (Me) 2 CH2CO 2 H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidiniun, I- 7- -pyrrolidine 7- -N-methyl-pyrrolidiniun,

I-

7- -N-methyl-morpholinium,

I-

7-M()-N'-methylpiperazine 7-M()-N'-dirnethylpiperaziniun.

I-

7 -NH-CBZ SRL 6045 Prefix Cpd# R-R 2

R

5 (RX)q (FFF. ax. yyy)

C

p 31 32 33 34 36 37 38 39 40 41 42 43 44 45 46 47 48 49 51 52 53 54 56 57 58 59 61 62 63

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2

C

2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-NHC(O)C5H 11 7-NHC(O)CH 2 Br 7-NH-C(NH)NH 2 7-(2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH 3 8-SCH 3 8-SOCH 3 8-S0 2

CH

3 8-SCH2CH 3 8-NH 2 8-NHOH 8-NCH 3 8-N(CH 3 )2 8-N+(CH 3 3

I-

8-NHC(=O)CH3 8-N(CH 2

CH

3 2 8-NMeCH 2

CO

2

H

8-N (Me) 2

CH

2

CO

2

H,

8-(N)-morpholine 8-(N)-azetidine 8-(N)-N-methylazetidinium,

I-

8-(N)-pyrrolidine 8-(N)-N-methyl-pyrrolidinium,

I-

8-(N)-N-methyl-morpholinium,

I-

8-(N)-N'-methylpiperazine 8-(N)-N'-dimethylpiperazinium,

I-

8-NH-CBZ 8-NHC C5Hi1 110 SRL 6045 Prefix (FFF. aC.

cpd# my) 64 66 67 68 69 71 72 73 74 75 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 93 96 97

CH

2 0C 2

H

5

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2

OC

2

HS

CH

2 0C 2

H

5

CH

2

OC

2

HS

CH

2

OC

2

H

5

CH

2 0C 2

H

5

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2 0C 2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

C

2

H

5

CH

2

OC

2

H

5

CH

2 0C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NHC(O)CH2Br 8-NH-C(NH)NH 2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyJ 9-tert-butyl 9-OH 9-OCH3 9-SCH 3 9-SOCH 3 9-SO2CH 3 9-SCH2CH 3 9-NH2 9-NHOH 9-NHCH 3 9-N(CH 3 2 9-N+(CH 3 3

I-

9-NHC(=O)CH3 9-N(CH 2

CH

3 )2 9-NeCH 2

CO

2

H

9-N (Me) 2 CH2CO 2 H, I- 9-(N)-morpholine 9- -azetidine 9-(N)-N-methylazetidinium,

I-

9-(N)-pyrrolidine 9-(N)-N-methyl-pyrrolidinium,

I-

9-(N)-N-methyl-morpholinium,

I-

9-(N)-N'-methylpiperazine 9-(N)-N'-dimethylpiperazinium,

I-

9-NH-CBZ 9-NHC(O)C5H 11 9-NRC(O)CH2Br

R

1

=R

2 RS (RX)q SRL 6045 Pref ix Cpd# Rl=R 2 RS (Rx)q (FFF.xxxc. yyy) 98 99 100 101 102 103 0* -fee*: F101.011 01 02 03 04 05 06 07 08 09 11 12 13 14 15 16 17 18 19 21 22 23 24 26 27 28

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2

OC

2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-NH-C (NH)NH 2 9- -thiophene 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8-OCH 3 7-methyl 7-ethyl 7- iso-propyl 7-tert-butyl 7-OH 7-OCH3 7-SCH3 7-SOCH3 7-SO2CH3 7-SCH2CH3 7-NH2 7 -NHOH 7-NHCH 3 7-N(CH 3 2 7-N+(CH3) 3

I-

7-NHC CH3 7-N(CH 2

CH

3 2 7 -NMeCH2CO2H 7-N+ (Me) 2 CH2CO 2 H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidinium, I- 7- -pyrrolidine 7- -N-methyl-pyrrolidinium, I- 7- -N-methyl-morpholinium, I- 7- -rethylpiperazine 7- -dimethylpiperazinium, I- SRL 6045 Prefix Cpd# R'=R 2 RS (Rx)ql (FFF. xxc. yyy) *000

S

0* S. S S a.

5 9 *5

S

S.

S

29 31 32 33 34 36 37 38 39 40 41 42 43 44 46 47 48 49 50 51 52 53 54 56 57 58 59 61 62

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-NH-CB Z 7-NHC 7-NHC (O)CH2Br 7-NH-C (NH)NH 2 7- -thiophene 8 -methyl 8-ethyl 8- iso-propyl 8-tert-butyl 8-OH 8-OCH 3 8-0 (iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH 3 8-SCH 2

CH

3 8 -NH 2 8-N'HOH 8 -NHCH 3 8-N(CH 3 2 8-N+(CH 3 3

I-

8-NHC

CH

3 8-N (CH2CH 3 2 8 -NMeCH 2

CO

2

H

8-N+ (Me) 2

CH

2

CO

2 H, I- 8-M()-morpholine 8- -azetidine 8- -N-methylazetidiniun,

I-

8- -pyrrolidine 8- -N-methyl-pyrrolidinium,

I-

8-M()-N-methyl-rnorpholinium,

I-

8-M()-N'-methylpiperazine 8-M()-N'-dimethylpiperazinium,

I-

8-NH-CBZ SRIL 6045 Pref ix Cpd# R 1

=R

2 RS (Rx)q (FFF. xxx. yyy) 9 9S 9 .9 9 9 9 9* 9 9 9* 9 9 9 9 9*9* *999 9*99 9 9 99 9 9999 9.

9 9999 999999 9 63 64 66 67 68 69 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 91 92 93 93 96

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2 Hs

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH(OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH(OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NHC 8-NHC (0)CH2Br 8-NH-C (NH) NH2 8- -thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9 -OCH3 9-0 (is o-propyl) 9-SCH 3 9 -SOC!!j 9-SO 2

CH

3 9-SCH2CH 3 9 -NH2 9-NHOH 9 -NHCH 3 9-N(CH 2 9-N+(CH3) 3

I-

9-NHC

CH

3 9-N(CH2CH 3 2 9 -NMeCH 2

CO

2

H

9-N+ (Me) 2

CH

2

CO

2

H,

9- -morpholine 9- -azetidine 9- -N-methylazetidiniun, I- 9- -pyrrolidine 9- -N-methyl-pyrrolidiniun,

I-

9- -N-methyl -morpholinium, I- 9- -iethylpiperazine 9- -dimethylpiperazinium, I- 9-NH- CBZ 9-NHC SRL 6045

S

0* *5 0 S. SO S S 0

*O

a S 0

S.

S

*SS 9 Prefix Cpd# (FFF.xxoc. yyy) 97 98 99 100 101 102 103 F101.012 01 02 03 04 05 06 07 08 09 11 12 13 14 15 16 17 18 19 21 22 23 24 26 27

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 O- 4 -picoline)

CH

2 O- 4 -picoliie)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- 4 -picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- 4 -picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- 4 -picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- 4 -picoline)

CH

2 O- 4 -picoline)

CH

2 O- 4 -picoline)

CH

2 O- (4-picoline)

CH

2 0- 4 -picoline) Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-NHC CH2Br 9-NH-C (NH) NH 2 9- -thiophene 7-OCH3, 8-OCH 3 7-SCH 3 8-OCH3 7-SCH3, 8-SCH 3 6-OCH3, 7-OCH 3 8-0CH 3 7-methyl 7-ethyl 7 -iso-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 (iso-propyl) 7- SCH 3 7-SOCH 3 7-SO2CH 3 7-SCH2CH 3 7 -NH2 7-NHOH 7 -NHCH 3 7-N(CH 3 2 7-N 4

(CH

3 3

I-

7 -NHC CH3 7-N(CH2CH 3 2 7 -NMeCH 2

CO

2

H

7-N 4 (Me) 2

CH

2

CO

2 H, I- 7- -morpholine 7- -azetidine 7- -N-xnethylazetidinium,

I-

7- -pyrrolidine 7- -N-rnethyl-pyrrolidinium,

I-

7- -N-methyl-morpholinium,

I-

7- -methylpiperazine

R

1

-R

2

R

5 (Rx) q

S.

SO S

S~

0555

S

555.

0O 55 5 0005

S

S.O.S.

S S SRL 6045 Pre fix (FF7. xao.

Cpd# my) 28 29 31 32 33 34 36 37 38 39 40 41 42 43 44 46 47 48 49 51 52 53 54 56 57 58 59 61

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- (4-picoline) Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- -N'-dimethylpiperazinium,

I-

7 -NH-CBZ 7-NHC (O)C 5 Hll 7 -NHC CH 2 Br 7-NH-C (NH) NH 2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH 3 8-SOCH3 8-SO2 CH 3 8 -SCH2CH 3 8 -NH2 8-NHOH 8-NHCH3 8-N(CH3) 2 8-N+(CH 3 3

I-

8-NHC

CH

3 8-N(CH 2

CH

3 2 8 -NMeCH2CO 2

H

8-N 4 (Me) 2

CH

2

CO

2 H, I- 8- -rorpholine 8- -azetidine 8- -N-methylazetidinium, I- 8- -pyrrolidine 8- -N-methyl-pyrrolidiniun, I- 8- -N-methyl-morpholiniun, I- 8-M()-N'-methylpiperazine 8-M()-N'-dimethylpiperaziniu, I- Rl~t2RS (RX)q 116 SRL 6045 Pref ix (FFF.xxxc.

Cpd# my) 62 63 64 66 67 68 69 71 72 73 74 75 76 77 78 79 81 82 R'=R2 RS q

CH

2 O- 4 -picoline)

CH

2 0- 4 -picoline)

CH

2 0- (4-picoline)

CH

2 0- (4-picoline)

CH

2 O- 4 -picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH-

2 0- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 O- (4-picoline)

CH

2 0- (4-picoline) Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph-.

Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NH -CBZ 8-N'HC C 5

H

1 1 8-NHC (0)CH 2 Br 8 -NH- C (NH) NH 2 8 (2 thi ophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-buty.

9-OH 9-OCH 3 9-0 (iso-propyl) 9-SCH 3 9-SOCH3 9-S02CH 3 9 -SCH2CH 3 9-NH 2 9-NHOH 9 -NHCH 3 9-N(CH 3 )2 9-N+(CM 3 3

I-

9-NRC (=O)CH 3 9-N(CH 2

CH

3 2 9 -NMeCH 2

CO

2

H

9-N+ (Me) 2CH2C0 2 H, I- 9- -morpholine 9- -azetidine 9- -N-methylazetidinium,

I-

9- -pyrrolidine 9- -N-methyl-pyrrolidinium,

I-

9- -N-methyl-morpholinium,

I-

9- -methylpiperazine 9- -dimethylpiperazinium,

I-

9 -NH-CBZ 117 SRL 6045 Pref ix Cpd# Rl=R 2 RS RX)q (FF. oac. yyy) 96 CH2O-(4-picoline) Ph- 9-NHC(O)C 5 Hll 97 CH2O-(4-picoline) Ph- 9-NHC(O)CH 2 Br 98 CH 2 0- (4-picoline) Ph- 9-NH-C(NH)NH 2 99 CH 2 O- (4-picoline) Ph- 9-(2)-thiophene 100 CH2O-(4-picoline) Ph- 7-0CH 3 8-OCH 3 101 CH 2 O-(4-picoline) Ph- 7-SCH 3 8-OCH 3 102 CH 2 O-(4-picoliie) Ph- 7-SCH 3 8-SCH3 103 CH 2 O-(4-picoline) Ph- 60OCH 3 70OCH 3 80OCH 3 0 0.

.00.

**o 0 000 0*0 00 Additional Structures of the Present Invention 00 (Rx)q 00.

Number 101 ethyl n-butyl OH H phenyl 102 ethyl n-butyl OH H phenyl 103__ n-butyl ethyl OH phenyl 104 ethyl n-butyl OH H phenyl 105 ethyl n-butyl OH H phenyl 106 ethyl n-butyl OH H phenyl 107 n-butyl ethyl OH H 4-(decyloxy)phenyl 108 ethyl n-butyl OH H phenyl 109 ethyl n-butyl OH H 4-(decyloxy)phenyl 011 OL0 ethyl n-butyl OH 1H phenylI 9* III n-butyl ethyl OH H 4-hydroxyphenyl 112 ethyl n-butyl OH H 00 s/

OH

113 ethyl n-butyl OH H 4-hydroxyphenyl 114 ethyl n-butyl OH H 4-methoxyphenyl 115 n-butyl ethyl OH H 4-methoxyphenyl 116 ethyl n-butyl OH H 4-methoxyphenyl 117 n-butyl ethyl OH H phenyl 118 ethyl n-butyl OH H phenyl 119 ethyl n-butyl -OH H- phenyl 120 n-butyl ethyl OH H phenyl 0

P.

0 0*@ 0** 0 ~0* a a *aa a a. a 0 0 0 *0 **a 0 a a. .a 0* 121 ethyl n-butyl OH H phenyl 122 n-butyl ethyl OH H phenyl 123 ethyl n-butyl OH H phenyl 124 n-butyl ethyl OH H phenyl 125 ethyl n-butyl OH H phenyl 126 n-butyl ethyl OH H 4-fluorophenyl 127 n-butyl ethyl OH H 4-fluorophenyl 128 ethyl n-butyl OH H 4-fluorophenyl 129 ethyl n-butyl OH H 4-fluorophenyl 131 ethyl n-butyl OH H 4-fluorophenyl 132 ethyl n-butyl OH H phenyl 133 ethyl n-butyl OH H phenyl 134 ethyl n-butyl OH H phenyl 135 ethyl n-butyl OH H phenyl 136 ethyl n-butyl OH H phenyl 137 n-butyl ethyl OH H phenyl 138 n-butyl ethyl OH H phenyl 139 n-butyl ethyl OH H phenyl 141 142 ethyl n-butyl H OH

H

143 ethyl n-butyl OH H 3-methoxyphenyl 144 ethyl n-butyl OH H 4-fluorophenyl 262 ethyl n-butyl OH H 3-methoxyphenyl 263 ethyl n-butyl H OH

H

264 ethyl, n-butyl OH H 3-tn fluoromethyiphenyl a. a.

a

S..

0 SA a S a a a 0 0 S SO p..

a. a Sea 5.5 a S a. 0*a S S SO 55 5* *5 265 ethyl n-butyl H OH

H

0) 266 ethyl n-butyl OH H 3-hydroxyphenyl C0 267 ethyl n-butyl OH H 3-hydroxyphenyl

U'

268 ethyl n-butyl OH H 4-fluorophenyl 269 ethyl n-butyl H OH

H

270 ethyl n-butyl OH H 4-fluorophenyl 271 ethyl n-butyl OH H 3-methoxyphenyl 272 ethyl n-butyl H OH

H

273 ethyl n-butyl H OH

H

274 ethyl n-butyl OH H 4-fluorophenyl 275 ethyl n-butyl H OH

H

276 ethyl n-butyl OH H 3-mcthoxyphey 277 ethyl n-butyl OH H 3-fluorophenyl 278 ethyl n-butyl H OH 2-fluorophenyl 279 ethyl n-butyl H OH 3-fluorophenyl 280 ethyl n-butyl OH H 2-fluorophenyl 281 ethyl n-butyl OH H 4-fluorophenyl 282 ethyl n-butyl OH H 4-fluorophenyl 283 ethyl n-butyl HT OH

H

284 ethyl n-butyl OH H 4-fluorophenyl 286 ethyl ethyl OH H phenyl 287 ethyl ethyl OH H phenyl 288 methyl methyl OH H phenyl 289 n-butyl n-butyl OH H phenyl 290 n-butyl n-butyl OH H phenyl 291 n-butyl n-butyl OH H phenyl 122 SRL 6045 z 000 1001 ethyl n-butyl 1002 ethyl n-butyl 1003 ethyl n-butyl

N(CH

2

CH

3 3 03 Br n-butyl OH H t-4 Lfl

CF

3 COo- 0 IN

(CH

3

CH

2 3

NN

H

OH H

CF

3 COO- 0

(CH

3

CH

2 3 N Nz OH H/

FN

~N

n-butyl t n-butyl n-butyl I I Br- 1007 n-butyl n-butyl OH H

I-

NJ

N(H

2

CH

3 3 03 1008 n-butyl n-butyl OH H I-

N

.+1 0N 1009 n-butyl n-butyl OH H

NIN

3 1010 n-butyl n-b ty OH Hi 3-fluoro.-4-methoxyphenyl 1011 n-butyl n-butyl OH- 1] 3 -fluoro- 4 -(5-tricthiylartnrnoii~npentyloxy)phenyl, tri Iluoroacetate saltcn 0Q

I'-

S

55. S S S SS S S S S* S S *S S S S S 55 5* 55 55 5 1012 n-butyl n-butyl OH H 4-hydroxyphenyl 1013 n-butyl' i-buty1 OH H

F

N0 3 3 14 n-butyl n-butyl OH H 4-methoxyphenyl 1015 n-butyl n-butyl OH H FBr 1016 n-butyl n-butyl OH H N CO 2

H

(I)

0'n V. 0. oo oe so 0 1017 n-butyl n-butyl OH H

C)

1018 n-butyl n-butyl OH H I h I I I n-butyl n-butyl eg 000 4* 0 00 09 0. 00 0 00 0 0 0 4 0 .0 of* 0. 0 00 0: 0 00 0 0 0 0 0 00 00 00 00 0 OH H F I

CF

3

CO

2 -0 I (OH 2 4

(OH

2 4 OH H F N 0 NCHCH-3, 0 n-butyl S. 9 S S Se S

S

S

S

CS'.

S S S 555 5*S SS* S 5 59** S. 5 5 C S 55 *5* S S S 55 *5 5.

S

1022 n-butyl n-butyl OH H 1023 n-butyl n-butyl OH H 0 0 0 n-butyl a. a a a ee *e ec an OH H e g. a a a.

.2 a eC 3

-N

P n-butyl

N(CH

2

CH

3 3 0 -butyl OH H 9 1) )HIH1I n-butyl n-butyl n-butyl n-butyl

F

N I (H 2 4

(CH

2 4 0 0

CF

3

CO

2

N(CH

2

CH

3 3 9 .00 690 00 Go Ih -pn 134 SRL 6045 z 0 .0 .0 0 n-butyl *see

CA)

OH H ta 0.

I- U,

N

03

~IIIJ

1038 n-butyl n-butyl OH H I 1039 n-butyl n-butyl OH H phenyl 1040 n-butyl n-butyl OH H

F

CF

3

CO

2

I(OCH

24 (CH4 o 0 N(CH 2

CH

3 3 1041 n-butyl n-butyl OH H N1 +1 31 tI:-

ON

C0 l.' Hn 0 0

B

B B

B

B

B B B B B B 004 BBB *BB B B B BB Be B. B B B B BC B B *B *BB B C B OB CC B. *B B 1042 n-butyl n-butyl OH H

I-

>1

N(C

6

H

5 3 0 1043 n-butyl n-butyl OH H I>0

N

H

1044 n-butyl n-butyl OH H

F

CF

3

CO

2 I

N(CH

2

CH

3 3 0 1045 n-butyl n-butyl OH H -F

CF

3

CO

2 (OH 2 8 0 +N(CH

CH

3 9* a a p 0 p p a p p a p a p a p p p a a.

pa. *pp p p p p a p *p p p p pp a a app a p p. pp *a p 1046 n-butyl n-butyl OH H 3-aminophenyl 1047 n-butyl n-butyl OH H 0

N(CH

2

CH

3 2 1048 n-butyl n-butyl OH H

N(CH

2

CH

3 3 1049 n-butyl n-butyl OH H FBr NJ +1 4* 4 OH H 0ge S. S S IS~e 5 005 S 5e* S SS* S S S SCW S S 5 5 0 S S 5 5 0.

S S a S AS 55 5 55 n-butyl n-butyl OH cn

(OH

2 3 o

N

OH H

CD

n-butyl En n-butyl O n-butyl OH O H H 3 OH. H

F

Br- 0 n-butyl n-butyl n-butyl 143 SRL 6045 o 0 0 144 SRL 6045 z.

z0 a a a.

a a a a a.

a a a. *aa a a a a a a. *a a. a 146 SRL 6045 00 9: 0 4 qe e.

V

V

V V V V

V

V V V. V V V V. *VV *VV V V *b V V V. S V V *V V V Vt *VV V U. V V V. VV Vt te V 1073 n-butyl n-butyl OH H F Br 1074 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1075 n-butyl n-butyl OH H 4-fluorophenyl 1076 n-butyl n-butyl OH H

I

N (OH 3 3 1077 n*-but I n-butvi OH H 3-hydroxymethylphenyl 1078 ethyl n-butyl OH H 4-hydroxyphenyl 1079 ethyl n-butyl OH 1 0.dt

I

NI-

I

0% 0 1080 n-butyl n-butyl OH H 3 1082 n-butyl n-butyl OH I H 2-pyridyl 1083 n-butyl n-butyl OH I H I

L

a a.

S a a *a a a a a a. a 1084 n-butyl n-butyl OH H I~ +1 1085 n-butyl n-butyl OH H thiophen-3-yl 1086 n-butyl n-butyl OH H 0 1087 n-butyl n-butyl OH H

ZNI-

1088 ethyl n-butyl OH H I3,4-inethylenedioxyphenyl n-butyl se se see n-butyl OH H 4-methoxyphenyl n-butyl OH H 0

U,

N

J

n-butyl OH H 4,n r)

H

S S S

CI)

J 109 n-btyl nbuty6OH.

n-uy OH H *9 9 9 9** n-butyl n-butyl n-butyl too n-butyl OH H 0)i 0

A;.

NI

n-butyl OH H ZN o n-butyl n-butyln-uy n-butyl .a

C)

H'K ~F CF 3

CO

2 Ul n-butyl V g a .:S 0* 0,1 o' SS S S S S OH H Br 0 'I OH H 3-pyridyl N~ 'I OH H

FL

n-butyl *0 to to: 0 0 0 to to to 0.0SS* *Uy **bty OH H 5 5 uty nbuyl H F CF 3

CO

2 0 n-butyl ethyl *t a n-butyl OH H 0 I- 111 0

N(CH

3 3 n-butyl OH H 3-fluoro-4-hydroxyphenyl n-butyl OH H Hn n coI n-butyl see 00 So 0* 0 :0 55 5 see n-butyl OH H0 a' 00 n-butyl OH H

B

0 NNN (C CH,)2 2

L

ethyl

V..

