AU2017229591B2

AU2017229591B2 - Calpain modulators and methods of production and use thereof

Info

Publication number: AU2017229591B2
Application number: AU2017229591A
Authority: AU
Inventors: Brad Owen BUCKMAN; Shendong Yuan
Original assignee: Blade Therapeutics Pty Ltd
Current assignee: Blade Therapeutics Pty Ltd
Priority date: 2016-03-09
Filing date: 2017-03-08
Publication date: 2021-08-19
Anticipated expiration: 2037-03-08
Also published as: WO2017156074A1; AU2017229591A1

Abstract

The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.

Description

parallel beta- sheets", Organic & Biomolecular Chemistry, (2013), vol. 11, no. 3, pages 425 - 429 CHEN, H. et al., "New Tripeptide-Based Macrocyclic Calpain Inhibitors Formed by N- Alkylation of Histidine", Chemistry & Biodiversity, (2012), vol. 9, no. 11, pages 2473- 2484 PEHERE, A. D. et al., "New beta-strand templates constrained by Huisgen cycloaddition", Organic Letters, (2012), vol. 14, no. 5, pages 1330 - 1333 STUART, B. G. et al., "Molecular Modeling: A Search for a Calpain Inhibitor as a New Treatment for Cataractogenesis", Journal of Medicinal Chemistry, (2011), vol. 54, no. 21, pages 7503 - 7522 JONES, M. A. et al., "Efficient large-scale synthesis of CAT811, a potent calpain inhibitor of interest in the treatment of cataracts", Australian Journal of Chemistry, (2009), vol. 62, no. 7, pages 671 - 675 ABELL, A. D. et al., "Molecular modeling, synthesis, and biological evaluation of macrocyclic calpain inhibitors", Angewandte Chemie, International Edition, (2009), vol. 48, no. 8, pages 1455 - 1458 WO 2008048121 A2 WALKER, M. A. et al., "General method for the synthesis of cyclic peptidomimetic compounds", Tetrahedron Letters, (2001), vol. 42, no. 34, pages 5801 - 5804

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2017/156074 A1 14 September 2017 (14.09.2017) WIP 0 I P CT

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 245/02 (2006.01) A61P 29/00 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 273/08 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K38/12 (2006.01) A61P 43/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, (21) InternationalApplicationNumber: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, PCT/US2017/021288 KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (22) International Filing Date: MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, 8 March 2017 (08.03.2017) NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (25) Filing Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW.

(30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/306,040 9 March 2016 (09.03.2016) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: BLADE THERAPEUTICS, INC. [US/US]; TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 442 Littlefield Avenue, South San Francisco, CA 94080 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (US). DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor: BUCKMAN, Brad Owen; 2042 Leimert LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Boulevard, Oakland, CA 94602 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventor: NICHOLAS, John Beamond (deceased). Published: (72) Inventor: YUAN, Shendong; 2328 Elan Lane, San Ra- - with internationalsearch report (Art. 21(3)) mon, CA 94582 (US). - before the expiration of the time limit for amending the (74)Agent:MALLON,JosephJ.;Knobbe,Martens,Olsen& claims and to be republished in the event of receipt of Bear LLP, 2040 Main Street 14th Floor, Irvine, CA 92614 amendments (Rule 48.2(h)) (US).

(54) Title: CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF

f4 (57) Abstract: The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic dis ease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.

CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF BACKGROUND

Field of the Invention

[0001] The present disclosure relates to small molecule calpain modulatory compounds, pharmaceutical compositions comprisingthe compounds, and methods of using the compounds and compositions to modulate calpain activity, including methods to treat diseases and conditions mediated at least in part by the physiologic effects of CAPNI, CAPN2 or CAPN9, or combinations thereof.

Description of the Related Art

[00021 Fibrotic disease accounts for an estimated 45% of deaths in the developed world but the development of therapies for such diseases is still in its infancy. The current treatments for fibrotic diseases, such as for idiopathic lung fibrosis, renal fibrosis, systemic sclerosis, and liver cirrhosis, are few in number and only alleviate some of the symptoms of fibrosis while failing to treat the underlying cause.

100031 Despite the current limited understanding of the diverse etiologies responsible for these conditions, similarities in the phenotype of the affected organs, across fibrotic diseases, strongly support the existence of common pathogenic pathways. At present, it is recognized that a primary driver of fibrotic disease is a high transforming growth factor-betaTGF) signaling pathway which can promote the transformation of normally functioning cells into fibrosis-promoting cells. Termed "myofibroblasts," these transformed cells can secrete large amounts of extracellular matrix proteins and matrix degrading enzymes, resulting in the formation of scar tissue and eventual organ failure. This cellular process is transformative and termed "myofibroblast differentiation" (which includes Epithelial-to-Mesenchymal Transition (EpMT) and its variations like Endothelial-to-Mesenchymal Transition (EnMT) and Fibroblast-to-Myofibroblast Transition (FMT)). This process is a major target for the treatment of fibrotic diseases. Myofibroblast differentiation has also been shown to occur within cancer cells that have been chronically exposed to high TGF3, causing stationary epithelial cells to become motile, invasive, and metastasize. Thus, within the context of cancer, the signaling has been documented to associate with the acquisition of drug resistance, immune system evasion, and development of stem cell properties.

[0004] Despite the tremendous potential of myofibroblast differentiation-inhibiting drugs, and the numerous attempts to develop a working treatment, the data gathered thus far has yet to translate into practical therapy. This is partly due to the lack of an ideal target protein. Initial strategies to target the myofibroblast differentiation process focused on proximal inhibition of the TGF3 signaling pathway by various methods, including targeting ligand activators (e.g., alpha-v integrins), ligand-receptor interactions (e.g.. using neutralizing antibodies) or TGF receptor kinase activity (e.g., small molecule chemical compound drugs to block signal transduction). Unfortunately, TGFP is a pleiotropic cytokine with many physiological functions such that global suppression of TGF signaling was also associated with severe side effects. Additionally, current data suggests that such proximal inhibition may be vulnerable to pathologic workaround strategies (i.e., due to redundancy or compensation), that would limit the utility of such drugs. Further complicating matters is that, in cancer, TGF3 signaling early on functions as an anti-tumorigenic growth inhibitor but later becomes tumor promoting and is another reason why selective inhibition of pathogenic elements of signaling is so strongly desired. In light of these inherent limitations, current treatment strategies have refocused on identification and inhibition of critical distal events in TGFP signaling, which in theory would preferentially target the pathologic, but not physiological functions of TGF- signaling.

SUMMARY OF THE INVENTION

[00051 The inventors have found a series of keto-amide compounds that inhibit CAPNI, CAPN2, and/or CAPN9 and affect a chain of cellular effects so as to elicit therapeutic benefits. In some embodiments, compounds are inhibitors clapains. In some embodiments, compounds are selective and/or specific calpain inhibitors. In some embodiments, compounds are specific inhibitors of one of: CAPNI, CAPN2 or CAPN9. In some embodiments, compounds are selective inhibitors of one of. CAPN1, CAPN2 or CAPN9. In some embodiments, compounds are selective inhibitors of: CAPNI and CAPN2, or CAPNi and

CAPN9, or CAPN2 and CAPN9. In some embodiments, compounds are effective inhibitors of CAPN1, CAPN2 and/or CAPN9.

[0006] Combination therapy through one molecule is unique in pharmacology since most drugs have only one or two enzymatic targets. Keto-amide compounds of the present invention are broadly effective in treating a host of conditions arising from fibrosis or inflammation, and specifically including those associated with myofibroblast differentiation. Accordingly, compounds of the invention are active therapeutics for a diverse set of diseases or disorders that include or that produces a symptom which include, but are not limited to: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders. [0006a] In one aspect, the present invention provides a compound comprising Formula I:

R2 R3 A R2 LN NR 22 R2 R

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of:0 and S;

A

NR1

each Ris R

3 17678412_1 (GHMatters) P109779.AU each Rand R3 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-CI1 cycloalkyl, substituted C3-C1O cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2, NHR2 , SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R1 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted Ci-C8 alkyl, Ci-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-CO cycloalkyl, substituted C3-CO cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R 2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH2, C(R2)2, CHR 2, 0, NH, NR 2 , C(=O), C(=S), S, S(=O), S(=0)2, -C-, -CH-, a C3-C12 spirocyclic group R2-(R2)m of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C3-C12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl

3a 17678412_1 (GHMatters) P109779.AU ring structure, a C3-C12 heterocyclic ring structure, and a C3-C12 fused heterocyclic ring structure; and wherein W. does not form an (S) -1-CH 2CH 2C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[0006b] In another aspect, the present invention provides a compound comprising a formula selected from the group consisting of Formula II, XV, XVI or XVIII:

R2 R20 L'N NN N'R 2 R2 R 2 1

Formula II

-wn

R3 A R2 A L4R 2 N R R2-Z-R1 NN 2 R 2 2 A I1

Formula XV

-wn

R2 R3 0 R20 2ZRl N N N >2 R R2 2y 41

Formula XVI

3b 17678412_1 (GHMatters) P109779.AU

- wn R3 A 2

R 1 -Z- 2 R4 R'Z-4 "A R2 R2 2 A

Formula XVIII

where:

when the formula is Formula II: n is from 1-11;

when the formula is Formula XV or XVIII: n is from 1-12, and each A is independently selected from the group consisting of 0 and S;

A

N 1 when the formula is Formula XVI: n is from 1-12;each Ris

each Rand R 3 is independently selected from the group consisting of: hydrogen, Ci C8 alkyl, substituted Ci-C8 alkyl, Ci-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-CI1 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2, NHR 2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R1 substituent may be covalently bonded to or share another R1 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted Ci-C8 alkyl, Ci-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C cycloalkyl, substituted C3-C1 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9

3c heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH2, C(R2)2, CHR 2, 0, NH, NR 2 , C(=O), C(=S), S, S(=O), S(=0) 2 , -C-, -CH-, a C3-C12 spirocyclic group of R2-(R2)m where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

Z is selected from the group consisting of: C-C alkyl, substituted C1-C alkyl, C-C alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted C1-C8 alkynyl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 )2, CHR2 , 0, NH, NR 2, S, substituted sulfonyl, sulfinyl, substituted sulfinyl , and a covalent bond;

and wherein any two or more W groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C3-C12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl ring structure, a C3-C12 heterocyclic ring structure, and a C3-C12 fused heterocyclic ring structure;

and wherein Wn does not form an (S) -- CH 2CH 2C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group; and wherein ----- is a single bond;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

[0006c] In yet another aspect, the present invention provides a compound comprising a formula selected from the group consisting of Formula III-XIV:

3d 17678412_1 (GHMatters) P109779.AU

RR 2 R2 0R3R2 R 2 0 R2 R2 0 2 N \N R3 >'! "I R 2 )4P 0 R o R2 0O L4 ., NNSR_2L4' Z 2 R ~R2Z1 R12 2 2 R NIZR zl-z2

' R2 R2 N' R2N IR ko Formula III Formula IV Formula V

2 R1R R R220 20 R1 R20 R2O0NR R3 N) R1 R20

R2R2R1 2 RRR 0?q

R2 z 0 0 R2 O2t

34~ 04 3-3 -z2*~~ L Nz z 4 6Z

0 z R2 R 0Z L 4 -N- 2 R2Z

FormulaI FormulaXVI FormulaXVII

Ri -Ri i Ri3e 1767412(GN' 0 \NP0979.A

1 1 R1 R1 RN-R1R1R RN 'N' R 0 0 0 ZR) R2 R 0 'N z1 'Z 8 ' z2'z ze -Z 6 R Z -Z 1o 'N 1 z" 10 R NN z9 R z1

0 Z3~ 0Z O R' R-N 0 2 R3 N 0 Z5 6 R3N 0 Z6'z

L4 L 4 _N- z z2Z4 L z1 z4

' 2 RdR _z3

Formula XII Formula XIII Formula XIV

where:

when the formula is Formula III:

Z' is selected from the group consisting of: CH2,C(R)2,CHR, O, NH, NR, C(=O), R2-(R2)m

C(=S), S, S(=O), andS(=0) 2 , aC3-C12 spirocyclic group of where m is 1-19;

when the formula is Formula IV-XIV:

ZI, Z 2 , Z 3, Z 4 , Z 5 , Z 6 , Z 7, Z 8 , Z 10, Z" and Z 12 are each independently selected from the group consisting of:CH2, C(R 2)2,CHR2, 0, NH, NR 2 , C(=0), C(=S), S, S(=0), S(=0) 2 , -C-, R2-(R2)m

CH-, aC3-C12 spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CR=CR' or C--C;

each Rand R3 is independently selected from the group consisting of: hydrogen, Ci C 8 alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, C-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C 9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2, NHR 2, SR2 , substituted

3f sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R 2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein when the formula is Formula V-XIV,

any and all Z groups do not form an (S)-- CH 2 CH2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and any two or more Z groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C3-C12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl ring structure, a C3-C12 heterocyclic ring structure, and a C3-C12 fused heterocyclic ring structure;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

[0006d] In a further aspect, the present invention provides a compound comprising Formula XVII:

3g 17678412_1 (GHMatters) P109779.AU

-- - L3

14,''R 2 A Z R1 4 NR N 2A R2 R 22

Formula XVII

where:

each A is independently selected from the group consisting of:0 and S; A

NR1

each R4 is R1

each R' is independently selected from the group consisting of: hydrogen, C-C8 alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-CI1 cycloalkyl, substituted C3-C1O cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2, NHR2 , SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R1 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted C1-C8 alkenyl, C1-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-CO cycloalkyl, substituted C3-CO cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any

R 2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

3h 17678412_1 (GHMatters) P109779.AU

L' is a group containing 1-8 atoms and is selected from the group consisting of: C-C8 alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted C1-C8 alkynyl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 )2, CHR 2, 0, NH, NR 2, S, substituted sulfonyl, sulfinyl, and substituted sulfinyl;

Z is selected from the group consisting of: C-C alkyl, substituted C1-C alkyl, C-C alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted C1-C8 alkynyl, Ci-C8 alkoxy, substituted C1-C8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 )2, CHR2 , 0, NH, NR 2, S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;

wherein each L' and Z are capable of being covalently bonded to the same or other R2 functional groups such that a bicyclic or spirocyclic ring system is formed;

and wherein L' and Z do not form an (S) -- CH 2 CH 2C(O)NH- group in the ring starting from the carbon atom closest to the keto-amide or thio-keto-amide functional group; and wherein ----- is a single bond;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

[0006d] In a further aspect, the present invention provides a compound having the structure

H 0 NH NA

31 or pharmaceutically acceptable salts thereof.

[0006e] In yet a further aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds as defined herein and a pharmaceutically acceptable excipient.

3i

[0006f] In another aspect, the present invention provides a kit comprising a composition including a compound as defined herein and instructions for use.

[0006g] In yet another aspect, the present invention provides a method for treating fibrotic disease by decreasing the expression level and/or activity of a calpain, wherein the calpain is CAPN1, CAPN2, or CAPN3, comprising administration of an effective amount of a composition comprising a compound as defined herein to a subject in need thereof, wherein the fibrotic disease is liver fibrosis, lung fibrosis, or a combination thereof.

[0006h] In a further aspect, the present invention provides a method of treating a fibrotic disease, wherein the disease is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post vasectomy pain syndrome, and rheumatoid arthritis,

wherein the treatment decreases the expression level and/or activity of a calpain, wherein the calpain is CAPN1, CAPN2, or CAPN9,

wherein the treatment inhibits myofibroblast differentiation, Fibroblast-to-Myofibroblast Transition (FMT), or Epithelial to Mesenchymal Transition or Endothelial to Mesenchymal Transition or treats a disease associated with myofibroblast differentiation, wherein the myofibroblast differentiation is a TGF3-mediated myofibroblast differentiation,

wherein the fibrotic disease is stiff skin syndrome (SKS) or a cancer of epithelial origin selected from the group consisting of breast cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, brain, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, prostate cancer, and renal cell carcinoma. wherein the subject is a mammal or a human,

3j 17678412_1 (GHMatter) P109779.AU wherein the route of administration is selected from the group consisting of: enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal.

[0006i]In a yet a further aspect, the present invention provides a method of inhibiting myofibroblast differentiation comprising contacting a cell with a compound as defined herein, wherein the cell is in a fibrotic tissue, a cancerous tissue, or a tissue with high TGF signaling.

[0006j] In another aspect, the present invention provides a method for inhibiting calpain, the method comprising contacting a compound as described herein with a CAPN1, CAPN2, and/or CAPN9 enzyme residing inside a subject.

[0006k] In yet another aspect, the present invention provides a method of competitive binding with calpastatin (CAST), the method comprising contacting a compound as defined herein with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject, wherein the compound specifically inhibits one or more of the enzymes selected from the group consisting of: CAPN1, CAPN2, and CAPN9 by at least one of the following values: i) 4-foldand with at least an ICso value of 15 pM; ii) 10-fold, and with at least an ICso value of 15 pM; or ii) 100-fold, and with at least an ICso value of 15 pM.

[00061]In a further aspect, the present invention provides the use of a compound as defined herein for the manufacture of a medicament for treating fibrotic disease.

[0006m] In yet a further aspect, the present invention provides the use of a compound as defined herein for treating fibrotic disease.

[0006n] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutic compound for treatment, prevention or reduction of a symptom of a fibrotic disease or a fibrotic condition, wherein the therapeutic compound is a calpain modulator present in the composition in an amount effective to alter the fibrotic state of at least one tissue in a human subject to whom the composition is administered and wherein the therapeutic compound is a compound comprising Formula I:

3k 17678412_1 (GHMatter) P109779.AU

Wn ' R3 A 2 L412 R R L!2 NR N -K N R2 A R2 R R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

A

N R1 k

each R 4 is

each Rand R' is independently selected from the group consisting of: hydrogen, C1 -C alkyl, substituted C1 -C 8 alkyl, C1 -C 8 alkenyl, substituted C1 -C8 alkenyl, C1 -C8 alkynyl, substituted C1 -C 8 alkynyl,C 3-C 7 aryl, substitutedC 3-C 7 aryl, cyano,C 3-C10 cycloalkyl, substitutedC3-C1Ocycloalkyl,C3-C9 heterocycloalkyl, substitutedC3-C9 heterocycloalkyl,C3 C 9 heteroaryl, substitutedC 3-C 9 heteroaryl, C1 -C 8 alkoxy, substituted C1 -C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR 2, NH 2, NHR2 , SR 2, substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R1 substituent to form aC3 -C1 2cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R 2 is independently selected from the group consisting of: hydrogen, C1 -C8 alkyl, substituted C1 -C 8 alkyl, C1 -C 8 alkenyl, substituted C1 -C 8 alkenyl, C1 -C 8 alkynyl, substituted C 1-C 8 alkynyl,C 3 -C 7 aryl, substitutedC 3-C 7 aryl, cyano, OH, C1 -C8 alkoxy, substituted C1 -C alkoxy, amino, substituted amino,C 3-C10 cycloalkyl, substitutedC 3-C10 cycloalkyl, C 3-C 9 heterocycloalkyl, substitutedC 3 -C9 heterocycloalkyl,C 3-C9 heteroaryl, substitutedC 3-C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form aC3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

31 17678412_1 (GHMatter) P109779.AU each W is independently selected from the group consisting of: CH 2 ,C(R 2)2 , CHR2 , 0,

R 2-(R 2)m

NH, NR 2 , C(=O), C(=S), S, S(=O), S(=0) 2 , -C-, -CH-, a C 3 -C 12 spirocyclic group of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C=C;

L 4 is selected from the group consisting of: R 2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C 3-C 1 2 fused cycloalkyl ring structure, a C 3-C1 2 aryl ring structure,

a C 3-C 12 fused aryl ring structure, a C3 -C1 2 heteroaryl ring structure, a C 3-C1 2 fused heteroaryl ring structure, a C3 -C1 2 heterocyclic ring structure, and a C 3-C1 2 fused heterocyclic ring

structure;

and wherein Wa does not form an (S) -- CH 2CH 2C(O)NH- group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[00060] In yet another aspect, the present invention provides a method for the treatment, prevention or reduction of a symptom of a fibrotic, sclerotic or post inflammatory disease or condition comprising the step of administering to a human subject in need thereof a pharmaceutical composition comprising a therapeutic compound, wherein the therapeutic compound is a calpain modulator present in the composition in an amount effective to alter the fibrotic, sclerotic or post-inflammatory state of at least one tissue in the human subject and wherein the therapeutic compound is a compound comprising Formula I:

3m 17678412_1 (GHMatters) P109779.AU

-wn 2 R 3 A R2 L4 R2 I R R4 N x- 1N R2 A R2 R2 R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

A

N R1 k

each R 4 is

each R 2 is independently selected from the group consisting of: hydrogen, C1 -C8 alkyl, substituted C1 -C 8 alkyl, C1 -C 8 alkenyl, substituted C1 -C 8 alkenyl, C1 -C 8 alkynyl, substituted C 1-C 8 alkynyl,C 3 -C 7 aryl, substitutedC 3-C 7 aryl, cyano, OH, C1 -C8 alkoxy, substituted C1 -C alkoxy, amino, substituted amino,C 3-C10 cycloalkyl, substitutedC 3-C10 cycloalkyl, C 3-C 9 heterocycloalkyl, substitutedC 3 -C9 heterocycloalkyl,C 3-C9 heteroaryl, substitutedC 3-C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2

3n 17678412_1 (GHMatter) P109779.AU substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH 2 ,C(R 2)2 , CHR2 , 0,

R2-(R 2)m,

structure;

and wherein Wa does not form an (S) -1-CH 2CH 2C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein the therapeutic compound is a selective calpain modulator selected from a specific calpain-9 modulator, a selective calpain-9 modulator, a selective calpain-9 and calpain-1 modulator, a selective calpain-9 and calpain-2 modulator, or a selective calpain-9, calpain-2 modulator, and calpain-1 modulator.