1127 n-butyl n-butyl OH H 1128 n-butyl n-butyl OH H 3-fluoro-4-hydroxyphenyl 1129 n-butyl n-butyl OH H 4-fluorophenyl 1130 n-butyl n-butyl OH H 'I-chloro-4-fluorophenyl 1131 ethyl n-butyl OH H 4-methoxyphenyl 1132 n-butyl n-butyl OH H I- N K 0 1133 n-butyl n-butyl OH Hf 4-cyanomethylphenyl 1, i 1134 ethyl n-butyl OH H 1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl 1136 n-butyl n-butyl OH H 0 1137 n-butyl n-butyl OH H 4-fluorophenyl 1138 n-butyl n-butyl OH H 0 1139 n-butyl n-butyl OH H 3 ,4-difluorophenyl 1140 n-butyl n-butyl OH H 3-methoxyphenyl 1141 n-butyl n-butyl OH H 4-fluorophenyl 1142 n-butyl n-butyl OH HF 0 -11 fN(CH 2

CH

3 2 L 2 1143 n-butyl n-butyl H OH

H

1144 n-butyl n-butyl OH H 1145 n-butyl n-butyl OH H 4-methoxyphenyl 1146 n-butyl n-butyl OH H (C H 2 1 0, 0

N(CH

3 3 1147 n-butyl n-butyl OH H 3-methoxyphenyl 1148 n-butyl n-butyl OH 4-fluorophenyl 1149 n-butyl n-butyl OH H 4-fl uorophenyl 1150 n-butyl n-butyl OH H 3-methoxyphenyl 1151 n-butyl ethyl OH H 3-fluoro-4-methoxyphenyl 1152 n-butyl n-butyl OH H phenyl 1153 n-butyl n-butyl OH H 4-fltiorophcny I 0* 0 ~0 0** 0 0 0** 0 0** ~0 *00 000 *00 0 0 0 0* 0* 0 0 00 *0 00 00 1154 n-butyl n-butyl OH H 3-methoxyphenyl 1155 n-butyl n-butyl OH H 4-fluorophenyl 1156 n-butyl n-butyl OH H 4-fluorophenyl 1157 n-butyl n-butyl OH H 4-fl vorophenyl 1158 n-butyl n-butyl OH H 4-pyridinyl, hydrochloride salt 1159 n-butyl ethyl OH H phenyl 1160 n-butyl n-butyl OH H 4-fluorophenyl 1161 n-butyl n-butyl OH H 3,5-dichloro-4-methoxyphenyl 1162 n-butyl n-butyl OH H -phenyl 1163 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1164 n-butyl n-butyl OH H 4-pyridinyl 1165 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1166 n-butyl n-butyl OH H 3-hydroxyphenyl 1167 n-butyl n-butyl OH H ci 1168 n-butyl n-butyl OH 4-hydroxyphenyl 1169 n-butyl n-butyl OH phenyl 1170 n-butyl n-butyl OH H 3-methoxyphenyl 1171__ n-butyl n-butyl OH H 4 -(trifluoromethylsulfonyloxy)phenyI 1172 n-butyl n-butyl OH H 4-pyridinyl __1173 n-butyl n-butyl OH H 4-fluorophenyl 1174 ethyl___ 1.175 1 ethyl _In-butyl OH -H 3-methoxyphenyl 9* 0 0 0 0*e

S

S S S

SO*

S SO

S

500 555 555 5 5 55*5 S S S S S 5 *s 55s S S S S 5* 55 55 55 1176 n-butyl n-butyl OH H 4-fluorophenyl 1177___ n-butyl n-butyl OH H 3-methoxyphenyl 1178__ n-butyl n-butyl OH H 3-(trifluoromethylsulfonyloxy)phenyI 1179 n-butyl n-butyl OH H phenyl 1180 n-butyl n-butyl OH H phenyl 1181 n-butyl n-butyl OH H 4-fluorophenyl 112n-butyl n-butyl OH H 4-(dimethylamino)phenyl 1183 n-butyl n-butyl OH H 3-methoxyphenyl 1184 n-butyl n-butyl OH H 4-fluorophenyl 1185 n-butyl n-butyl OH H 4-fluorophenyt 1186 n-butyl n-butyl OH H __phenyl 1187 n-butyl n-butyl OH H 4-fluorophenyl 1188 n-butyl n-butyl OH H 4-methoxyphenyl 1189 n-butyl n-butyl OH H 3,4-di fluorophenyl 1190 n-butyl n-butyl OH H 2-bromophenyl 1191 n-butyl n-butyl OH H 4-(dimethylamino)phenyl 1192 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1193 n-butyl n-butyl OH H 4-(2-(2-methylpropyl))phenyl 4 4.

4* 4* 4ee p 4** 4 4 4* *44 9*ee A 4* a 4*4 444 4 4 4 4. 4 4 S 4 44.

4 4 4 4 44 q4 .4 44 p I r I I I IY4 l-tIutyI n-butyl OH H n-butyl I OHI H I4-methoxyphenyl .9 9 9** 9** 9** 9* 9 9* 9. 9. .9 1196 n-butyl n-butyl OH H

N(CH

3 3 1197 n-butyl ethyl R3 R4 R3 R4 phenyl 1198 n-butyl n-butyl OH H 4-(pyridinyl-N-oxide) OH S S S SS S 555 5 5 5 5* 5 55 553 0. 0* I I I I I LUL n-Duty' n-butyi N (CH 3 3 1203 n-butyl n-butyl OH H 1204 n-butyl n-butyl OH H 4-fluorophenyl 1205 n-butyl n-butyl OH H NJ3 1206 n-butyl n-butyl OH H Br I

N(CH

2

CH

3 3 1207 n-butyl n-butyl OH 1208 n-butyl -n-butyl OH H 4-methoxyphenyl 1209 n-butyl _n-butyl__ acetoxy H phenyl 1210 n-butyl n-butyl OH H 2 -(dimethylamino)phenyl 1211 ethyl n-butyl OH H

'K'K

1212 n-butyl n-butyl OH H 4-methoxyphenyl 1213 n-butyl ethyl H OH

H

1214 n-butyl ethyl OH H phenyl 1215 n-butyl n-butvl OH H 4-methoxyphenyl 1216 1 ethyl n-butyl _OH H @9 9 9 9 9* 9..

9 9* 9..

9.

9*9 9 9 9** 9 9*9* 9 9 9 9 1217 n-butyl n-butyl OH H 4-carboxyphenyl 1218 n-butyl n-butyl OH H 4-methoxyphenyl 1219 n-butyl n-butyl OH H

N(CH

3 2 1220 n-butyl n-butyl OH H 3-methoxyphenyl 1221 n-butyl n-butyl OH H

CO

2

CH

3 1222 n-butyl n-butyl OH -H 3-methoxyphenyl 1223 n-butyl n-butyl OH H _phenyl 1224 n-butyl n-butyl OH H 3-n itrophenyl 1225 n-butyl ethyl OH H 3-methyI henyI 1226 ethyl n-butyl OH H 1227 n-butyl n-butyl OH H 4-fluorophenyl 1228 n-butyl n-butyl OH H 2-pyrrolyl 1229 1 n-butyl In-butyl OH H 3-chloro-4-hydroxyphenyl 1230 n- butyl n-butyl -OH 1-I phenyl *0 .00 0 0.* *0 OH H 0) Ai, H OH 3tipey OH H

KI.

9O~ 0 S50 0 0 n-butyl n-butyl OH H 0) l.

N(CH

2

CH

3 2 n-butyl n-butyl OH H 4-(bromomethyl)phenyl n-butyl n-butyl OH H N (C-

S.

*e 5* S S 5

S

S St 5 9 S S S S S S

S

S

S S *45 .55 S V. lo5 5 00 lo 55.5 1239 n-butyl n-butyl OH H

F

>1 Br 0 1240 n-butyl n-butyl OH H 4-methoxy-3-methylphenyl 1241 n-butyl n-butyl OH H 3-(dimethylaminomethyl)phenyl 1242 n-butyl n-butyl OH H

F

C'

1243 n-butyl n-butyl OH H 4

N(CH

3 3 124 -utl n-butyl OH H 3-methoxyphenyl cn n-butyl 00 0' G OH H

I-

OH HBr a'n n-butyl n-butyl n-butyl n-butyl n-butyl N N(0H 3 3 1259 ethyl n-butyl H OH

H

1260 ethyl -n-butyl OH H 3-hydroxyphenyl 1261 n-butyl n-butyl OH H ~KL~ 3 1262 n-butyl n-butyl OH H 2-thiophenyl 1263 n-butyl n-butyl- OH H 1264 n-butyl n-butyl OH H 4-fl uorophenyl 1265 n-butyl n-butyl OH H- 4-fluorophenyl OH H. I n-butyl

N(CH

2

CH

3 3 n-butyl n-butyl n-butyl n-butyl n-butyl OH cn 00 0 NI OH H C0 2

H

N co n-butyl n-butyl

(CH

2 8

CH

3

I

N- (CH 2 8

CH

3 n-butyl n-butyl 00 0 00: .0 0 0 0 f *o S Ch, -0 OH HF

FI

n-butyl n-butyl n-butyl

(CH-

2 6 CH (Cl-I) 2

I

(CH-

2 6

CH(CH

3 2 a. a, 4, :a OH H

F

1280 n-butyl n-butyl OH H

F

N '11 N(0H 3 2 1281 n-butyl n-butyl OH H 1282 ethyl n:-butyl OH H 3-tluoro-4-methoxyphenyl 1283 n-butyl n-butyl OH H 4-hydroxymethylphenyl 1284 n-butyl n-butyl OH H 4-fluorophenyl 1285 n-butyl ethyl OH H phenyl 1286 n-butyl n-butyl OH H FFC2 2 3

CH

3 3 1287 n-butyl ethyl OH H 4-hydroxyphenyl n.-butyl OH OH H 1- 00 I- (CH 2 7

CH

3 0 +1 n-butyl n-butyl n-butyl n-uy n-butyl n-butyl n-butyl OH H F r CF 0 NI OH H I-f

.P(C

6

H

5 3 n-butyl nbuy n-butyl OH. Ln n-butyl n-butyl n-butyl n-butyl

(CH

3 3

C\

Z: ,0 n-butyl n-butyl

N(CH

2

CH

3 2

E

OH H I 1 0 I-b 0 0 S S

S

S S S S. S S 5 55 **S S S S S S* S* S 1303 n-butyl n-butyl OH H 0 1304 n-butyl n-butyl OH H 3-methoxyphenyl 1305 n-butyl n-butyl OH H 4-fluorophenyl 1306 n-butyl n-butyl OH H o

CF

3 1307 n-bu yl n-butyl OH H H

C.

C

0 C C C

C

C

C C C

C

*CC *CC C C C C C. C C*

C

C. *C r 7 I I I 3U0 ethyl n-Duty'

F

0 0s 0A 1309 n-butyl n-butyl OH H 4-methoxyphenyl 1310 ethyl n-butyl OH H phenyl 1311 n-butyl ethyl OH H phenyl 1312 n-butyl ethyl OH H phenyl 1313 n-butyl ethyl OH H phenyl 1314 ethyl n-butyl OH H phenyl 1315 ethyl n-butyl OH H phenyl 1316 n-butyl ethyl OH H phenyl 1317 n-butyl ethyl OH H phenyl 1318 ethyl n-butyl OH H phenyl 1319 ethyl n-butyl OH H 3-methoxyphenyl 1320 ethyl n-butyl OH H phenyl 1321 n-butyl_ ethyl OH H phenyl n-butyl t. 4 I *t 0 60 0 e V *V V V VVV OH H FI- 0

N

N.N

H

I H n-butyl n-butyl n-butyl n-butyl *n 1H H JJ~L n-butyl n-butyln-ul n-butyl n-butyl e 00 00 00: *S S S OH H

C>'

0,

U,

01 OH H F

CF

3

CO

2 n-butyl n-butyl .n OH H 00 0 0 OH H OH H n-butyl n-butyl 0. .0 1335 n-butyl n-butyl OH H 0

N

1336 n-butyl n-butyl O HH

I-/

6 -loN 0. 6* I I I I 1 1 n-Duty' n-butyl OH

(H

3

C)

3

N

1338 n-butyl n-butyl OH H 4-methoxyphenyl 1339 n-butyl n-butyl OH H 0

N

1340 n-butyl ethyl OH H 1341 n-butyl n-butyl acetoxy H 3-methoxyphenyl 1342 n-butyl n-butyl OH H 1343 ethyl n-butyl OH H phenyl 1344 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 0 0** 0 0** 0 000 *00 0 0 0 *0* 0 0 0 0 0* 00 00 0 1345 -ethyl n-butyl OH H phenyl 1346 ethyl n-butyl OH H phenyl

C

1347 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 111 1348 isobutyl isobutyl OH H phenyl 1349 ethyl n-butyl OH H phenyl 1350 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1351 n-butyl n-butyl OH H

CF

3

CO

2

(CH

3

CH

2

)(CH

3 2

N

1352 n-butyl n-butyl OH H Br- 0

(CH

3

CH

2

CH

3

CH

2 3

N

a.

a a a a..

*aa a a a a a a a a. a a a a a.

a a a. a a a a. *a a. *a 1353 n-btyl n-utyl OH H F

CF

3

CO

2 I -K4

N(CH

2

CH

33 1354 n-butyl n-butyl OH Hf

F

N-

1355 n-butyl n-butyl OH H 0 on'

C)

LI'

LII

0' p. a a a a.

1356 n-butyl n-btyl OH JH C C C C C C

C

C C* C *C C C CC CCC C C CC CC CC CC C Y I I 1359 n-butyl n-butyl I. 4 4 4 1360 n-butyl n-butyl N N I I I 1 198 SRL 6045 z__ \7z 0 a% OH HTn V C I C3

V.

9* 0 000 0 0 V V V V V VV V 0 V V 0 0** 0** OVV OVO OVO V 0 0 V V 0 00 0 V V V *V 0 V *0 *0* C V 0 OV *V *V *V V I 7 T 1 I 1.50V fi-butyl n-butyl OH En 0u r' 0n

H~

1 I I 4n-butyl n-butyl

OH

1370 n-butyl n-butyl OH u0 3

A

9. V .0 GO: 9* 9* 9 9 131n-butyl n-butyl OH H 0 137 *-uy n-uy OH H S 9* S S S S S S o0 Ot t 0 Go: *0 Go* 0 0*S to so. S n-butyl OH

J

138 n-b.y uy OH H 1383 n-butyl n-butyl OH H

CD~

0n n-uy *-uylO H n-butyl n-butyl OH H F0 I -ir,.,,N(CH 2

CH

3 3 0C t *0 138 uy n- uy O H H 6 6 0* 1390 n-butyl n-butyl OH H I I_ I 9 C C

C

C C CCC CCC C C C *WC* C C C C CC C C Ce CC.

C C C C CC CC CC C* C *1 I Y Y 1391 n-butyl n-butyl 1392 n-butyl n-butyl OH H 3 .0 C 0 0 0 A 00 0N O H H 0 U* V b9* A 0. A S A A S *n I 1396 n-butyl n-butyl OHH I I) I In n-butyl V I II *so*by .I' OH H f a

F

N(0H 3 3 n-butyl n-butyl bul n-butyl n-butyl o 0. OH H**V V VV** V VVV OH HI +1

I--

+1 U n-butyl n-butyl

N~N+

n-butyl n-butyl OH Ch OH H1-1' n-butyl n-butyl n-butyl 9~ 9* 9* St S (a n-butyl n-butyl OH H 1

I

I 1411 n-butyl n-butyl OH H

F

P(H

2 0H 3 3 1412 n-butyl n-butyl OH H3 K

N

H 0 vi 217 SRL 6045 z z

I

0 0 0O 0 t 0 OH H 141 .*bty n-uy OH H

OH

1418 n-butyl n-butyl OH' H F I f n-butyl 5 0 0 0 66 0 6 0 C'n OH H I- 0) N N OH H It I ICD n-butyl @6 S@ 0 66 @6 0@ 0*S 0 6SO) S S See.

6 6 606* 3*S* @566 ~0O 0. 660 0 @05 0 6 es 0 @66 S C S I I 1422 n-butyl n-butyl OH 0 0 N(0H 2 0H 3 3 1423 n-butyl n-butyl OH H

I+

N

w I. T~T 1427 n-butyl n-butyl OH t I T 1428 n-butyl n-butyl w 0

N

0

V..

S

S* S S a S

S

1429 n-butyl n-butyl OH H Br 1430 n-butyl n-butyl OH H NCH) Br n-butyl

H

a' C H 2N(CH 2

CH

3 3 H 2 U S S *S S* S S Sa% 143 *5bty *-uy OH H 5 S 55* SS S S S5555 S S S S S. S

ON

n-butyl 9 O H H T S SS S 5 9 5**

ON

0 I V .n H. H *03 L VV V V V V V V VA.-* n-butyl n-butyl n-butyl n-butyl buy n-butyl n.-butyl n-butyl N *S S S S S SS S S S S3

H

Na Na+ 144 **bty n-uy OH H 4. 4 e~e 9 4 4e* 9* Ve 00 do .0, *s *0 Go' Compound Number [6 (Rx)g 101 H0 0 0 0 'N N H 10,fo H

O

the_7-position 102 H 7-trimethylammonium iodide H 7-trimethylammonium iodide 104 H 7-dimethylamino 105 H 7-methanesul fonamido 106 H 7-(2'-bromoacetamido) 107 -H 7-amnino 108 H 7-(hexylamido) 109 H 7-amino H 7-acetarnido 111H 7-amino

S.

*5

S

SS S S S

S

S *95 S S S 5 Se S. S S S S 95 S S S C 5* *S 112 H ____7-amino 113 H 7-amino 114 H 7-amino 115 H 7-(O-benzylcarbamato) 116 H 7-(O-benzylcarbamato) 117 H 7-(O-benzylcarbamato) 118 H 7-(O-benzylcarbamato) 119 H 7-(O-tert-butylcarbamato) 120 H. 7-(O-benzylcarbamato) 121 H 7-amino 122 7-amino 123 H 7-hexylamino 124 H 7-(hexylamino) 125 HI 3+ the 8-position 126 H 7-(O-benzylcarbamito) 127 H 7-amino 128 H 7-(O-benzylcarbaimato) 129 H 7-amino

C)

Ul a a. a a a a. a..

a a a a a. a. a. *a a 131 H 1 0 0I1 I at the 7-position 132 H0 N- W J3 the 8-position 133 H 8-(hcxyloxy) 00 S S S S S S SO 0 5 (n a a C CC. a C C a a C C C C C. C C C CCC C C a C C a C C C C C CC*** a a a a C C C C C C C C C C C C a a a. aa CC CC C H 00 1 0 a' the 7-position 140 141 142 3-methoxy-phenyl 7-methylmercapto 143 H 7-methylmercapto 144 H 7-(N-azetidinyl) 262 H 7-methoxy 263 3-methox y-phen yl 7-methoxy 264 H 7-methoxy 265 3-trifluoro-methyl- 7-methoxy ____phenyl 266 H 7-hydroxy 267 H 7-methoxy 268 H 7-methoxy 269 4-fluoro-phenyl 7-methoxy 270 H 7-hydroxy 271 H 7-bromo 272 3-methoxy-phenyl 7-bromo 273 4-fluoro-phenyl 7-fluoro 274 H 7-fluoro 275 3-methoxy-phenyl 7-fluoro 276 H 7-fluoro 277 H 7-methoxy 278 H 7-mcthoxy 279 H 7-methioxy 280 H j7-niethoxy 0 14h a 0 0,0 0 C C C

C

C C C C C C C C C C CC CCC C C -C CC CC C* C 281 H 7-methyl mercapto 282 H 7-methyl 283 4-fluoro-phenyl 7-mcthyl 284 H 7-(4'-morpholino) 286 H 7-(O-benzylcarbamato) 287 H 7-amino 288 H 7-amino 289 H 7-amino 290 H 7-amino 291 7-(O-benzylcarbamato) 292 H 7-amino 293 H 7-benzylamino 294 H 7-dimethylamino 295 H 7-amino 296 H 7-amino 1000 H 7-dimethylamino 1001 H 7-dimethylamino 1002 H 7-dimnethylamino 1003 H 7-dimethylarnino 1004 H 7-dimethylamino 1005 H 7-dimethylamino 1006 H 7-dimethylamino 1007 H 7-di methylamino 1008 H 7-dimethylamino 1009 H 7-dimnethylamino 1010 H 7-dirmethylainino 239 SRL 6045 o 0 0 0 -0 0 0 0 0 0'- E E

E

S

S

S

S

S S S S S S S S 555 555 5 S S S *5 S S S S 5 55 *SS S S S S S. S. S 1037 H 7-dimethylamino 1038 H 7-dimethylamino 1039 H 7-dimethylamino 1040 H 7-dimethylamino 1041 H 7-dimethylamino 1042 H 7-dimethylamino 1043 H 7-dimethylamino 1044 H 7-dimethylamino 1045 H 7-dimethylamino 1046 H 7-dimethylamino 1047 H 7-dimcthylamino 1048 H 7-dimcthy lamino 1049 H 7-dimethylamino 1050 H 7-di methylamino 1051 H 7-dimethylamino 1052 H 7-dimethylamino 1053 H 7-dimethy lamino 1054 H 7-dimethylamino 1055 H 7-dimethylamino 1056 H 7-dimethylamino 1057 H 7-dimcthylamino 1058 H 7-diinethylamino 1059 H 7-dimethylarnino 1060 H S7-methylamino 1061 H 7-methylamino 1062 H 7-rncthy lani no

I

a a a.

a a .aa a a a a a. a a a.

a a. a a a a a. *a a. 1063 H 7-methylamino 1064 H 7-methylamino 1065 H 7-dimethylamino 1066 H 7-di methylamino 1067 H 9-dimethylamino 1068 H 7-dimethylamino 1069 H 7-dimethylamino; 9-dimethylamino 1070 H 7-dimethylamino 1071 H 7-dimethylamino 1072 H 7-dimethylamino 1073 H 7-dimethylamino 1074 H 7-dimethylamino 1075 H 7-dimethylamino; 9-dimethylamino 1076 H 7-dimethylamino 1077 H 7-dimethylamino 1078 H 7-dimethylamino 1079 H 7-dimethylamino 1080 H 7-dimethylamino 1081 H 7-dimethylamino 1082 H 7-dimethylamino 1083 H 7-dimethylamino 1084 H 7-dimethylamino 1085 H 7-d imethylami no 1086 H 7-dirncthylamino 1087 H 7-diincthylaiinino S S S S S

S

S

S S S S S S

S

5.5 555 S S S SSSS *S S S S S S S *S 555 S S S S 55 5* 55 55 1088 H 7-dimethylamino 1089 H 7-dimethylamino 1090 H 7-dimethylamino 1091 H 7-dimethylamino 1092 H 7-dimethylamino 1093 H 7-dimethylamino 1094 H 7-dimethylamino 1095 H 7-dimethylamino 1096 H 7-dimethylamino 1097 H 7-dimethylamino 1098 H 7-dimethy lamino 1099 H 7-dimethylamino 1100 H 7-dimethylamino 1101 H 7-dimethylamino 1102 H 7-dimethylamino 1103 H 7-dimethylamino 1104 H 7-dirnethylamino 1105 H 7-dimethylamino 1106 H 7-dimethylamino 1107 H 7-dimethylamino 1108 H 7-dimcthylamino 1109 H 7-ditnethylamino 1110 H 7-diinethylainino 1111 H 7-diirnethylainino 1112 H 7-dimethylamino 1113 H 7-dimethylainino 9 9 9* *9 1114 H 7-methylamino 1115 H 7-dimethylamino 1116 H 7-dimethylamino 1117 7-dimethylamino 1118 7-dimethylamino 1119 H 7-dimethylamino 1120 H 7-dimethylamino 1121 H 7-dimethylamino 1122 H 7-dimethylamino 1123 H 7-dimethylamino 1124 H 7-dimethylamino 1125 H 7-dimethylamino 1126 H 7-dimethylamino ____1127 H 7-dimcthylamino 1128 H 7-dimethylamino ____1129 H 9-dimethylamino 1130 H 7-di methylami no 1131 H 7-dimethylamino 1132 H 7-dimethylarnino 1133 H 7-dimcthylamino 1134 H 7-dimethylamino 1135 H 7-dimethylamino 1136 H 7-dimethylamino 1137 H 9-(2',2'-dimethylhydrazino) 1138 H 7-dimethylamino 1139 H 7-dimethylamino 0* S .955 S. S S S S S *S 595 S S S

S

S. 55 S* 55 7 2 2 -dimet hylhydrazi 7 -ethylmecthylamino 7 -dimeth vlamino 7 -dimethylamino 9-dimethylamino 7-dimethylamino 7 -diehylimino '-dimethylsulfonium, fluoride salt 7 -ethylamino 7 -clh Ilmethylamnino 7 -dimethylamino 7-(ethoxymcthyl) methylamino 7 -methylamino 9-methoXY 7-methyl 7- methy mercup to 7-fl voro; 9 -dimethylamino 7 -methomy 7 -dimethylammio 7-diethylamino 7 -dimethylarnino 7 -diinethylamino 7-methoxv 0* 99 9 99 9e 9 9 9 9 999 9 C9* 999 999 9 9 9 9999 *9 9 *999 9 9 99 *99 9 9 9 9 99 99 *9 9 1164 H 7-methoxy 1165 H 7-trimethylammonium iodide 1166. H 7-trimethylammonium iodide 1167 H 7-dimethylamino 1168 H 7-trimethylammonium iodide 1169 H 8-dimethylamino 1170 H 7-ethyipropylamino 1171 H 7-dimethylamino 1172 H 7-methoxy 1173 H 7-ethylpropylamino 1174 H -7-phenyl 1175 H 7-methylsulfonyl 1176 H 9-fluoro 1177 H 7-butylmethylamino 1178 H 7-dimethylamino 1179 H 8-mcthoxy 1180 H 7-triinethylammonium iodide 1181 H 7-butylmethylamino 1182 H 7-methoxy 1183 H 7-fluoro 1184 H 7-fluoro; 9-fluoro 1185 H 7-fluoro 1186 H 7-fluoro; 9-fluoro 1187 H 7-mcthyl 1188 H 7-tritnethylammonium iodide 1189 H 7-tri met hylammon iurn iodide A U S UC 5 7-byroo Ob

LI,

1215 H 9-methy Imercapto 1216 H 7-bromo 1217 H 7-dimethylamino 1218 H 9-methylsulfonyl 1219 H 7-dimethylamino 1220 H 7-isopropylamino 1221 H 7-dimethylamino 1222 H 7-ethylamino 1223 H 8-bromo; 1224 H 7-fluoro ____1225 H 7-dimethylamino ____1226 H 7-bromo ____1227 H 7-(tert-butylamino 1228 H 8-bromo; 1229 H 7-dimethylamino 1230 H 9-dimethylamino; 7-fluoro 1231 H 7-dimethylamino 1232 H 9-dimethylamino 1233 H 7-dimethylarnino 1234 H 7-dimcthylamino 1235 H 7-dimethylamino 1236 H 7-dimethylamino 1237 H 7-dirnethylarnino 1238 H 7-dimethylamino 1239 H 7-dimethy lamino 1240 H 7-dimethylamino 1241 H methylamino 1242 H ____7-dimethylamino 1243 H 7-dimethylamino 1244 H I'-methyihydrazido) 1245 H 7-dimethylamino 1246 H 7-dimethylamino 1247 H 7-dimethylamino ____1248 H 7-dimethylamino ____1249 H 7-dimethy lamino ____1250 H 7-dimethylamino 1251 H 7-dimethylamino 1252 H 7-dimethylamino 1253 H 7-dimethylamino 1254 H 7-dimethylamino 1255 H 7-dimethylamino 1256 H 7-diinethylamino 1257 H 8-bromo; 7-dimethylamino 1258 H 9-(tert-buitylamino) 1259 phenyl 7-dimethylamino 1260 H 7-dimethylamino 1261 H 7-dimethylamino 1262 H 7-d imethylamino 1263 H 7-bromo

S

S

S S

S

S S S *5 55 *S S 1264 H 7-isopropylamino 1265 H 9-isopropylamino 1266 H 7-dimethylamino 1267 H 7-carboxy, methyl ester 1268 H 7-dimethylamino ____1269 H 7-dimethylamino ____1270 H 7-dimethylamino ____1271 H 7-dimethylamino 1272 H 7-dimethylamino 1273 H 7-dimethylamino 1274 H- 7-dimethylamino 1275 H 7-dimethylamino 1276 H 7-dimethylamino 1277 H 7-dimethylamino 1278 H 7-dimethylamino 1279 H 7-dimethylamino 1280 H 7-di methylamino 1281 H 7-dimethylamino 1282 H 7-trimethylammonium iodide 1283 H 7-dimethylamino 1284 H 9-ethylamino 1285 H 7-dimethylamino 1286 H 7-dimethylamino 1287 H 7-di methylami no 1288 H 7-dimethylamino 1289. H 7-d imethy lam ino

S

S

S

S S S S S S S S

S**

S S S 1290 H 7-dimethylamino 1291 H 7-di methylamino 1292 H 7-dimethylamnio 1293 H 7-dimethylamino 1294 H 7-dimethylamino 1295 H 7-dimethylamino 1296 H 7-dimethylamino 1297 H 7-dimethylamino 1298 H 7-dimethylamino 1299 H 7-dimethylamino 1300 phenyl 7-dimethylamino 1301 H 7-trimethylammonium iodide 1302 H 9-hydroxy 1303 H 7-dimethylamino 1304 H 7-tert-butylamino 1305 H 9-methylamino 1306 H 7-dimethylamino 1307 4-methoxy-phenyl 9-(4'-morpholino) 1308 H 7-dimethylamino 1309 H 9-fluoro 1310 H 7-amino 1311 H 7-(hydroxylamino) 1312 H 8-hexyloxy 1313 H 8-cthoxy 1314 H 7-(hydroxylamino) 1315 H 7-(hcxyloxy) 1317 .n 0

O$%X}N(CH

3 3 H 0

H

1321 0 at the 8-position 7-dimethylamiflo 7-dimethylamilo 7dimethylailo 7dirncthylanilo 7-di mcth lami no 7 -di methylamino 7-dirncthylamino 0 0 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

7-dimethylamino 7-dimethylamiflo 7-dimethylamino 7-dimethylamino 7--meth I ain1 7-dimethylamino 7-dimethylamiflo 7 timethylamfin ode 7-dmetylai 0 at the 8-position 1347 H 77-dimethylamino 1348 H 7-dimeth ylamino 1349 H 7-dimethylamino 1350 H 7-trimethvlammonium iodide 1351 H 7-dimethylamino Ve 0. 0. 0.0 Go**.

____1352 H 7-dimethylamino 353 7-dimethylamino ____1354 H 7-dimethylamino ____1355 H 7-dimethylamino 1356 H 7-ditnethylamino 1357 H 7-dimethylamino 1358 H 7-dimethylamino 1359 H 7-dimethylamino 1360 H 7-dimethylamino 1361 H 7-dimethylamino 1362 H 7-dimethylamino 1363 H 7-dimethylamino 1364 H 7-dimethylamino 1365 H 7-dimethylamino 1366 H 7-dimethylamino 1367 H 7-dimethylamino 1368 H 7-dimethylamino 1369 H 7-dimethylamino 1370 H 7-diinethylamino 1371 H 7-dimethylamino 1372 H 7-dimethylamino 1373 H 7-dimcthylainino 1374 H 7-dirnethylamino 1375 H 7-dimethylamino 1376 H 7-dimethylamino 1377 H 7-dimethylainino

A

a. a a. a a *a a a a. n a ft.

9* ft 99 0@ .4 9 *990 9 9 9 9999 999 *999 999.

9 -00 000 4.99 1404

H

1405

H

1406

H

1407

H

1408

H

1409

H

1410

MH

1411

H

1412

H

1413

H

1414

H

1415

H

1416

H

1417

H

1418

H

1419

H

1420

H

1421

H

1422

H

1423

H

1424

H

1425

H

1426

H

1427

H

1428

H

1429

H

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylarnino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethvlamino 7-dimethylarnino 7-dimethylamiflo 7-dimcthy lani no 1430 H 7-dimethylamino 1431 H 7-dimethylamino 1432 H 7-dimethylamino 1433 H 7-dimethylamino 1434 H 7-dimethylamino 1435 H 7-dimethylamino 1436 H 7-dimethy lamino 1437 H 7-dimethylamino 1438 H 7-dimethylamino 1439 H 7-dimethylamino 1440 H 7-dimethylamino 1441 H 7-dimethylamino 1442 H 7-dimethylamino 1443 H 7-dimethylamino 1444 H 7-dimethylamino 1445 H 7-dimethylamino 1446 H 7-methoxy; 8-methoxy 1447 H 7-dimethylamino 1448 H 7-dimethylamino 1449 H 7-dimethylamino 1450 H 7-dimethylamino 1451 H 7-dimethylamino SRL 6045 PEG 3400 molecular weight polyethylene glycol polymer chain H3C\ H3CI\ PEG 3400 molecular weight polyethylene glycol polymer chain 258 SRL 6045

CH

3

H

3 C' NrT PEG 3400 molecular weight polyethylene glycol polymer chain 0

H

3

CI-

259 SRL 6045 02 02 s

H

2 N b K' 02

S

*02 Ia

LIM

11 2 i~OH K 02

K'

260 SRL 6045 002 022

SS

020

:S.

OH

C s C.

IC

SRL 6045

IHOHN'

262 SRL 6045 002 b H W0I s- *HO S

:OH

0 S 02 ro s 263 SRL 6045 02 02 020 sS *b H 02 *0

C-

OH

C..07 264 SRL 6045 02 02 02 S 02 ses.

C OH 44 4 too.*: 9 265 SRL 6045 In further compounds of the present invention, R and R 6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, Nalkylpiperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C 1 to C, 10 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, dioxyalkylene, where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R 5 or R 6 is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di- 20 substituted. Among the species which may constitute the substituents on the aryl ring of R 5 or R 6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R 5 or R 6 is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p- 266 SRL 6045 hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, inme thoxyphenyl, p-N, N-diinethylaminophenyl, rn-N, Ndime thylaininophenyl, I- p- (CHO) -N*-phenyl, I- m- (CH 3 phenyl, I- m- (CH 3 3 2

CH

2 (OCH 2

CH

22 -O-phenyl, I- p- (CH 3 3 -N--CH 2 CH 2 -(OCH 2 CH 2 2 -O-phenyl, I- n- Ndimethylpiperazinium)

-CE

2 (OCHCH 2 2 -O-phenyl, 3inethoxy-4-fluorophenyl, thienyl-2-yl, cholorothienyl-2-yl, 3,4-difluorophenyl, I- p-(N,Ndime thylpiperaz iniun) (OC 2

CH

2 ),-O-phenyl, 3fluoro-4-rnethoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3pyridinyl, N-inethyl-4-pyridiniun, I- N-methyl-3pyridinun, 3, 4-dioxyrnethylenephenyl, 3,4dioxyethylenephenyl, and p-methoxycarbonylphenyl.

:Preferred compounds include 3-ethyl-3-butyl and 3butyl-3-butyl compounds having each of the above preferred R 5 substituents in combination with the Rx substituents shown in Table 1. It is particularly preferred that one but not both of R' and R' is .**hydrogen.

It is especially preferred that R and R 6 be hydrogen, that R' and R' not be hydrogen, and that R3 and R 5 be oriented in the same direction relative to the plane of the molecule, both in a- or both in I9-configuration. It is further preferred that, where Rp2 is butyl and R' is ethyl, then R1 has the same orientation relative to the plane of the molecule as R and R 5 Set forth in Table 1A are lists of species of R 1/R 2

R

5 and R.

267 SRL 6045 Table IA: Alternative R Groups R' (Rx )q RR 6 9* 9 *9 9.

*99999

R

2 ethyl n-propyl n-butyl n-perityl n-hexyl iso-propyl iso-butyl iso-pentyl

CH

2 C (=O)C 2

H

5

CH

2

OC

2

H

5

CH

2 CH (OH) C 2

H

5

CH

2 O- (4-picoline)

R

3

R

4

HO-

H-

R

5 Php-F-Phrn-F-Php-CH 3 O-Php-CH 3 O-Phm-CH 3 -Php- (CH 3 2 N-Phm- (CH 3 2 N-Phm- (CH 3 3 -N-Ph- I- P- (CH 3 3

-N*-CH

2

CH

2

(OCH

2

CH

2 2 O0Ph-

M-(CH

3 3

-N+-CH

2

CH

2

(OCH

2

CH

2 2 -O-Php-(N,Ndime thylpiperazine)

)-CH

2

(OCH

2

CH

2 2-0 Phm-(N,Ndimethylpiperazine)

)-CH

2

-(OCH

2

CH

2 2

-O-

Phrn-F, p-CH 3 O-Ph- 3, 4, dioxymethylene-Ph

M-CH

3 p-F-Ph- 4-pyridine N-methyl-4-pyridinium, I- 3 -pyridine N-methyl-3-pyridinium, I- 2-pyridine p-CH 3

O

2 C- Phthienyl-2-yl 5-Cl-thienyl-2 -yl (RX) 9 7-methyl 7-ethyl 7-iso-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 (iso-propyl) 7-SCH 3 7 -SOCH 3 7-SO 2

CH

3 7-SCH 2

CH

3 7 -NHOH 7 -NHCH 3 7-N(CH 3 2 7-N*(CH 3 3

I-

7 -NHC CH 3 7-N(CH 2

CH

3 2 7 -NMeCH 2

)CO

2 jH 7-N*(Me) 2

CH

2

CO

2 H, I- 7- -morpholine 7- -azetidine 7- -N-methylazetidinium,

I-

7- -pyrrolidine 7- -N-methylpyrrolidinium, I- 7- -N-methylmorpholinium, I- 7- -N'-methylpiperazine 7- dimethylpiperazilium,

I-

7 -NH-CBZ 7-NHC CSH 1 7-NHC (0)CH 2 Br 7-NH-C (NH) NH 2 7- -thiophene continued next page...

SRL 6045 to..

066e 0 0 RI, R 2

R

3

R

4 RS (WX) q 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH 3 (iso-propyl) 8-SCH 3 8 -SOCH 3 8-SO 2

CH

3 8-SCH 2

CH

3 8-NH 2

B-NHOH

8 -NHCH 3 8 -N (CH 3 2 8-N*(CH 3 3

I-

8-NHC (=O)CH 3 8-N (CH 2

CH

3 2 8 -NMeCH 2

)COH

8-N (Me) 2

CH

2 C0 2 H, I- 8- -morpholine 8-M()-azetidirie 8- -N-methylazetidinix,

I-

8- -pyrrolidine 8- -N-methylpyrrolidinium, I- 8- -N-methylmorpholinium, I- 8- -methylpiperazine 8- dimethylpiperaziniun, 8-NH-CBZ 8 -NHC C 5

H

1 1 8-NHC CH 2 Br 8-NH-C (NH) NH 2 8-(2)-thiophene continued next page...

SRL 6045

R

1

R

2

R

3

R

4

R

5 q 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 3 9-O(iso-propyl) 9 -SCM 3 3 9 -SO 2

CH

3 9-SCH 2

CH

3 9-NHOM 9 -NHCM 3 9-N (CM 3 2 9-N-(C 3 3

I-

9-NMC (=O)CH 3 9-N(CH 2

CH

3 2 9 -NMeCM 2

CO

2

H

9-N*(Me) 2

CH

2 C0 2 H, I- 9-M()-morpholine 9-M()-azetidine -N-methylazetidinium,

I-

9- -pyrrolidine 9- -N-methylpyrrolidiniun, I- 9- -N-methylmorpholinium, I- 9-M()-N'-methylpiperazine 9- dimethylpiperaz inium,

I-

9-NH-CBZ 9 -NHC CSM 1 1 9-NHC C 2 Br 9-NH-C (NM) NH 2 9- -thiophene 3 8-0CM 3 7-SCM 3 8-0CH 3 7-SCM 3 8-SCM 3 3 7-0CM 3 8-0CM 3 Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise: 270 SRL 6045 (OL

R

7 RX S 8 1 2 /'24 (Formula

DIV)

or: (O R 7 8

(R

x 3 5 4 (Formula DIVA) w 2 3 4 6 5 6 7 8 where R 1

R

2

R

3 R, R, R 5

R

6

R

7

R

8 X, q and n are as 1 0 defined above, and R 5 is either a covalent bond or arylene.

The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, 15 polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one-or more carbon replaced by O, NR 7

N'RR

8 S, SO, SO2, S*R'R PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 1 3 SRL 6045 1R 3 14 13 1313 13 13 14 NRR SR ,S(O)R 13 S02R ,S03R ,NR OR 1R 3 14 15 13 13 14 NRNR R ,N02, C02R ,CN, OM, SO2OM, S02NRR 13 14 13 13 14 13 14 C(O)NR R ,C(O)OM, COR P(O)R R ,P R R RiSA-, P(0R 13 S*RR"A, and N'R 9

R

11 R 1 2

A-;

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups 7 7 8 7 selected from the group consisting of OR NR R SR 7 7 7 7 7 8 78 9 *S(O)R S02R ,S03R C02R CN, oxo, CONR R N R R R A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R R P R R A ,and P (OR 7

)OR

8 and wherein said alkyl, alkenyl, alky-nyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR 7 7 8 7 7 +7 8 N R RA-, S, SO, S02, S R PR P P R R or a phenylene.

Exemplary core moieties include: 26 27 26 o27

R

SRL 6045

S

*5

S

k 027

R

6 0 1 27 2 9k 1? 4 k R2 wherein: *R2 is selected from the group consisting of C and N, and *R2 and R 27are independently selected from the group consisting of: 273 SRL 6045 (0) -CH2r 0 I

S

I I -C -1 0 -C -O,

S

I I -C

R

3 1

N+

-t 0- NH -NH

NH

-NHSO

2 and N \NH2 0 0 wherein R 2

R

9

R

3 0 and R n are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl, A is a pharmaceutically acceptable anion, and k 1 to In compounds of Formula DIV, R 2

R

2

R

2 in Formulae DII and DIII, and R 23 in Formula DIII can be bonded at any of their or 9- positions to In compounds of Formula DIVA, it is preferred that R S5 comprises a phenylene moiety bonded at a m- or p-position thereof to R 9 In another embodiment, a core moiety backbone, R 19 as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, R 2 R R and R 2 as discussed above, through multiple functional groups within the core moiety backbone.

SRL 6045 The core moiety backbone unit, R 19 can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R 1 9 The more preferred benzothiepine moieties comprising R R R and/or R" conform to the preferred structures as outlined above for Formula I. The 3-carbon on each benzothiepine moiety can be achiral, and the substituents 20 R 2

R

3

R

4

R

5 and Rx can be selected from the preferred groups and combinations of substituents as discussed above.

The core structures can comprise, for example, poly(exyalkylene) or oligo(oxyalkylene), especially poly- or oligo(exyethylene) or poly- or oligo(oxypropylene).

Dosages, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact'of these compounds with their site of action in the body, for example in the ileum of a mammal, a human.

For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se. Pharmaceutically 275 SRL 6045 acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.

The anions of the definition of A- in the present 20 invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.

The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unitdose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.

SRL 6045 These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.

The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.

In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from .eoo about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single 15 dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.

Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 20 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.

Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form.

277 SRL 6045 The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention.

Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight o e to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more 15preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng S 20 to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.

Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal sublingual), and parenteral subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present 278 SRL 6045 invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory :ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a freeflowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sublingual) administration include lozenges comprising a compound of the present invention in a flavored base, .usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally 279 SRL 6045 contain from 0.1 to 5% w/w of a compound disclosed herein.

Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.

Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generallY present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

Transdermal administration is also possible.

Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis' of the recipient for a prolonged period of time. Such patches *S suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer.

A

suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 318 (1986).

In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.

The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as SRL 6045 sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. 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, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable I.dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile 20 injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Pharmaceutically acceptable carriers encompass all the foregoing and the like.

Treatment Regimen The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, atherosclerosis, or to protect SRL 6045 against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment 20 with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.

282 SRL 6045 The following non-limiting e~amples serve to illustrate various aspects of the present invention.

p p* p p p pp pp p p a p.

pp p pp. p p p pp a p p p.

p p p p SRL 6045 283 EXAMPLES OF SYNTHETIC PROCEDURES Preparation 1 2-Ethyl-2-(mesyloxymethyl)hexanal (1) 0 11

CH

3

SO

II CH

H

1 To a cold (10 oC) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2- 10 (hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30 OC. The

*S

reaction mixture was stirred at room temperature for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO 4 and concentrated in vacuo to give 24.4 g of brown oil.

Preparation 2 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2) SRL 6045 A mixture of 31 g (0.144 mol) of 2mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2- (mesyloxymethyl)-hexanal 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at ref lux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 niL of 10% NaO{, dried over MgSO 4 and concentrated in vacuo to remove 2methoxyethyl ether. The residue was purified by HPLC EtOAc-hexane) to give 20.5 g of 2 as an oil.

Example 1 3 -Butyl-3 -ethyl- 5-phenyl-2, 3 -dihydrobenzothiepine cis -3 -Butyl 3-ethyl 5-phenyl 3 -dihydrobenzothiepin- (5H) 4 one (4a) and trans-3 -Butyl1- 3-ethyl 5-phenyl 3 -dihydrobenzothiepin- (5H)4-one (4b) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl and 80 niL of anhydrous ethylene glycol SRL 6045 dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5 OC. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by i* 9 HPLC (hexane) to give 0.07 g of 4a in the earlier S.fraction and 0.1 g of 4b in the later fraction.

Example 2 cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin- (5H)4-one-l,l-dioxide (5a) and trans-3-Butyl-3-ethyl-5phenyl-2,3-dihydro-benzothiepin- (5H)4-one-1, 1-dioxide S2 S02 Sa To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in mL of methylene chloride, was added 0.59 g (1.75 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO., and concentrated in SRL 6045 vacuo. The residual syrup was purified by HPLC EtOAchexane) to give 0.2 g (30%)of 5aas an oil in the first fraction and 0.17 g of 5b as an oil in the second fraction.

Example 3 (3a,4ct,53) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5.

tetrahydrobenzothiepine-1, 1-dioxide (3a,43, 5a) 3- Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4, benzothiepine-1,1-dioxide (3a,4a, 5a) 3-Butyl-3-ethyl- 4-hydroxy-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3ax,43,5) 3-Butyl-3-ethyl-4-hydroxy-5phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (6d)

V

V

V

V.

V.