[000 6 p] In a further aspect, the present invention provides a use of a therapeutic compound comprising Formula I:

3o 17678412_1 (GHMatter) P109779.AU

Wn ' R3 A 2 L412 R R L!2 NR N -K N R2 A R2 R R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

A

N R1 k

each R 4 is

3p 17678412_1 (GHMatter) P109779.AU substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH 2 ,C(R 2)2 , CHR2 , 0,

R2-(R 2)m,

structure;

and wherein Wa does not form an (S) -1-CH 2CH 2C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein the therapeutic compound is a selective calpain modulator selected from a specific calpain-9 modulator, a selective calpain-9 modulator, a selective calpain-9 and calpain-1 modulator, a selective calpain-9 and calpain-2 modulator, or a selective calpain-9, calpain-2 modulator, and calpain-1 modulator, in the manufacture of a medicament for the treatment, prevention or reduction of a symptom of a fibrotic, sclerotic or post inflammatory disease or condition.

3q 17678412_1 (GHMatter) P109779.AU

[0007] Certain embodiments of the present invention are directed toward using these keto amide compounds to treat diseases or conditions or that produces a symptom in a subject which include, but not limited to: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases.

[0008] In certain embodiments methods are provided for alleviating or ameliorating a condition or disorder, affected at least in part by the enzymatic activity of CAPN1, CAPN2, and/or CAPN9, or mediated at least in part by the enzymatic activity of CAPN1, CAPN2, and/or CAPN1 wherein the condition includes or produces a symptom which includes: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis,

3r 17678412_1 (GHMatters) P109779.AU systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischernic reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and/or rheumatoid arthritis.

[00091 In some embodiments, the methods, compounds, and/or compositions of the present invention are used for prophylactic therapy.

[00101 In some embodiments, the CAPNI, CAPN2, and/or CAPN9 inhibiting compounds demonstrate efficacy in animal models of human disease. Specifically, in-vivo treatment of mice, rabbits, and other mammalian subjects with compounds of the present invention establish the utility of these compounds as therapeutic agents to modulate CAPNI, CAPN2, and/or CAPN9 activities in humans and thereby ameliorate corresponding medical conditions.

[00111 Some embodiments provide compounds, pharmaceutical compositions, and methods of use to inhibit myofibroblast differentiation. Some embodiments provide compounds, pharmaceutical compositions, and methods of use for inhibiting CAPNI, CAPN2, and/or CAPN9 or combinations of these enzyme activities such as CAPN1 and CAP3N2, or CAPNI and CAPN9, or CAPN2 and CAPN9. Some embodiments provide methods for treatment of diseases and disorders by inhibiting CAPN, CAPN2, and/or CAPN9 or combinations of these enzymatic activities.

[00121 Certain embodiments provide novel small molecules that are specific or selective inhibitors of CAPNi, CAPN2, and/or CAPN9 activity, or selective inhibitors of combinations

of CAPN1, CAPN2 and CAPN9 activities, e.g., selective inhibitors of CAPN Iand CAPN2, or CAPN1 and CAPN9, or CAPN2 and CAPN9.

[00131 In certain embodiments, the compound has a structure represented by Formula 1:

'wn 2 R3 A R2

A R 2 R2R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

A

R1

each R is independently selected from the group consisting of: - and R

each Rand R 3 is independently selected from the group consisting of: hydrogen, C1 -Cs alkvl, substituted C 1-Cs alkyl, C-Cs alkenyl, substituted C1-Cs alkenyl, C-Cs alkynyl, substituted C1 -Cs alkvnyl, C 3-C7 aryl, substituted C 3-C7 aryl, cyano, C 3-C1 0 cycloalkyl. substituted C 3-C 1 0 cycloalkyl, C 3 -C 9 heterocycloalkyi, substituted C3-C heterocycloalkyl, C3 C 9 heteroaryl, substituted C 3-C 9 heteroarvl, C 1-Cs alkoxy, substituted C1 -Cs alkoxv, amino, substituted amino, alkylthio, substituted alkythio, OH, OR', NH 2, NHR2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form a C3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R is independently selected from the group consisting of: hydrogen, C1-Calkyl, substituted C1-Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, OH, C1 -Cs alkoxy substituted C1 -C alkoxy, amino, substituted amino, C 3 -C1 0 cycloalkyl, substituted C 3-C1 0 cycloalkyl, C3-C 9 heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C 3-C 9 heteroaryl, substituted C 3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently selected from the group consisting of: CH2, C(R2) 2 , CHR', 0, R2-R2)mi

NH, NR2 C(=0), C(=S), S, S(=0), S(=0),2, -C-, -CH-, a C3I-C 1 spirocyclic group of where in is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form cRi=CR or C C;

L" is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a CrC12 cycloalkyl ring structure, a C-C 2 fused cycloalkyl ring structure, a C3 -C2 aryl ring structure, a C3 -C 1 2 fused aryl ring structure, a C3 -C heteroaryl ring structure, a C3 -C fused heteroaryl ring structure, a C3 -C heterocyclic ring structure, and a C3 -C fused heterocyclic ring structure;

and wherein W1 does not form an (S) -1-CH 2 CH 2C(O)NH- groupintheringstarting from the carbon attached to R2 which is adacent to the keto-amide or thioketo-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[00141 Some embodiments include a compound selected from the group consisting of:

H 0 O-H 0 O ONH .. HHNN / H 2

H 0 H O O HN- H' N N H H

H H O H H O H N N H O N N 0 .N- N

7 NyNj CH Ny H HH

0 H) H C) 0C HC)_ OA- H ",-\o)Q A H N,

12/

C)H (D )I-JN >d 1 -D (D i HN-l NI

H \7

13 1

:K C) HN- ,%,N H 0 H N- ,C,), 0)~C

H I _NH 0) H X0 N- N N,"

16 17IS

H C) H C) C)C)N ~ Njj 0 C) NC N j

HN"H

19 20 21 /

HH H1H N N" HN- 6 22 23 24

0 0 HN~k~ N C)C)C)0 0HN- Nyl QIC)H F / W/'~ HN H'N'" 25 26 olll~ ~N C) 27 H

C)))H"NN0 ~ HN N 00' vHC. NH~" NH_) NOi H. N H-

H 0H H NNO HN N N N kH NN -x / N NN 32 ---

1 3r

H 0 /N 0 HN N

H H 3, I 34 35

H0

-- NW H H

36 37 or a pharmaceutically acceptable salt thereof

[0015] In a related aspect, pharmaceutical compositions are provided that include an effective amount of one or more compounds of Formula I-XVIII described herein and a pharmaceutically acceptable excipient.

[0016 In certain embodiments, methods are provided for inhibiting CAPNi, CAPN2 or CAPN9 that includes contacting (in vivo or in vitro) cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I XVIII described herein.

[00171 In certain embodiments, methods are provided for selectively inhibiting one of: CAPNI, CAPN2, or CAPN9 that includes contacting (in vivo or in viro) cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

[00181 In other embodiments, methods are provided for selectively inhibiting two of: CAPNI., CAPN2, or CAPN9 (e.g.. CAPNI and CAPN2, or CAPNI and CAPN9 or CAPN2 and CAPN9) that includes contacting (in vivo or in vitro) cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I XVIII described herein.

[00191 In other embodiments, methods are provided for specifically inhibiting one of: CAPNi, CAPN2, or CAPN9 that includes contacting (in vivo or in vitro) cells (including neurons/microglia/invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

100201 In other embodiments, methods are provided for specifically inhibiting two of. CAPNI, CAPN2, or CAPN9 (e.g., CAPNI and CAPN2, or CAPNI and CAPN9 orCAPN2 and CAPN9) that includes contacting (in vivo orin vitro) (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I XVIII described herein.

[00211 In an aspect, a method is provided for treating a disease or disorder affected at least in part by CAPN1, CAPN2, and/or CAPN9, where the method comprises administering to a subject in need of treatment an effective amount of one or more compounds of Formula I XVIII or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of one or more compounds of Formula I-XVIII described herein.

[0022 In one aspect, an article of manufacture is provided for use in inhibiting CAPNI, CAPN2, and/or CAPN9 and treating a disease or disorder affected at least in part by CAPN1, CAPN2, and/or CAPN9, wherein the article comprises a a compound of Formula I-XVIII as provided herein. The diseases affected at least in part by CAPNI, CAPN2, and/or CAPN9 are as provided herein. In some embodiments, the article of manufacture further includes a label with instructions for using the composition to treat a disease or disorder affected at least in part by CAPN1, CAPN2, arid/or CAPN9.

[00231 These and other embodiments are described in further detail herein.

DETAILED DESCRIPTION OF THE INVENTION

Utility

[00241 Compounds of the present invention inhibit calpain. Specifically, these compounds of Formula I-XVII inhibit CAPN 1, 2, and/or 9. Such compounds are useful for the treatment or therapy of fibrotic and other diseases.

Definitions

[00251 Terms used in the claims and specification are defined as set forth below unless otherwise specified. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[00261 As used herein and in the appended claims, singular articles such as "a," "an" and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the upper and lower bounds of the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0027 Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C 14, P and S5 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

100281 As used herein, "a fibrotic disease" includes, for example, liver fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary chronic disease), renal fibrosis (eg., resulting from chronic inflammation, infections or type II diabetes), lung fibrosis idiopathicc or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma autoimmunee disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders) cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, especially surgical implants, injection fibrosis and secondary conditions and disease states of fibrosis. Secondary conditions and disease states which occur as a consequence of or associated with fibrosis include for example, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome and rheumatoid arthritis, among others.

[00291 The term "ameliorating" refers to any therapeutically beneficial result in the treatment of a disease state, e.g., an inflammatory disease state, including lessening in the severity or progression, remission, or cure thereof. In some embodiments, "ameliorating" includes prophylaxis of a disease state.

[00301 The term "in vitro" refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[00311 The term "in vivo" refers to processes that occur in a living organism.

[00321 The term "mammal" as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[00331 The term "sufficient amount" means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate protein aggregation in a cell.

[00341 The term "therapeutically effective amount" is an amount that is effective to ameliorate a symptom of a disease. A therapeutically effective amount can, in some embodiments, be a prophylacticallyy effective amount" as prophylaxis can be considered therapy.

[00351 Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[00361 The compounds of the present technology can exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology can exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[00371 "Subject" refers to a mammalian organism treated using a compound of the present invention. The"subject" can be a human or non-human mammalian organism.

[00381 "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring N- moiety and a ring=N moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[00391 "Treating" or "treatment" of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3)amelioratingoralleviating the cause of the regression of the disease or disorder.

[00401 Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[00411 As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[00421 As used herein, "naturally occurring amino acid side chain" will be understood to be the substituent of a natural amino acid. Naturally occurring amino acids have a substituent attached to the ---carbon Naturally occurring amino acids include the list shown below. Charged: • Arginine - Arg - R • Lysine - Lys - K • Aspartic acid - Asp - D "Glutamic acid - Glu - E

Polar (may participate in hydrogen bonds): " Glutamine - Gin - Q • Asparagine - Asn - N • Histidine - His - H • Serine - Ser - S • Threonine - Thr - T • Tyrosine - Tyr - Y • Cysteine - Cys - C • Methionine - Met - M • Tryptophan - Trp - W

Hydrophobic (normally buried inside the protein core): • Alanine - Ala - A • Isoleucine - Ile - I " Leucine - Leu - L " Phenylalanine - Phe - F " Valine - Val - V

" Proline - Pro - P " Glycine - Gly - G.

[00431 As used herein, "non-naturally occurring amino acid side chain" will be understood to be the substituent of a non-naturally occurring amino acid. Non-naturally occurring amino acids have a substituent attached to the a-carbon. Non-naturally occurring amino acids include the list described below. Non-natural amino acids include -amino acids (p3 and 2), Homo-amino acids, Proline and Pyruvic acid derivatives, 3-substituted Alanine derivatives, Glycine derivatives, Ring-substituted PhenvIalanine and Tyrosine Derivatives, Linear core amino acids and N methyl amino acids. Exemplary non-natural amino acids are available from Sigma-Aldridge, listed under "unnatural amino acids & derivatives." See also, Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285: 11039-11044.

[00441 As used herein, the phrase "modulating or inhibiting (the activity of) CAPN1, CAPN2, and/or CAPN9" refers to use of any agent capable of altering the cellular expression levels and/or biological activity of the CAPNI, CAPN2, and/or CAPN9 gene, messenger RNA, or protein. In some embodiments, an agent that modulates or inhibits the biological activity of CAPNI, CAPN2, and/or CAPN9 directly interferes with the expression (such as transcription, splicing, transport, etc.) of the gene encoding the CAPN1, CAPN2, and/or CAPN9 mRNA. in other embodiments, an agent that modulates or inhibits the activity of CAN1, CAPN2, and/or CAPN9 directly interferes with the biological activity or production of the CAPN1, CAPN2, and/or CAPN9 proteins (such as though inhibition of translation, post-translational modifications, intracellular transport, disruption of interactions between one or more proteins, etc.). In yet other embodiments, an agent that modulates or inhibits the activity of CAPN1, CAPN2, and/or CAPN9 does not directly affect the expression level or activity of CAPNI, CAPN2, and/or CAPN9 but, instead, alters the activity or expression levels of a protein whose function directly impacts the expression or activity of CAPNI, CAPN2, and/or CAPN9 (such as, for example, calpastatin). in other embodiments, an agent may specifically inhibit one or more CAPN1, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent may selectively inhibit CAPNI, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent may both specifically and selectively inhibit one or more CAPNI, CAPN2, and/or CAPN9 enzymes. In yet other embodiments, an agent is neither a specific nor selective inhibitor for one or more CAPNI, CAPN2, and/or CAPN9 enzymes, but is still active for the inhibition of one or more of the CAPNI, CAPN2, and/or CAPN9 enzymes. Calpains are also expressed in cells other than neurons, microglia and invading macrophages. In particular, they are important in skeletal muscle and herein inhibition of calpains also refers to inhibition in these cells as well.

[00451 As used herein, an agent is said to be "specific" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target (for example, a protein, such as CAPN9, CAPN2, or CAPNI as well as a nucleic acid encoding the same) than it does with alternative substances, especially as compared to substances that are structurally related to the target, e.g., an isoform of the target. For instance, an antibody "specifically binds" to a target protein (such as CAPN9 CAPN2. or CAPN1 if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances.

[0046 In some embodiments, anagent is "specific" for a target if a concentration of the agent that produces a maximal effect in an in vitro or in vivo target assay (e.g., a binding assay or an enzyme activity assay) produces no measurable effect ina comparable assay carried out using another substance, especially one or more substances that are structurally related to the target.

[0047] As used herein, an agent is said to be a"specific inhibitor" of CAPNi, CAPN2 or CAPN9 if it inhibits the biological activity and/or expression level of CAPN1, CAPN2 or CAPN9 without inhibiting the biological activity and/or expression level of other members of the calpain family of proteases or other members of the TRP family of calcium channels.

100481 As used herein, an agent is an agent is said to be "selective" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target or a small set of structurally-related targets (for example, a protein, such as CAPN9, CAPN2, or CAPNI as well as a nucleic acid encoding the same) than it does with alternative substances, especially as compared to other substances that are structurally related to the target or small set of structurally-related targets, e.g., an isoform of the target. In certain embodiments, a"selective" agent reacts similarly with multiple related targets, whereas a

"specific" agent reacts with its target in a manner that is markedly differently from the way it interacts with other biological molecules. For instance, an antibody "selectively binds" to a target protein (such as CAPN9, CAPN2, or CAPNI if it binds with greater affinity, avidity, more readily, and/or with greater duration to two related targets (e.g., CAPN9, CAPN2) than it binds to other substances.

[00491 In some embodiments, an agent is "selective" for a set of targets if a concentration of the agent that produces a maximal effect in an in vitro or in vvo assay (e.g., a binding assay or an enzyme activity assay) with a first target molecule produces a measurable effect in a comparable assay carried out using a second target molecule. In some embodiments, an agent is selective if it binds to two or more targets (especially structurally-related targets) with Kd or IC50 (or other related measures) ratios of first to second target that are within a range of 1:1 to about 1:500.

[0050] As used herein, in some embodiments, an agent is said to be a "selective inhibitor" of CAPNiorAPN9 if it can be shown to inhibit the biological activity and/or expression level of two or three of CAPN, CAPN2 or CAPN9 (e.g., CAPN1 and CAPN2, or CAPNI and CAPN9, or CAPN2 and CAPN9 or CAPN, CAPN2 and CAPN9) without inhibiting the biological activity and/or expression level of level of other members of the calpain family of proteases or other members of the TRP family of calcium channels.

[0051] As used herein, the term "contacting," as used herein, includes both directly contacting cells, for example, in vivo, in vitro, or ex vivo, or indirectly contacting cells, such as, for example, by administering an agent to a subject. Further, "contacting" a cell with an agent includes administering or applying a prodrug version of the agent. In some embodiments, the cell is in a fibrotic tissue, a cancerous tissue, and/or tissue with high TGF signaling.

100521 As used herein, the term "fibrosis" refers to the increased extracellular matrix protein synthesis and deposition that results in the accumulation of scar tissue. Similarly,asused herein, the term fibroticc tissue" refers to tissue that has high levels of extracellular matrix proteins (i.e., collagen), undergone extensive remodeling (though activity of matrix metalloproteinases) and exhibits progressively diminished physiological function, due to the activity of cells that have undergone myofibroblast differentiation (such as, EIT and/or FMT). In some embodiments, the cell is in a cancerous tissue, such as in tissue that comprises at least one cancer cell. In some embodiments, the cell is in a tissue with high TGFP signaling.

[00531 As used herein, the term "inhibit," "decrease" and grammatical derivations thereof, refers to the ability of an agent to block, partially block, interfere, reduce or deactivate a pathway or mechanism of action. Thus, one of ordinary skill in the art would appreciate that the term "inhibit" or "decrease" encompasses a complete and/or partial loss of activity, e.g., a loss in activity by at least 10%, in some embodiments, a loss in activity by at least20O%, 30%, 50%, 75%, 95%, 98%, and ip to and including 100%.

[00541 As used herein, the term "expression level and/or activity of a calpain" refers to the amount of a calpain found in a cell, tissue and/or subject, and/or a function of a calpain. Such functions can include, without limitation, its protease ability, its function in modulating TGFp signaling, its function in myofibroblast transition (such as EMT and/or FMT). Income embodiments, the expression level of a calpain refers to mRNA expression level. In other embodiments, the expression level of a calpain refers to protein expression level. In some embodiments, the myofibroblast transition is EMT (such as a TGF P-mediated EMT). In some embodiments, at least one agent inhibits Fibroblast-to-Myofibroblast Transition (FMT). In some embodiments, the calpain is CAPN9, CAPN1, and/or CAPN2.

[00551 As used herein, the terms "prevent," "preventing,"'"prevention," "prophylactic treatment" and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition. Thus, in some embodiments, an agent can be administered prophylactically to prevent the onset of a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition.

100561 For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about" even though the term "about" may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term "about," when referring to a value can be meant to encompass variations of, in some aspects, 100% in some aspects + 50%, in some aspects 20%, in some aspects ±10%, in some aspects + 5%, in some aspects ±1%, in some aspects

+ 0.5%, and in some aspects 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0057 Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. 100581 "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from I to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH -), 3 ethyl (C-1 C-1 3 2-),n-propyl

(CH1CH 2 CH2 -), isopropyl ((CH3)2CH-), n-butyl (CCH2CH2C(H 2-), isobutyl

((CH 3) 2CH1ICH2-), sec-butyl ((C13)(C 3 CI)CH-), t-butyl ((C1)3C-), n-penty 3CCH 2-).Cx alkyl refers to an alkyl group 2-), and neopentyl ((CH14) (CHICH 2 CH2 C 2 CH having x number of carbon atoms.

[00591 "Alkenyl" refers to straight or branched hydrocarbyl groups having from 1 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least I and preferably from I to2 sites of unsaturation (>C=C).Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers. C, alkenyl refers to an alkenyl group having x number of carbon atoms.

100601 "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least I and preferably from I to 2 sites of acetylenic (-0C-) unsaturation. Examples of such alkynyl groups include acetylenyl (- CH), and propargyl (-CH 2 OCiCH1). C, alkynyl refers to an alkynyl group having x number of carbon atoms.

[00611 "Substituted alkyl" refers to an alkyl group having from Ito 5, preferably I to 3, or more preferably I to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[00621 In some embodiments the substituted alkyl groups include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[00631 "Cycloalkyl" or"Cyclyl alkyl" refers to a saturated or partially saturated, butnot aromatic, group having from I to 10 ring carbon atoms and no heteroatoms. Cycloalkyl encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more of the rings can be cycloalkyl, aryl, heterocycloalkyl, or heteroaryl provided that the point of attachment is through the original non-aromatic cycloalkyl ring.

[00641 "Substituted alkenyl" refers to alkenyl groups having from I to 3 substituents, and preferably I to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, carboxyll ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroaryithio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[00651 "Substituted alkynyl" refers to alkynyl groups having from I to3 substituents, and preferably I to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.

[00661 "A" refers to any group which is aromatic. This group must be cyclic; however, it may contain heteroatoms or may not.

[00671 "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, -butoxy, sec-butoxy, and n-pentoxy.

[00681 "Substituted alkoxy" refers to the group -O-(substitutedalkyl) wherein substituted alkyl is defined herein. Preferred substituted alkyl groups in -O-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[00691 "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-. alkvnvl-C(O)-, substituted alkynyl-C(O)-, cvcloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" groupC 3 C()-.

[00701 "Acylamino" refers to the groups -NR 30 C(O)alkyl, -NR30 C(O)substituted alkyl, -NR 3 0C(O)cycloalkyl, -NR3 0C(O)substituted cycloalkyl, -N R3 °C(O)alkenyl, -NR3°C(O)substituted alkenyl, alkoxy, substituted alkoxy-NR30 C(O)alkynyl, -NR °C(O)substituted alkynyl, -NR 3°C(O)aryl, -NR"°C(O)substituted aryl, -NR 3°()heteroaryl, -NR°C(O)substituted heteroaryl, -NR3°C())heterocyciic, and -NR 3 (O)substituted heterocyclic wherein R3° is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00711 "Aminoacyl" refers to the groups H-C(N)-, alkyl-C(N)-, substituted alkyl-C(N)-, alkenyl-C(N)-, substituted akenyl-C(N)-, alkynyl-C(N)-, substituted alkynyl-C(N)-, cycloalkyl-C(N)-, substituted cycloalkyl-C(N)-, aryl-((N)-, substituted aryl-C(N) heteroarvi-C(N)-, substituted heteroaryl-C(N)-, heterocyclic-C(N)-, and substituted heterocyclic-C(N)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CH 3C(N)-.

[00721 "Acyloxy" refers to the groups alkyl-C(O))-, substitutedalky-C()O alkenyi-C(0)0-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(O)O-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[00731 "Amino" refers to the group -NH 2

.

[00741 "Substituted amino" refers to the group -NRiR 3 where RM and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R 'and R 2 are optionally*joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R3 and R are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aiyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R' is hydrogen and R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R and R are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R or R3 2 is hydrogen but not both. When referring to a disubstituted amino, it is meant that 1 neither R nor R are hydrogen. 4

[00751"Aminocarbonyl" refers to the group -C((O)NR R where R3 3 and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R3 3 and R3are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl. substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00761"Aminoacyl carbonyloxy" refers to the group-C(NR3)OR where R3 3 and R3are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0077 "Amninothiocarbonyl" refers to the group -C(S)NR R3 where R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00781 "Aminocarbonylamino" refers to the group---NR3C(O)NR 3 R3 4 where R30 is hydrogen or alkyl and R 3 and R34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl. substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00791 "Aminothiocarbonylamino" refers to the group -NR3°C(S)NR R34 where R 0is hydrogen or alkyl and R and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. 3

[00801 "Aminocarbonyloxy" refers to the group -O-C(O)NR3 R" where R and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R3 4 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00811 "Aminosulfonyl" refers to the group -SO 2 NR33 R where R3 and R3are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocvclic, and substituted heterocyclic and where R3 3 and R 4 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaiyl, heterocyclic and substituted heterocyclic are as defined herein.

R 4 where R

[00821 "Aminosulfonyloxy" refers to the group -O-SO2NRR and R are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00831 "Aninosulfonylarnino" refers to the group -NR -SO 2 NR R 3 4 where R is hydrogen or alkyl and R3 3 and R 34 are independently selected from the group consisting of hydrogen., alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 3 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted a]kynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00841 "Amidino" refers to the group -C(=NR )NR R3 4 where R , R l and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocvclic, and substituted heterocyclic and where R 3and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaiyl, heterocyclic and substituted heterocyclic are as defined herein.

[00851 "Substituted aryl" refers to aryl groups which are substituted with I to 5, preferably I to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbony, arninocarbonylamino, aminothiocarbonylamino. aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3-, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

100861 "Aryloxy" refers to the group -- aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[00871 "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.

[00881 "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[00891 "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.

100901 "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-.

[00911 "Carboxy" or "carboxyl" refers to -COO-I or salts thereof

[00921 "Carboxyl ester" or "carboxy ester" refers to the groups -C(O)O-alkyl, -C(O)0-substituted alkyl, -C(O)O-alkenyl, -C(0)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(0)0-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[00931 "(Carboxyl ester)amino" refers to the group -NR _-C(O)O-alkyl, -NR3 0-C(0)0-substituted alkyl, -NR 0 -C(0)0-alkenyl. -NR3 -C(O)O-substituted alkenyl, -NR 3°-C(0)0-alkynyl, -NR3°-C(0)0-substituted alkynyl, -NR3 °-C(0)0-aryl, -NR3-C(O)O-substituted aryl, -NR30 -C(0)0-cycloalkyl, -NR 3°-C(O)0-substituted cycloalkyl, -NR'3 0-C(0)0-heteroaryl, -NR°-C(0)0-substituted heteroaryl, -NR3°-C(0)0-heterocyclic, and -NR 3"-C(0)0-substituted heterocyclic wherein R3 °is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arvI, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[00941 "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, -0-C(O)O-substituted alkyl. -0-C(0)0-alkenl, -0-C(O)O-substituted alkenyl, -0-C(O)O-alkynyl, -0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(O)O-substituted aryl, -O-C(O)O-cvcloalkvl, -0-C(O)O-substituted cycloalkyl, -- C(O))0-heteroaryl, -O-C(O)0-substituted heteroaryl, -O-C(O)O-heterocyclic, and -)-C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyv, cycloalkyl. substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[00951 "Cyano" refers to the group -C-N.

[00961 "Cycloalkyl" refers to a saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Cx cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring. "Substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 or preferably I to 3 substituents selected from the group consisting of oxo, thione, alkyl. substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)arnino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S0 3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[00971"Cycloalkyloxy" refers to -O-cycloalkyl. 100981 "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl).

[00991 "Cycloalkylthio" refers to -S-cycloalkyl

[00100] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).

[001011 "Ethylene glycol" refers to the group ---O-CH 2CH 2-0-E, wherein E is either H or CH 3 .

[001021 "Guanidino" refers to the group-NHC(=NH)N 2 .

6 1001031 36 "Substituted guanidino" refers to -NR C(=NR 3 )N(R 3 ) where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R3 6 groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R is not hydrogen, and wherein said substituents are as defined herein.

[001041 "Halo" or'"halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.

[001051 "Hydroxy" or "hydroxyl" refers to the group -OT. 1001061 "Heteroaryl"refers to an aromatic group of from Ito 10 carbon atoms and I to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N---->O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[001071 "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from I to 5, preferably I to 3, ormore preferably I to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[001081 "Heteroaryloxy" refers to -0-heteroaryl. 1001091 "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[001101 "Heteroarylthio" refers to the group -S-heteroaryl.

[00111] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[00112] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having from I to 10 ring carbon atoms and from I to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. C, cycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, ayl or heteroaryl provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.

[001131 "Substituted heterocyclic" or "substituted heterocycloalkyl" or"substituted heterocyclyl" refers to heterocyclyl groups that are substituted with from I to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[00114] "Heterocyclyloxy" refers to the group -0-heterocycyl.

[001151 "Substituted heterocyclyloxy" refers to the group -O-(substitutedheterocycyl). 1001161 "Heterocyclylthio" refers to the group -S-heterocycyl.

[00117] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl).

[00118] Examples of heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothI zole, phenazine, isoxazole, phenoxazine, phenothI zine, imidazolidine, inidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,.7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thI morpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[00119] "Nitro" refers to the group -NO 2

.

[001201 "Oxo" refers to the atom (=0) or (-0). 0

[001211 "Phthalimido" refers to the group . Phthalimide functional groups are well known in the art and can be generated by covalently bonding a nitrogen atom to a

C 6 H4 (CO) 2 group.

[001221 "Poliethylene glycol" refers to the group -O-(CH 2 CH2 -0),E,wherein E is either H or CH 3, where n is between 2-20,000.

1001231 "Spirocyclic ring system" refers to a ring system with two rings that has a single ring carbon atom in common to both rings. Herein used the term bicyclic can incorporate up to four heteroatoms in either ring.

[00124] "Bicyclic ring system" refers to a ring system with two rings that has two ring carbon atoms in common, and which can located at any position along either ring. Herein used the term bicyclic ring system can incorporate up to four heteroatoms in either ring.

[00125] "Sulfinyl" refers to the divalent group -SO

[001261 "Sulfonyl" refers to the divalent group -S(O) 2-. 1001271 "Substituted sulfonvl" refers to the group -SO2-alkyl, -S0 2 -substituted alkyl, -S0 2 -OH, -S()2-alkenyl, -SO2 -substituted a]kenyl, -S02-cycloalkyl, -S0 2 -substituted

cylcoalkyl, -S0 2-arvl, -SO2p-substituted aryl, -S0 2-heteroaryl, -SO2p-substituted heteroaryl, -S0 2-heterocyclic, -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SO 2 -, phenyl-S) 2-, and 4-methylphenyi-SO2-. Preferred substituted alkyl groups on the substituted alkl-S-), include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[001281 "Substituted sulfinyl" refers to the group -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cylcoalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[001291 "Sulfonyloxy" or"substituted suifonyloxy" refers to the group -OS0 2-alkyl,

-OS02-substituted alkyl, -0SO2-OH, -OSO2 -alkenyl, -OSO 2-substituted alkenyl, -OSO 2-cycloalkyl, -OSO2 -substituted cylcoalkyl, -OSO 2-aryl, -OS0 2-substituted aryl, -OS0 2 -heteroaryl, -OS0 2-substituted heteroaryl, -OS0 2-heterocyclic, -OSO2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynvl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[001301 "Substitution" or "substitution" generally refers groups which are covalently bonded to an atom to replace a hydrogen atom. The atom in this general context can be a carbon atom or a heteroatom, for example a nitrogen atom.

[001311 "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkvnvl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroarl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[00132] "Mercapto" or "thiol" refers to the group -SH.

[001331 "Formyl" refers to the group -C(O)H.

[001341 "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[001351 "Thione" refers to the atom (=S).

[001361 "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.

[001371 "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[00138] Stereoisomers of compounds (also known as optical isomers) include all chiral,. diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and d or I enriched stereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[001391 The compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[001401 "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[001411 Herein any substituted functional group is substituted at from one to three different positions, and those one to three substituting groups are capable of each independently being substituted at one to three positions, wherein any and each substituting group is independently selected from the group consisting of: halogen, hydroxyl, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1-Cs alkenyl, substituted C1 -Cs alkenyl, C1-Cs alkynyl, substituted C1 -Cs alkynyl, acyl, acylamino, aminocarbonylamino, aminoacyl, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminoacyl carbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, C 3 -C 7 aryl, substituted C-C 7 aryl, CC7 aryloxy, substituted C3 -C aryloxy, C3 -C arylthio, substituted C 3 -C 7

arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, C3 -Ci cycloalkyl, substituted C3 -CO cycloalkyl, C-C7 heterocycloalkyl, guanidino, substituted guanidino, C3 -C heteroaryloxy, C3 -C7 substituted heteroaryloxy, CC 7 heteroarlthio, CC7 substituted heteroarylthio, sulfonyl, substituted sulfonyl, sulfinyl, substituted sulfinyl, sulfonyloxy, substituted sulfonyloxy, thioacyl, alkylthio, substituted alkylthio, C3 -C 7 heteroaryl, and substituted C1C heteroaryl.

[00142] Herein any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of: 0, N, and S.

[00143] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that each functional group is substituted (at from one to three positions) and that any and all of those substituent groups may be substituted one more time (at from one to three positions).

[001441 It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

[001451 Throughout this application, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology.

[001461 Compound numbering used herein is merely for convenience and meant for the specific section, scheme, or table in which they appear. They should not be construed or confused with the same numberings, if any, used in other sections, schemes, or tables.

Compoundsof the resent technolov

[001471 The present technology is directed to compounds, compositions, and methods of using said compounds or compositions to inhibit CAPNI, CAPN2, and/or CAPN9. Also provided are methods useful in order treating diseases or disorders which are affected at least in part byCAPNI, CAPN2, and/or CAPN9.

[001481 In one aspect, the present technology provides for one or more compounds of a core structure of a mono- or di- amino acid or tri-amino acid wherein the compounds may be substituted by one or more organic functional groups at the C-teminus, N-terminus, and/or the side-chain.

[001491 In some embodiments, the invention is a compound comprising Formula I:

2 '"R3 -R2 O L4 ' I AR N NNN N N' 2 R2 R2 2 I1

Formula 1

where:

n is from 1-11;

each Rand R* is independently selected from the group consisting of: hydrogen,C 1 -Cs alkyl, substituted C1 -Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -C8 alkynyl, substituted CI-Cs alkynyl, C 3 -C aryl, substitutedC 3-C7 aryl, cyano,C -C 3 10 cycloalkyl, substituted( 3 -C 1 0 cycloalkyl, C 3-C9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C 3 C 9 heteroaryl, substituted C 3-C 9 heteroaryl, C 1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, 2 2 substituted amino, alkylthio, substituted alkvlthio, OH, OR , NH 2 ,NHR SR ,substituted sulfonyl, and substituted sulfinyl, wherein any R1 substituent may be covalently bonded to or share another R! substituent to form a C 3-C cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; eachR 2 is independently selected from the group consisting of: hydrogen, C-C8 alkyl, substituted C 1-Cs alkyl, C1-Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted Ci-Cs alkynyl, C 3-C- aryl, substituted C 3-C` aryl, cyano, 01-C1 -Cs alkoxy, substituted Ci-Cs alkoxy, amino, substituted amino, C 3-C 10 cycloalkyl, substituted C3 -C 0 cycloalkyl, C 3-C9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C3 -C9 heteroaryl, substituted C3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently 22 selected from the group consisting of: Cl-z,, C(R )2, CH-R% , NH, NR2, C(=O), C(=S), S, S(=O), S(=0)2, -C-, -CH-, a C 3 -C1 2 spirocyclic group of R2 (R 2 )

Xl where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl,

wherein any two adjacent W atoms may form CR 1=CR 1 or C--C;

L4 is selected from the group consisting of: R2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form aC 3 -C1 cycloalkyl ring structure, a ('3-C12 fused cycloalkyl ring structure, a C 3-C 1 2 aryl ring structure, aC 3 -C 12 fused aryl ring structure, a C 3 -C heteroaryl ring structure, a C3 -C1 2 fused heteroaryl ring structure, a C 3-C heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure; and wherein W, does not form an (S)- CH 2 CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[00150] In some embodiments, the invention is a compound comprising Formula111:

R2 R2 R30 N 2 0 R2 R2 0 N R2

Formula III

where:

Z' is selected from the group consisting of: CH2, C(R')2, CHRI , NH, NRI, C(=O), R2-_(R2)m

C(=S), S, S(=O), and S(=0)2, a C3 -C 2 spirocyclic group of where m is 1-19;

each Rand R 3 is independently selected from the group consisting of: hydrogen,C-Cs alkyl. substituted C-Cs alkyl, C-Cs alkenyl. substituted C-Cs alkenyl, C-Cs alkynyl, substituted C-Cs alkynyl, C-C7 aryl, substituted CC 7 aryl, cyano, C3 -Co cycloalkyl, substituted C3 -C 1 0 cycloalkyl, C3 C 9 heterocycloalkyl, substituted C-C9 heterocycloalkyl, C3 C 9 heteroaryl, substituted C3 C 9 heteroaryl, C-Cs alkoxy, substituted C-CS alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 NHR2 , SR 2 , substituted sulfonyl, and substituted sulfinyl, wherein any RI substituent may be covalently bonded to or share another R! substituent to form a CC 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted C-Cs alkyl, C-Cs alkenyl, substituted C-Cs alkenyl, C-Cs alkynyl, substituted C-Cg alkynyl, C 3 -C7 aryl, substituted C 3 C 7aryl, cyano, OH, C-Cs alkoxy, substituted Cr-C alkoxy, amino, substituted amino,C 3 -C cycloalkyl, substitutedCrCicycloalkyl, C3 -C 9 heterocycloalkyl, substituted C 3-C9 heterocycloalkyl, C-Cqheteroaryl, substituted C3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C]2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L4 is selected from the group consisting of: R, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sufinyl, thioacyl, aminoacyl, phthalimido, and formyl;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

1001511 In some embodiments, the invention is a compound comprising Formula IV:

R3 2 0 N 0 -R2 L4 0 NN! Z 1-Z 2 2 R2zz 2 R1 R2 N'

Formula IV

where:

Z Iand Z 2 are each independently selected from the group consisting of: CH2,C(R )2 ,