V

V

OH

6b A. Reduction of 5a and 5b with Sodiumn Borohydride To a solution of 0.22 g (0.59 nimole) of 5b in 10 rnL of ethanol was added 0.24 g (6.4 nimole) of sodium borohydride.

The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue 287 SRL 6045 was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g of 6a as a 10 syrup. The second fraction was 0.2 g of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to be a give 0.077 g of 6c in the third fraction as a solid.

Recrystallization from hexane gave a solid, mp 179-181

°C.

Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g of 6d in the fourth fraction as a solid.

Recrystallization from hexane gave a solid, mp 160-161 OC.

B. Conversion of 6a to 6c and 6d with NaOH and PTC 20 To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL

CH

2 C1 2 was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-3 36 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of icecrystals then was extracted with CHC1, (3x10 ml), dried over MgSO 4 and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg of 2 -(2-benzylphenylsulfonylmethyl)-2ethylhexenal in the first fraction, 30.9 mg of 6c in the second fraction and 90.0 mg of 6d in the third fraction.

288 SRL 6045 28 Oxidation of 6a to To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of

CH

2 C1 2 was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH 2 C1 2 The filtrate was concentrated in vacuo to recover 167 mg of 5b as a 10 colorless oil.

Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1dioxide (7) S 0 2 1s To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CHC12was added 10 g (31.9 mmole)of 50-60% MCPBA (mchloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N2 and was triturated with mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH 2

,C

2 (4x20 mL). The CH 2 Cl 2 extract was dried over MgSO 4 and evaporated to dryness to recover 4.9 g of an opaque viscous oil.

Example (laa,2p,8ba 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8btetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) 289 SRL 6045 (1acx,2L, 8bcz) 2 -Butyl-2 -ethyl- 8b-phelYl- la, 2, 3, 8b-tetrahydrobenzothiepino 5-b] oxirene-4,4-dioxide (Sb) S02 b To 1.3 g (4.03 mole) of 3 in 25 niL of CHCl 3 was added portionwise 5 g (14.1 mmole) of 50-60 MCPBA causing a mild exotherm. The reaction mixture was stirred under N,.

overnight and was then held at ref lux for 3 h. The insoluble ~.white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50 niL), once with brine, dried over MgSO., and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two ***.isomers. Trituration of this crystalline product in hexane recovered 141.7 mg of a white crystalline product.

This isomer was characterized by NMIR and mass spectra to be the (laa,2f3,8ba) isomer. 8a. The hexane filtrate was concentrated in vacuo to give 206 mig of white film which is a mixture of 30% 8a and 70% Sb by 1H NMVR.

Example 6 cis-3-Butyl-3-ethyl-5-phelyl-2, 3,4,5-tetrahydrobenzothiepine-1, 1-dioxide trans-3-Butyl-3-ethYl-S phenyl 3, 4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide and 3-ButyJ.-3ethy-4hydroxy5-cyclohexyidile-2,3, 4 tetrahydrobenzothiepile-l, 1-dioxide 290 SRL 6045 SO2 SO2 V 9b 9a

SO

2 S 010 A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H, for 5 h and filtered.

The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg of 9b. The second fraction, 5.0 mg was a 50/50 10 mixture of 9a and 9b. The third fraction was 8.8 mg of 6a The fourth fraction was 25.5 mg of 6b. The fifth fraction was 9.6 mg of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg of a mixture of 6d and one of the isomers of 10, Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHC1, under air was hydrogenated in 100 mL of methanol using 1 g of Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g of 9b, 0.45 g of 9a, 0.27 SRL 6045 g of 6a, 0.51 g of 6b, 0.02 g of 6c, 0.06 g of one isomer of 10, 10a and 0.03 g of another isomer of 10, Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) S CH 0 0 .O H O 11 To an ice bath cooled solution of 9.76 g (0.116 mole of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days diluted with ether, and was washed successively with dilute HC1, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 OC) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) 292 SRL 6045 S S 12 To a mixture of 2.61 g (0.04 mole) of zinc dust and mL of DME was added 7.5 g (0.048 mole) of TiC1 3 The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO, and concentrated.

The residual oil (2.5 g) was purified by HPLC to give 2.06 g of 12 as an oil in the second fraction.

Example 15 (laa,2a,8ba) 2-Ethyl-8b-phenyl-la,2,3,8b-tetrahydrobenzothiepino-[4,5-b]oxirene-4,4-dioxide (13) SO2 13 To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHC1, was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K 2

CO

3 (4x50 ml), water (twice with SRL 6045 293 ml) and brine. The organic layer was then dried over MgSO 4 and evaporated to dryness to recover 1.47 g of an off white solid. 1H NMR indicated that only one isomer is present.

This solid was slurried in 200 ml of warm Et20 and filtered to give 0.82 g of 13 as a white solid, mp 185-186.5

OC.

Example 11 (3a,4p,5a)- 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydro-benzothiepine-1,l-dioxide (14a), (3a,4p,5p) 3- Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (14b), and cis-3-Ethyl-5-phenyl-2,3,4,5tetrahydro-benzothiepine-l,l-dioxide SO2 A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO, solution followed by 89 g of NaHCO, powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 ml), then the SRL 6045 organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg of in the first fraction, 272 mg of 14a as a solid, mp 142-143.5 oC, in the second fraction, and 35 mg of impure 14b in the third fraction.

Example 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16)

-OH

S CH OH

H

16 A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HC1 and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residue.

Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil.

Example 13 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) 295 SRL 6045 I CH 2 0 17 A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through 5 a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18) 18 s SA mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiC1 3 and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HC1 and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO., and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g of 18 as an oil in the early fraction.

296 SRL 6045 Example (laa,2a,8ba 2-Butyl-2-ethyl-la,2,3,8b-tetrahydrobenzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and (laa,2p,8ba) 2 -Butyl-2-ethyl-8b-phenyl-la,2,3,8b-tetrahydrobenzothiepino[4,5-b]oxirene-4,4-dioxide (19b) S02

SO

2 O

O

19a 19b S. To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in mL of methylene chloride was added 2.2 g (3.2 mmole) of 60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHC1, and was held at reflux for 18 h under N 2 The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC EtOAc-hexane) to give 0.12 g of syrup in the first fraction.

Recrystallization from hexane gave 0.08 g of 19a, mp 89.5-105.5 OC. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.

Example 16 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5tetrahydro-benzothiepine-1,1-dioxide 297 SRL 6045 SO2 H O H This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.

5 Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5tetrahydro-benzothiepine-l1,-dioxide (21) \21 A mixture of 25 mg (0.085 mole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 102 NaOH and brine, dried over MgSO and concentrated in vacuo to give 0.19 g of semisolid which contain substantial mounts of diphenyl disulfide. This material was purified by HPLC EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by 1H NMR and mass spectra.

SRL 6045 298 Example 18 Alternative Synthesis of 6c and 6d A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2ethylhexanal (2) Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2ethylhexanal (44) cso 2 .S 02 H0 0 H 4 0 44 *l To a solution of 9.0 g (0.025 mole) of compound 2 in 10 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136 °C Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2ethylhexanal 299 SRL 6045 S02 2' o 0 H A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.

15 Step 3. (3a,4a,5a 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide and (3a,40,5p) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (6d) To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 oC with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20. min, quenched with 300 ml of HC1 and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil.

Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g of 6c in the second fraction and 6.5 g of 6d in the third fraction.

SRL 6045 300 B. Preparation from 2-hydroxydiphenylmethane Step 1. 2-mercaptodiphenylmethane (46)

SH

46 To a 500 ml flask was charged 16 g (0.33 mol) of sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of 10 DMF in 1 h while temperature was maintained below 30 oC by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at o. 15 once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280- 300 OC in a kugelrohhr pot under house vacuum for 30 min.

The residue was kugelrohr distilled at 1 torr (180-280 OC).

The distillate (56.3 g) was crystallized from methanol to give 37.3 g of the rearranged product dimethyl S-2benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was SRL 6045 made acidic with concentrate HC1, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g of 2mercaptodiphenylmethane as a yellow solid.

Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)

S

0 H 47 4 10 A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of 15 concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was 0 purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2ethylhexanal SRL 6045 To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 °C was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The 10 methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

Step 4. (3a,4a,5a) 3 -Butyl-3-ethyl-4-hydroxy-5-phenyl- 15 2,3, 4 ,5-tetrahydrobenzothiepine-l,l-dioxide and (3a,40,5p) 3 -Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1l,-dioxide (6d) Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC.

Example 19 (3a,4p,50) 3 -Butyl-3-ethyl-4-hydroxy-8-methoxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-l1,-dioxide (25) and (3a,4a,5a) 3 -Butyl- 3 -ethyl-4-hydroxy-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (26) Step 1. Preparation of 2 2 -benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22) 303 SRL 6045 0 H3 0 \O 22 2 -Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be 5 isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed.

The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 oC as previously described. The improved isolation procedure which avoided a chromatography step was described below.

j 9 9 The crude pyrolysis product was then heated at 65 OC in 100 ml of methanol and 100 ml of THF in the presence of g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5 NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2 -mercapto-4-methoxybenzophenone (2.3 g) was isolated.

2 -mercapto-4-methoxybenzophenone can readily be converted to the 2 -benzoyl-4-methoxyphenylthio)methyl)- 2-ethylhexanal (22) by reaction with 2-ethyl-2- (mesyloxymethyl)hexanal as previously described.

304 SR.L 6045 Step 2. 2- 2 -Benzoyl-5-methoxyphenylsulfonyl)methyl) 2-ethyihexanal (23) *f.

*tJ *9 4J 9 9 9**b 9 9 9.

9 p 5 Substrate 22 was readily oxidized to 2-((2-benzoyl-5methox-yphenyl-sulfonyl )methyl) -2 -ethyihexanal (23) as described in example 18.

Step 3. 2- -benzyl-5-methoxyphenylsulfonyl )methyl) -2ethyihexanal (24) Suif one 23 was then reduced to 2-((2-benzyl-5methoxyphenyl-sulfonyl )methyl) -2 -ethyihexanal (24) as described in example 18.

Step 4. (3a,43,53) 3 -Butyl-3-ethy14-hydoxy-8-methoxy- -phenyl 3, 4, 5 -tetrahydrobenzothiepine 1, 1 -dioxide 305 SRL 6045 and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1, 1-dioxide (26)

SO

2

OH

O

SO

:J

OH

26 5 A 3-neck flask equipped with a powder addition funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 OC internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 OC.

After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10 HC1. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. 'H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.

The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 oC. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by SRL 6045 addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.

Example (3a,4a,5a) 3-Butyl-3-ethyl-4, 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (27) :i HO SO 2

OH

27 9 In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 ml methylene chloride were cooled to 78 OC with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaC1 and then water.The organic layer was dried over magnesium sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.

Example 21 General Alkylation of phenol 27 A 25 ml.flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole).

The reaction was stirred at room temperature overnight.The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After 307 SRL 6045 stripping off the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NMR and mass spectra.

This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.

S St S St Formula for Table 1 Compound No.

27 26 28 29 30 31 Table 1

R

H

Me Et hexyl, Ac (CH2) 6-N-pthalimide Example 22 (3a, 4a, 5a) 3-Butyl-3-ethyl-4-hYdroxy-7-hydroxyamino-5phenyl-2, 3,4, S-tetrahydrobenzothiepine-1, 1-dioxide (37) and (3a,43, 50) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (38) Step 1. Preparation of 2-chloro-S-nitrodiphenylmethane (32) SRL 6045 Cl

NO

2 32 Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps( trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and combined with two 500 ml methylene chloride extractions of the aqueous layer.

The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.

Step 2. Preparation of 2-((2-benzyl-4nitrophenylthio)methyl)-2-ethylhexanal (33) SRL 6045 N02 33 The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 5 mole) of lithium sulfide was added and the solution was stirred at 75 oC for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in ml DMSO. The reaction mixture was heated to 80 oC under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary. Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgS04. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5 ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.

Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2ethylhexanal (34) 310 SRL 6045 The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

*r 9 Step 4. Reduction of 34 to 2-((2-benzyl-4hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal

HONH

A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.

Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(tbutoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2ethylhexanal (36).

311 SRL 6045 O H3

H

3 C- C-OH 3 I0

OH

3 01

H

3 C-C-O-C ONS0

OH

3 0

H

36 A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml 5 THF. Heated at 60 *C overnight. Striped of f THF and redissolved in methylene chloride. Extracted with 1 HC1; and then 5% sodium bicarbonate.

The product was further purified by column .chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-(t- *::*butoxycarbonyl) derivatives by proton NMR.

Step 6. (3ct,4cL,5cx) 3 -Butyl- 3-ethyl -4 -hydroxy- 7 15 hydroxyamilo-5-phefll 2 3 4 i 5-tetrahydrobeflzothiepiflelI 1dioxide (37) and (3c1,413,5J) 3-Butyl-3-ethy14-hydroxy- 7 2 3 4 ,5-tetrahydrobeflzothiepinelI 1dioxide (38) S0 2

HONH

312 SRL 6045

SO

2

HONH

OH

38 A 250ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 oC under a nitrogen atmosphere. Slowly add 2.29 g 5 potassium tert-butoxide(20.4 mmoles) with stirring and maintaining a -78 OC reaction temperature. After 1 h at -78 C the addition of base was completed and the temperature was brought to -10 °C by means of a ice/salt bath. After 3 h at -10 OC, only trace 36 remained by TLC. Next add 35 ml of 10 deionized water to the reaction mixture at -10 OC and stirred for 5 min. Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over 15 sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g).

Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1 (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.

SRL 6045 313 Example 23 (3a,4a,x) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and (3a,43,5p) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41) Step 1. 2-((2-Benzyl-4-(nhexylamino)phenylsulfonyl)methyl)-2-ethyihexanal (39)

H

4 4.

39 In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under nitrogen.

Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually 4" increasing the mobile phase to 70/30 hexane/ethyl acetate.

The product was characterized by NMR and mass spectra.

Step 2. (3,4a,5Ca) 3 Butyl 3-ethyl -7 (n-heylaino) -4 2, 3, 4, 5-tetrahydrobenzothiepine -1,11-dioxide and (3ax,40,5p) 3-Butyl-3-ethyl-7-(n-hexylamino)-4- -phenyl- IN-tetrahydrobenzothiepine-1, -dioxide (41) SRL 6045 SO2- S02 NH NH 41 A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous

THF

under nitrogen. Cool to -10 oC by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10 oC all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HC1 and stirred at -10 OC for 5 min. Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by 15 silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 53.2 mg); 41(58.9 mg).

o Example 24 Quaternization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.

Example (3a,4p,5p) 3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (42) 315 SRL 6045

OH

42 4 64*4 4**4 4* 4 @4 @4 6 .4 44 4 9 4.

4 4 4 44**

C

4**e 4 4 6t 4**S 4 444* 4 44 S 4 9 @44.46 9 In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d 0.67 g of mercuric trif late were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was 5 added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; ml of saturated KI and dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F.

10 Et al.Mass spectrum indicated a mixture of 6d mono iodide 42 and a diiodide adduct. The mixture was separated by colun chromatography and 42 was characterized bt NI"R and mass spectra.

15 Example 26 (3L,4J3,5p) 3 -Butyl-5-(4-carbomethoxyphenyl)..3-.ethyl-4hydroxy- 2, 3, 4, 5 -tetrahydrobenz othiepine- 1, 1 -dioxide (43) O=c 11O

H

A 0.1 g sample of 42 0.212 mmole), 2.5 ml dry 316 SRL 6045 methanol, 38 pl triethylamine (0.275 mmole) 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 OC overnight. The catalyst was filtered and a high yield of product was isolated.

The product was characterized by NMR and mass spectra.

Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.

Example 27 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide and (3a,4p,5p) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl- G. 15 2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (49) Step 1. 2-Mercapto-5-methoxybenzophenone

C

SH O OCH3 *eas Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.

Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2ethylhexanal (51) 317 SRL 6045

H

3C" Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure 5 for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC ethyl acetate-hexane) to give 1.7 g of 51.

Step 3. 2- ((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyl-hexanal (52)

H

3

C,*

A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g of 52 as a yellow oil.

SRL 6045 Step 4. 2- 2 -Benzyl-4-methoxyphenylsulfonyl)maethyl) 2-ethyihexanal (53) Hydrogenation of 1.1 g of 52 according to the procedure 5 of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

Step S. (3a, 4a, Sc) 3 -Butyl-3-ethyl-4-hydroxy-7-methoxy- 5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (48), and 3cx, 43, 50) 3 -Butyl- 3-ethyl -4-hydroxy-7 -methoxy- 5 -phenyl.

2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide (49) A solution of 1.1 g of 53, 0.36 g of potassium tbutoxide and 25 ml of anhydrous THF was held at ref lux for 2 319 SRL 6045 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg of 48 as crystals, mp 153-154 OC and 90 mg of 49 as solid, mp 136-140 OC.

Example 28 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57) Step 1. l-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)

S

O

54 To a cold (OC'mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol.

The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 2. l-(mesyloxymethyl)cyclohexanecarboxaldehyde 320 SRL 6045 0

II

OSCH

3 1 1

OH

0 To a cold (0 C'mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HC1 and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 3. 0. 15 Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56) O- H 56 A mixture of 69 g (0.303 mole) of 2mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil.

HC1 and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column SRL 6045 EtOAc: Hexane) and gave 18.6 g of yellow oil.

Proton NMR and mass spectra were consistent with the product.

Step 4. 5-Phenyl-2, 3 -dihydrospirobenzothiepine-3,1'cyclohexane (57)

S

57 To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiC1 3 (16.8 g, 0.108 mole) The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91 C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 29 8b-Phenyl-la,2,3,8b-tetrahydrospiro(benzothiepino[4,5b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58) 322 SRL 6045 SO2 O 58 To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. This was recrystallized from Hexane/EtOAc to give 4.31 g of yellow solid, mp 154- 155 C. Proton and carbon NMR and mass spectra were consistent with the product.

Example trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (59)

SO

OH

O59 A mixture of 0.5 g (1.4 mmoles) of 58 20 ml of ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg as a white solid, mp 99-100 C. Proton NMR showed this was a trans isomer. The second SRL 6045 fraction gave 200 mg of solid which was impure cis isomer.

Example 31 2 3 4 I spiro(benzothiepile- 3 -cyclohexane) -1,1-dioxide V.S02

.OH

To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml o~f CH i- 2 C1 2 was added 8 g of 50% NaOH and one drop of Aliquat-3 36 (methyltricaprylyl8.Imonium. chloride) phase transfer 6c.#10 catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and 9*the mixture was extracted with CH 2 Cl 2 (3x10 ml) washed with V...**water, brine and dried over MgSO, and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized V15 from Hexane/EtOAc to give 125 mg of white crystal, mp 209- 210 C. Proton and carbon NMR and mass spectra were consistent with the product.

Examiple 32 (3a,4c, 5a) 3 -Buty-3ethy-4hydroy5-phenyl- 2 3 4 tetrahydrobeflzothiepine and (3c1,4p,53) 3-Butyl- 3 2 3 4 (62) 324 SRL 6045 S S OH OH 61 62 To a solution of 0.5 g (1.47 mmole) of compound 47 in ml of anhydrous THF was added 0.17 g (1.47 mmole) of potassium t-butoxide. The reaction mixture was stirred at 5 room temperature for 18 h and quenched with 10 ml of HC1. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.

Example 33 (3a,4a,5a) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l1,-dioxide (63) and (3a,4p,50) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64)

SO

2

NH

2 325 SRL 6045

SO

2

NH

2

OH

64 An autoclave was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 Pd/C. After purging with nitrogen the dlave was charged with 100 psi hydrogen and heated to 55 C.

The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 000 0 10 63. This same procedure was used to produce 64 from 38.

Example 34 (3a,4cx,5c) 3 -Buty1-3-ethy-4-hydroxy7methoxy....(3.methoxyphenyl) 2,3, 4, 5 -tetrahydrobenzothjepine- 1, 1 -dioxide and (3a,43,53) 3 -Butyl-3-ethyl-4-hydroxy-7methoxy-5-.

(3 1 -methoxyphenyl) 2 3 4 5 -tetrahydrobenzothiepine-1, 1dioxide (66).

S0 2

CH

3

O-

OCH

3 SRL 6045 S0 2

CH

3 0

OH

66

OCH

3 Alkylatioi of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. Chemn.

Soc, 2431 (1958) gave 4-methoxy-2- (3 -methoxybenzyl) phenol in 35% yield. This material was converted to compound mp 138.5-141.5 and compound 66, mp 115.5-117.5 by the procedure similar to that in Example 18 method B.

Example (3a,4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (trifluoromethyl) phenyl) 1,1-dioxide and (3ct,413,5f) 3-Butyl-3-ethyl-4-hydroxy- 7-methoxy-5-(31-(trifluoromethyl)phenyl)-2,3,4,5tetrahydrobenzothiepine-1, 1-dioxide (68).

*S02-

OH

67

CF

3 327 SRL 6045

CH

3 0O

OH

68

CF

3 a 9*

V

9.

9 9 *99 V .99

V

9*9* 9

V.

*a*fJ a.

V

9 Alkylation of 4-methoxyphenol with 3- (trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'- (trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228 oCt and compound 68, mp 188- 190*C, byu the procedure similar to that in Example 18 method B.

Example 36 (3a,4ct,5a) 3-Buty1-3-ethy1-5-(41-fluorophenyl)-4hydroxy-7-methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,43,53) 3-Bxutyl-3-ethyl-5-(4,- 15 fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4; tetrahydrobenzothiepine-1, 1-dioxide 02 02 S

S

H3OH 3 CO OH

"OH

F 6 Alkylation of 4-methoxyphenol with 4-f luorobenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4 -methoxy-2-(4'-fluorobenzyl)phenol.

SRL 6045 This material was converted to compound 69 and compound by the procedure similar to that in Example 18 method B.

Example 37 (3c,4a,Sa) 3 -Butyl-3-ethyl--(3-fluorophenyl)4hydroxy-7-methoxy-.2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3ax,403,50) 3-Eutyl-3-ethyl-5-(3'fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5tetrahydrobenzothiepine1,1.dioxide (72).

02 02 S H3CO

H

3

CO

OH

'OH

*.71 72 Alkylation of 4-methoxyphenol with 3-f luorobenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-methoxy-2- (3 -f luorobenzyl) phenol.

This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.

ExamTple 38 (3a,4ca,5a) 3-Butyl-3-ethyl--(2-fluorophenyl).4hydroxy-7-methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,40,50) 3-Butyl-3-ethyl-5-(21fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5tetrahydrobenzothiepine-1, 1-dioxide (74).

SRL 6045 a a. a a a.

a.

73 74 Alkylation of 4-methoxyphenol with 2-f luorobenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-methoxy-2-(2'-fluorobenzyl)phenol.

5 This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.

Example 39 (3a,4ct,5ax) 3 -Eutyl-7 -bromo-3 -ethyl -4 -hydroxy- 5- (3' 10 methoxyphenyl) 2, 3,4, 5 -tetrahydrobenzothiepine- 1, 1 -dioxide and (3a,43,53) 3-Butyl-7-bromo-3-ethyl-4-hydrox-y-5- (3 '-methoxyphenyl) 5-tetrahydrobenzothiepine-1, 1dioxide (76).

02 02 S S Br Br H "OH OCH3

IOCH

3 76 Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-bromo-2-(3'-xnethoxybenzyl)phenol.

This material was converted to compound 75, mp 97-101.5 0

C,

330 SRL 6045 and compound 76, mp 102-106 0 C, by the procedure similar to that in Example 18 method B.

Example (3a,4ci,5a) 3-Butyl-3-ethyl-7-fluoro-5- fluorophenyl) -4-hydroxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3ci,40,53) 3-Butyl-3-ethyl-7-fluoro-5-(4'fluorophenyl) -4-hydroxy-2, 3,4, 5-tetrahydrobenzothiepine-1,12dioxide (78).

02 02 S S F. F F F 77 78 Alkylation of 4-fluorophenol with 4-f luorobenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-fluoro-2-(41-fluorobenzyl)phenol.

This material was converted to compound 77, mp 228-230 'C, and compound 78, mp 134.5-139 0 C, by the procedure similar to that in Example 18 method B.

Example 41 (3a,4x, 5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3' methoxyphenyl) 5-tetrahydrobenzothiepine-1, 1-dioxide and (3a,403,503) 3-Butyl-3-ethyl-7-fluoro-4Ohydroxy-5- (3 '-methoxyphenyl) 5-tetraliydrobenzothiepine-1, 1dioxide SR.L 6045 79 Alkylation of 4-f luorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-fluoro-2-(3 '-methoxybenzyl)phenol.

5 This material was converted to compound 79, as a solid and compound 80, mp 153-155 by the procedure similar to that in Example 18 method B.

Example 42 (3a,4f3,50) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4hydroxy-7-methylthio-2, 3,4, 5-tetrahydrobenzothiepine.-1, 1dioxide (81).

A mixture of 0.68 (1.66 nunol) of compound 77, 0.2 g mmol) of sodium methanethiolate and 15 ml of anhydrous DD4F was stirred at room temperature for 16 days. The reaction 332 SRL 6045 mixture was dilute with ether and washed with water and brine and dried over MSO,. The ether solution was concentrated in vacuo. The residue was purified by HPLC ethyl acetate in hexanes). The first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4-hydroxy-7-methylthio-5- (4'-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1dioxide. The second fraction was compound 81, mp 185-186.5 oC.

Example 43 (3a,4p,5p) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4hydroxy-7- (1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (82).

*0 2 N

OH

F

82 A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over MSO,. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177 OC.

333 SRL 6045 ExamPl1e 44.

(3cL,4P3,5I 3 3 -Butyl 3 ethY15-(41 fuorophenyl)hydroxy- 7 (1-morpholiflyl) -2,3,4,5S-tetrahydrobeflzothiepile- 1,1-dioxide (83).

02

S

N

83 A mixture of 0.4 g (0.98 nmmol) of compound 78 and 5.0 g (56 mmol) of morpholifle was held at ref lux for 2 h and concentrated in vacuo. The residue was diluted with ether ml) and washed with water and brine and dried over M 9SO 4 The ether solution was concentrated in vacuO. The residue Swas recrystallized from ether-hexanes to give compound 83, mp, 176.5-187.5 0

C.,

S ExLamle (3ca,4cL,5c1) 3 -utyl-3ethyl-5(4fluorophey)-4 hydroxy- 7 -methyi-2, 3 4 S-tetrahydrobeflzothiepine-i, 1-dioxide and (3ct,4P,53) 3 -ButYl- 3 ethyl(4fluorophyl)hydroxy- 7 -methyl-2, 3 4 S-tetrahydrobeflzothiepine-i, i-dioxide SRL 6045

H

3 C H 3

C-

S

S

S.

S.

S

S

84 Alkylation of 4-methyiphenol with 4-f luorobenzyl chloride according to the procedure described in J. Chem.

Soc, 2431 (1958) gave 4-methyl-2- luorobenzyl) phenol).

5 This material was converted to compound 84 and compound by the procedure similar to that in Example 18 method B.

Example 46 (3a,40,50) 3-Butyl-3-ethyl-4-hydroxy-5-(4'hydroxyphenyl) -7-methoxy-2, 3,4, 1,1-dioxide and (3cz,4f3,5P) 3-Butyl-3-ethyl-4,7- (4 '-hydroxyphenyl) -2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (87).

HO HO 86 87 To a solution of 0.52 (1.2 mmol) of compound 66 in ml of methylene chloride was added 1.7 g (6.78 inmol) of born tribromide. The reaction mixture was cooled to -78 0 C and 335 SRL 6045 was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78 OC for 1 h and quenced with 2 N HC1. The organic was extracted into ether. The ether layer was washed with brine, dried over MSO,, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173 oC.

The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264 OC (dec).

Example 47 (3a,4p,5p) 3 -Butyl-3-ethyl-4,7-dihydroxy-5-(4'fluorophenyl) -2,3,4, 5 -tetrahydrobenzothiepine-1, 1-dioxide 15 (88).

02 *H

OH

H HO'11-

'OH

F

88 Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.

Example 48 (3a,4p,5p) 3 -Butyl- 3 -ethyl-5-(4'-fluorophenyl)-4hydroxy-7- (1-azetidinyl) -2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (89).

336 SRL 6045 9. .9 9* 9 9* 9 9999 99 9 *99* 9.

9 999* 9 999*99 *9 A mixture of 0.20 g (0.49 mmol) of compound 78, and g (35 mmol) of aztidine was held at ref lux for 3 h and concentrated in vacuo. The residue was diluted with ether 5 (30 ml) and washed with water and brine and dried over MgSO4. The ether solution was concentrated on a steam bath.

The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5

'C.

Example' 49 (3zL,4,5cx) 3 -Butyl-3 -ethyl- 5- (31 -methoxyphenyl) -4 hydroxy-7-methylthio- 2 i 3,4, 5-tetrahydrobelzothiepile-1,1dioxide (3az,453,50) 3-Butyl-3-ethyl5( 39 methoxyphelyl) -4-hydroxy-7-methylthio- 2 .3,4,5tetrahydrobenzothiepiflels 1-dioxide (91).

H

3

CS

H

3

CS-

91 A mixture of 0.4 g (0.95 inmol) of compound 79, 0.08 g SRL 6045 (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 oC for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60 oC for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over MSO, and concentrated in vacuo. The first fraction (0.1 g) was compound 90, mp 117- 121 oC. The second fraction (0.16 g) was compound 91, mp 68-76 oC.

Example Preparation of polyethyleneglycol functionalized benzothiepine A.

O

0 0 *n 0

OCH

3 02 HO S SO 2

OH

HO

No. 136 No. 141 A 50 ml rb flash under a nitrogen atmosphere was charged with.0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.055 g Compound No. 136, 0.326 C)CO, and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5 days and then the solution was 338 SRL 6045 filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC Si02). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (Spectrum® 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present.

This material was active in the IBAT in vitro cell assay.

Example 51 Preparation of Compound 140 o..

./0 °°HO

I

S:

No. 140 339 SRL 6045 0 2 No. 111 A 2-necked 50 ml round bottom Flask was charged with 0.42g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG- Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, 0.100g of Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27 OC. TLC indicated the S 10 disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water.

The organic layer was evaporated to dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer 15 was dissolved in water and then dialyzed for 48 hours at o C through a cellulose dialysis tube (spectrum® 7 ,45mm x ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 NMR was consistent with the desired product B.

340 SRL 6045 Example 52 I No. 134 5 A 10 cc vial was charged with 0.21 g of Compound No.

136 (0.5mmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF.

The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer 10 was stripped to dryness and the desired product Compound No.

134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.

SRL 6045 Example 53 9* p.

9

OH

No. 112 Example 54 No. 113 342 SRL 6045 A two necked 25 ml round bottom Flask was charged with 0.5g (1.24mmoles) of 69462, 13 mis of anhydrous DMF, 0.055g of 60% NaH dispersion and 0.230g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10 OC under nitogen. Next, the reaction was slowly heated to 40 oC. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water.

The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane).

Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example

S

S

S.

S S

S

I OH 0 No. 135 No. 136 In a 50 ml round bottom Flask, add 0.7g (1.8 mmoles) of SRL 6045 Compound No. 136, 0.621g of potassium carbonate, 6 ml DMF, and 0.33g of 1,2-Bis [2-iodoethoxylethanel. Stir at 40 °C under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.

Examples 56 and 57 (Compound Nos. 131 and 137) The compositions of these compounds are shown in Table 3.

The same procedure as for Example 55 except appropriate benzothiepine was used.

Example 58 (Compound No. 139) The composition of this compound is shown in Table 3.

S.Same procedure as for Example 55 with appropriate S 15 benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].

Example 59 (Compound No. 101) ""IOH 0S OH HNN, II

C-N

H

No. 101 This compound is prepared by condensing the 7-NH, benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.

344 SRL 6045 Example 60 (Compound No. 104) 0\ No. 104 2-Chloro-4-nitrobenzophenone is reduced with .triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme Reduction of the sulfone-aldehyde

XXV

formaldehyde and 100 psi hydrogen and 55 C for 12 hours 15 catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative

XXVIII.

Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.

SRL 6045 Scheme 6

H

2 -PdIC R 6

CH

2 0H 4 4 44.4 4.

4 4**S 4

NH

XXIV

potassium t-butoxide,

~THF

R 6 N'

H

xx XI~cXXI~d 346 SRL 6045 Example 61

I-

*1

I

No. 102 A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50 °C for 4 days. The quat. Salt Compound No. 192 was isolated by 10 concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.

Example 62 o

OH

N

No. 125 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0 OC and then capped and warmed to room temperature. The reaction was stirred SRL 6045 overnight and the desired product was isolated by removing solvent by rotary evaporation.

Example 63 (Compound No. 295) 'iOH No. 295 No. 295 .4 4 4 4.

4 44 4 No. 113 Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0 °C was reacted with 0.248 mmoles (.10 g) of Compound No. 54 in 2.5cc of acetonitrile at 0 OC. Next, 0.(980g 2.48 mmoles) of 1,2-Bis [2-iodoethoxylethane].

After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.

348 SRL 6045 Example 64 (Compound No. 286) PhCH 2 H SC No. 286 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound :0 was prepared and purified as a colorless solid; mp 180-181 0 C; H NMR (CHC1 3 5 0.85 J 6 Hz, 0.92 J 6 Hz, 3H), 1.24-1.42 (in, 2H), 1.46-1.56 (mn, 1H), 1.64-1.80 (in, 1H), 2.24-2.38 (in, 1H), 3.15 (AB, 15 Hz, Av 42 Hz, 2H), 4.20 J 8 Hz, 1H), 5.13 2H), 5.53 1H), 6.46 1H), 6.68 1H), 7.29-7.51 (mn, 10H), 7.74

J

8 Hz, 1H), 8.06 J 8 Hz, 1H). FABMS m/z 494 too. 15 HRMS calcd for 494.2001, found 494.1993. Anal., Calcd.

.for

C

28

H

31 NO5S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; 9 H, 6.56; N, 2.74.

Example 65 (Compound No. 287)

HI,

2

H

No. 287 Following a procedure similar to the one described in SRL 6045 Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 0 C, 1 H NMR (CDCl 3 6 0.84 J 6 Hz, 3H), 0.92 J 6 Hz, 3H), 1.28, J 8 Hz, 1H), 1.32-1.42 1H), 1.48- 1.60 1H), 1.64-1.80 lH), 2.20-2.36 1H), 3.09 (AB, J, 15 Hz, Av 42 Hz, 2H), 3.97 (bs, 2H), 4.15 J 8 Hz, 1H), 5.49 1H), 5.95 1H), 6.54 J 7 Hz, 1H), 7.29-7.53 5H), 7.88 J 8 Hz, 1H); ESMS 366 Anal. Calcd. for C 20

H

25 N0 3 S: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Compound No. 288)

"OH

i" 15 No. 288 Following a procedure similar to the one described in '"Example 89, infra (see Compound No. 121), the title compound OtOQQ was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186'C; I H NMR (CDCI 3) 81.12 3H), 1.49 3H), 3.00 J Hz, 1H), 3.28 J 15 Hz, 1H), 4.00 1H), 5.30 (s, IH) 5.51 1H) 5.97 1H) 6.56 (dd, J 2.1, 8.4 Hz, 1H), 7.31-7.52 5H), 7.89 J 8.4 Hz, 1H). MS (FAB+) m/z 332.

Example 67 (Compound No. 289) 350 SRL 6045 No. 289 0 0000 4*WO

SO..

*4 0 4

S

0 0 0 *c 4 54 Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206 OC; 'H NMR (CDC1,) 6 0.80-0.95 6H), 1.10-1.70 7H), 2.15 (m, 1H), 3.02 J 15.3 Hz, 2H), 3.15 J 15.1 Hz, 2H), 3.96 br, 2H), 4.14 J 7.8 Hz, 1H), 5.51 1H), 5.94 J 2.2, 1H), 6.54 (dd, J 8.5, 2.2 Hz, 1H), 7.28- 7.50 6H), 7.87 J 8.5 Hz, 1H). MS (FAB): m/z 388 Example 68 (Compound No. 290)

-OH

No. 290 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 96-98 oC, 'H NMR (CDC1,) 6 0.92 J 7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 J 8 Hz, 1H), 3.09 (AB, J, 18 Hz, Av 38 SRL 6045 Hz, 211), 3.96 (bs, 2H), 4.14 J 7 Hz, 1H), 5.51 (s, lE) 5.94 lH) 6.56 J 9 Hz, 1H) 7.41-7. 53 (mn, 6H), 7.87 J 8 Hz, 1H); FABMS m/z 416 (M H).

Examiple 69 0,0 0

N

PhCH 2

KNO

H DO No. 291 10 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid: 1H NMR (CDC1,) 5 0. 91 J 7 Hz, 6H), 1.02-1.52 (in, l1H), 1.60- 1.70 (in, lH), 2.23 J 8 Hz, 1H) 3.12 (AB, J; 18 Hz, Av 36 Hz, 2H), 4.18 J 7 Hz, 1H) 5.13 2H) 5.53 1H), 6.43 1H), 6.65 1H), 7.29-7.52 (in, 7.74 J 9 Hz, 1H), 8.03 J =8 Hz, 1H); ESVS m/z 556 (M+Li).

352 SRL 6045 Example 70 (Compound No. 292) No. 292 Following a procedure similar to the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 111- 112.5 0 C, 1 H NMYR (CDCl 3 5 0 .9 0 J 8 Hz, 6Hi), 1.0 3 -1.5 0 (in, 10H), 1.55-1.70 (mn, 2H), 2.18 J 12 Hz, 2H), 3.07 (AB, J A 15 Hz,' Av 45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 1H), 6.55 J =9 Hz, 1H), 7.10 J 7 Hz, 2H), 7.46 J 6 Hz, 2H), 7.87 J 9 Hz, 1H).

SRL 6045 Example 71 (Compound No. 293) 0

O

PhCH 2N No. 293 During the preparation of Compound No. 290 from Compound No. 291 using BBr 3 the title compound was isolated: 'H NMR (CDC1,) 6 0.85 J 6 Hz, 6H), 0.98-1.60 10H), 1.50-1.66 2H), 2.16 J 8 Hz, 1H), 3.04 (AB, J 15 Hz, Av 41 Hz, 2H), 4.08 1H), 4.12 (s, 1H), 5.44 1H), 5.84 1H), 6.42 J 9 Hz, 1H), 7.12 J 8 Hz, 2H), 7.16-7.26 10H), 7.83 J 8 Hz, 1H); ESMS m/z 512 (M+Li).

Example 72 (Compound No. 294) Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: H NMR (CDC1,) 6 0.90 J 6 Hz, 6H), 1.05-1.54 9H), 1.60-1.70 (m, 1H), 2.24 J 8 Hz, 1H), 2.80 6H), 3.05 (AB, JB Hz, Av 42 Hz, 2H), 4.05-4.18 2H), 5.53 1H), 5.93 1H), 6.94 J 9 Hz, 1H), 7.27-7.42 4H), 7.45 (d, J 8 Hz, 2H), 7.87 J 9 Hz, 1H); ESMS m/z 444 Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.

Examples 73-79, 87, 88 and 91-102 Using in each instance a method generally described in 354 SRL 6045 those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and positions (R 3

R

4

R

5

R

6 and in the indicated position on the benzo ring Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.

Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]- 15 nitrobenzene.

In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mls S. chlorobenzene. Slowly add 60 gms acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.

In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq).

25 Chill solution with ice bath while purging with N2. Slowly add 40.3g aluminum chloride (1.2 eq 0.3 mole). Stir under

N

2 for 24 hrs.

After 24 hrs, the solution was poured into 300 mls 1N HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgSO4, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57g (mixture of meta, ortho and para).

SRL 6045 Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 C1 12.15 12.16 With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

4-Chloro-3- 4 -methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2 -chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can 15 be synthesized from the procedure used to prepare compound S"121.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with o triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with 25 lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for 14 hours.

The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in 356 SRL 6045 the presence of 35 g of potassium carbonate and stirred at room temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.

The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at 0 C to yield compounds 117 and 118 which were separated by silica gel column chromatography.

Examples 89 and Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to 15 warm to room temperature. Reaction is complete after hours. The reaction is quenched by addition of potassium carbonate at 0 C and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.

Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except 25 that fluorobenzene was used as a starting material in place of anisole.

SRL 6045 Table 3: Specific Compounds (#102-111, 113-130, 132-134, 136, 138, 142-144, 262-296) 0 0

/I

SR

x 2 RR6 Cp# R1 R2

R

3 102 Et- n-Bu- HO 103 n-Bu- Et- HO- H-

R

5 Ph- Ph- Ph- Ph- Ph- 104 105 Et- Etn-Buri-Bu-

HO-

HO 106 Et- ri-Bu- HO- H- 107 n-Bu- Et- HO- H- p-n- ClOH21--O- Ph- 108 Et- n-Bu- HO- H- Ph-

R

6

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

H-

q 7- (CH3) 3N+- 7- (CH3) 3N+- 7 (CH3 2N- 7- CH3502 NH- 7-Br-CH2-

CONH-

7-Nli2- 7- C5 Hi11CONH 7-NH2- 7 -CH3CONH- 7-NH2- 7-NH2- 7-NH2- 109 Et- ra-Bu- HO- 110 ill 113 114 Etn-Bu- Et- Etn-Bu- Etn-Bun-Bu-

HO-

HO-

HO

HO-

H- p-n- ClOH2l--O- Ph- H- Ph- H- p-HO-Ph- H- p-HO-Ph- H- p-CH3O-Ph- 115 n-Bu- Et- HO- H- p-CH30-Ph- H-7NCB H- 7-NH-CBZ SRL 6045 Cp# 116 117 118 119 Etri-Bu- Et- Etn-Bu- Etn-Bun-Bu-

R

3

HO-

HO-

HO-

HO 120 n-Bu- EL- HO- H-

R

p-CH3O-Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- (Rx) q 7-NH-CBZ 7 -NH-CBZ 7 -NH-CBZ 7-NHCO2-t- Bu 7-NHCO2-t- Bu 7 -NH2 7 -NH2 7-n-C6H13-

NH-

7-i-C 6H13

NH-

121 122 123 Etn -Bu Etn-Bu- Etn-Bu- HO

HO-

HO 124 n-Bu- Et- HO- H- 125 EL- n-Bu- HO- H- 126 127 128 129 130 n-Buri- Bu Et- Et- Et- EtLn-Bun-Bun-Bu- HO HO

HO-

HO-

HO-

Php-F-Php-F-Php-F-Php-F-Ph- Ph- 8- (CH3) 3) N+ CH2CH2O) 3- 7-NH-CBZ 7-NH2- 7 -NI{-CBZ 7 -NH2- 8- (CH3) 3N+ C6H12O- 8-phthalirnidyl C6H12O- 8-n- Cj0H21- 132 Et- n-Bu- HO- 133 Et- n-Bu- HO- H- Ph- Ph- 359 SRL 6045 Cp# 134 136 138 142 143 144 too* *0 0*00 .00.

6606.

262 263 264 265 266 267 268 269 270 271 272 273 274 Et- Etn-Bu- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Et- Etn-Bu n-Bu- Etn -Bu n-Bun -Bu n -Bu n-Bun -Bu n-Bun-Bun-Bura-Bun-Bun-Bun -Bu n-Bun-Bun-Bu-

R

3

R

4 HO- H- HO- H- HO- -H- H- HO- HO- H- HO- H- HO

H-

HO

H-

HO-

HO HO

H-

HO HO

H-

H-

HO

H-

HO

H-

HO

H-

H-

H-

HO-

H-

H-

HO HO

H-

Ph- Ph- Ph-

H-

rn-CH3 0-Php -F -Ph m-CH3O-Ph-

H-

m-CF3 -Ph-

H-

rn-HO-Phrn-HO-Php-F-Ph-

H-

p-F-Phrn-CH3 0-Ph-

H-

H-

p-F- Ph-

R

6

H-

H-

H-

m-CH3O-Ph-

H-

H-

H-

m-CH30-Ph-

H-

m-CF3 -Ph-

H-

H-

H-

p-F-Ph-

H-

H-

m-CH3O-Ph- P-F-Ph-

SH-

(RX)q 8- 1- (C2H 4 0) 3- 8- HO- 8- CH3CO2- 7-CH3S- 7-CH3S- 7- azetidine 7-CH3O- 7 -CH3O- 7-CH3O- 7 -CH3O- 7-HO- 7 -CH3O- 7-CH3O- 7-CH3O- 7-HO- 7-Br- 7-Br- 7-F- 7-F 360.

SRL 6045 Cp# 275 276 277 278 279 280 281 282 283 284 Et- Et- Et- Et- Et- Et Et- Et- Et- Etn-Bun-Bun-Bun-Bun -Bu n -Bu n-Bun-Bun -Bu

H-

HO-

HO-

HO-

H-

HO-

HO HO

HO-

HO-

HO-

HO-

H-

HO-

HO

HO-

H-

H-

HO-

HO-

H-

m-CH3O-Phrn-F-Ph-

H-

H-

o -F -Php-F-Php-F-Ph-

H-

p-F-Ph-

S

*5S*

S

S

*SSS

S

R

6 rn-CH3O-Ph-

H-

H-

o-F-Phrn-F-Ph-

H-

H-

H-

p-F-Ph-

H-

H-

H-

H-

H-

H-

H-

H-

H-

(Rx) q 7-F- 7-F- 7-CH3O- 7-CH3O- 7-CH3O- 7-CH3O- 7-CH3S- 7 -CH3 7-CH3- 7- morpho line 7- pyrrolidine 7 -NH-CBZ- 7-NH2- 7-NH2- 7-NH2- 7-NH2- 7 -NH-CBZ- 7-NH2- 285 Et- n-Bu- HO- H- p-F-Ph- 286 Et- Et- HO- H- Ph- 287 Et- Et- HO- H- Ph- 288 CH3- CH3- HO- H- Ph- 289 n- n- HO- H- Ph- C3H7- C3H7- 290 n-Bu- n-Bu- HO- H- Ph- 291 n-Bu- n-Bu- HO- H- Ph- 292 n-Bu- n-Bu- HO- H- p-F-Ph- SRL 6045 CP* Rl R 2

R

3

R

4 293 n-Bu- n-Bu- HO- H- 294 n-Bu- n-Bu- HO- H- 295 Et- n-Bu- HO- H-

RS

Ph- Php-I- (C2H40) 3- Ph- (RX) q 7- PhCH2N- 7- (CH3) 2N- 7 -NH2 296 Et- n-Bu- HO- H-

C

p- (CH3) 3N+(C 2H40) 3 -Ph- 7 -NH2 SRL 6045 TABLE 3A Bridged Benzothiepines (#101, 112, 131, 135, 137, 139-141) a a a .a a a.

a a *aaa a a CPD 101 (Example 59)

H

2

,N

CPD #112 (Example 53) CPD 131 (Example 56) 363 SRL 6045 CPD #135 (Example b CPD #137 (Example 57) CPD #139 (Example 58) SRL 6045

S.