CHR,,NH, NR, C(=0),C(=S),S,S(=0),S(=0) 2, -C-,-CH-, a C 3 -C spirocVclic group of R2 -(R )m

where m is 1-19, wherein any two adjacent Z atoms may form CR:=CR or CEC;

each Rand R3 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1 -Cs alkenyl, C 1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3-C 7 aryl, substituted C 3-C7 aryl, cyano, C3-C 10 cycloalkyl, substituted C3-C1 0 cycloalkyl, C3 -C9 heterocycloalkyl, substituted C3-C 9 heterocycloalkyl, C3 C9 heteroaryl, substituted C 3-C 9 heteroaryl, C 1 -Calkoxy, substituted C1 -Cs alkoxy, amino, 2 2 substituted amnino, alkylthio, substituted alkylthio, 01-, OR , NH2, NHR SR ,substituted sulfonyl, and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R substituent to form a C 3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2isindependently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C1-Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -C alkoxy, amino, substituted amino, C3-C1 0 cycloalkyl, substituted C 3-C1 0 cycloalkvl, C3-C9 heterocycloalkyl, substituted C-C 9 heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3-C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any two or more Z groups can be bonded together to form a C 3 -C 2 cycloalkyl ring structure, a C3 -C 12 fused cycloalkyl ring structure, a C 3-C aryl ring structure, aC 3 -Cu fused aryl ring structure, a C 3 -C, heteroaryl ring structure, a C3-C fused heteroaryl ring structure, a C3-C 1 2 heterocyclic ring structure, and aC 3-C1 2 fused heterocyclic ring structure;

or a tautomer and/or a pharmaceutically acceptable salt thereof

1001521 In some embodiments, the invention is a compound comprising Formula V:

R2 R O0 R3 \L...J// R2 N O"- - -I,1 R1 O N L4 z3 R N z1-z 2 p2 R2

Formula V where:

Z , Z2, and Z3 are each independently selected from the group consisting of: C- 2

, C(R 2)2, CHR2, 0, NH, NR 2 , C(=), C(=S), S, S(=), S(=0)2, -C-, -CH-, a C 3-C2 spirocyclic R2 -(R2)m

group of where m is 1-19, wherein any two adjacent Z atoms may form CR=CR' or C-C;

each Rand R. is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C 1-Cs alkyl. C 1-Cs alkenyl, substituted Ci-Cs alkenyl, C1-Cs alkynyl, substituted C1-Cs alkynyl, C 3 -C7 aryl, substituted C3 -C7 aryl, cyano, C 3 -C10 cycloalkyl, substituted C 3 -C 1 0 cycloalkyl, C 3-C heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C3 C heteroaryl, substituted C 3-C heteroaryl, C 1-Cs alkoxy, substituted C1 -C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH, NHIR2 , SR2, substituted sulfonyl, and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R' substituent to form a C 3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1-Cs alkyl, C1-Cs alkenyl, substituted C1-Cs alkenyl, C1-Cs alkynyl, substituted C 1-C 8 alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -C8 alkoxy, amino, substituted amino, C3-C1 0 cycloalkyl, substituted C 3-C1 0 cycloalkvl, C3-C heterocycloalkyl, substituted C-C heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3-C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L4 is selected from the group consisting of: R 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any and all Z groups do not form an (S) -CH 2 CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amidefunctional group; and wherein any two or more Z groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C 3-C 1 2 fused cycloalkyl ringstructure, a C3-C1 2 arylringstructure, a C 3 -C 1 2 fused aryl ring structure, a C 3 -Cl heteroaryl ring structure, a C3 -C 12 fused heteroaryl ring structure, a C 3-C 2 heterocyclic ring structure, and a C 3 -C12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof

[001531 In some embodiments, the invention is a compound comprising Formula VI:

R2R R2 0 R1 R3 r R2 R "N z4 RR

R2 R2

Formula VI

where:

Z , Z 2 , Z 3 , and Z4 are each independently selected from the group consisting of: CH2

, C(R 2) 2 , CHR, 0, NHNR 2 , C(=0), C(=S), S, S(=0), S(=0) 2, -C-, -CH-, a C3-C 2 spirocyclic R2 -(R 2)m

group of where m is 1-19, wherein any two adjacent Z atoms may form CR=CR or ( C;

each Rand R 3 is independently selected from the group consisting of: hydrogen,C 1 -Cs alkyl, substituted C1 -Cs alkyl, C-Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C1 -Cs alkynyl, C3-C 7 aryl, substituted C3 -C7 aryl, cyano, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C 3 -C9 heterocycloalkyl, substituted C3 -C heterocycloalkyl, C3 C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, C1 -Cs alkoxy, substituted C1 -CS alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, )H, OR2 , NH2 , NHR 2 , SR, substituted sulfonyl, and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R substituent to form a C 3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2isindependently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1-Cs alkenyl, C1 -Cs alkynyl, substituted C1-Cs alkynyl, C 3-C, aryl, substituted C 3 -C- aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C3-C 10 cycloalkyl, substituted C 3-C 1 0 cycloalkyl, C-CQ heterocycloalkyl, substituted C 3-C heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S) - 2 C1 2 C(O)NH group in the ring starting from the carbon attached toR which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C 3 -C 2 cycloalkyl ring structure, a C3 -C 12 fused cycloalkyl ring structure, a C 3-C aryl ring structure, aC 3 -Cu fused aryl ring structure, a C 3 -C, heteroaryl ring structure, a C3-C fused heteroaryl ring structure, a C 3 -C 12 heterocyclic ring structure, and aC 3-C 1 2 fused heterocyclic ring structure;

or a tautomer and/or a pharmaceutically acceptable salt thereof

100154] In some embodiments, the invention is a compound comprising Formula VII:

O R2 0

R2 _R 1 R1 R3 R 00 Oz N R272' R2

Formula VII

where:

ZZ 2 ,Z 3 ,Z 4 , and Zare each independently selected fromthe group consistingof CH4 2 , C(R) 2 . CHR, O2, NI NR', C(O), C(=S), S, S(:0), S(0)2 -C-, -CH-, a C3-C12 R2-(R2)m-.

spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CR 1=CR or C--C;

each Rand R 3 is independently selected from the group consisting of: hydrogen, C 1-C 8 alkyl, substituted C1 -Cs alkyl, C 1 -Calkenyl, substituted C 1 -Calkenvi,C 1-Cs alkynyl, substituted C1 -Cs alkynyl, C-C7 aryl, substituted C 3 -C7 aryl, cyano, C 3 -C1 0 cycloalkyl, substituted C 3-C 10 cycloalkyl, C 3-C 9heterocycloalkyl, substituted C 3 -C 9 heterocycloalkyl, C 3 C 9 heteroaryl, substituted C 3-C 9 heteroaryl, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2, NHR2 , SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R substituent to form a C 3 -C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R is independently selected from the group consisting of: hydrogen,C-Cs alkyl, substituted C1 -Cs alkyl, C-Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3-C- aryl, substituted C 3-C, aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C 3-C 1 0 cycloalkyl, substituted C 3-C1 0 cycloalkyl, C 3-C heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C 3-C heteroaiyl, substituted C3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3-C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S)H' group in the ring starting from the carbon attached to R 2 which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C 3-C1 2

cycloalkyl ring structure, a C 3-C2 fused cycloalkyl ring structure, a C 3 -C12 aryl ring structure, a C 3-C 12 fused aryl ring structure, a C 3 -C 1 2 heteroaryl ring structure, a C 3-C1 2 fused heteroaryl ring structure, a C 3 -C 1 2 heterocyclic ring structure, and a C 3-C1 2 fused heterocyclic ring structure;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

[00155] In some embodiments, the invention is a compound comprising Formula VIII:

0 R2R R2 R2 0 R2 Z6

o z2z R2

Formula VIII

where: I ' 4 Z 5 , and Z 6 are each independently selected from the group consisting of: 5 Z , ZZZ, CH2, C(R 2 ), CHR 2, 0, NH, NR 2, C(=O), C(=S), S,S(=0),S(=) 2 ,-C-, -CH-, a C3-C12

R2 -(R 2 )m_

spirocyclic group of where in is 1-19, wherein any two adjacent Z atoms may form CR'=CR' or CC;

each Rand R 3 is independently selected from the group consisting of: hydrogen, C1 -Cs alkvl, substituted C 1-Cs alkyl, C1-Cs alkenyl, substituted C1 -Cs alkenyl, C1-C alkynyl, substituted C1-Cs alkvnyl, C 3-C7 aryl, substituted C 3-C7 aryl, cyano, C 3 -C 0 cycloalkyl, substituted C 3 -C10 cycloalkyl, C 3 -C 9 heterocvcloalkyi, substituted C3-C heterocycloalkyl, C 3 C 9 heteroaryl, substituted C 3 -C9 heteroarvl, C1-Cs alkoxy, substituted C1-Cs alkoxy, amino, substituted amino, alkylthio, substituted alkythio, OH, OR', NH 2, NHR2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form a C3-C cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R is independently selected from the group consisting of: hydrogen, C-C alkyl, substituted C1-Cs alkyl, C1-Cs alkenyl, substituted C1-Cs alkenyl, C1-Cs alkynyl, substituted C1-Cs alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, OH, C1-Cs alkoxy substituted C1 -Cs alkoxy, amino, substituted amino, C 3 -C 0 cycloalkyl, substituted C 3-C 0 cycloalkyl, C 3 -C 9 heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C 3-C 9 heteroaryl, substituted C 3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S)-- CH 2CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C3-Cu cycloalkyl ring structure, a C 3 -C 2 fused cycloalkyl ring structure, a C3 -C1 aryl ring structure, a C3-C f used aryl ring structure, a C3-C12 heteroaryl ring structure, a C 3-C fused heteroaryl ring structure, aC 3 -Cu heterocyclic ring structure, and a C-C, 3 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof

[00156] In some embodiments, the invention is a compound comprising Formula IX:

R 1 R1 \N-R1 0

20 0 R22 z7 R2 \Z6

R 3 -N

L_4 - z71-z-2 - z 1 R2 R2

Formula IX

where:

Z1, 2, 3, 4, Z , 6, and Z7 are each independently selected from the group consisting of:QCH 2 ,C(R ,CHR, 0, NH, NR, C(=O), C(:=S), S, S(=O), S(=O)2, -C-, -CH-, aC3-C 2 R2- (R2 )mT

spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CRI=CR' or C--C;

each Rand R 3 is independently selected from the group consisting of: hydrogen, C 1-C8 alkyl, substituted C1 -Cs alkyl, C1 -Cs alkenyl, substituted C1 -C alkenyl, C-Cs alkynyl substituted C 1 -Cs alkynyl, C3-C- aryl, substitutedC 3-C7 aryl, cyano, C 3 -C10 cycloalkyl, substituted C 3-C 10 cycloalkyl,C 3-C 9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C3 C 9 heteroaryl, substituted C 3-C 9 heteroaryl, C 1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2. NHR2 , S2, substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R substituent to form a C 3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2isindependently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1-Cs alkenyl, C1 -Cs alkynyl, substituted C1-Cs alkynyl, C 3-C, aryl, substituted C 3 -C- aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C3-C 10 cycloalkyl, substituted C 3-C 1 0 cycloalkyl, C-CQ heterocycloalkyl, substituted C 3-C heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

or a tautomer and/or a pharmaceutically acceptable salt thereof

[00157] In some embodiments, the invention is a compound comprising Formula X:

0 R2 8 Z Z

R2 NzR2Z-Z R2 /N z2- zi

RL , z2 R2

Formula X

where: 1 2 3 44 5 6 6 7 z,z, 3 ,z ,Z Z , , Z, and Z are each independently selected from the group consisting of: C.H2, C(R 2 )2 , CHR 2, 0, NH, NR 2, C(=),C(=S),S(=0),S(=0)2,-C-, -CH-, a R2 (R 2)m

C 3-C 12 spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CR 1 =CR' or C C

each Rand R3 is independently selected from the group consisting of: hydrogen, C1 -C alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1 -Cs alkenyl, C 1 -Cs alkynyl, substituted C 1-Cs alkynyl,C 3-C 7 aryl, substitutedC 3-C7aryl, cyano, C3-C 10 cycloalkyl, substituted C3-C1 0 cycloalkyl, C3 -C9 heterocycloalkyl, substitutedC 3 -C 9 heterocycloalkyl, C3 C9 heteroaryl, substituted C 3-C9 heteroaryl, C 1 -Calkoxy, substituted C1 -Cs alkoxy, amino, 2 2 substituted amino, alkylthio, substituted alkylthio, -1, OR , NH2,NHR , SR , substituted sulfonyl. and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R substituent to form aC 3 -C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

eachR 2 is independently selected from the group consisting of: hydrogen, C1 -Calkyl, substituted C 1 -Calkyl, C1-Calkenyl, substituted C1 -Cs alkenyl, C 1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3 -C 7 aryl, substituted C 3 -C7 aryl, cyano, O-1, Ci-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C 3-C10 cycloalkyl, substituted C3 -C 0 cycloalkyl, C 3-C9 heterocycloalkyl, substituted C 3-C9 heterocycloalkyl, C 3-C9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3 -C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S) -2 H7C2C - (0 NHF-1. group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C 3-C1 2

cycloalkyl ring structure, a C 3 -C12 fused cycloalkyl ring structure, a C 3-C1 2 aryl ring structure, a C 3 -C 12 fused aryl ring structure, a C3-C 1 2 heteroaryl ring structure, a C 3-C1 2 fused heteroaryl ring structure, a C 3 -C 1 2 heterocyclic ring structure, and a C 3 -C 12 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[001581 In some embodiments, the invention is a compound comprising Formula X:

R1 0 'N-R1

R2 0 R2 FR2 N Xz9

& R3 Nz' L4 R2 4 Z Z 5 Z6 N- Zl' "Z3' "Z '

R2 R2

Formula XI

where:

Z , Z2,Z, Z4, Z, Z, Z7, Z 8and Z9 are each independently selected from the group consisting of: CH 2, C(R ) 2, CHR 2, 0, NH, NR2, C(=0), C(=S). S, S(=0), S(=0)2, -C-, -C--, a

R 2- R2)m

C3-C.I2spirocyclicgroupof ' where is 1-19,wherein any twoadjacentZatoms may form CR:=CR 1 or CEC;

each Rand R 3 is independently selected from the group consisting of: hydrogen, C1 -Cs alkvl, substituted C 1-Cs alkyl, C-Cs alkenyl, substituted C1-Cs alkenyl, C-Cs alkynyl, substituted C1 -Cs alkvnyl, C 3-C7 aryl, substituted C 3-C7 aryl, cyano, C 3-C1 0 cycloalkyl, substituted C 3-C 10 cycloalkyl, C 3-C 9 heterocvcloalkyi, substituted C3-C heterocycloalkyl, C3 C 9 heteroaryl, substituted C 3-C 9 heteroarvl, C 1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkythio, OH, OR', NH 2, NHR2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form a C3-C cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R 2 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1-Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3-C 7 aryl, substituted C 3-C 7 aryl, cyano, OH, C1 -Cs alkoxy substituted C1 -Cs alkoxy, amino, substituted amino, C 3-C1 ycloalkyl, substituted C 3-C10 cycloalkyl, C3-C 9 heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C 3-C 9 heteroaryl, substituted C 3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3-C 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S)-+CH 2 CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C3-Cu cycloalkyl ring structure, a C 3-C 1 2 fused cycloalkyl ring structure, a C3 -C1 2 aryl ring structure, a CC1 2 fused aryl ring structure, a C3-C 12 heteroaryl ring structure, a C 3-C1 2 fused heteroaryl ring structure, aC3 -C12 heterocyclic ring structure, and a C-C 3 1 2 fused heterocyclic ring structure; or a tautomer and/or a pharinaceutically acceptable salt thereof.

[00159] In some embodiments, the invention is a compound comprising Formula Xi:

0 N-R R2 R2 z '~N zi 0 'z 8 ' 'z 6 R2 z O R2 z4' 3 R3 -

L 4 _N 2 2 F

Formula XII

where:

ZI, Z2, Z3, Z4, Z , Z6, Z7, Z, 8Z9 and Z1" are each independently selected from the group consistingof: C12, C(R 2, CHR 2 , 0, NH, NR2, C(=O), C(=S). S, S(O), S(=O)2, -C-, -CI-, a R2-(R 2)m

C 3-C 1 2 spirocyclic group of where i is 1-19, wherein any two adjacent Z atoms may form CR =CR or C-C;

each Rand R 3 is independently selected from the group consisting of: hydrogen, C 1-C8 alkyl, substituted C1 -Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cs alkenvl, C-Cs alkynyl. substituted C1 -Cs alkynyl, C3-C- aryl, substituted C 3-C aryl, cyano, C 3-C10 cycloalkyl, substituted C 3-C 1 0 cycloalkyl, C 3 -C 9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C 3 C 9 heteroaryl, substituted C 3-C 9 heteroaryl, C 1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2. NHR2 , SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or

5o share another R substituent to form a C 3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2isindependently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1-Cs alkenyl, substituted C1-Cs alkenyl, C1 -Cs alkynyl, substituted C1-Cs alkynyl, C 3-C, aryl, substituted C 3 -C- aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C3-C 10 cycloalkyl, substituted C 3-C 1 0 cycloalkyl, C-CQ heterocycloalkyl, substituted C 3-C heterocycloalkyl, C 3 -C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any two or more Z groups can be bonded together to form a C 3 -C 2 cycloalkyl ring structure, a C3 -C 12 fused cycloalkyl ring structure, a C 3-C1 2 aryl ring structure, aC 3 -C 12 fused aryl ring structure, a C 3 -C, heteroaryl ring structure, a C3-C1 2 fused heteroaryl ring structure, a C 3 -C 1 2 heterocyclic ring structure, and aC 3 -C 1 2 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof

1001601 In some embodiments, the invention is a compound comprising Formula XII:

Ri R

02 0 2 11 N'Z 2R `N zz 2 R 0zi

0 zz6 R3-N L4 N 2z z4 R4

Formula XIII

where:

ZZ 2 ,Z 3 ,Z 4 ,Z 5 ,Z 6 ,ZZZ9 , Z anid Z" are each independently selected from the group consisting of: CH 2,C(R2)2, CHR2, O, NH,NR2, C(=O), C(=S), S, S(=0), S(=0) 2 , -C-, R2- R2)m

CH-, aC 3 -Cu spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CR1 =CR or C.C;

each Rand R 3 is independently selected from the group consisting of: hydrogen,C 1 -Cs alkyl, substituted C1 -Cs alkyl, C-Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C1 -Cs alkynyl, C3 -C, aryl, substituted C 3 -C7aryl, cyano,C 3 -C 10 cycloalkyl, substitutedC 3-C 1 0 cycloalkyl.C 3-C9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl,C 3 C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, C1 -Cs alkoxy, substituted C1 -CS alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2 , N-IR 2, SR2, substituted sulfonyl, and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R substituent to fon a C-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C1-Csalkvnyl, C 3 -C7 arvl, substituted C 3 -C 7 aryl, cyano, OH, C1 -Cg alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino,C 3-C1 0 cycloalkyl, substitutedC 3 -C 1 0 cycloalkyl, C 3-C9 heterocycloalkyl, substituted C 3-C9 heterocycloalkyl, C-Cqheteroaryl, substituted C3-C heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

and wherein any and all Z groups do not form an (S) group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and wherein any two or more Z groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C 3-C 1 2 fused cycloalkyl ring structure, a C 3-C 1 2 aryl ring structure, a C 3 -C 1 2 fused aryl ring structure, a C3-C 1 2 heteroaryl ring structure, a C 3 -C 12 fused heteroaryl ring structure, aC 3 -C 1 2 heterocyclic ring structure, and aC 3 -C1 2 fused heterocyclic ring structure; or a tautomer and/or a pharmnaceuticaly acceptable salt thereof.

[001611 In some embodiments, the invention is a compound comprising Formula XIV:

R1 R1 ,N' 0 1 R2

2 R

R3_N 0 L4 NP 1Zj' 'Noz 1 z 2R2 \ Rz2-za~ ,

Formula XIV

where: z, zz, 3z, 4z, Z ,ZZZZ Z" and Z 1 are each independently selected from the group consisting of: CH2. C(R 2)2,CHR ONH,NR 2 ,(=0),C(=S),S,S(=0),S(=0) 2 ,-C-, R 2 - R2)m

CH-, a C 3 -C 1 2 spirocycic group of where m is 1-19, wherein any two adjacent Z atoms may form CR'=CR' or C--C;

each RIand R' is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1-C. alkenyi, substituted C 1 -C 8 alkenyl, C1 -Cs alkynyl, substituted C 1 -Cs alkynyl, C 3-C7 aryl, substituted C 3 -C7 ayl, cyano, C 3-C 10 cycloalkyl, substituted C 3 -C 1 0 cycloalkyl, C 3 -C 9 heterocycloalkyl, substituted C3 -Ce heterocycloalkyl, C3 C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, C 1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2, NIH 2 , NR2, SR 2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form a C 3-C cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C 1 -Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3-C, aryl, substituted C 3-C- aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C 3-C1 0 cycloalkyl, substituted C 3 -C0 cycloalkyl, C3-C

heterocycloalkyl, substituted C3 -C 9 heterocycloalkyl, C 3-C 9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R 2 substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any and all Z groups do not form an (S) +CH 2 CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group; and wherein any two or more Z groups can be bonded together to form a 3-C12 cycloalkyl ring structure, a(C3-C12 fused cycloalkyl ring structure, a C 3-C 12 aryl ring structure, aC 3-C 12 fused aryl ring structure, aC 3-C1 2 heteroaryl ring structure, aC3 -C 12 fused heteroaryl ring structure, aC 3-C1 2 heterocyclic ring structure, and aC3-C1 2 fused heterocyclic ring structure; or a tautomer and/or a pharmaceutically acceptable salt thereof

[001621 In some embodiments, the invention is a compound comprising Formula XV:

R2 R3 A R2 A L4 R%'t N R2-Z-R1

R2 A R2 R R2 A 1

Formula XV

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

each Rand R 3 is independently selected from the group consisting of: hydrogen,C 1 -Cs alkyl, substituted C1 -Cs alkyl, C1 -Cs alkenyl. substituted C1 -Cs alkenyl, C1 -Cs alkynIyl substituted CI-Cs alkynyl, C3-C- aryl, substitutedC 3-C7 aryl, cyano, C 3-C1 0 cycloalkyl, substitutedC 3-C 10 cycloalkyl,C 3-C 9 heterocycloalkyl, substituted C3 -C9 heterocycloalkyl, C 3 C 9 heteroaryl, substitutedC 3-C 9 heteroaryl, C 1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 NHR 2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any RI substituent may be covalently bonded to or share another R! substituent to form a C3 -C 12 cyclic, heterocvclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system:

each R2 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C1-Cs alkenyl, substituted C1 -Cs alkenyl, C-Cs alkynyl, substituted C 1-Cg alkynyl, C 3 -C 7 aryl, substitutedC 3-C 7aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cg alkoxy, amino, substituted amino,C 3-C1 0 cycloalkyl, substituted(C 3-C 10 cycloalkyl, C 3 -C9 heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C3-Cq heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any RI2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

2 ), each W is independently selected from the group consisting of: CH, C(R CHR2 ,0, NH, NR 2, C(=O), C(=S), S, S(=O), S(=O) 2, -C-, -CH-, a C 3 -C 12 spirocyclic group of R2 - (R 2)m

where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl,

wherein any two adjacent W atoms may form CR'CR' or CEC;

Z is selected from the group consisting of: C1 -Cs alkyl, substituted C1 -Cs alkyl, C1 -CS alkenyl, substituted C 1-Cs alkenyl, C1 -Cs alkynyl, substituted C1 -Cs alkynyl, C1 -CS alkoxy, substituted C1 -Cs alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R2 ) 2

, CHR 2 , 0, N-, NR2 , S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;

L! is selected from thegroup consisting of: R acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a cycloalkyl ring structure, a C3 -C 12 fused cycloalkyl ring structure, a C 3 -C12 aryl ring structure, a C 3-C 1 2 fused aryl ring structure, a C 3 -C 1 2 heteroaryl ring structure, a C 3 -C12 fused heteroaryl ring structure, a C 3 -C 1 2 heterocyclic ring structure, and a C 3-C12 fused heterocyclic ring structure;

and wherein W1 does not form an (S) - - CH 2 CH DONH-group in the ring starting

from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

[00163] In some embodiments, the invention is a compound comprising Formula XVI:

'56

W11 R2 R3 0 R2 0 R2ZR N'N N N' 2 R2 R2 2 1

Formula XVI

where:

n is from 1-12;

each Rand R3 is independently selected from the group consisting of: hydrogen, C1 -C alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1 -Cs alkenyl, C 1 -Cs alkynyl, substituted C 1-Cs alkynyl, C 3-C 7 aryl, substituted C 3-C7 aryl, cyano, C3-C 10 cycloalkyl, substituted C3-C1 0 cycloalkyl, C3 -C9 heterocycloalkyl, substituted C3-C 9 heterocycloalkyl, C3 C9 heteroaryl, substituted C 3-C 9 beteroaryl, C 1 -Calkoxy, substituted C1 -Cs alkoxy, amino, 2 2 substituted amino, alkylthio, substituted alkylthio, OH, OR , N2,NHR SR ,substituted sulfonyl, and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R! substituent to form a C 3 -C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

eachR 2 is independently selected from the group consisting of: hydrogen, C1 -Calkyl, substituted C 1 -Calkyl, C1-Calkenyl, substituted C1 -Cs alkenyI, C 1-Cs alkynyl, substituted C 1-Cs alkynyl, C 3 -C 7 aryl, substituted C 3 -C 7 aryl, cyano, 01-, Ci-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C 3-C10 cycloalkyl, substituted C3 -C0 cycloalkyl, C 3-C9 heterocycloalkyl, substituted C 3-C9 heterocycloalkyl, C 3-C9 heteroaryl, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C 3 -C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently 22 selected from the group consisting Of: CH2, CR u, )2, CHRi NH, NR 2, C(=0::), C(=::S), S, S(=0::), S(=0)2, -C-, -CH-, a C3-C 12 spirocyclic group Of

R2 - -R 2 )M

where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may forn CR'=CR' or C C

Z is selected from the group consisting of: C1 -Cs alkyl, substituted C1 -CS alkyl, C-C alkenyl, substituted C 1 -Cs alkenyl, C1 -Cs alkynyl, substituted C 1-Cs alkynyl, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl,C(R )2

, CIRI, , NH, NR2 , S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;

and wherein any two or more W groups can be bonded together to form a CrC12 cycloalkyl ring structure, a C3 -C 12 fused cycloalkyl ring structure, a C-C 12 aryl ring structure, a C3 -C2 fused aryl ring structure, a C 3 -C2 heteroaryl ring structure, a C-C 12 fused heteroaryl

ring structure, a CC 1 2 heterocyclic ring structure, and a C-C 12 fused heterocyclic ring structure;

and wherein W, does not form an (S) 2 CH 2 CO)NH-group in the ring starting '-CH from the carbon attached to R2 which is adjacent to the keto-amide functional group;

or a tautomer and/or a pharmaceutically acceptable salt thereof

[001641 In some embodiments, the invention is a compound comprising Formula XVII:

L3 R2 A R _,N 2 R4

Formula XVII

where:

each A is independently selected from the group consisting of: 0 and S;

A

NR1 each R4 is independently selected from the group consisting of: H and

each Rand R* is independently selected from the group consisting of: hydrogen,C 1 -Cs alkyl, substituted C 1 -Cs alkyl. C1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -C8 alkynyl, substituted C 1-Cs alkynyl, C-C 7 aryl, substituted C-C7 aryl, cyano, C3 -Cio ccloalkyl, substituted C3 -Cio cycloalkyl, C3 -C heterocycloalkyl, substituted C3 -C heterocycloalkyl, C3 C heteroaryl, substituted C3 -C heteroaryl, C 1-Cs alkoxy, substituted C1 -C 8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2, NHR 2 , SR2, substituted sulfonyl, and substituted sulfinyl, wherein any RI substituent may be covalently bonded to or share another R' substituent to form a CC1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Cs alkenyl, substituted C1 -Cs alkenyl, C1 -CS alkynyl, substituted C 1-Cs alkynyl, C3 -C aryl, substituted C3 -C aryl, cyano, OH, C1 -Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C-C 10 cycloalkyl, substituted C3 -C 10 cycloalkyl, CCQ heterocycloalkyl, substituted C 3 -C heterocycloalkyl, C3 -C 9 heteroary, substituted C3 -C 9

heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R substituent may be covalently bonded to or share another R substituent to form a C3 -CI cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L is a group containing 1-8 atoms and is selected from the group consisting of: C1 -CS alkyl, substituted C1 -Cs alkyl, C1 -Cs alkenyl, substituted C1 -Cg alkenyl, C1 -CS alkynyl, substituted C1 -Cs alkynyl, C-Csalkoxy, substituted C-C alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R )2, CHR 2, 0, N, NR2 , S, substituted sulfonyl, sulfinyl, and substituted sulfinyl;

Z is selected from the group consisting of: C1 -Cs alkyl, substituted C1 -Cs alkyl, C1 -C alkenyl, substituted C 1 -Cs alkenyl, C1 -C alkynyl, substituted C 1-Cs alkynyl, C-Cs alkoxy, substituted C1 -Cs alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl,C(R )2 ,

CH ,, N-, NR 2, S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;

L4 is selected from the group consisting of: R', acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO- polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

wherein each L 3 and Z are capable of being covalently bonded to the same or other R2 functional groups such that a bicyclic or spirocyclic ring system is formed; - CH2CH2C(0)NH-, and wherein L 3 and Z do not form an (S) - group in the ring starting from the carbon atom closest to the keto-amide or thio-keto-amide functional group;

or a tautomer and/or a pharmaceutical acceptable salt thereof

[001651 In some embodiments, the invention is a compound comprising Formula Formula XVIII:

wn 2 R3 A R2

R 1 -Z-L 4 >'J "- N RR R2 2 A

Formula XVIII

where:

n is from 1-12;

each A is independently selected from the group consisting of: 0 and S;

A

NR1

each R4 is independently selected from the group consisting of: H and R ;

each Rand R. is independently selected from the group consisting of: hydrogen, C-Cs alkyl, substituted C-Cs alkyl, C-Cs alkenyl, substituted C-Cs alkenyl, C-Cs alkynyl, substituted CICs alkynyl,C 3-C7 aryl, substituted C3 -C, aryl. cyanoC3-C1 0 cycloalkyl, substitutedC 3-C 1 0 cycloalkylC 3-C heterocycloalkyl, substitutedC 3 -C9 heterocycloalkyl,C3

C 9 heteroaryl, substituted C3-C heteroaryl, C 1-C alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, alkylthio, substituted alkylthioOH, OR2, N2, NIR , SR2 , substituted sulfonyl. and substituted sulfinyl, wherein any R substituent may be covalently bonded to or share another R' substituent to form a C 3 -C c yclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of hydrogen, C1 -Cs alkyl, substituted C1 -Cs alkyl, C 1 -Calkenyl, substituted C1 -Cs alkenyl, C 1 -Cs alkynyl, substituted C1-Cs alkynyl, C 3-C 7 aryl, substituted C 3-C 7 aryl, cyano, OH, C1-Cs alkoxy, substituted C1 -Cs alkoxy, amino, substituted amino, C3-C1 cycloalkyl, substituted C3 -C1 o cycloalkyl, C 3 -C 9 heterocycloalkyl, substituted C 3-C 9 heterocycloalkyl, C 3-C 9 heteroary, substituted C 3 -C 9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3-Cu cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently selected from the group consisting of: C- 2 , C(R 2 ,CHR 2 ,O,

NH, NR , C(=0), C(=S), S, S(:O). S(:0)2 , -C-, -Cl-, a C3-C12 spirocyclic group of R2 -(R2

where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR'=CR' or C--C;

Z is selected from the group consisting of: C1 -Cs alkyl, substituted C1 -Cs alkyl, C-C8 alkenyl, substituted C1 -Cs alkenyl, C1 -Cs alkynyl, substituted C1 -Cs alkynyl, C1-Cs alkoxy, substituted C1 -Cs alkoxy, substituted amino, alkyithio, substituted alkylthio, sulfonyl. C(R) 2 ,

CHR ,0, NH, NR 2 S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond

L4 is selected from the group consisting ofR 2 , acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a C3-Cu cycloalkyl ring structure, a C3 -C 2 fused cycloalkyl ring structure, a C3 -C12 aryl ring structure, aC 3 -C 1 fused aryl ring structure, a C 3 -C 2 heteroaryl ring structure, a C 3 -CI2 fused heteroaryl ring structure, aC3 -C 12 heterocyclic ring structure, and aCC 12 fused heterocyclic ring structure; and wherein W, does not form an (S) - group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; or a tautomer and/or a pharmaceutically acceptable salt thereof.

[001661 In one aspect, the present technology provides two or more compounds of Formula I-XVIII described herein.

[001671 In some embodiments, the compound is of Formula I-XVHI, wherein all R' and R are H. 1001681 In some embodiments, the compound is of Formula II-XVIII, wherein R' is H and all N-R2 are N-H.

[001691 In some embodiments, the compound is of Formula II, wherein W contains a heteroatom.

[001701 In some embodiments, the compound is of Formula H, wherein W contains an oxygen heteroatom. In some embodiments, the compound is of Formula 1, wherein W contains a sulfur heteroatom. In some embodiments, the compound is of Formula i, wherein W contains a nitrogen heteroatom.

[001711 In some embodiments, the compound is of Formula 1, wherein W contains sulfonyl functional group.

[001721 In some embodiments, the compound is of Formula II, wherein one R is an alkyl functional group.

[00173] In some embodiments, the compound is of Formula II, wherein one R is an aromatic functional group.

[00174] In some embodiments, the compound is of Formula I1, wherein one Rt is an alkyl functional group.

[001751 In some embodiments, the compound is of Formula Il, wherein Z' is nitrogen. 1001761 In some embodiments, the compound is of Formula 1I, wherein Z' is CH 2 .

[001771 In some embodiments, the compound is of Fornula III, wherein one R on the

carbon atom is H and the other is CH(CH3)2

.

[001781 In some embodiments, the compound is of FormulaIII, wherein one R on the

R2N2 carbon atom is H and the other is CH -CH(CH)2. 2

[001791 In some embodiments, the compound is of FormulaIII, wherein one R o s the

R22carbon atom is H and the other is Ar.

[00180] In some embodiments, the compound is of Formula III, wherein one L4 forms a carbamate functional group.

[001811 In some embodiments, the compound is of Fornula.III, wherein one L 4 forms a sulfamate functional group.

[001821 In some embodiments, the compound is of Formula I, wherein one L4 is C(O)C(CH 3)3 .

4

[001831 In some embodiments, the compound is of Formula 1111, wherein one L is C(O)C(CH 3) 3 .

1001841 In some embodiments, the compound is of Formula IV, wherein Z! is CH2 and I is H.

[001851 In some embodiments, the compound is of Fornula IV, wherein Z is CH2, Z2 is CH 2, and one Rl is H.

[001861 In some embodiments, the compound is of Formula IV, wherein Z' is CH 2 . Z 2 is 0, and one R' is H.

[001871 In some embodiments, the compound is of Formula V, wherein Z' is C- 2 , Z2 is NH, and both R! are H.

1001881 In some embodiments, the compound is of Formula VI, wherein Z! is CH2, Z2 is NH, and both R' are H.

[001891 In some embodiments, the compound is of Fornula III-XIV, wherein R' is H, both

N-R 2 are N-H, and L4 is O 0 a re

[001901 In some embodiments, the compound is of Formula III-XIV, wherein both R 0

H, both N-R are N-H, and L4isA O

.

[00191] In some embodiments, the compound is of FormulaII-XIV, wherein both R are 0 H, both N-R 2 are N-H1-, andi

1001921 In some embodiments, the compound is of Formula III-XIV, wherein both R are, 0 Ar-_~ both N-R2 are N-H, and L 4 is

[001931 In some embodiments, the compound is of Formula III-XIV, wherein both R' are

H, both N-R 2 are N-H, one R 2 oR2 is H and the other isH3 C CH 3 and L4 is

00

[001941 In some embodiments, the compound is of Formula II-XIV, wherein both R' are,

R2N2 H3C '.CH3 both N-R 2 are N--, one R of is - and the other is OH3 ,and L Is 0 Ph'Ob

[00195] In some embodiments, the compound is of Formula I-XIV,wherein both R" are,

both N-R2 are N--, one R 2 of R2'\ 2 is - and the other is H 3C CH3, and L4 is

F /

1001961 In some embodiments, the compound is of Formula III, wherein both R' are, both 4~4W 0

R2 2 . a .H 3C CH, 4- Ar--0)YV N-R are N-I-, one R'-of 1s Hn and the others

[00197] In some embodiments, the compound is of Formula Ill, wherein both R are, both 0

N-R2 are N-H, one R 2 o is H and the other is H 3 H3 , and L4 i

[001981 In some embodiments, the compound is of Formula II, wherein one R is H, both 0 k Ar_ 2 R2N2H 3 C>' 1CH3 N-R are N-H, one R ofR2 is H and the other is H and L is

[001991 In some embodiments, the compound is of Formula IV, wherein one R is H, both 0 2R2N2 .. H3C CH, L4 -iAr N-R are N-H, one R2 of is - and the other is H, andL 1s

.

[002001 In some embodiments, the compound is of Formula IV, wherein both R are H, N 0

2 both N-R are N-H, one R of is H and the other is H3C CH and L4 iS

[002011 In some embodiments, the compound is of Formula IV, wherein both R are H, 0 Ar both N-R are N-H, one R 2 ofR2 2 is H and the other isH3C CH 3 and L4 is

[002021 In some embodiments, the compound is of Formula V wherein both R are -,

R2 2 H C H3 CH both N-Ri are N--, one R of is - and the other isH 3 3 ,andL is 0

Ar'^AO

[00203] In some embodiments, the compound is of Formula V, wherein one R' is H, both 0 32 HC ICH N-R are N-H, one R of is H and the other is 3 and L4 is

1002041 In some embodiments, the compound is of Formula V, wherein both R are H, 0 Ar_9 both N-R are N-H, one R2 ofR2 2 is H and the other is H3C 1CH 3 and L 4 is

[002051 In some embodiments, the compound is of Formula VI, wherein both R are H,

2 both N-R are N-H, one R of R2\2 is H and the other is H3 C "C 3 ,and L 4 is 0

[002061 In some embodiments, the compound is of Formula VI, wherein both R1 are H

2 R2 2 H3C CH3 4 both N-R 2 are N-H, one R of is H and the other is 3 and L is

[00207] In some embodiments, the compound is of Formula VI, wherein both R are H, 0 / \' Ar-_ both N-R2 are N--, one R of R2N2 is - and the other is H3C 'CH3OH ,and1L4 IS I 1 3

[002081 In some embodiments, the compound is of Formula VII, wherein both R' are H,

2 R 2 isH3C' CH3 4i both N-Riare N-H, one RI of 2is H and the other isH 3 Hand L4 is 0 Ar-^-Ao

[00209] In some embodiments, the compound is of Formula VII, wherein both R' are H, S: 0 2 R2 isHC CH both N-Ri are N-H, one R 2 of is H and the others 3, andL4 is 0

[002101 In some embodiments, the compound is of Formula VII, wherein both R are -, 0 Ar both N-R2 are N-H, one R of 22 is H and the other is H3 , and L4 is

.