NH,, H 2

N

PEG =3400 molecular weight polyethyleneglycol bridge CPD 140 (Example 5 1)

H

3 CO 0 10 9 CPD #141 (Example 365 SRL 6045 Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R 3

R

4

R

s

R

6 and in the indicated position on the benzo ring o *oe 366 SRL 6045 Table 4: Alternative compounds #1 (#302-312, 3 14-430) 0 0 (Rx) q Et n-Bu

OH

S

S a.

a

S

a a a.

a a Cpd# 302 303 304 305 306 307 308 309 310 311 312 314 315 316 317 318 319

RS

p-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Phm-CH 3 O-Ph m-CH 3 O-Phm-CH 3 O-Phm-CH 3 O-Phm-CH 3 O-Phm-CH 3 0-Ph- (RX) c 7- (1-aziridine) 7-EtS- 7-CH 3 S 7-CH 3 S 2 7-PhS- 7-CH 3

S-

9 -CE 3 7-CH 3

O-

9 -CH 3

O-

7-Et- 7-iPr- 7- t-Bu 7- (1-pyrazole) 7- (1-azetidine) 7- (1-aziridine) 7-EtS- 7-CH 3 S 7-CH 3 S 2 7-PhS- 367 SRL 6045 320 321 322 323 324 325 a a. a a a.

a a a a a a a a.

a a a a a 326 327 328 329 330 331 332 333 334 335 336 337 m-CH 3 O-Ph rn-CH 3 0-Ph rn-CH 3 0-Ph in-CH 3 O-Ph m-CH 3 O-Ph p-F-Php-F-Php -F -Php -F -Ph p -F -Ph p -F -Ph p -F -Php -F -Ph p -F -Ph p-F-Php-F-Php-F-Php-F-Ph- 7-CH 3

S-

9-CH 3

S-

7 -CH 3

O-

9 -CH 3 0- 7-Et- 7-iPr- 7-t-Bu- 6-CH 3 0- 7 -CH 3

O-

8-CH 3 0- 7- (1-azetidine) 9-CH 3 7-EtS- 9-CH 3 7-CH 3 S 9-CH 3 7-CH 3 S 2 9-CH 3 7-PhS- 9-CH3- 7 -CE 3 9 -CH 3 7-CH 3

O-

9 -CE 3 7 -CH 3 9-CH 3 7-CH 3 0- 9-CH 3 0- 7- (1-pyrrole) 7- N' -iethylpiperaziie Ph- SRL 6045 338 339 340 341 342 343 344 345 346 347 348 349 350 351 p -F -Ph p -F -Ph p-F-Php-F-Php-F-Php-F-Phm-CH 3 O-Phm-CH 3 O-Phin-CE 3 O-Phm-CH 3 O-Phm-CH 3 O-Phm-CE 3 O-Phm-CH 3 O-Phm-CE 3 O-Phm-CH 3 O-Phm-CE 3 O-Phm-CH 3 O-Phm-CH 3 O-Phm-CH 3 0-Ph- 7-CH 3 C (=CH 2 7 -cycipropyl 7- (CE 3 2

NHN-

7- -azetidine 9-CH 3

S-

7- (N-pyrrolidiie) 9-CH 3

S-

7- (CH 3 2

N-

9-CH 3

S-

7- (1-pyrazole) 7- -iethylpiperazine Ph 7-CH 3 C (=CH 2 7 -cyclopropyl 7- (CE 3 2

NHN-

7- -azetidine 9-CH 3

S-

7- (N-pyrrolidine) 9-CH 3

S-

7- (CE 3 2

N-

9-CH 3

S-

6-CH 3

O-

7 -CH 3

O-

8-CH 3

O-

7- (1-azetidine) 9-CE 3 7-EtS- 9-CH 3 7-CH 3 S(0) 9-CE 3 352 353 354 355 356 SRL 6045 Is..

s* 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 m-CH 3 O-Phm-CH 3 O- Phm-CH 3 0-Phm-CH 3 Q-Phm-CH 3 0-Phm-CH 3 0-Phthien-2-yl thien-2 -yl thien-2-yl thien-2 -yl thien-2 -y.

thieri-2 -yl thiera-2-y.

thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2-yl thien-2 -yl thien-2 -yl 7-CH 3 S 2 9-CH 3 7-PhS- 9 -CH 3 7-CH 3

S-

9 -CH 3 7-CH 3 0- 9 -CH 3 7 -CH 3 9-CH 3 7 -CH 3 0- 9-CH 3

O-

7- (l-aziridine) 7-EtS- 7-CH 3 S(0) 7-CH 3 S 2 7-PhS- 7-CH 3

S-

9-CH- 3

S-

7 -CH 3 0- 9 -CH 3

O-

7-Et- 7-i Pr 7-t -Bu 7 (1 -pyrrol1e) 7-CH 3 0- 7-CH 3

S-

7- (1-azetidine) 7-Meaa a a Oa a a a .a.a a *aaaaa a 370 SRL 6045 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 5-C1-thiera-2-yl 5-C1-thien-2-yl 5 -C1-thien-2 -yl 5-C1-thien-2-yl 5-C1-thieri-2-yl 5-C1-thien-2 -yl 5-Cl-thien-2-yl 5-C1-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-C1-thien-2-yl 5-C1-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl thieri-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thien-2 -yl thieri-2 -yl 7- (1-azetidine) 7- (1-az iridine) 7-EtS- 7-CH- 3 S(0) 7-CH 3 S 2 7-PhS- 7-CH- 3

S-

9-CH- 3

S-

7 -CH 3

O-

9-CH- 3 0- 7-Et- 7-iPr- 7-t-Bu- 7-CH 3 0- 7 -CH 3 7-Me 7- (1-azetidine) 9-C- 3 7-EtS- 9 -CH 3 7-CH 3 S(0) 9-C- 3 7-CH 3 S 2 9-CH- 3 7-PhS- 9-CH 3 7-CH 3

S-

9-CH 3 7-CH 3

O-

9-CH 3 371 SRL 6045 4

SS

S. S SS 55

S

S

S. SO S 4 4* S S

S

545S 0 5.55

-S

S S 0*

OS

S

S

*SSSS.

5 399 400 401 402 403 404 405 406 407 408 409 411 412 413 414 415 416 417 418 419 thien-2-yl thien-2 -yl thien-2 -yl thieri-2 -yl thiera-2 -yl thien-2 -yl thien-2 -y2.

thien-2 -yl thien-2 -yl thieri-2 -yl thien-2 -yl 5-C1-thien-2-y1 5-C1-thien-2-y1 5-C1-thien-2-yl 5-C1-thien-2-y1 5-C1-thien-2-yl 5-C1-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yJl 5-C1-thien-2-yl 7-CH 3 9 -CH 3 7-CH 3

O-

9 -CH 3

O-

7- (1-pyrazrole) 7- -methylpiperazile Ph- 7-CH 3 C (=CH 2 7 -cycipropyl 7- (CH 3 2

NHN-

7- -azetidirie 9-CH 3

S-

7- (N-pyrrolidile) 9-CH 3

S-

7- (CE 3 2

N-

9-CH 3

S-

7- (l-pyrazrole) 7- -iethylpiperazile Ph- 7-CH 3 C (=CH2) 7 -cyclopropyl 7 (CE 3 2

NHN-

7- -azetidine 9-CE 3

S-

7- (N-pyrrolidile) 9-CH 3

S-

7- (CH 3 2

N-

9-CH 3

S-

372 SRL 6045 420 421 422 423 424 425 426 427 428 429 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2 -yl 5-Cl-thien-2-yl 5-Cl-thieri-2-yl 5-Cl-thien-2-yl thieri-2 -yl 5-Cl-thien-2 -yl 7- (1-azetidine) 9 -CE 3 7-EtS- 9-CE 3 7-CH 3 S 9-C- 3 7-CH 3 S 2 9-CE 3 7-PhS- 9-CH 3 7-CH 3

S-

9-CH 3 7-CH 3

O-

9-CE 3 7-CE 3 9 -CH 3 7 -CH 3

O-

9 -CE 3

O-

6-CH 3

O-

7-CH 3

O-

8-CH 3 0- 6-CH 3

O-

7-CH 3

O-

8-CH 3 0- 430 373 SRL 6045 Examples 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R 3

R

4

R

5

R

6 and in the indicated position on the benzo ring o Example 1395 Dibutyl 4-fluorobenzene dialdehyde sB u Bu

OHC

F N Br Step 1: Preparation of dibutyl 4-fluoro benzene 20 dialdehyde To a stirred solution of 17.5 g (123 mmol) of difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO) and SRL 6045 concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g of fluorobenzene dialdehyde as a yellow oil: IH NMR (CDC13) d 0.87 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.5-1.78 (m, 4H), 3.09 2H), 7.2-7.35 IH), 7.5-7.6 2H), 9.43 IH), 10.50 J 2.62 Hz, IH).

Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of Sethyl acetae to quench the excess of DIBAL, followed by 3 N HC. The mixture was extracted with ethyl acetate, washed with water, dried (MgSOJ 4 and concentrated in vacuo.

Silica gel chromatographic purification of the crude product gave 13.5 g of recovered starting material, and 8.1 g of the desired fluorobenzyl alcohol as a colorless 20 oil: IH NMR (CDC13) d 0.88 J 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 4H), 1.94 (br s, IH), 3.03 2H), 4.79 2H), 6.96 (dt, J 8.46, 3.02 Hz, IH), 7.20 (dd, J 9.47, 2.82 Hz, IH), 7.42 (dd, J 8.67, 5.64, IH), 9.40 (s,

IH).

Step 3: Preparation of dibutyl 4 -fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich).

The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgS04), and concentrated in vacuo. The mixture was stirred in small 375 SRL 6045 amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g of the desired product as a colorless oil: 1 H NMR (CDC13) d 0.88 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.55-1.78 4H), 3.11 2H), 4.67 (s, 2H), 7.02 (dt, J 8.46, 3.02 Hz, 1H), 7.15 (dd, J 9.47, 2.82 Hz, 1H), 7.46 (dd, J 8.67, 5.64, 1H), 9.45 1H).

Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide To a solution of 8.5 g (25 mmol) of sulfide obtained :..,from Step 3 in 200 mL of CH 2 C1 2 at 0 OC was added 15.9 g mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na 2 CO,, dried (MgSOand concentrated in vacuo to give 10.2 g of the 20 desired product as a colorless oil: 1 H NMR (CDC13) d 0.91 J 7.05 Hz, 6H), 1.03-1.4 8H), 1.65-1.82 2H), 1.90-2.05 2H), 3.54 2H), 5.01 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J 8.87, 2.42 Hz, 1H), 8.03 (dd, J 8.86, 5.64, 1H), 9.49 1H).

376 SRL 6045 Generic Scheme X

RXC

C'CHO

1. Li 2 S, DMSO, heat 2. mesylate aldehyde, heat

CHO-

CHO

CHO

i butyl lithium, PMETA, deg C, THF 2. DMF Rx :PIf

R'

Rx<)4

CHO

Br PMETA BrPh 3 PBr, -40 deg C

DMF

DEBAL, THF, deg C

RI

Rx0

CHO

OH

MCPBA

MCPBA m-chloroperbenzoic acid 0

R

R2

CHO

Br R B (OR) 2 heat Pd(Ph 3

P)

4 Na 2

CO

3 Ethanol, toluene, or DME

-~RR

02 :,N

CHO

base potassium t-butoxide)

R

5 SnR 3 heat Pd(Ph 3

P)

4 solvent R H, or CI-C 6 ailcyl 02 RXI4 R2

R

SRL 6045 Example 1396 0

S

/O

H S\ *0O OH Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO etc), followed by the addition of dialkyl mesylate aldehyde provided a dialkyl benzene 10 dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z.

Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate

W.

Preparation of N-propylsulfonic acid To a solution of 51 mg (111 pm) Compound X in ethanol (400 pl) was added 1,3 propane sultone (19.5 4l, 222 um).

The reaction was stirred in a sealed vial at 55 oC for hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 1H NMR (CDCL,) d 0.82-0.96 6H), 1.11-1.52 (m of m, 378 SRL 6045 1.58-1.72 1H), 2.08-2.21 1H), 2.36-2.50 2H), 2.93 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76 2H), 4.15 1H), 5.51 1H), 6.45-6.58 1H), 6.92-7.02 (m, 1H), 7.35-7.41 1H), 7.41-7.51 2H), 8.08 J 8.1 Hz, 1H), 8.12-8.25 1H); MS ES- M-H m/z 579.

Example 1397 The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these 15 analogs.

3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.

0 Bu MeS OH

OH

F

A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at C for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C then was concentrated in vacuo. The residue was triturated with water and extracte 379 SRL 6045 wiith ether. The ether extract was dried over MgSO 4 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164- 165.5 %C.

3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepinel,1-dioxide and 7,9-Bis(dimethylamino)-3,3-dibutyl-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide.

MeN O O Me 2 N O O Bu Me*

N

F

OH

OH

F

F

F

A solution of 0.105 g of 3 3 -dibutyl-7,9-difluoro-5a- (4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-l,l-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgSO 4 and concentrated in vacuo. The resdue was purified by HPLC EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a- 4 '-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-l,l-dioxide, MS (CI) m/e 480 (M and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a- 380 SRL 6045 hydroxy-2,3,4,5-tetrahydrobenzothiepine-l, -dioxide, MS (CI) m/e 505 (M The compounds of this invention can also be synthesized using cyclic sulfate below) as the reagent as shown in the following scheme. The following example describes a procedure for using the cyclic sulfate as the reagent.

a a.

a oo SRL 6045 SOC1 2 R 2 If 0 RuCI 3 NaIO 4 a.

a.

a a (Ry)p- 1.NaH, diglyme 9aRX)qd 2.

0i 0 3. H,S0 4 PCC, CHCI (Ry)

MCPBA

(Rx) (Rx) (Ry)

(R%

KOtBu (Rx)q (Ry)p SRL 6045 Dibutyl cyclic sulfite: 0

II

O/SO

*e A solution of 2 ,2-dibutyl-1,3-propandiol (103g, 0.548 mol) and triethylamine (221g, 2.19 mol) in anhydrous S 5 methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was 1 0 stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) was consistent with the product.

To a solution of the above compound (127.5g 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left.

The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite.

The filtrate was concentrated under vacuum and gave the 383 SRL 6045 cyclic sulfate 133 g as an oil. Proton, carbon NMR and MS were consistent with the product.

2-[(2-(4'-Fluorobenzyl)-4-methylphenylthio)methyl]-2butylhexanol:

H

3 C

OH

0F Sodium hydride (60% oil dispersion), 0.27 g (6.68 o mmole) was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2e0o* o methoxyethyl ether (diglyme) and the mixture was cooled in oo o an ice bath. A solution of 1.55 g (6.68 mmole) of fluorobenzyl)-4-methylbenzenethiol in 10 ml of 2methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2-methoxyethyl ether was added once and stirred for 30 min at 0 C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HCI and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated under vacuum to give 2.47 g SRL 6045 92.5%) of an oil. Proton NMR consistent with the product.

13 C NMR and MS were 2-[(2-(4'-Fluorobenzyl)-4 -methylphenylthio)methyl] -2butylhexanal: To a solution of the above product (2 g 4.9 mmol) in 40 ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 10 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel. The filtrate was concentrated under vacuum to give 1.39 g of an oil.

Proton, carbon NMR and MS were consistent with the product.

2-[(2-(4'-Fluorobenzyl)-4 -methylphenylsulfonyl)methyl] 2-butylhexanal To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% m-chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for 385 SRL 6045 18 hrs and filtered. The filtrate was washed successively with 10% NaOH water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g of an oil. Proton, carbon NMR and MS were consistent with the product.

3,3-Dibutyl-7-methyl-5a-(4'-fluorophenyl)-4a-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide: 02 H3C oo.o

OH

F

mixture of 0.37 g (0.85 mmol) of the above product in 30 ml of anhydrous THF was stirred at 0 Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material 15 left. The crude reaction mixture was acidified with 10% HC1 and extracted with ether. The ether extract was washed successively with water and brine, dried with MgSO 4 and concentrated under vacuum. The residue was purified by HPLC EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white solid, 0.27 g Proton NMR and carbon NMR were consistent with the desired product. Mass spectrum (CI) also confirmed the product, m/e 433 (M 1).

SRL 6045 Example 1398 Step 1 Cl 0 NO2

C

1

,H

4 1 CINO fw=291.69 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml round bottom flask. Fit flask with a N2 inlet adapter and suba seal. Remove from inert atmosphere and begin N 2 purge. Add 50mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1 via syringe and begin stirring with magnetic stir bar.

Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 15 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N 2 purge. Stir at room temperature overnight. After stirring at room temperature for place in oil bath and heat at 50C for lhr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere.

In inert atmosphere, dissolve acid chloride with 105mls anhydrous anisole (0.97 mole Aldrich 29,629-5).

Place solution in a 2-necked 500ml round bottom flask.

Weigh out 45.1gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel. Fit reaction flask with addition funnel and a N2 inlet adapter.

Remove from inert atmosphere. Chill reaction solution with ice bath and begin N 2 purge. Slowly add AlCl, to chilled solution. After addition is complete, allow to warm to room 387 SRL 6045 temperature. Stir overnight Quench reaction by pouring into a solution of 300 mis IN HC1 and ice. Stir 15 min. Extract twice with ether.

Combine organic layers and extract twice with 2% NaOH, then twice with deionized

H

2 0. Dry with MgSO filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%. Obtain NMR and mass spec (m/z=292).

Step 2 Co CH3 o 2

C

14 ,HC1NO 3 fw=277.71 15 Dissolve 3 8.10gms (0.131 moles) of the benzophenone from step 1 in 250mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N, inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.

Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Stir 5 minutes after addition is complete.

Prepare a solution of 22.85 gms triethyl silane (0.197mole Aldrich 23,019-7) and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Stir 5 minutes after addition is complete.

Prepare a second solution of 39.32 gms trifluoromethane 388 SRL 6045 sulfonic acid and 170mls anhydrous methylene chloride.

Place in addition funnel and add dropwise to chilled solution under N 2 Stir 5 minutes after addition is complete.

Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under After all additions are made allow to slowly warm to room temperature overnight. Stir under N, overnight.

Prepare 1300 mls saturated NaHCO, in a 4 liter beaker.

Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min.

Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride. Dry organic layers with MgSO,.

Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278).

Step 3

HCH

NO2

C

25

HNO

4 S fw=443.61 Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N, inlet, and stopper. Add 1.84 gms Li 2 S (0.040 moles Aldrich 389 SRL 6045 21,324-1). Place flask in oil bath and heat at 75 0 C under N 2 overnight then cool to room temperature.

Weigh out 10.59 gms dibutyl mesylate (0.040 moles).

Dissolve with anhydrous DMSO and add to reaction solution.

Purge well with N 2 heat overnight at 80 0

C.

Cool to room temperature. Prepare 500 mls of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times.

Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

Step 4 **0

O

0 o/CH 3 NO2 C2sH 3 NOS fw=475 .61 Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N2 inlet and stopper. Chill solution with ice bath under N2 purge. Slowly add 11.54 gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, After addition is complete warm SRL 6045 to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% K 2 CO,. Extract aqueous layer twice with methylene choride. Combine organic layers and dry with MgSO,. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).

*Step

OCH

N

H3C CH3 C,,H,,NOS fw=473.68 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N, atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H,.

Heat to 55 0 C under Run reaction at 200 psig and a stir rate of 250 rpm. Run overnight under these conditions.

391 SRL 6045 Cool reactor and vent H 2 Purge with N 2 Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether. Rotovap and redissolve with ether. Extract with water. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry on vacuum line.

Charge reactor again with same amounts, seal reactor and run overnight under same conditions. After second run 0 all of the material has been converted to the desired product. Cool and vent H 2 pressure. Purge with N 2 Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO,, filter and rotovap to dryness.

Dry on vacuum line. Obtain NMR and mass spec (m/z=474).

Step 6 .O H3 0 C2,H,,NOS fw=473.68 Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N 2 inlet and stopper.

Chill solution with ice/salt bath under N, purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at SRL 6045 monitoring by TLC. Once reaction is complete, quench by adding 135 mls 10% HCI stirring 10 min. Extract three times with ether. Dry organic layer with MgSO 4 filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).

Step 7 0 H3C

CH

3 10 C 26H 37NO 4S fw=459 06 0* 60.00 0w .:::.Dissolve 4.67 gms (0.01 moles) of product 6 with 100 :mls anhydrous chloroform. Place in a 250 ml round bottom S• 15 flask with magnetic stir bar. Fit flask with N 2 inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a N 2 purge. Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature. Monitor reaction progress by TLC.

Reaction is usually complete in 3 hrs.

Chill solution with ice bath. Quench with 100 mls K 2CO 3 while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer.

Extract organic layer once with 10% HCI, once H2 0, and once with saturated NaCI solution. Dry organic layer with MgSO 4 filter and rotovap to dryness. Crystallize product from 393 SRL 6045 ether. Obtain NMR and mass spec (m/z=460).

Step 8 0 S """OH 0

\CH

H

3 C CH 3 C H NOSI fw=701.71 Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper.

Chill NaH with ice bath and begin N, purge.

Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms KCO, (9.57 mmoles Fisher P-208).

15 Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40°C overnight under

N,.

Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H20, and saturated NaC1. Dry organic layer with MgSO,, filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).

394 SRL 6045 Step 9

N

H

3 C \CH3

C

3

,H,,N,O,SI

fw=802.90 Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mis anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mis anhydrous acetonitrile. Purge well with N, then close system Heat at 45 0 C. Monitor reaction by TLC.

Reaction is usually complete in 48 hrs.

Perform cleanup by.removing acetonitrile under vacuum.

Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether. Repeat several times.

Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).