[00211] In some embodiments, the compound is of Formula lII-XIV, wherein one Ris -,

CH 3 0

both N-R 2 are N-H, one R 2of is H and the other is H , and L4 is

[00212] In some embodiments, the compound is of FormulaII-XIV, wherein one R is -,

CH 3 0

both N-R are N-H, one R 2 of 2is H and the other is 3 , and L 4 is Ph O

[002131 In some embodiments, the compound is of Formula III-XIV, wherein one R is H

CH 3

both N-R 2 are N-, one t of R R2 is - and the other is H3 and L4 is _- 0

1002141 In some embodiments, the compound is of Formula III-XIV, wherein one R 1 is H,

2R2 both N-R are N-H, one R2o is H and the other is selected from the group consisting

of: N HHAH, and 6/ H -- 0

andL 41 i

[002151 In some embodiments, the compound is of Formula III-XIV, wherein both R' are

H, both N-R 2 are N--1, one R2 of is H and the other is selected from the group

consisting of: N ,NH HeJ HOHJ/H66 ,

0

and 7 ~~ and L is-Ph OASN .

[002161 In some embodiments, the compound is of Formula IH-XIV, wherein both R are

-, both N-R are N-H one R 2 of R 2is and the other is selected from the group

consisting of: N H H H H6 /

-- 0

and , and L4 is .

[002171 In some embodiments, the compound is of Formula V-XIV, wherein both R1 are

H, all N-R' are N-H, and L" is

[00218] In some embodiments, the compound is of Formula V-XIV, wherein one R' is H 0 4 is Ar--^0 all N-R are N-H, and L

1002191 In some embodiments, the compound is of Formula V-XIV, wherein one R is H, 0 4 O t all N-R2 are N-H, and L is Ph-

[00220] In some embodiments, the compound is of Formula V-XIV, wherein one R' is H, 0

all N-R2 are N-H, and L 4 is

[002211 In some embodiments, the compound is of Formula V-XIV, wherein one R is1-,

R 2 all N-R are N-H, two R2 of the two groups on separate carbon atoms are H and one of 0

the other two R 2 groupsis H3 C CH 3 , and L4 is

[00222] In some embodiments, the compound is of Formula V-XIV, wherein one R' is H,

R2>R all N-R2 are N-H, two R 2 of the two 2 groups on separate carbon atoms are - and one of 0

the other two R groups is HC CH 3, and L isPh0O

[002231 In some embodiments, the compound is of Formula V-XIV, wherein both R, are

1-1, all NR are N-H, two R of the two groups on separate carbon atoms are 1- and 0

one of the other two R2 groups is H3C"CH3, and L4 is

[002241 In some embodiments, the compound is of Formula X1, wherein both R' are H,

2 R2 2 all N-R are N-H, two R2 of the two groups on separate carbon atoms are H and one of 0

the other two R2 groupsis H3C CH 3 , and L4 isA

[00225] In some embodiments, the compound is of Formula XIII, wherein both R' are H,

R R2 all N-R2 are N-H, two R 2 of the two 2 groups on separate carbon atoms are - and one of 0

the other two R 2 groupsis H 3 C CH3 , and L- is

[002261 In some embodiments, the compound is of Formula XIII, wherein one R is H, all

N-R2 are N-H, two R of the two groups on separate carbon atoms are H and one of 0

the other two R groups is H3C CH 3 , and L4 is

[002271 In some embodiments,the compound is of Formula XIV, wherein one R' is H, all

R2 2 N- R are N-H, two R2 of the two groups on separatecarbon atoms are H and oneof 0

the other two R- groups is O , and L s

[002281 In some embodiments, the compound is of Formula XIV, wherein both R are -,

7 .H3C CH 4 si OJ both N-2 are N-H, two R2 of the two 2 groups on separate carbon atoms are H and one 0

ofthe othertwo groups is H 3 C CH3, and L 4 is .

1002291 In someembodiments,thcompounisofFormulaXIV,whereinbothFRareH,

-s2'K2 all N-R 2 are N-H-,two R 2 of the two R22groups on separate carbon atoms are1-1Iand one of 0

the other tvoFR_2groups is H3 O-IH 3 amnd124i S

[002301 In some embodiments, the compound is of Formula XV, wherein both R are H, all

N-R 2 are N-H, two R2 of the two groups on separate carbon atoms are H and one of 0

the other two R2 groups is H3C CH 3 , and L4 isA

[00231] In some embodiments, the compound is of Formula XV, wherein both R1 are H, all

2 2 ~ R2 '2 N-R 2 are N-I, two R of the two groups on separate carbon atoms are H and one of 0

the other two R 2 groupsis H 3C CH3 and L- is

[002321 In some embodiments, the compound is of Formula XV, wherein both R are H, all

the other two R groups is H3C CH 3 , and L4 is

[002331 In some embodiments,the compound is of Formula XVI, wherein both R' are H,

R2 2 all N-R are N-H, two R of the two groups on separate carbon atoms are H and one of 0

the other two R 2 groups is H3C CH 3 and L4 is

[002341 In some embodiments, the compound is of Formula XVI, wherein both R are -,

all N-R are N-H, one R ofR2 is H and the other is H 3 C H 3 and L4 is .

[00235] In some embodiments, the compound is of FormulaXVI, wherein R is H, all N-R 2

R2 2 are N-H, two R2 of the two groups on separate carbon atoms are H and one of the 0 Ar_9 other two Ri groups is H3C CH 3 , and L4 is 8

[002361 In some embodiments, the compound is of Formula XVII, wherein both R are1-1,

the other two R2 groups is H3C CH 3 , and L4 isA

[002371 In some embodiments, the compound is of Formula XVII, wherein both R are H,

R R2 all N-R 2 are N-H, two R 2 of the two 2 groups on separate carbon atoms are - and one of 0

the other two R 2 groupsis H 3 C CH3 , and L- is

[002381 In some embodiments, the compound is of Formula XVII, wherein one R' is H, all

the other two R groups is H3C CH 3 , and L4 is

[002391 In some embodiments,the compound is of Formula V-XIV, wherein one R" is H,

R2 2 all N-R are N-H, two R of the two groups on separate carbon atoms are H and one of

CH 3 0

the other two R groups is H3 ,and L4 is

[002401 In some embodiments, the compound is of Formula V-XI, wherein both R are

R2 2 H, all N-R2 are N-, two R 2 of the two groups on separate carbon atoms are H and

CH 3 0

one of the other two R' groups is GH 3 , and L4 is Ph^"'O

[002411 In some embodiments, the compound is of Formula V-XVII, wherein both RN are

H, all N-R 2 are N-H, two R2 of the two groups on separate carbon atoms are H and

CH 3 F \ one of the other two R2 groups is H3 ,andL 44 is .

1002421 In some embodiments, the compound is of Formula V-XVII, wherein one R' is H,

R2N 2 all N-R 2 are N-, two R of the two groups on separate carbon atoms are H and one of

the other two R2 groups is selected from the group consisting of:

0 H NH HYHK , and ,and L- is

[002431 In some embodiments, the compound is of Formula V-XVIII, wherein one R is H,

R2 2 all N-R2 are N--, two R 2 of the two groups on separate carbon atoms are H and one of

the other two R2 groups is selected from the group consisting of:

N IH N H6/ H H , H- and and1L4 iS

[002441 In some embodiments, the compound is of Formula V-XVIII, wherein both R are

R2 2 H, all N-R2 are N-I, two R 2 of the two groups on separate carbon atoms are H and

one of the other two R2 groups is selected from thegroup consisting of:

> FN/ 0H H6 61 NHHand and L is

[002451 In some embodiments, the present technology includes a compound which is selected from the compound of the tables below:

WO 2017/156074

TABLIEI

Macrocycles

yNW

5U

IN N

4 4

C N Ni iN I P -.- N / '~'N \ 2/ <N <NN

/ Nt

21 /

I Ni

K~w'~>x &< NfA<N rKsg ~ It 2 _' A /

25 >t x~\ N

/ ¾Nm

~N~? ..- ~ -' 2 ½N*CA

7 <1' p 1 V I N

AxN ~. 2/""' N

2jL~] / <N 0 <N -N Is 1-< ""-' .'j ~1 / <~ ii N A / ./ -'< A 'N N <N <N '-N --N

Q Nt *"" 'N-:.

Zn 34

/ N

/ N H N -~ NN-< A

is)

31--1

' - S \ N

NH2N

41 42

INH

F46

49 L5

7 67

IF62. I

I No

/ - UK0 ------------------------------------------------------------- ----------------------------------------------------------

------- LN7

6 ------------------------------- ----------------------------

773 --- - - - - -- - - - - -- - - - - - -- - - - - -- - - --- -- - - - - -- - - - - -- - - - - -- - - - - - -

c~ >r > ~ :N \/ ~ ~ N '~.N \WN7 N.77

N HN / KT -- -------------------------------------------- -- - -- - - -- ---- ---- -

N ------- N --------------- --------------------------- 2 ------------ -----------------------------------------------¾.--

K /- - - - - -------- / 0 log F, -1c]

102T

--- - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - ------------ --

-I /t~\ v

- -- - - - - -N- -

NIt -~. ..... ,

NVt IN80

IN N,~

133---- 134- - - ------

81I

NI

Nm

----- 15 T5

149- 150

---- ---- ---- ---- -- 0

N8

-7 - 3 -----

0 oi

165 166

I - - -----

Ii 82

201I

---- ------ 1 ' I~r - ~ AN ::0:6]

~-'~ ~ 85

221 2-2-2 o~NN

217 C

------- ....... ....

>L7~'~ ~ 0 86

229 '>30

----------- j -1 73

L/ J

241 'V 42

s. NN~NXI .- ~JL A

i~u7

249 50O

111L

---------------------

57 7 -- ---- - - - - -- -----

N4

-------- .......

I 88

NN

269~ ----- ----- ---- A---

277

V-z\'

I,0

89N

2 81 '282

N ~N

/ \1

INN

Nx 7 NN yi

90~

(N / 4 N 3W / ~

4 N -A - N N

' 11 12

-~ -k 'N /=N~ (N A' if - N N ,r t / (N ~ N N " <N

/1

/ '7 A'~ A- Ii. 'N r N A j) A

XN~ ~ ~' 1/ NN,..A N

V Mt

19 -1 A

C' ft /7 N N N 11 NO '0 'r'-C-' N / ~,0 Nr~~N U ~rN I 'N

~> AN MN:.>

:247 23

/D X

27

31 32

NH

>-7x~ --- r ------

359

NN

39

~' Xe- / JL"

-0 0

7 VN

55jNN/0 ~

59N

/93

6' 68

2-11~ i

:5]

71 7

IN/I zwK

8 94

I C C N N C ~ N -N .- N~ N N K-i N

//7' C 'N -

N N 'N ~N*. - NM,

91 92 7NN 7 r~~'\

U o / r=r ii

XX " r N K / ~

4 NNN A

NN~

0 N '~'~-v 0 N " ~z' ~v N C y~N 'N-N "N "N ' 'N 7 - ~ NM 2

7 / ~, ~ NN N

H 'N~< ;~ - H

-~ AS

- -.

" -- -- -- --- --- --- --- 1 7 ]

<NK

>~ N p~~~IN~~ 5

A9

WO 2017/156074

11912

Nw

1231 124

1271 /-- -----

K9

------ TIE

------------ 1477 L4 /

98~

1s

N~" - 5 N

"N N

04:

-----------------------

7----------- '~'-~

99 " "<N A

-------- ----- E l

C3C

- /-------

,5,

INN

1-91 11IT-

- N< N< N961

~ if *'T

N' -10N

199 -- 00

----- ---

20N

KIL N r 0,Jt ~

21 21/

21 5 -216

2' -2724

L2 7 T' El

- - - - - --- - -:-- -

c/31N

235 -236

N 7 N

N.N 1

------ ---- ---- 7 ~ ~

E51 ; 4 I -52

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r a tautomer and/or a pharmaceutically acceptable salt thereof

[002461 In some embodiments, the present technology is a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.

[002471 In one embodiment, the compounds of the present invention or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, can be administered in combination with any other pharmaceutical compound approved for treating fibrotic or myofibroblast differentiation associated diseases or disorders.

Compositions and Methods of the Present Technolo V

[002481 The compounds represented by Formula I-XVII or their tautomers and/or pharmaceutically acceptable salts thereof can effectively act as CAPNI, CAPN2, and/or CAPN9 inhibitors and treat conditions affected at least in part by CAPN1, CAPN2, and/or CAPN9. In one aspect of the present technology, the present technology provides pharmaceutical compositions comprising one or more compounds of Formula I-XVIII and a pharmaceutically acceptable excipient. In another aspect of the present technology, the present technology provides a method for treating a fibrotic disease with an effective amount of one or more compound of Formula I-XVIII as provided herein.

[002491 In another aspect of the present technology, the present technology provides a method for inhibiting CAPNI, CAPN2, and/or CAPN9 and/or a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9 with an effective amount of one or more compound of Formula I-XVIII as provided herein.

[002501 The compounds of the present technology are useful in inhibiting CAPNI, CAPN2, and/or CAPN9 enzymes and/or treating disorders relating to fibrosis or myofibroblast differentiation.

[002511 In one of its method aspects, the present technology is directed to a method for inhibiting CAPNI, CAPN2, and/or CAPN9 which method comprises contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compound of Formula I-XVII as described herein.

1002521 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one ormore compounds of Formula IXVIII or a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[002531 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds of Formula I-XVIII or a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[002541 In an aspect, a method for inhibiting CAPNi, CAPN2, and/or CAPN9 is provided wherein the method comprises contacting cells with an effective amount of one or more compounds of Formula I-XVIII. In one aspect, the method for inhibiting CAPNI, CAPN2, and/or CAPN9 is performed in-vitro or in-vivo.

[002551 Calpains are also expressed in cells other than neurons, microglia and invading macrophages. In particular, they are important in skeletal muscle and herein inhibition of calpains also refers to inhibition in these cells as well. Selective inhibition

[002561 In another aspect, a method is provided for competitive binding with calpastatin (CAST), the method comprising contacting a compound of any one of claims 1-56 with CAPNI, CAPN2, and/or CAPN9 enzymes residing inside a subject. In such a method, the compound specifically inhibits one or more of the enzymes selected from the group consisting of: CAPN, CAPN2, and CAPN9 by at least 2-fold, by at least 3-fold, by at least 4-fold, by at least 5-fold, by at least 10-fold, by at least 15-fold, by at least 20-fold, by at least 50-fold, by at least 100-fold, by at least 150-fold, by at least 200-fold, by at least 400-fold, or by at least 500-fold.

[002571 In another aspect, a method is provided for selectively inhibiting CAPNI in the presence of CAPN2 and CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

[002581 In another aspect, a method is provided for selectively inhibiting CAPNin the presence of CAPNI and CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

1002591 In another aspect, a method is provided for selectively inhibiting CAPN9 in the presence of CAPN2 and CAPNwhich includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

[002601 In another aspect, a method is provided for selectively inhibiting CAPNI and CAPN2 in the presence of CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVI- described herein.

[002611 In another aspect, a method is provided for selectively inhibiting CAPNI and CAPN9 in the presence of CAPN2, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

[002621 in another aspect, a method is provided for selectively inhibiting CAPN2 and CAPN9 in the presence of CAPN1, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds of Formula I-XVIII described herein.

[002631 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPN1, CAPN2, and/or CAPN9, said compounds being selected from Formula I-XVII or a pharmaceutical composition comprising one or more compounds from Formula IXVI and a pharmaceutically acceptable excipient.

1002641 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPNI, CAPN2, and/or CAPN9, said compounds being selected from Formula I XVIII or a pharmaceutical composition comprising one or more compounds from Formula I XVIII and a pharmaceutically acceptable excipient.

[002651 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPNI, CAPN2, and/or CAPN9, said compounds being selected from Formula I-XVIII or a pharmaceutical composition comprising one or more compounds from Formula I-XVII and a pharmaceutically acceptable excipient.

1002661 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPNI, CAPN2, and/or CAPN9, said compounds being selected from Formula I XVIII or a pharmaceutical composition comprising one or more compounds from Formula I XVIII and a pharmaceutically acceptable excipient.

[002671 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:5.

[002681 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9in a ratio of at least :1:10

[002691 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.

[002701 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:50.

[002711 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:100.

[002721 In another aspect, the present technology is directed to a method for treating a fibrotic disease. which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN, CAPN2, and CAPN9 in a ratio of at least 1:1:200. 1002731 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one ormore compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNi, CAPN2, and CAPN9 in a ratio of at least 1:1:250.

[002741 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:500.

[002751 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.

[002761 in another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNi, CAPN2, and CAPN9 in a ratio of at least 1:1:10.

[002771 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:20.

[002781 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:50.

[002791 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:100.

[002801 In another aspect, the present technology is directed to a method for treating a fibrotic disease. which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN, CAPN2, and CAPN9 in a ratio of at least 1:1:200.

1002811 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNi, CAPN2, and CAPN9 in a ratio of at least 1:1:250.

[002821 In another aspect, the present technology is directed to a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:500.

[002831 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.

[002841 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:10.

[002851 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibitswo or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.

[002861 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:50.

[002871 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibitstwo or more enzymes selected from the group consisting of CAPN, CAPN2, and CAPN9 in a ratio of at least 1:1:100.

[002881 in another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:200.

[002891 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNCAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:250.

1002901 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:500.

[002911 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:5.

[002921 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:10.

[002931 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:20.

[002941 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9in a ratio of at least 1:1:50.

[002951 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:100.

[002961 In another aspect, the present technology is directed to a method for treating a disease affected at least in part byCAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:200.

[002971 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPNI, CAPN2, and CAPN9 in a ratio of at least 1:1:250.

[002981 In another aspect, the present technology is directed to a method for treating a disease affected at least in part by CAPNI, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting ofCAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:500.

[002991 In another aspect, a method is provided for prophylactic therapy or treatment of a subject having a fibrotic disorder wherein said method comprising administering an effective amount of one or more compounds of Formula I-XVIII to the subject in need thereof.

[003001 In another aspect, a method is provided for prophylactic therapy or treatment of a subject having a disorder affected by CAPNI, CAPN2, and/or CAPN9 wherein said method comprising administering an effective amount of one or more compounds of Formula I-XVIII to the subject in need thereof.

[003011 in another aspect, a method for inhibiting myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)) is provided wherein the method comprises contacting cells with an effective amount of one or more compounds of Formula I-XVIII disclosed herein. In one aspect, the method for inhibiting myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchyma Transition (EpMT/EniMT)) is performed in-vitro or in-vivo.

[003021 In some embodiments, the present technology is a method for treating a disease or condition selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases, wherein which method comprises administering to a subject an effective amount of one or more compounds Formula I-XVIII to a subject in need thereof.

[003031 In some embodiments, the present technology is a method for treating liver fibrosis.

[003041 In some embodiments, the present technology is a method for treating cardiac fibrosis.

[003051 In some embodiments, the present technology is a method for treating fibrosis in rheumatoid arthritis diseases.

[003061 In some embodiments, the present technology is a method for treating a condition affected by CAPNI, CAPN2, and/or CAPN9, which is in both a therapeutic and prophylactic setting for subjects. Both methods comprise administering of one or more compounds of Formula I-XVIII to a subject in need thereof.

[003071 In some embodiments, the present technology is a method for treating stiff skin syndrome.

[003081 In another aspect, the present technology is directed to a method wherein one or more compounds of Formula I-XVIII may be administered with other CAPN1, CAPN2, and/or CAPN9 inhibitor agents, such as anti-CAPNI, CAPN2, AND/OR CAPN9 antibodies or antibody fragments, CAPNi, CAPN2, and/or CAPN9 antisense, iRNA, or other small molecule CAPNI, CAPN2, and/or CAPN9 inhibitors, or in combination with other agents as described in detail herein.

[003091 Diseases and/or disorders or produced symptoms associated or affected at least in part by CAPNI, CAPN2, and/or CAPN9 include those selected from the group consisting of: liverfibrosis,renalfibrosis,lungfibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis.