SRL 6045 395 Example 1399 Step 1. Preparation of 1 Br Ct "OCH 3 To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel. Stirred at ambient temperature for fifteen minutes. Poured reaction 0 contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO 4 and concentrated in vac-uo. Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g of 1 as a clear colorless liquid. 1

H

15 NMR (CDC1 3 d 3.39 3H), 4.42 2H), 7.18-7.27 2H), •7.12 J 7.45, 1H), 7.50 1H).

Step 2. Preparation of 2

I

-,,OCH

3 To a cooled (-78 solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C, cooled to -10 °C and to it was added 6 g of Pd(PPh) 4 (5.2 mmol) and 125 g 2 ,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 quenched with water, SRL 6045 partitioned between ethyl acetate and water, and washed organic layer with IN HCL and with 1N NaOH. The organic layer was dried over MgSO, and concentrated in vacuo.

Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43 of 2 as an orange oil. 'H NMR (CDC1,) d 3.40 3H), 4.51 2H), 7.12-7.26 3H), 7.47 J 7.50, 1H), 7.57 (d, J 7.45, 1H), 7.73 J 7.45, 1H), 7.80 1H).

Step 3. Preparation of 3 .S NB u 0 OH 9 S, OCH 3 A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 and 60.7 g of X' (the 15 cyclic sulfate compound of example 1397) (242.8 mmol) in mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo. Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO, and condensed in vacuo.

Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate hexanes as elutant gave 42.9 g (48 of 3 as a yellow oil. 'H NMR (CDC1 3 d 0.86 J 7.25 Hz, 6H), 1.10 1.26 12H), 2.83 2H), 3.32 2H), 3.40 3H), 4.48 3H), 7.02 (dd, J 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J 8.19 Hz and 2.82 Hz, 1H), 7.45 J 7.65 Hz, 1H), 7.56-7.61 2H), 7.69 J 7.85 Hz, 1H), 7.74 1H).

397 SRL 6045 Step 4. Preparation of 4 Bu F CH 2 0H

F

N. OCH 3 To a cooled (-40 solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20 OC for two hours, quenched with water and warmed to ambient temperature. Partitioned between methylene chloride and water, dried the organic layer over MgSO, and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4 as a oil. 1H NMR (CDC1 3 d 0.89 J 7.05 Hz, 6H), 1.17 1.40 12H), 1.46 J 5.84 Hz, 1H), 2.81 2H), 3.38 3H), 3.43 J 5.23 Hz, 2H), 4.16 2H), 4.42 2H), 6.80

J

9.67 Hz, 1H), 6.90 J 8.46 Hz, 1H), 7.09 J 7.45 Hz, 1H), 7.15 7.21 2H), 7.25 7.32 2H), 7.42 (m, 1H).

Step 5. Preparation of rBu

CHO

,,OCH 3 To a cooled (15-18 solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HC1 398 SRL 6045 (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed in vacuo to give 23.1 g (96 of 5 as a light brown oil. 1H NMR (CDC1,) d 0.87 J 7.05 Hz, 6H), 1.01 1.32 8H), 1.53 1.65 4H), 2.98 2H), 3.38 3H), 4.15 2H), 4.43 2H), 6.81 (dd, J 9.66 Hz and 2.82 Hz, 1H), 6.91 J 8.62 Hz, 1H), 7.07 J 7.46 Hz, 1H), 7.14 1H), 7.19 J 7.65 Hz, 1H), 7.26 7.32 1H), 7.42 (dd, J 8.66 Hz and 5.64 Hz, 1H), 9.40 1H).

Step 6. Preparation of 6 \I Bu

CHO

CH 3 To a cooled (0 solution of 23.1 g (53.6 mmol) of 15 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na 2

SO,,

partitioned between water and methylene chloride. Dried organic layer over MgSO 4 and condensed in vacuo to give 24.5 g of 6 as a light yellow oil. 'H NMR (CDC1 3 d 0.86 1.29 14H), 1.58 1.63 2H), 1.82 1.91 2H), 3.13 2H), 3.39 3H), 4.44 2H), 4.50 2H), 6.93 J 9.07 Hz, 1H), 7.10 7.33 5H), 8.05 1H), 9.38 1H).

399 SRL 6045 Step 7. Preparartion of 7 Bu LY S

BL

Me 2

N-

1

C

H O ,.OCH 3 To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo.

Purification by silica gel chromatography (Waters Prep-500) 10 using 15 ethyl acetate/hexanes gave 21.8 g (84 of 7 as a clear colorless oil. 'H NMR (CDCl 3 d 0.85 J 7.25 Hz, 6H), 0.93 1.29 8H), 1.49 1.59 2H), 1.70 1.80 2H), 2.98 8H), 3.37 3H), 4.41 2H), 4.44 (s, 2H), 6.42 1H), 6.58 (dd, J 9.0 Hz and 2.61 Hz, 1H), 15 7.13 J 7.45 Hz, 1H), 7.21 1H), 7.28 J 7.85 Hz, 1H), 7.82 J 9.06 Hz, 1H), 9.36 1H).

Step 8. Preparation of 8 o,

°S

MeN B u c" >BH Me 2 N

'"OH

0 -,OCH 3 A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride. The organic layer was 400 SRL 6045 partitioned between ethyl acetate and water, dried over MgS04 and concentrated in vacuo. Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi) m/e 494.6. HRMS calculated for M+H 487.2756. Found 487.2746.

Step 9. Preparation of 9

O

Bu MeaN

'OH

Br A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient 15 temperature for thirty minutes. Cooled reaction to -10 °C and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO 4 and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g of 9 as a white solid. MS (FABH') m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.

Step 10. Preparation of o, s/^Bu Me 2 N

BU

OH

A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 401 SRL 6045 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/ diethyl ether gave 1.19 g of 10 as an off white solid. MS (FAB') m/e 535.5.

Example 1398 Step 1. Preparation of 2 O O Bu

CHO

NO2 a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic 15 acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g of the title compound as a yellow solid. 1 H NMR (CDC1,) d 0.88 J 7.45 Hz, 6H), 0.99-1.38 8H), 1.62-1.75 2H), 1.85-2.00 2H), 3.20 2H), 4.59 (s, 2H), 6.93 (dd, J 10.5 and 2.4 Hz, 1H), 7.15 (dt, J 8.4 and 2.85 Hz, 1H), 7.46-7.59 2H), 8.05-8.16 3H), 9.40 1H).

Step 3. Preparation of 3 402 SRL 6045 o0 0 F Bu

'"OH

"NO

2 A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0 °C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 Stirring was continued for minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned 10 between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CHC1 2 as eluent yielded 4.3 g of 3 as a pale yellow foam. 'H NMR (CDC1 3 d 0.93 J 7.25 Hz, 15 6H), 1.00-1.55 8H), 1.59-1.74 3H), 2.15-2.95 (m, 1H), 3.16 (qAB JAB 15.0 Hz, AV 33.2 Hz, 2H), 4.17 J 6.0 Hz, 1H), 5.67 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J 8.5 and 2.9 Hz, 1H), 7.64 J 8.1 Hz, 1H), 7.81 J 8.7 Hz, 1H), 8.13 (dd, J 9.9 and 3.6 Hz, 1H), 8.23-8.30 1H), 8.44 1H). MS(FABH m/e (relative intensity) 464.5 (100), 446.6 HRMS calculated for M+H 464.1907. Found 464.1905.

403 SRL 6045 Step 4. Preparation of 4 I Bu Me'OH

OH

NO

2 To a cooled (0 solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g of 4 as a yellow solid. 'H NMR (CDC1,) d 0.80-0.95 (m, 6H), 0.96-1.53 8H), 1.60-1.69 3H), 2.11-2.28 (m, 15 1H), 2.79 6H), 3.09 (qAB, JAB 15.0 Hz, DV= 45.6 Hz, 2H), 4.90 J 9.0 Hz, 1H), 5.65 1H), 5.75 J 2.1 Hz, 1H), 6.52 (dd, J 9.6 and 2.7 Hz, 1H), 7.59 J 8.4 Hz, 1H), 7.85 J 7.80 Hz, 1H), 7.89 J 9.0 Hz, 1H), 8.20 (dd, J 8.4 and 1.2 Hz, 1H), 8.43 1H).

MS(FABH m/e (relative intensity) 489.6 (100), 471.5 HRMS calculated for M+H 489.2423. Found 489.2456.

404 SRL 6045 Step 5. Preparation of 0 0 fV\Bu Me 2

N

CLOH

NH

2 To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g palladium on carbon. The reaction vessel was sealed, purged twice with H,2 then charged with H 2 (100 psi) and heated to 10 4.5 "C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g of 5. 'H NMR (CDC1,) d 0.80-0.98 6H), 1.00- 1.52 10H), 1.52-1.69 1H), 2.15-2.29 1H), 2.83 6H), 3.07 (qAB, JAB 15.1 Hz, DV 44.2 Hz, 2H), 3.70 2H), 4.14 1H), 5.43 1H), 6.09 J 2.4 Hz, 1H), 6.52 (dd, J 12.2 and 2.6 Hz, 1H), 6.65 (dd, J 7.8 and 1.8 Hz, 1H), 6.83 1H), 6.93 J 7.50 Hz, 1H), 7.19 J 7.6 Hz, 1H), 7.89 J 8.9 Hz, 1H).

20 MS(FABH m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670.

Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6 mmol) TEA. The reaction was stirred minutes, then partitioned between ethyl acetate and brine.

The organic layer was dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a 405 SRL 6045 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g of 6 as a pale yellow oil. 'H NMR (CDC1,) d 0.84-0.95 6H), 1.02-1.53 10H), 1.53-1.68 1H), 1.80-2.00 4H), 2.12-2.26 4H), 2.38 J 6.9 Hz, 2H), 2.80 6H), 3.07 (qAB, JAB 15.6 Hz, DV 40.4 Hz, 2H), 3.43 J 6.9 Hz, 2H), 4.10 1H), 5.51 1H), 5.95 J 2.4 Hz, 1H), 6.51 (dd, J 9.3 and 2.7 Hz, 1H), 7.28 1H), 7.32-7.41 (m, 2H), 7.78 J 8.1 Hz, 1H), 7.90 J 9.0 Hz, 1H).

Step 7. Preparation of 7

O

OH

*B

a 0"To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml *Bu acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile) gave 0.8 g of 7 as a white foam. 1H NMR (CDC1,) d 0.80-0.96 6H), 0.99-1.54 (m, 19H), 1.59-1.84 3H), 2.09-2.24 1H), 2.45-2.58 (m, 2H), 2.81 6H), 3.09 (qAB, JAB 15.6 Hz, DV 18.5 Hz, 2H), 3.13-3.31 8H), 4.16 1H), 5.44 1H), 6.08 (d, J 1.8 Hz, 1H), 6.57 (dd, J 9.3 and 2.7 Hz, 1H), 7.24 (t, J 7.5 Hz, 1H), 7.34 J 8.4 Hz, 1H), 7.56 J 8.4 Hz, 1H), 7.74 1H), 7.88 J 9.0 Hz, 1H), 9.22 (s, SRL 6045 1H). HRMS calcd 642.4304; observed 642.4343.

Example 1400 Step 1

OH

OMe

F

C

1 4

H

1 3 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with 10 reflux condenser, N 2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride 7 83.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.

After 15 h. refluxing, the mixture was cooled to room 20 temperature and poured into H 2 0 (2.5 After 20 min.

stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min.

The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq.

KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried (MgSO 4 filtered and concentrated in vacuo. The crude product was purified by Kugelrohr 407 SRL 6045 distillation to give a clear, colorless oil (449.0g/39% yield). 120-130 C/50mtorrHg. 1 H NMR and MS H) 233] confirmed desired structure.

Step 2

S

/CH

3 0

NCH

3 O M e *o F

C

17

H

18

NO

2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/l.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room 15 temperature, dimethylthiocarbamoyl chloride (242.4g/l.961mol) was added. After 15 h, the reaction mixture was poured into H 2 0 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H 2 0 and saturated aqueous NaC1, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1 H NMR and MS 320] confirm desired structure.

408 SRL 6045 Step 3

SH

OMe

F

C

14

H

13 0FS fw=248.32 A 12-liter, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to 10 reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with H 2 0.

The aqueous extracts were combined, acidified with concentrated HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1 H NMR confirmed desired structure.

409 SRL 6045 Step 4

HO

S

O M e

F

C

2 5

H

3 5 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with

N

2 gas adaptor and mechanical stirrer. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H 2 0. The aqueous solution was 15 washed with ethyl ether, and concentrated H 2

SO

4 was added.

The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO 4 filtered, and conc'd in vacuo to give an amber oil (143.94g/85% yield). 1 H NMR and MS H) 419] confirm the desired structure.

410 SRL 6045 Step Bu OMe

F

C

25

H

33 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with

N

2 gas adaptor, and mechanical stirrer. The system was purged with N 2 The corresponding alcohol (1 4 3 .94g/343.8mmol) and CH 2 C12 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (1 40 5 3g/651.6mmol) was added. After 6 CH 2 C12 was added. After 20 min, the mixture was filtered through silica gel, washing with

CH

2

C

1 2. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1 H NMR and MS [(M 417] confirm the desired structure.

SRL 6045 Step 6

C

25

H

33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with

N

2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide (110.6g/265.5mmol) and CH 2 Cl 2 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K 2

CO

3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgS0 4 filtered, and concentrated in vacuo to give the product (93.2g, 78% yield).

the desired structure.

1H NMR confirmed 412 SRL 6045 Step 7 0 o Bu Bu

F

F OHH OMe

C

25

H

33 0 4 FS fw=448.59 5 A 2-liter, 4-neck, round-bottom flask was equipped with

N

2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde 93 .2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide 2 3.35g/208.1mmol) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO 4 filtered, and concentrated in.vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60g/ combined yield: 1 H NMR confirmed the desired product.

413 SRL 6045 Step 8 Me 2

N

C

27

H

39 0 4 NS fw=473.67 0a** A Fisher porter bottle was fitted with N 2 line and magnetic stirrer. The system was purged with N 2 The corresponding fluoro-compound (28.1g/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.

Dimethylamine (17.lg/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaC1, dried (MgSO 4 filtered, and concentrated in vacuo to give a white a a.

a solid (28.5g/96% yield).

structure.

1H NMR confirmed the desired I (I 414 SRL 6045 Step 9 0

S

Bu Bu Me 2 N

O

OH

OH

C

26

H

37 0 4 NS fw=459.64 5 A 250-mL, 3-neck, round-bottom flask was equipped with

N

2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.

6 2g/14.0mmol) and CHC1 3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.

5 0g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2

CO

3 (100 mL) After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 15 and ether extracts were combined, washed with saturated aqueous NaC1, dried (MgS0 4 filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1 H NMR confirmed the desired structure.

415 SRL 6045 Step

S

Bu

(H

3

C)

2 N Bu

OH

N

5 In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 1 72 .10g/mole) Aldrich D8, 720-1 (2.4 mmol,4.12g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous 10 potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg 2.6 mmol) and 34 ml of DMF. Cool to ice 15 temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/l% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec and H1 NMR) 416 SRL 6045 Step 11 0V Bu

(H

3

C)

2 N Bu S OH 5 The product from step 10 0.57gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether 10 was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9 H NMR).

ooo"*: 417 SRL 6045 Example 1401 Step 1

OH

OMe

F

C

14

H

13 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N 2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry 10 of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.

After 15 h. refluxing, the mixture was cooled to room temperature and poured into H 2 0 (2.5 After 20 min.

stirring, the layers were separated, and the organic layer 20 was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min.

The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All aqueous KOH solutions were combined and acidified with concentrated HC1.\ The acidic solution was extracted three times with ethyl ether, dried over MgSO 4 filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil 418 SRL 6045 (449.0g/39% yield), 120-130 C/50mtorrHg. 1 H NMR and MS H) 233] confirmed desired structure.

Step 2

S

/CH 3 O

N-_CH

3 OMe 5 F

C

17

H

18

NO

2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/1.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H 2 0 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H 2 0 and saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1 H NMR and MS 320] confirm desired structure.

419 SRL 6045 Step 3

SH

O M e

F

C

14

H

13 0FS fw=248.32 A 12-liter, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4 -Fluoro-2-(3-methoxybenzyl)phenyldimethylthiocarbamate (605.3g/l.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to 10 reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h.

Potassium hydroxide.(425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with H 2 0.

The aqueous extracts were combined, acidified with conc.

HC1, and extracted with ethyl ether. The ether extracts 20 were dried (MgSO filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1 H NMR confirmed desired structure.

420 SRL 6045 Step 4

OH

Bu Bu O M e

F

C

25

H

35 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with

N

2 gas adaptor and mechanical stirrer. The system was yi purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride 9 .68g/383.2mmol) was added slowly, and the mixture was .allowed to warm to room temperature 2 2 -Dibutylpropylene sulfate (110.

8 9g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H20. The aqueous solution was o* 15 washed with ethyl ether, and.conc.

H

2

SO

4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgS0 4 filtered, and concentrated in vacuo to give an amber oil (1 4 3.94g/85% yield). 1H NMR and MS H) 419] confirm the desired structure.

SRL 6045 Step 0 Bu Bu

C

25

H

33 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with

N

2 gas adaptor, and mechanical stirrer. The system was purged with N 2 The corresponding alcohol (143.94 g/343.8 mmol) and CH 2 C12 (1.0 L) were added and cooled to 0 C.

Pyridinium chlorochromate (140.53g/651.6mmol) was added.

10 After 6 CH 2 C12 was added. After 20 min, the mixture was filtered through silica gel, washing with CH 2 C1 2 The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1 H NMR and MS H) 417] confirm the desired structure.

Step 6

C

25

H

33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with 422 SRL 6045

N

2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide (110.6g/265.5mmol) and CH 2 C12 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K 2

CO

3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1H NMR confirmed the desired structure.

Step 7 0

S

Bu Bu

F

O

OMe

C

25

H

33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with

N

2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35g/208.1mmol) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was 423 SRL 6045 extracted three times with ethyl ether, dried (MgSO 4 filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60g, combined yield: 1 H NMR confirmed the desired product.

Step 8 0

S

Bu Me 2

N

OH

1. 0 OMe

C

27

H

39 0 4 NS fw=473.67 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N 2 The 15 corresponding fluoro-compound (28.1g/62.6mmol) was added, S• and the vessel was sealed and cooled to -78 C.

Dimethylamine (17.1g/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaC1, dried over MgS0 4 filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1H NMR confirmed the desired structure.

424 SRL 6045 Step 9 0 Bu Bu Me 2 N

O"

OH

C26H3704NS fw=459.64 5 A 250-mL, 3-neck, round-bottom flask was equipped with

N

2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.62g/14.0mmol) and CHC1 3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide 10 (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2

CO

3 (100 mL).

After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 15 and ether extracts were combined, washed with saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1 H NMR confirmed the desired structure.

425 SRL 6045 Step

N

Bu (H3C)2N B 5 In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of 1N KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice 15 temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above.

Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/l% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec and HI NMR) 426 SRL 6045 Step 11 Bu

(H

3

C)

2 N Bu

SOH

N

5 The product from step 10 (0.57gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9, 'H NMR).

15 BIOLOGICAL ASSAYS The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.

In Vitro Assay of compounds that inhibit IBAT-mediated uptake of ["C]-Taurocholate (TC) in H14 Cells Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 427 SRL 6045 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.

On the day of assay, the cell monolayer is gently washed once with 100 pl assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose 0.2% fatty acid free bovine serum albumin- (FAF)BSA). To each well 50 pi of a two-fold concentrate of test compound in assay buffer is added along with 50 pg of 6 pM C]-taurocholate in assay buffer (final concentration of 3 pM 4 C]-taurocholate). The cell culture plates are incubated 2 hours at 370 C prior to gently washing each well twice with 100 pl 4° C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 pl 4° C PBS without (FAF)BSA. To each 200 pl of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a 20 Packard Top-Count instrument.

428 SRL 6045 In Vitro Assay of compounds that inhibit uptake of

C

1-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.

In Vivo Assay of compounds that inhibit Rat Ileal uptake of ["C]-Taurocholate into Bile (See"Metabolism of 3a,7P-dihydroxy-7a-methyl-5pcholanoic acid and 3a, 7 acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae luer lock, tapered female adapter) is inserted at 12 cm from the junction of ***the small intestine and the cecum. A slit is cut at 4 cm ****from this same junction (utilizing a 8 cm length of ileum).

20 ml of warm Dulbecco's phosphate buffered saline, pH 0* (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed 25 for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample (["C]-taurocholate 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure.

After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the joop is washed out for 21 min with warm PBS at 429 SRL 6045 0.25 ml/min. A second perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform:methanol After homogenization and centrifugation the supernatant was separated and dried under initrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically,. using a 15 combination of cholesterol oxidase and peroxidase, as S: described by Allain, C. et al. (1974) Clin. Chem. 470.

Measurement of Hepatic HMG CoA-Reductase Activity (HMG

COA)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was S.e. resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 370 C in the presence of 1C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HC1 followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting.

(Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

430 SRL 6045 Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL LDL) Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol C11, Catalog No. 276- 64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.

15 Measurement of Hepatic Cholesterol 7-a-Hydroxylase Activity (7a-OHase) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for .cholesterol 7-a-hydroxylase activity by incubating for minutes at 370 C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ o00 ~25 methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a C, reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. et al. (1994) J. Clin. Invest. 93, 2084).

Measurement of Fecal Bile Acid Concentration

(FBA)

Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram was weighed out and extracted into an organic solvent SRL 6045 (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3ahydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, et al. (1981) Clin. Chem. 27, 1352).

_[HItaurocholate Uptake in Rabbit Brush Border M mbrane Vesicles

(BBMV)

Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica .Biophysica Acta, 554, 259). The method for measuring 15 taurocholate was essentially as described by Kramer et al.

(Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 1l instead of 100 pi.

Briefly, at room temperature a 190 pl solution containing 2PM ['H]-taurocholate(0.75 pCi), 20 mM tris, 100 mM NaC1, 20 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 pl of brush border membrane vesicles (60-120 pg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of ml of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 pm pore) and an additional 5 ml wash with stop buffer.

Acyl-CoA;cholesterol Acyl Transferase

(ACAT)

Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 pM Oleoyl-CoA (0.05 pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 BSA and 432 SRL 6045 200 pg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 370 C and was terminated by the addition of 8.0 ml of chloroform/ methanol To the extraction was added 125 pg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing.

The chloroform phase was taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into.the cholesterol oleate spot on the TLC plate with a Packard instaimager.

Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows: *oo 433 SRL 6045 TABLE a.

a a a a.

a a COMPOUND IC50 In vitro of Control UM* Inhibition Inhibition Transport of TC in of TC of Alanine Rat Ileum 0.1mM Uptake Uptake 100 tiM 100 um Benzothiaze 2 0 45.4 0.7 pine= 12 3 0 4a 3 34 40 0 7 2 9 ±5.4 4b 9 18 6 14b 18 14a 13 13 23 19a 0 19b 8a 41 Mixture of 69 8a and 8b Mixture of 6 9a and 9b SRL 6045 ii 6a *9*9 9*9* 9* *9 9 6b 9a 5 0% 25 g.m 53.7 Mixture of 13 6a and Mixture of 0.8 14% 6d and 10a 21a 37 21c 52 21b 6c 2 58.5 68.8 at 0.4 mM 6d 0.6 77.7 16.1 mM 30.2 0.9 0.15 mM 17 7 50 49.3 10a 7 77.6 62.4 2.5 0.2 nm 15 68.6 0.1 4% 10 pM 26.0 +-3.3 26 2 31% 25 87.9 27 5 7 2 pM~ 28 8 31% @2pgM 29 1 8 8 .o 09 0 435 SRL 6045 3 0 31 37 38 41 42 43 96 50 p.M 41 50 p.M 3 0 .3 49 50 p.M 2 1.5T 0 of 0 0000 a..

000.

aOo 0% 5 p.M 11% 5pM 0% 20 p.M 16%

P.M

22%

P.M

21% 200

PM

59 20.6 5.7

F

48 2 49 0.15 21.2 2.7 58 59 61 62 63 64 9 30 51 50 pM 20 50 p.M 90 6 pM 100 6 pm 175 i *In vitro Taurocholate Cell Uptake Unless otherwise noted Comparative Example is Example No. 1 in WO 93/16055 SRL 6045 TABLE 6 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H114 Ilea. (BBMV) (liver) intestine cells) Loop EC(50) IC(50) IC(50) COMP. 1 PM 74 pM 3pgM 20Wp 2 0 p

EXAMPLE*

6d 0 .6 pLM 3 1 pM 1. 5 piM 25 pM 20 pM 38 0.3 pM 12 p.M 2 pLM 15 piM N.D.

49 0.1 PM 12 p1M N.D. 6 pM N.D.

0.1 Ji 20OpM 0.8 P 8pjM 8W t 0 000.

9* Comparative Example is Example No. 1 in WO 93/16055 SRL 6045

I,

S. TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS PARAMETER CONTROL 4% CHOLES- 0.2% TYRAMINE CPD. NO. WEIGHT (mean SEN. *p<Q*Q5, A-Student's t, B- Dunnett' s) day 1 117 114(6) 117(5) day 14 127(3) 127(3) 132(4) LIVER WEIGHT 5.4(0.3) 4.9(0.4) 5.8(0.2) SER.CHOL(mg%) 143(7) 119(4)*A,B 126(2)*A,B HDL-CHOL(mg%) 89(4) 76(3)*A,B 76(1)*A,B VLDL LDL 54(7) 42(3)*A 50(3) TGI(mg%) 203(32) 190(15) 175(11) HEPATIC CHOL(mg/g) 2.5(0.3) 1.9(0.1)*A,B 1.9(0.1)*A,B HMG COA (pm/mg/min.) 15.8(7.6) 448.8(21.6)* 312.9(37.5)*A A,B ,B 7a-OHase (pm/mg/min.) 235.3(25.1 24 HR. FECAL Wt )357.2 291.0(6.0)*A FBA (n/24H/lO0g) 2.3(0.1) A, B 2.4(0.04) 6.2 2. 7(0. 1) B 11. 9(0. 5) B 12 .3 iB 9 S 999 438 SR. 6045 TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP

MODEL

PARAMETER CONTROL 20 MPL/DAY CPD. NO. WEIGHT

(G)

(mean SEM, *p<0.05, A-Student's t, B- Dunnett' s) dayl1 day 8 LIVER WEIGHT

(G)

SER. CHOL (mg%) HEPATIC CHOL (mg/g) HMG COA pm/mg/min 7 a-OHase (pm/mg/min) 24 HR. FECAL WT (G) FBA (1m1/24H/lO0g) 307 (4) 330 (4) 15.5 (0.6) 85 (3) 21 (0.03) 75.1 (6.4) 281.9 (13.9) 5.8 (0.1) 17.9 (0.9) 307 (3) 310

B

14.6 (0.4) 84 (3) 2.0 (0.03) 318.0 (40.7)*A,B 535.2 (35.7)*A,B 5.7 (0.4) Additional taurocholate uptake tests were conducted in the following compounds listed in Table 9.

SRL 6045 Table 9 Biological Data for Some Compounds of the Present Invention Compound Human TC Alanine Uptake Number IC0Percent Inhibition (@lJim 101 _0 102 0.083 103 13 0.25 104 0.0056 105 106 107 14.0 0.063 108 109 2.0 0.063 110 0.09 111 2.5 112 113 0.1 114 0.19 115 116 0.3 117 12.0 0.625 118 0.4 119 1.3 120 34.0 121 0.068 122 1.07 123 1.67 124 14.0 6.25 125 18.0 126 18 1.25 127 0.55 128 129 0.035 131 1.28 132 5.4 0.063 133 16.0__ 134 135 22.0 136 0.09__ 137 2.4 138 139 >25.0 140__ 141__ 440 SRL 6045 00.

142 143 0.03__ 144 0.053 262 0.07 263 0.7 264 0.2 265 266 267 0.073 268 0.029 269 0.08 270 0.12 271 0.07__ 272 0.7 273 1.9 274 275 5.0 0.25 276 0.23__ 277 0.04__ 278 279 280 0.18 281 0.019 282 0.021 283 0.35__ 284 285__ 286 287 288 10.0 6.25 289 0.23__ 290 0.054 291 0.6 292 0.046 293 1.9 294 0.013 295 1.3 296 1.6 1000 1001 1002 1003 1004 1005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 SRL 6045 1012 1013 1014 1015 1016 1017

I

0.0015 0.002 0.002 0 .002 0 .002 I 0.002 1018 j0.002 1019 0.002 1020 0.002 1021 1 0.002 1022 j0.002 1023 1 0.002 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1 043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 0.002 0.002 0.02 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0 .002 0 .002 0.002 0.0022 0.0025 0.0026 0.003 0.003 0 .003 0. 003 0 .003 0. 003 0.003 0.003 0.003 0.003 0-.003- 0-.003-

I

0 003 0 .003 0.003__ 0.-003 0.003 0 .003- 0.003 0. 003 0.0036 0 .004 442 SRL 6045 0* 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 1082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093 0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 443 SRL 6045 'o oboe.

1112 0.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 1126 0.013 1127 0.013 1128 0.017 1129 0.018 0.018 1131 0.02 1132 1133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.029 11_f46 0.029 1147 0.029 ff48 0.03 1__149 0.03 1150is 0.03 1151is 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.04 1158 1159 0.06 1160 0.062 1161 0.063 444 SRL 6045 see* *000 06.0 6 **0 1162 0.063 1163 0.09 1164 0.093 1165 0.11 1166 0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14 1173 1174 1175 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 -1182 0.25 1183 1184 0.28 1185 1186 1187 1188 0.35 1189 1190 0.55 1191 0.65 1192 1.0 1193 1194 1.6 1195 1.7 1196 1197 1198 2.5 1199 4.0 1200 6.1 1201 8.3 1202 40.0 1203 0 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209 0 0.063 1210 0.14 1211 0.28 445 SRL 6045 44@* 4 44 44 4 44 44 4 4 4 4. .4 4 4 4 44 4 49* 4 444 4 4444 4*44 4 44 4 4 44 4 4.

4 4 4 4444 4 1212 0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.2 1221 0.041 1222 0.065 1223 0.28 1224 0.33 1225 0.12 1226 0.046 1227 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1233 0.15__ 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 1249 1250 0.013 1251 0.62 1252 1253 1254 0.85 1255 0.69 1256 0.011 1257 0.1 1258 0.12 1259 1260 0.012 1261 0.019 SRL 6045 1262 0.03 1263 0.079 1264 0.21 1265 1266 0.2 1267 0.29 1268 0.035 1269 0.026 1270 0.026 1271 0.011 1272 0.047 1273 0.029 1274 0.028 1275 0.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055 1282 0.17 1283 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1301 0.15 1302 1.4 1303 0.26 1304 1305 1306 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 SRL 604547 1312 1313 6.1 1314 0.26 1315 1.67 1316 3.9' 1317 21 .0 1318 1319 11.0 0.25 1321 11.1 1322 .0 0.0063 1323 4.0__@_0.0063 132 43. .0 0 132 1. *006 132 -T0 0.00 132 3.*006 132 680* .06 132 2. n 133 9. 006 V 1 3 15 0 0 0 133 43 '0 0 1343810@02 1344 .6 1345 1.0 0.253 1346 1347 0.0036 1348 1349 1350 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.01 1360 0.003 1361004 448 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014 *5 5 i The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Novel compositions of the invention are further illustrated in attached Exhibits A and B.

The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, we note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that we intend each of those words to be so interpreted in construing the foregoing description and/or the following claims.

449 SRL 6045 Exhibit A Table C2: Alternative Compounds #2 (Families F1Ol-F123) 0 Fail Cpd 3 5 2R~ 1*J F101 Fl102 Fl103 Fl104 Fl105 F106 Fl107 F108 F109 F110 F111 F112 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 Php-F-Phrn-F-Php-CH 3 0- Phrn-CH 3 0-Php- (CH 3 2 N-Phn- (CH 3 2 N-Ph rn-(CH 3 3 -N'-Php- (CH 3 3

-N+-CH

2

CH

2

(OCH

2

CH

2 2 -O-Phn- (CH 3 3

-N+-CH

2

CH

2

(OCH

2

CH

2 2 -O-Php-(N,Ndirnethylpiperazine)

CH

2

(OCH

2

CH

2 2 -0-Ph- CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 450 SRL 6045 F113 F114 F115 F116 F117 F118 F119 F120 F121 F122 F123 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1' m-(N,Ndimethylpiperazine)-(N')-

CH

2

-(OCH

2

CH

2 2 -O-Phm-F-Php-CH 3 0- 3,4,dioxy-methylene-Phm-F-Php-F-Phm-CH 3 0p-F-Ph- 4-pyridine N-methyl-4-pyridinium 3-pyridine N-methyl-3-pyridinium 2-pyridine p-CH 3 0 2 C-Ph- CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 CHOSEN FROM TABLE 1 Similar families can be generated where R 1 is not equal to

R

2 such as R 1 Et and R 2 n-Bu, but (RX)q is chosen from table C1.

SRL 6045 Exhibit B

(H

3

C)

2

N

a.

ObH

N(CH

3 2 *t a a.

a a le 2 0( J0 452 SRL 6045

H

3 CO S H 3 CO S b H

OH

02

N(CH)

3 0 2 02 HO

S

F

453 SRL 6045 02 02 R 3 3 R

OHN

H

3

COK

F

02 0

H

3 CO

H

3

CH

9, .9.'02 HO0 R4'

F

OH

IO(

Claims (24)

1. A compound having the structural formula XVI- 1: R 102 -R 103 R 11 XV'-' S S S wherein R 1 02 and R1 03 are independently alkyl, and R' 4 is selected from the group consisting of halogen and -b4 4 (CH 2 CH 3 3

2. A compound of claim 1 having the structural formula XVI-l A: N N S S S XWI-lA. 455

3. A compound of claim 1 having the structural formula XVI-1B: NN

4. A compound of claim 1 having the structural formula XVIC: OH WI-ic A compound of claim 1 having the structural formula XVI-ID): 456 "Br WI-iD

6. A compound of claim 1 having the structural formula XVI-1E: OH N Br S. S S S S S. *5 S S S S. S S S 55 S S S .555 S S. *S S S S S SS S S S. 55*555 S XVI-1E.

7. A compound of claim 1 having the structural formula XVI-1F: OH N Br XVI-1F.

8. A process for the preparation of a compound having the formula: R1 R2 (RXRq H XLI comprising: treating a thiophenol with an abstracting agent; coupling the thiophenyl and a cyclic sulfate to form an intermediate comprising a sulfate group; and removing the sulfate group of the intermediate to form the compound of formula XLI; wherein: q is an integer from 1 to 4; R' and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyallcyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR 9 Ro 10 N+R'R"RA-, SR 9 S R 9 R'OA-, P R 9 R'oR"A-, S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' O wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 N+R 9 RA, S, SO, SO 2 S R 9 P R 9 R' O or phenylene, or R' and R 2 taken together with the carbon to which they are attached form C 3 -CI 0 cycloalkylidene; wherein R 9 R' 0 and R' are independently selected from the group consisting of H, S.. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; 458 wherein R" and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 Ro, SR9, S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R10, wherein R 9 and R 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or R" and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 9 SR 9 S(O)R 9 S0 2 R 9 and SO 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quatemary heterocycle, quaternary heteroaryl, halogen, oxo, OR' 3 NR' 3 R' 4 SR 13 S(O)R13, S0 2 R 1 3 SO 3 R' 3 NR130R 1 4 NR13NR1 4 R1 5 NO 2 CO 2 CN, OM, S0 2 0M, SO 2 NR 1 3 R' 4 C(0)NRIR' 4 C(O)OM, COR 1 3 P(O)R' 3 R 14 PR 13 R 14 R 15 A, P(OR 13 )0R 1 4 S+R1 3 R1 4 and N R 9 R" 'R 12 A, wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 SR 7 S(O)R 7 S0 2 R 7 S0 3 R 7 C0 2 R 7 CN, oxo, CONR 7 R 8 NR7R'R9A alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quatemrnary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 PR 7 R 8 R 9 and P(O)(OR 7 and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 NR 7 RA, S, SO, SO 2 S+R 7 PR 7 P(O)R 7 P+R 7 R 8 A, or phenylene, and R1 3 R' 4 and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quatemrnary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, V.000wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9 N+R 9 R' O A, S, SO, SO 2 S R9A, PR9, P+R9R'OA-, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and 459 R" 3 R' and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaterary heterocycle, quaterary heteroaryl, OR 9 NR 9 R' 0 N-4R 9 R' 1 R1 2 SR 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO 2 OM, S0 2 NR 9 R" 0 PO(OR' 6 )OR' 7 P+R 9 S+R 9 R 0 and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or R 1 4 and R' 5 together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 dR 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R' are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR' 3 NR' 3 R 1 4 SR 13 S(O)R 1 3 S(O) 2 R 1 3 SO 3 R' 3 S+R 1 3 R1 4 ,a' 3 OR 14 R 3 jqN R 1 R 5 NO 2 CO 2 R' 3 CN, OM, SO 2 OM, S0 2 NR1 3 R 1 4 NR' 4 C(O)R 1 3 C(O)NR' 3 R' 4 NTR1 4 C(O)R 1 3 C(O)OM, C0R 13 S(O)nNR' 1,NjR3R,NR8OR 1 4 N+R 9 R" R1 2 P+R 9 R" R 1 2 A- amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl., cycloalkyl, aryl, polyalcyl, heterocycle, acyloxy, arylalkyl, haloalcyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be fuirther substituted with OR, NR 9 R 10 NWR 9 R" R 1 2 SR 9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO 2 OM, SO 2 NR 9 R' 0 PO(OR' 6 )0R, P+R 9 R'I 1 2 A, S+R 9 R 0 or C(O)OM, and weenR 18is selected from the group consisting of acyl, arylalkoxycarbonyl, *:arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NRR 0 NWR 9 R 1 R 1R 2 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 3 R 9 SO 2 OM, SO 2 NR 9 R' 0 PO(OR' 6 )OR' 7 and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by 0, INR' 3 WR 1 3 R 4 A-, 13 13 13 14 S, SO, SO 2 S+R PR' 3 P(O)R' P R R A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, 460 wherein in said polyalcyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N+R 9 R 0 S, SO, S02, S+R 9 A-, PR, P+R 9 R 0 or P(O)R 9 *wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl,. alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR' 3 NIR1 3 R 1 4 SR 1 3 S(O)R 13 S0 2 R 13 S0 3 R 1 3 N-I 3 OR 1 4 INRI 3 NR 1 4 R' 5 NO 2 C0 2 R 1 3 CN, OM, S0 2 0M, S0 2 NR1 3 R 1 4 C(O)N7RI 3 R 1 4 C(O)OM, COR 1 3 P(O)R1 3 R 14 P+R 1 3 R1 4 R1 5 A-, P(OR' 3 )OR' 4 S+R'R R'A, and N+R 9 R 1 R R'A.

9. The process of claim 8 wherein the cyclic sulfate has the formula: R 2 0 S 0 0" 0 XL and the thiophenol has the formula: a. a a wherein R1, R 2 R 5 R' and q are as defined in claim 8. XVIIIA 461 The process of claim 8 or 9 wherein the sulfate group is removed by treating the intermediate with a hydrolyzing agent.

11. The process of claim 10 wherein the hydrolyzing agent is a mineral acid.

12. The process of claim 10 wherein the hydrolyzing agent is selected from the group consisting of hydrochloric acid and sulfuric acid.

13. The process of any one of claims 8 to 12 wherein the abstracting agent is a base having a pH of at least about

14. The process of any one of claims 8 to 12 wherein the abstracting agent is an alkali metal hydride. The process of any one of claims 8 to 12 wherein the abstracting agent is sodium hydride.

16. The process of any one of claims 8 to 15 wherein R' and R 2 are alkyl.

17. The process of any one of claims 8 to 15 wherein R 1 and R 2 are selected from the group consisting of ethyl; n-butyl, iso-butyl and pentyl.

18. The process of any one of claims 8 to 15 wherein R' and R 2 are n-butyl.

19. A process for the preparation of a compound having the formula I: 462 [on R 8 R" R R I comprising: reacting a cyclic sulfate with a thiophenol to form an alcohol; oxidizing said alcohol to form a sulfone-aldehyde; and cyclizing said sulfone-aldehyde to form the compound of formula I; wherein: n is an integer from 0 to 2; q is an integer from 1 to 4; R' and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR 9 Ro, N+R 9 RiOR"A, SR 9 S+ R'RoA, PRR'RIOR"A S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R' O wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 N+R 9 R'A, S, SO, SO 2 S R 9 P R 9 R'OA, or phenylene, or R' and R 2 taken together with the carbon to which they are attached form C 3 -CIO cycloalkylidene; 463 wherein R9, R1o, and R" are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; wherein R 1 and R' 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR 9 Ro 1 0 SR 9 S(O)R 9 SO 2 R 9 SO 3 R 9 CO 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 cannot be OH, NH 2 or SH, or R' 1 and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 3 ishydroxy; R 4 is hydrogen; RS 5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9, SR 9 S(O)R 9 SO 2 R 9 and SO 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 NR' 3 R'4, SR 13 S(O)R 1 3, SO 2 R 3 SO 3 R3, NR' 3 OR 1 4 NR 1 3 NR1 4 NO 2 C0 2 R 13 CN, OM, SO 2 0M, SO 2 N1 3 R 4 C(O)NR' 3 R 4 C(O)OM, COR 1 3 13 14 93 14 15 112 3 1 P(O)R 3R P+R 3 R 4 R 15 A, P(OR 3 )OR 4 S+R 13 R 14 A, and N R9R"RA, wherein: SA is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR, NR 7 SR 7 S(O)R 7 S0 2 R 7 S0 3 C0 2 R 7 CN, oxo, CONR 7 R 8 N R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 P+R 7 R 8 R 9 A, and P(O)(OR)R, and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 NR 7 R 8 A, S, SO, SO 2 S+R 7 A, PR 7 P(O)R 7 P+R 7 R 8 A, or phenylene, and R' 3 R 4 and R' 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, 464 arylailkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have. one or more carbons replaced by 0, NR 9 N+R 9 R' 0 S, SO, S02, S+R 9 PR 9 P+R 9 R' 0 A-, P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R" 3 R' 4 and R' 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R' 0 N+R 9 R 'R1 2 SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 SO 2 OM, S0 2 NR 9 R' 0 PO(OR' 6 )OR' 7 P+R 9 R' 0 S+R 9 R' 0 and C(O)OM, wherein R 1 6 and R 1 7 are independently selected from the substituents constituting R 9 and M; or 14 1 R and R' together with the nitrogen atom to which they are attached, form a cyclic ring; R 6 ishydrogen; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloatkyl, cycloalcyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR' 3 N' 3 R1 4 SR 13, S(O)R'1 3 S(O) 2 R 1 3 SO 3 R' 3 S+R1 3 R 14 NR' 3 0R 1 4 NR 3 1N4RI 4 NO,, COR 1 3 CN, OM, S0 2 0M, S0 2 NR 1 3 R1 4 NR' 4 C(O)R 1 3 C(O)NR 3 R 1 4 NR1 4 C(O)R 3 C(O)OM, COR' 3 OR" 8 S(O)nNIR NR1 3 NR' 8 0R 14 N+R 9 R''R' 2 A, P+R 9 R''R'A, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be fturther substituted with OR,.NR 9 R' 0 N+R 9 R" R 2 SR 9 S(O)R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 2 0M, SO 2 NR 9 R' 0 PO(OR' 6 )OR' 7 P+R 9 R' 'R' 2 A, S+R 9 R 0 or C(O)OM, and wherein R1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, **:wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR 9 R' 0 N+R9RIIR 12A, SR 9 465 S(O)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 S0 3 R 9 SO 2 OM, S0 2 NR 9 R" 0 PO(OR 1 6 )OR' 7 and C(O)OM,, wherein in one or more carbons are optionally replaced by 0, NR1 3 N+R 3 R 1 4 A, S, SO, SO 2 S+R 3 PR' 3 P(O)R' 3 P+R' 3 R'A, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyallcyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 N 4 R 9 R' 0 S, SO, SOL, S+R 9 A-, PR 9 P+R 9 R' 0 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl., polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylailkyl, halogen, oxo, OR'1 3 NR'3 R 1 4 SR 13, S(O)R'1 3 S0 2 R 1 3 SOR 1 3 NR1 3 0R 1 4 NR'1 3 NR1 4 R' 5 NO,, COR'1 3 CN, GM, SO 2 OM, SONR' 3 R 4 C(O)NR 3 R 1 4 C(O)OM, COR 1 3 P(O)R1 3 R 1 4 P +R1 3 R1 4 R1 5 A-, P(OR 1)OR 1, S+R 3 R 1 4 A, and N+R9R1 R 12A. The process of claim 19 wherein the cyclic sulfate has the formula: R R2 0 XL and the thiophenol has the formula: 466 SH (RX)q XVIIIA wherein R 2 R 5 R X and q are as defined in claim 19.

21. The process of claim 19 or 20 wherein R' and R 2 are alkyl.

22. The process of claim 19 or 20 wherein R' and R 2 are selected from the group consisting of ethyl, n-butyl, iso-butyl and pentyl.

23. The process of claim 19 or 20 wherein R' and R 2 are n-butyl.

24. The process of any one of claims 19 to 23 wherein the alcohol is oxidized with an oxidizing agent to form an aldehyde.

25. The process of claim 24 wherein the aldehyde is oxidized with an oxidizing agent to form a sulfone-aldehyde. i. 26. The process of any one of claims 19 to 25 wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is a base having a pH between about 8 to about 9.

27. The process of any one of claims 19 to 25 wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is an alkali alkoxide base.

28. The process of any one of claims 19 to 25 wherein the sulfone-aldehyde is cyclized with potassium tert-butoxide. +7. oooo• 467

29. The process of any one of claims 19 to 23 wherein the alcohol is oxidized with pyridinium chlorochromate to form an aldehyde; the aldehyde is oxidized with metachloroperbenzoic acid to form a sulfone-aldehyde; and the sulfone-aldehyde is cyclized with potassium tert-butoxide. DATED this 18 day of March 2003 G. D. SEARLE CO., By its Patent Attorneys, E. F. WELLINGTON CO., (Bruce Wellington) *oo BA.4064b *eo