[003101 In one embodiment, therapeutically effective amount is a specific amount which causes a specific physiological effect which results in the amelioration of the disorder being treated or protects against a risk associated with the disorder.

[003111 The compounds of the present technology are useful in the diagnosis and treatment of a variety of human diseases selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post vasectomy pain syndrome, and rheumatoid arthritis. The compounds of the present technology are particularly useful in treating disorders arising from fibrosis and complications thereof.

[003121 In another aspect, the present technology is directed to a method wherein one or more compounds of Formula I-XVIII which are used as a means to inhibit myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpIMT/EnMT)). In particular, one or more of these compounds which are inhibitors of one or more (or all three) CAPN1, CAPN2, and/or CAPN9, alone or in combination with other TGF signaling inhibitors, could be used to treat or protect againstor reduce a symptom of a fibrotic, sclerotic or post inflammatory disease or condition including: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post vasectomy pain syndrome, and rheumatoid arthritis.

[003131 Compounds of the present technology are shown to have improved safety and potency, such as the potency of inhibiting CAPN1, CAPN2, and/or CAPN9 at low micromolar concentrations and possessing low relative cytotoxicity. In general, compounds of the present technology are shown to have potency, ameliorate, and/or possess efficacy in treating diseases or disorders which include, as a component, some form of fibrosis or inflammation.

1003141 The amount of active compound administered will vary depending upon the disease treated, the mammalian species, and the particular mode of administration, etc. Suitable doses forthe compounds of the present technology can be, for example, between 0.1 mg to about 1000 mg, between I mng to about 500 mg, between I mg to about 300 mg, or between I mg to about 100 mg per day. Such doses can be administered once a day or more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably I or 2 times per day. In some embodiments, the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration or 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of days, a number of weeks or months, and in some cases,years. It will be understood, however, that the specific dose level for any particularsubject will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

General Synthetic Methods

[003151 The compounds of the present technology can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[003161 Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art.For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

[003171 If the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

[003181 The starting materials for the following reactions are generally known compounds or canbe prepared by known procedures or obvious modifications thereof. Forexample, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Synthesis RotestoCompoundsof thesPreent Technofgy

[003191 In one general embodiment, the method involves starting with an appropriately N protected amino acid compound with an alkene functionalized side-chain, and coupling it with an appropriately C-protected amino acid compound with an alkene functionalized side chain as a coupling partner to give the di-finctionalized di-amino acid derivative. ftis appreciated that other suitable coupling conditions and reagents, such as HOBt and/or DMAP, may be used to form a requisite di-amino acid derivative. di-amino acid derivative is then cyclized upon with a metathesis reaction using, for example, the Grubbs catalyst. The skilled artisan will appreciate that there are many synthetic conditions and catalysts which are capable of metathesizing the olefin groups. Such synthetic methods and catalysts are well within in the scope of the present technology disclosed. The C-protection is removed by reduction with DIBAL to directly give the aldehyde. Alternatively, the C-protection can be reduced with LAH (other reduction conditions such as birch reduction and so forth will work as well) to afford the corresponding alcohol, which is then oxidized with PCC (or DMP conditions or like) to the aldehvde. The aldehyde then undergoes a cyanohydrin reaction upon treatment with KCN, which is then hydrolyzed under acidic conditions in alcohol to the corresponding a-hydroxy ester. At this point, any desired groups may be placed onto the nitrogen atom of the keto-amide by a substitution reaction, such as with an alkyl iodide, or perhaps with reductive amination. The skilled artisan will note that if the desired compound has functionality on the nitrogen of the amide, the synthesis can use NaNH 2 or a strong base of the like in the step before the cyanohydrin reaction, in order to selectively place a differing group onto those nitrogen atoms as opposed to the nitrogen atom of the keto-amide. Finally, the a-hydroxyl group is oxidized under conditions for Dess-Martin Periodinane oxidation

(with hypervalent iodine) or by an oxidizing agent such as PCC (pyridinium chlorochromate) or the like. The skilled artisan will once again appreciate that there are many other oxidizing conditions and agents which are within the scope of this disclosure to oxidize the hydroxyl group. Of course it is recognized that at any point during this synthesis, the keto compounds may be interchanged with thio-keto compounds as treatment with Lavesson's reagent or the like will give the corresponding thio-carbonyl compound. This synthesis route is generally shown in Scheme 1.

[003201 In one example, the compounds of general Formula I-XXIV can be generally prepared according to representative Scheme 1: Scheme I R2

C0 2H O HN-N, QP H

NH CO2 NHP CO2 GrLIs2st O HN N C 2P DIBAL S-- --- ----- ------------------ ECIHOBV IBEA MAWTH-C I [)C I IiPHN

R/ 2 2 F R R'_. 0 R2 NTSCN H HO O N A 0 N)HCI

PHN MeOH PHN \

[003211 As an alternative, the skilled artisan will appreciate that these keto-amide compounds can also be prepared by converting the amino acid side-chain of the starting material (N-terminus protected) into side-chain with heteroatom functionality. In this way, the heteroatom and substituent bond connection on the ring can be affected, optionally stereoselectively. Such functional group conversions are well known in the art and also allows for complex substitution at the ring juncture(s) and opens pathways for bicyclic ring systems. Typical substrates for these kind of intramolecular reactions are usually setup with functional groups, one electrophilic, one nucleophilic in nature and may include, but are not limited to: aldehydes, halides, alkenes, and ketones, and the like.Of course, either way the cyclization is affected, the skilled artisan will recognize that the requisite functional groups may be selected so that heteroatoms and multiple substituents can exist at any position of the ring. An ex

[003221 In one example, the compounds of general Formula I-XXIV can also be generally prepared according to representative Scheme 2:

Scheme 2 0 HN-1 O- bBut NP 2 Br 1) deprotection NH 0 0 0 0 2) M CPBA KN O N NN NN 0U 1 3) Ca(OTf) 2 OBut -0

H H -N --

0

Herein it is understood that amino, keto, thio, hydroxyl, and any other necessary protecting groups and their methods of deprotection are known in the art, such as those described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis. Third Edition, Wiley, New York, 1999.

[003231 Alternatively, the skilled artisan will recognize that there is additional synthetic functional group modifications that can use to prepare spirocyclic and other bicyclic compounds onto the cyclic keto-amide ring.

[003241 In one example, the compounds of general Formula I-XXIV can also be generally prepared according to representative Scheme 3: Scheme 3

NH SN-But Lewis Acid 0

-NH 0 ~ N---0 NN~ NH 0

0 HN - ACHNS ACHNS KS

[003251 Yet in another alternative aspect, the skilled artisan will recognize that other bicyclic systems can be prepared thru similar functional group transformations with groups on the amino acid side chain or on the nitrogen atoms outside the keto-amide ring.

Administration and Pharmaceutical Composition

[003261 The present technology provides novel compounds possessing CAPNi, CAPN2, and/or CAPN9 inhibitory activity and, accordingly, are useful in treating conditions and/or disorders affected by (or at least in part by) CAPNI, CAPN2, and/or CAPN9. Such conditions include fibrosis and/or complications thereof.

[003271 Methods for treatment of fibrotic diseases are also encompassed by the present invention. Said methods of the invention include administering a therapeutically effective amount of any one of compounds of Formula I-XVIII. The compounds and solvates of the invention can be formulated in pharmaceutical compositions. These compositions can comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials wel Iknown to those skilled in the art. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.

[003281 Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.

[003291 For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required. 1003301 A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

[003311 In general, the compounds of the present technolog will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of the present technology, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to the skilled artisan. The drug can be administered at least once a day, preferably once or twice a day.

[003321 An effective amount of such agents can readily be determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., ed. (1995) Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co.

[003331 A therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.

[003341 An effective amount or a therapeutically effective amount or dose of an agent, e.g., a compound of the present technology, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g, by determining the 11)50 (the dose lethal to 50 % of the population) and the EDo (the dose therapeutically effective in 50 % of the population). The dose ratio of toxic to therapeutic effects is therapeutic index, which can be expressed as the ratio LDo/ ED,. Agents that exhibit high therapeutic indices are preferred.

[003351 The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages particularly fall within a range of circulating concentrations that includes the EDo with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.

[003361 Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects; i.e., the minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[003371 The amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and thejudgment of the prescribing physician.

[003381 The present technology is not limited to any particular composition or pharmaceutical carrier, as such may vary. In general, compounds of the present technology will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another preferred manner for administering compounds of the present technology is inhalation.

[003391 The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MD) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the subject's respiratory tract. MDI's typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the subject's inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, therapeutic agent is formulated with an excipient such as lactose. A measured amount of therapeutic agent is stored in a capsule form and is dispensed with each actuation.

[003401 Pharmaceutical dosage forms of a compound of the present technology may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levitating, emulsifying, (nano/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present technology can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[003411 Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nim in which the active inaterial is supported on a crosslinked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[003421 The compositions are comprised of in general, a compound of the present technology in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[003431 Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[003441 Compressed gases may be used to disperse a compound of the present technology in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[003451 The present compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the present technology formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[003461 The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 99.99 wt % of a compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 80 wt %. Representative pharmaceutical formulations are described below. Formulation Examples The following are representative pharmaceutical formulations containing a compound of Formula I-XVIII.

Formulation Example I -- Tablet formulation The following ingredients are mixed intimately and pressed into single scored tablets. Quantity per Ingredient tablet, mg

compound of this the present technology 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Formulation Example2 -- Capsule formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Quantity per Ingredient capsule, mg

compound of this the present technology 200 lactose, spray-dried 148 magnesium stearate 2

Formulation Example 3 -- Suspension formulation The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount

compound of this the present technology 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilled-water qs.-to-100-mL

Formulation Example 4 -- Injectable formulation The following ingredients are mixed to form an injectable formulation. Ingredient Amount

compound of this the present technology 0.2 mg-20 mg sodium acetate buffer solution, 04 M 2.0 mL HC (IN) or NaOH (IN) q.s. to suitable pH

water (distilled, sterile) qs. to20 mL

Formulation Example 5 -- Suppository Formulation A suppository of total weight 2.5 g is prepared by mixing the compound of the present technology with Witepsol H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: Ingredient Amount

Compound of the present technology 500 mg Witepsol H-15 balance

[003471

[003481 The following synthetic and biological examples are offered to illustrate this the present technology and are not to be construed in any way as limiting the scope of this the present technology. Unless otherwise stated, all temperatures are in degrees Celsius.

EXAMPLES

[003491 Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.). but some experimental error and deviation should, of course, be allowed for.

[003501 The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g, T.E. Creighton, Proteins:Structures andV/olecularProperties(W.H. Freeman and Company, 1993); AL Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., MolecularCloning:A LaboratorvManual (2nd Edition, 1989); MethodsIn Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's PharmaceuticalSciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg .dvanced OrganicChemistry 3'"Ed. (Plenum Press) Vols A and B(1992).

[003511 The present technology is further understood by reference to the following examples, which are intended to be purely exemplary of the present technology. The present technology is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the present technology only. Any methods that are functionally equivalent are within the scope of the present technology. Various modifications of the present technology in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the appended claims.

[003521 In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. aq. = aqueous LC-MS = liquid chromatography-mass spectrometry MS mass spectrometry THF = tetrahydrofuran NaHCO, = sodium bicarbonate DIlEA diisopropylethylamine MS = mass spectrometry NaH = sodium hydride 0/n = overnight HATU = I-[Bis(dimethylamino)methyiene]-11-1-1,2,3 trl zoolo[4,5-b]pyridinium 3-oxid hexafluorophosphate r.t. = room temperature LAH = lithium aluminum hydride DCM dichloromethane DMF = dimethylformamide

DMSO = dimethyl sulfoxide EA = Ethyl Acetate equiv. = equivalent EtOAc = ethyl acetate EtOH = ethanol g = gram h = hours hrs hours HCi = hydrochloric acid HPLC = high-performance liquid chromatography HOAc = acetic acid M = molar MeOfI methanol mg = milligrams mL = milliliters mmnol = millimoils mp = melting point m/z = mass to charge ratio NaCl = sodium chloride Na2CO 3 = sodium carbonate NMR= nuclear magnetic resonance NaOH = sodium hydroxide Na 2 SO 4 = sodium sulfate PE Petroleum Ether sat. = saturated TLC = thin layer chromatography UV = ultraviolet Wt % = weight percent pM = micromolar Generalexperimentaldetails:

[003531 Final compounds were confirmed by HPLC/MS analysis and determined to be > 90%. 'H and "C NMR spectra were recorded in CDCW (residual internal standard CHCW= 6 7.26), DMSO-d (residual internal standard CD 3 SOCD2H = 6 2.50), methanol-d (residual internal standard C[)OD), or acetone-d6 (residual internal standardCD3OCD 2 1= 6 2.05). The chemical shifts (6) reported are given in parts per million (ppm) and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s:= singlet, bs = broad singlet, bm = broad multiplet = doublet, t:= triplet, q = quartet, p:= pentuplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, tt = triplet of triplet, and m = multiplet.

[003541 HPLC-MS analysis was carried out with gradient elution. Medium pressure liquid chromatography (MPLC) was performed with silica gel columns in both the normal phase and reverse phase. EXAMN'IPLE 1: Compounds synthesis procedure and data: EXA[MIPLE 1

BeIzyl ((1RS,7S,5SZ)-1-formy-4-isobutvl-3,6-dioxo-2,5-diazabicyclo 13.1.01hexadec 13-en-7-v1)carbamate (1)

b O 0 ~K~i------ 40 -50 C, TF I Ygr NHBO C--C - - - -- TsiNHNH2 N- BOC 1B HOAc 1C IA

TFA,CM O O CbzCl, E1N, DCM, 0 -10 `C, 14.5 h O g c Ph 10'2 2 -.FN------ O - -T.-NH -

1D 1E I LihOH 2

( !G'C:H 2Et- 8 C

3 N OE ID O HC|~F 2E 1G I-I~ H ~C--02E'iPS,M H , "IOA1H .

Hoveyda-G0rubbs ist 1 H, L HF HN O N Ph 0 HN- N Generation catalyst \ I jjH ED IOH T/ A d ;) O" H DCM,<C.01M, 50°C CbzHN'"N

/ 01-'Grubs ' 2>, L;.1-4 _

1J 0 H H

Cb HN - -- - - - - --- N - " T Geess-Martinper s ianc '\tl /O DCM H

1K 1

[003551 Stp 1: Synthesof pound 1B To a solution of compound IA (50 g, 194 mmol) in TIIF (500 mL) was added 3 butenylmagnesium bromide (0.522 M, 558 mL, 291 mmol) dropwise at -40 °C to -50'°C for 30 min. The mixture was stirred at -50 °C for 1.5 hrs. The mixture was quenched with sat. NHI4 C (100 mL) and separated. The aqueous layer was extracted with EA (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 5:1 to 3:1) to afford compound 1l (58.8 g, yield 96.5%) as white solid. MS(ESI)nwZ (M+Na_)335.9. H NMR (CDCl 3, 400MHz) o 5.90 - 5.71 (in, 1H), 5.19 - 4.89 (m, 3H), 4.31 - 4.15 (in, 3H), 2.65 - 2.42 (in, 4H), 2.38 - 2.26 (in, 2H), 2.20 - 2.08 (in, 111), 1.95 - 1.82 (m, 1H), 1.50 - 1.38 (in, 9H), 1.30 - 1.26 (in, 3H)..

[003561 Step 2: Synthesis of compound 1C

To a solution of compound 1B (58.8 g, 187.6 mmol) in AcOH (500 mL) was added 4 methylbenzenesulfonohydrazide (41.6 g, 223.3 mmol) at 10 °C. The mixture was stirred at 10 °C for I h. Then NaBH(OAc)3 (167 g, 788 mmol) was added to the mixture in portions. The mixture was stirred at 37 'C for 17 hrs. The mixture was quenched with water (500 mL) and extracted with EA (3 x 150 mL). The combined organic layers were basified to pH ~ 8 with 10% NaOH aqueous solution. Then the organic layer was separated and dried over anhydrous Na 2 SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO2 , petroleum ether/ethyl acetate:= 10/1 to 5/1) to afford compound IC (35.0 g, yield 62.3%) as colorless oil. 'H NMR (CDCl 3, 400MHz) e 5.90 - 5.71 (n, 111), 5.19 - 4.89 (m, 3H), 4.31 - 4.15 (in, 31), 2.15 - 1.95 (i, 2H), 1.90 - 156 (in, 11), 175 - 1.55(m, 1H), 1.52 - 1.22 (in, 1H).

[003571 Step 3: Synthesof compound 1D To a solution of compound IC (24.0 g, 80.2 mmol) in DCM (150 mL) was added TFA (70 nL) at 10 °C. The mixture was stirred at 10 °C for 2 h. The mixture was

concentrated to give compound ID (25.1 g, crude), which was used directly for next step without further purification. 'H NMR (CDCl 3, 400MHz) 6 7.97 - 7.50 (m, 3H), 5.89 - 5.67 (m, 11), 5.07 - 485 (in, 21), 4.38 - 4.22 (m, 2H), 413 - 3.96 (in, 11), 2.10 - 1.82 (m, 4), 1.53 - 1.20 (m, 911).

1003581 Step 4: Synthesi sof compound IE

To a solution of compound 11 (40 g, 128 mmol, TFA salt) in DCM (60 mL) was added EtN (619 ml, 446.9 mmol) and benzyl chloroformate (15.4 mL, 108.5 mmol) dropwise at 0 °C for 30 min. The mixture was stirred at 10 °C for 14 hrs. The mixture was quenched with water (200 mL) and separated. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2 SO 4 filtered and concentrated.

The residue was purified by column chromatography (Si0 2 ,petroleum ether/ethyl acetate= 5/1) to afford compound 1E (34g yield 79.9%) as yellow oil. 'H NMR (CDC[,, 400MHz) 6 7.45 - 7.27 (in, 5H), 5.90 - 5.70 (in, 1H), 5.39 - 5.25 (in, 1H), 5.12 (s, 2H), 5.04 - 4.90 (in, 21), 4.42 - 4.31I (m, I H), 4.28 - 4.05 (m, 2H), 2.12 - 1.98 (in, 21-), 1.91 - 1.76 (i, 1), 1.74 1.58 (in, 11-1), 146 - 116 (in, 9H)..

1003591 Step 5: Synthesis of compound IF

To a solution of compound 1 (34 g, 102.0 mmol) in 1-12 (106 mL) and MeOH (325 mL) was added LiOH' 20 (11.1 g, 265 mmol) at 7 °C. The mixture was stirred at 28 °C for 16 hrs. Then MeOH was removed under reduced pressure. To the residue was diluted with water(100mL). The mixture was extracted with MTBE (2 x 40 mL). The aqueous layer was acidified to pH - 3 with IM HCl and then was extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous Na 2SO 4 , filtered and concentrated to give compound IF (28.5 g., crude, yield: 91.5%) as fellow oil, which was used for next step directly. 1H NMR (CDCl 3, 40MHz) o 7.50 - 7.28 (m, 5H), 5.91 - 5.71 (in, 111), 5.34 - 5.09 (in, 3H), 5.08 - 4.85 (i, 2H), 4.50 - 4.34 (m, 1H), 2.06 - 1.99 (in, 2H), 1.96 - 1.81 (in, 1H), 1.77 - 1.63 (in, 1H), 1.49 - 1.29 (in, 6H).

[003601 Ste 6: Synthesisof compound 1H

To a solution of compound IF (2 g, 6.55 mmol) and compound IG (2 g, 6.55mimol, HC salt) in DCM (50 mL) was added DIPEA (5.7 mL, 32.75 mmol, 5 eq), EDCI (1.88 g, 9.82 mmol) and HO3t (884.9 mg, 6.55 imol) at 5 °C. The mixture was stirred at 5 °C for 15 hrs. The mixture was concentrated. To the mixture was added EA (150mL). The mixture was washed with IM HCl (20mL), sat. NaHC03 (4 x 20mL) and brine (20 mL), dried over Na 2 SO4 and concentrated to give compound 111 (3 g, crude), which was used in next step without further purification. 1H NMR (DMSO-d, 400MHz) 6 8.73 - 8.63 (m, 1H), 7.85 7.74 (in, IH), 7.40 - 7.20 (m, 511), 5.86 - 5.69 (in, 1H), 5.67 - 5.51 (in, 1H), 5.32 - 5.16 (in, 11-1), 5.12 - 4.84 (in, 51-1), 433 - 4.17 (in, 11-1), 411 - 3.90 (in, 41), 2.15 - 2.02 (in, H), 2.00 1.95 (in, 2fH 1.69 - 1.36 (in, 61-1), L35 - 1.05 (in,10H), 0.93 - 0.68 (in, 61-).

[003611 Step 7: Synthesisof compound 1J To a solution of compound 1H (1g, 1.80 mmol) in DCM (650 mL) was added Hoveyda-Grubbs' Ist Generation catalyst (108 mg, 179.95 umol) under N 2 atmosphere. The mixture was stirred at 50 °C under N 2 for 15 hrs. The mixture was concentrated and the residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 2:1 to 1:1) to afford compound 1J (500 mg. yield 52.6%) as white solid. NIS (ESI) mnz (M+H) 528.1.

[003621 Step 8: Synthesis of compound 1K To a solution of compound IJ (110 mg, 0.21 mmol) in THF (10 mL) was added LiAIHI (24 mg, 0.63 mmol) at 0°C. The mixture was stirred at 0C for I h. The mixture was diluted with EtOAc (20 mL), quenched with Hi0 (0.03 mL), 15% aq. NaOH (0.03 mL), H 2 0 (0.09 mL) at 0°C. The mixture was warmed up to 25°C and stirred for 15 min, MgSO 4 was added and the mixture was stirred for 15 min. After filtered, the filtrate was separated, and the organics were collected and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to give compound 1K (65 mg, yield 63.2%) as white solid. MS (ESI) m (M+H)- iz 486.3. 'H NMR (DMSO-d 6 400 MHz): 6 8.31 (br. s, I H), 8.14 (d, J= 7.6 H z, I H), 7.38 - 7.31 (m, 5H), 7.12 (d,j:= 7.6 Hz, 1H),5.49 - 5.43 (n, 1H), 5.12 - 5.05 (m, 1H), 4.99 (s, 2H), 4.26 - 4.05 (m, 2H), 3.74 - 3.60 (in, IH), 3.32 3.25 (m, 11), 2.34 - 218 (i, 111), 1.97 - 1.82 (m. 11), 1.71 - 1.33 (in, 7H), 1.32 - 1.05(m, 6H1), 0.97- 0.67 (m, 71).

[003631 Step 9: Synthesis of compound 1 To a solution of compound 1K (65 mg, 0,13 mmol) in DCM (20 mL) was added Dess-Martin periodinane (86 mg, 0.20 mmol). The mixture was stirred at 25°C for 2 hrs. TLC (PE: EA:= 2:1) showed the reaction was completed. The mixture was quenched with a solution of 10% aq. Na2 S 2 O3 and 10% aq. NaHCO 3 (v/v = 1/1, 20 mL). The organics were collected, washed with brine. The organics were collected, dried with Na 2 SO4 , filtered and concentrated to afford compound 1 (2L2 mg, yield: 32.7%) as white solid. MS(ESI) nz (M+H 484.3. 'H NMR (DMSO-d 400 MHz): 3 9.18 (s, 11), 8.77 (s, 1H), 8.35 - 8.20 (m, 11), 7.45 - 7.25 (m, 5H), 7.21 - 710 (in, 11), 5.63 - 5.50 (in, 11), 539 - 5.29(m, 11), 5.00 (s, 214), 430 - 4.19 (m, 114), 413 - 4.03 (m, IH), 231 - 2.17 (m, 1H), 210 - 199 (in, 111), 1.98 - 1.85 (m, 1H), 1.76 - 1.42 (in, 7H), 1.38 - 1.09 (m, 6H), 0.99 - 0.77 (in, 6H). EXAMPLE 2 Benzyl ((1R,4S,7S,5R)-I-formi-4-isobutyl-3,6-dioxo-2,5 diazabiecvelo113.1.01hexadecan-7-vI)carbainate (2)

H H H P N N Pd/C, H2 OHNN NHN I. MeOH. 5 C,2h ' . H2 N+ H2 N"

1K 2A 7B

CkzCI, EtN, DCM

Ph HN 0 HN IpV0H 0 OH

2C 2D

H 0 HN N IPh 0 H - NDess-Mart.n peiodinane, DCM 0 H Ph0 OVN ~~~~ -O sh'C / \~L 0

2C 2

1003641 Step 1: Synthesisof compounds2A and 2B To a solution of compound 1K (86 mg, 177.1 umol) in MeOI-L (20 mL) was added Pd/C (25 mg, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under 1-2 (15 psi) at 5°C for 2 hours. The mixture was filtered. The filtrate was concentrated to afford the mixture of 2A and 2B (crude) (60 mg) was obtained as yellow solid. MS (ESI) mz (M+H)354.2.

[003651 Stp 2: Synthes of pounds2C and 2 To a solution of compound 2A and compound 2B (60 mg) in DCM (10.00 mL) was added CbzCl (19.3 mg, 113.15 umol) and Et 3N (12.6 mg, 124.47 umol) dropwise at 0 °C. The mixture was stirred at 5 °C for ih. The mixture was quenched with water (20 mL) and separated. The aquous layer was extracted with DCM (2 x 15 mL). The combined organic layers were dried and concentrated. The residue was purified by preparatory-HPLC I(Cl condition) to afford compound 2C (16 mg, 14.50% yield) and 2D (38 mg, 34.30% yield) as a white solid.

[003661 Step 3: Syntheis of compound 2

To a solution of compound 2D (14 mg, 28.71 umol) in DCM (15 mL) and DMSO (1.5 mL) was added DMP (24.35 mg, 57.42 umol) at 0 °C under N 2 . The mixture was stirred at 5 °C for 16 hrs under N 2 . The reaction mixture was quenched by addition sat. Na 2 S 2 03 (10 mL), sat. NaHCO3 (10 mL) and stirred for 30 min. The mixture was separated. The organic layers were washed with water (10 mL x 3), brine (10 mL), dried over Na 2 SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated in (i-Pr)2O (3mnL) and filtered to afford compound 2 (12 mg, 23.72 umol, 41.31% yield, 95.97% purity) as a white solid. MS (ESI) m (M+H) 486.2. 1H NMR (DMSO-d6 , 400MHz) 6 9.36 (s, 1H), 8.69 - 8.53 (m, 1H), 8.28 - 8.06 (m, 1H), 7.45 - 7.23 (in, 5H), 7.11 - 6.94 (in, 1H), 5.00 (s21H), 4.32 - 4.04 (m, 2H), 1.78 - 1.07 (i, 20H), 0.99 - 0.76 (m, 6H). EXAMPLE 3

Benzvl ((3S,6S,15R)-15-formyl-3-isobutvl-15-meth1-2,5-dioxo-1,4 diazaccloentadecan-6-vcarbamnate-(3)

H 0 0 HN N 0 H

H

3

[003671 Synthesis of compound 3 Compound 3 was prepared from compound 2D following the procedure of compound 2. Compound 3 (13.3 mg, yield 47.7 %) was obtained as a white solid. iH NMR(400MHz, DMSO-ds) 6 9.24 (s, 1H), 8.67 - 8.58 (m, 1H), 8.24 - 8.13 (in, 1H), 7.38 - 7.23 (in, H), 7.17 - 7.09 (m, 1H), 5.04 - 4.95 (m, 2H), 4.58 - 4.46 (in, 1H), 4.14 - 4.02 (in, 1), 1.96 - 1.84 (m, 1H), 1.69 - 1.32 (in, 8H), 1.30 - 1.10 (in, 10H), 1.01 (s, 3H), 0.93 - 0.72 (in, 6H). MS (ESI) m(M+H) 488.3. EXAMPLE 4

Benzvl ((3S,6S,15R)-15-formyl-3-isobutvl-15-meth1-2,5-dioxo-1,4 diazavclopentadecan-6-yIlcarbamate (4)

CO2H HH

Grubb's2st O H .CO2Et NHNbz O N NHCO2

02Et EDCI HOStDIEA bzHN C H CbzHN H2N

AHN O HNC-ZH H \Y OH Meol-I dioxanie,HC

4C OH OOH 40)

0-KI H H H H

DMP CbzHN N IN DCM, D MSM O

4E

[003681 Step 1: Synthesis of compound 4A To a solution of (S)-2-(((benzyloxv)carbonvl)amino)non-8-enoic acid (5.22 g, 17.08 mmol), EDCI (4.91 g, 25.62 mnol), HOBt (2.31 g, 17.08 mnol) and DIEA (662 g, 51.24 mmol, 9 mL) in DCM (50 ml) was added a solution of ethyl (R)-2-((S)-2-amino-4 methylpentanamido)pent-4-enoate (5 g, 17.08 mmol, HCisalt) in DCM (50 mL) dropwise at 0 °C, and then the reaction was stirred at 15 °C for 26 hrs. The reaction mixture was partitioned between H20 (100 mL) and DCM (50 mL). The organic phase was separated and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=13:1 to 6:1) to give compound 4A (8 g, yield: 86.6%) as a white solid. 11 NIM (400MHz, DMSO-ds) o 8.25 (d, J= 7.3 Hz, 1H), 7.88 (d, J= 8.5 Hz, 111), 7.43 - 7.24 (in, 6H), 5.86 - 5.66 (in, 2H), 5.16 - 4.88 (in, 6H), 4.41 - 4.33 (m, 1H), 4.30 4.22 (m, 1H), 4.14 - 3.93 (m, 3H), 2.46 - 2.34 (in, 2H), 2.02 - 1.97 (m, 211), 1.67 - 1.54 (m, 2H), 1.52 - 1.39 (m, 3H), 1.38 - 1.20 (m, 6H), 1.16 (t, J= 7.2 Hz, 3H), 0.92 - 0.77 (m, 6H). MS(SI)mz (M+H) 544.1

[003691 Step 2: Synthesis of compound 4B To a solution of compound 4A (2 g, 3.68 mmol) in DCM (500 mL) was added Grubbs catalyst 2" generation (312 mg, 368 umol). The mixture was stirred at 40 °C for 16 hrs. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO, Petroleum ether/Ethyl acetate=5/1 ~ 2/1 - DCM: EtOAc = 3: 1) compound 4B (1.7 g, yield: 79.7%) was obtained as a grey solid. IH NMR (400MHz, DMSO-dS) 8.16 (d,J= 7.9 Hz, 2H), 7.32 (s, 5H), 7.05 (d,,J= 7.5 Hz, 1H), 5.44 - 5.23 (m, 2), 5.04 - 491 (in,2H),4.48 - 424 (in, 2H),4.13 - 3.99 (in, 3H), 2.40 (br. s., 1-), 2.28 2.13 (m, 1H), 1.92 (br. s., 2H), 1.73 - 1.62 m, IH), 1.60 - 139 (in,41), L37 - 1.04 (m, 8H), 1.03 - 0.93 (m, 111), 0.90 - 0.74 (in, 61). MS (ESI) il (M+H)+ 516.1L

1003701 Step 3: Synthesis of compound 4C To a mixture of LiAlH 4 (124 mg, 3.27 mmol) in THF (4 mL) was degassed and purged with N 2 for 3 times at 0 °C, and the solution of compound 4B (560 mg, 1.09 mmol) in THF (4 ml.) was added dropwise, and then the mixture was stirred at 15 °C for 2 hrs under N2 atmosphere at 0 °C. The reaction was quenched with 1-120 (0.1 mL), then added 15% NaOH (0.1 mL), and then diluted with THF (20 mL). The mixture was dried over Na 2 SO4 and stirred for 30 min, then filtered; the filtrate was concentrated under reduced pressure to give a residue. The residue was stirred in EtOAc (5 mL) for 30 min and filtered to give compound 4((475 mg, yield: 87.4%) as a white solid. MS(ESf) mz(M+H) 474.1.

1003711 Step 4: Synthesis of compound 4D To a solution of compound 4C (100 mg, 211.14 umol) in MeOH (5 mL) was added Pd/C (30 mg) under N2. The mixture was stirred at 15 Cfor 2 hrs under 1- balloon. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02 , DCM: MeOH = 10: 1) to give compound 4D (45 mg, yield: 51.8%) as a white solid. 1H NMR (400MHz, Methanol-d 4) 6 4.56 (t, J= 7.5 H-z, lH), 4.04 - 3.93 (in, 11-1), 363 - 3.61 (m, 1H), 3.47 - 338 (m, 2), 185 1.51 (m, 6H), 1.49 - 1.14 (in, 121-1), 1,13 - 1.03 (m, 11-1), 0.95 (t, J= 6.6 lz, 6H). IS (ESI) Iz (M+1-1) 342.1.

1003721 Step 5: Synthesis of compound 4E To a solution of benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (36 mg, 144.96 umol) and compound 41) (45 mg, 131.78 umol) in 120 (2 mL) and dioxane (4 mL) was added

K 2 CO3 (1821 mg, 131.78 umol). Then the solution was stirred at 15 C for 16 hrs. This solution was diluted with DCM (20 mL) and washed with 1H20 (20 mL), sat. NaHCO3 (20 mL), dried over Na2 SO4 , filtered and the solvent was removed in vacuo. The residue was purified by preparator-HPLC (HCI condition) to give compound 4E (40 mg, yield: 63.8%) as a white solid. 'H NMR (400MHz, CDC13 ) 6 7.47 (d, J= 8.4 Hz, 11), 7.31 (br. s., 5H), 705 (d, J= 7.5 Hz, 11), 5.79 (d, 7.1I Hz, 111), 5.05 (br. s., 21), 4.42 (d, 1= 6.2 Hz, 111), 4.28 (br. s., 111), 3.96 (br. s., 111), 3.55 - 3.38 (m, 211), 1.85 (br. s., 11-1), 1.54 (br. s., 511), 1.45 - 1.00 (in, 14H), 0.88 (br. s., 6H). MS (ESI) mlz (M+H) 476.1.

[00373] Step 6: Synthesis of compound 4 To a solution of compound 4E (100 mg, 211.15 umol) in DCM (10 mL) and DMSO (1 mL) was added DMP (269 mg, 633.45 umol). The mixture was stirred at 15 °C for 16 hrs. The reaction mixture was quenched by addition sat. NaHCO3 (10 mL) and Na 2 S 203 (10 mL) at 15 °C, and then the mixture was stirred until the solution was clear, and extracted with DCM (10 mL x 2). The combined organic layers were washed with H20 (20 mL x2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue in DCM: PE:= 10: 1 (20 mL) was stirred, filtered, the cake 4 (53 mg, yield: 50%) was obtained as a white solid. 11 NMR (400MHz, DMSO-ds) 5 9.42 (s, 1H), 8.38 (d, J= 7.5 Hz, 1H), 8.20 (d,,J= 8.8 Hz, 1H), 7.34 (br. s., 5H), 7.06 (d,,J= 6.6 Hz, 1H), 5.10 - 4.93 (in, 2H), 4.51 (d,1 = 7.5 Hz,1H), 4.36 (br. s.,1H), 4.15 (br. s.,1H), 1.79 (br. s., 1H), 1.70 - 1.39 (in, 6H), 1.38 - 0.98 (m, 12H), 0.89 (dd,,J= 5.5, 19.2 Hz, 6H). NIS (ESI) inz (M+H)+ 474.2. EXAMPLE 5 Benzvl ((3S,6S,15SE)-15-formyl-3-isobuty-2,5-dioxo-1,4-diazacvclopentadec-12-en-6 Vllcarbamate (5) and Benzyl ((3S,6S,15SZ)-15-formvi-3-isobutyl-2,5-dioxo-1,4-diazaevelo entadec-12-en-6 VI)carbamate (6)

H _10 HNN~. 0 - NH

zHN- C DCM,-DMS

4 E E

O NH0 NH NH

CbzHN o DM C-CM, DM30 N\

SE H. 0y-^O

0 0 N\H NI 0 'NH-K1NH j NH

OHH CDONA, DIMP H

6Z 6

[00374] Step 1: Synthesis of compounds 5E and 6Z The product 4Cwas separated by SFC to give two isomers. SFC method: Column:AD (250mm*30mm,5um), Mobile phase: A: CO2 B: IPA (0.05%

NH 3 1-120),Gradient: 30% of B Flow rate: 70 mL/min Column temperature: 35 °C) The product was separated by SFC to give compound 5E (Rt = 4.465 min, 200 mg) and compound 6Z(Rt= 4.608 min, 50 mg) both as white solid. Compound 5E: 1H NMR (400MHz, Methanol-.4) 6 7.33 (br. s., 5H), 5.37 (br. s., 2H), 5.16 4.99 (m, 2H), 4.50 (br. s., 1H), 4.15 (br. s., 1H), 3.89 (br. s., 1H), 3.53 - 3.36 (m,1H), 2.31 (d, J= 14.6 Hz, 11-1), 2.13 - 1.77 (m, 5H), 1.69 - 1.47 (m, 4H), 1.42 - 1.02 (m, 61-1), 0.91 (dd, J=5.7, 12.8 Hz, 6H). Compound 6Z: 11 NMR (400MI1z, Methanol-di) 6 7.33 (br. s., 51), 5.37 (br. s., 2-), 5.15 500 (m, 2-), .48 (br. s., 11-1), 4.10 (d, J= 6.2 Hz, 11) 3.93 (br. s., 11-1), 3.54 (br. s. 11-), 2.26 (br. s., 1H), 2.04 (br. s., 1H), 1.81 (br. s., 1H), 1.58 (br. s., 5H), 1.47 - 1.12 (m, 8H), 0.95 - 0.84 (m, 6H).

[003751 Synthesisof compound 5 Compound 5 was prepared from compound 5E following the procedure of compound 4. Compound 5 (100 mg, yield 44.7 %) was obtained as a white solid. IH NMR (400MHz,

DMSO-d) 6 9.40 (s, 1), 8.23 - 809 (in, 211), 7.35 - 7.25 (s, 51), 7.11 (d, J= 7.5 Hz, IH), 543- 5.33 (m, 1H), 5.32 - 5.23 (m, 1), 5.04 - 4.94 (m, 2H), 4.51 - 4.42(m, 1H), 4.28 (t, J= 7.7 Hz, 11), 4.10 (d, J= 3.1 Hz, 1H), 2.55 - 2.51 (m, 1H-), 2.12 - 1.91(m 31-), 1.74 - 1.64 (m, 1H), 1.63 - 1.40 (m, 4H), 1.34 - 1.12 (m, 5H), 1.00 (br. s., 1H), 0.93 - 0.72 (m, 6H). MS (ESI) mlz (M+H)' 472.2.

[003761 Synthesis of compound 6 Compound 6 was prepared from compound 6Z following the procedure of compound 4. Compound 6 (6 mg, yield 28.6 %) was obtained as a grey solid. 'H NMR (400MHz, DMSO-d6) 9.42 (s, 1H), 8.28 (d, J= 8.6 Hz, 1H), 8.03 (d, J= 7.0 Hz, 1H), 7.32 (s, 5H), 7.18 (d, J= 7.0 [Iz, 1), 5.35 - 5.29 (m, 1IH), 523 (br. s., 1H), 5.08 - 4.91 (m, 2H), 4.56 4.41 (in, 11-1), 436 - 4.25 (m, IH), 4.05 (br. s., 1H), 2.33 - 2.22 (m, IH), 2.05 - 190 (m, 21-1), 179 - 100 (in, 12H), 0.99 - 0.61 (m, 6). MS (ESI) m z (1+i)472 2. EXAMPLE 6 Compounds 7-13 CO 2 H EtNH!oc NIHE'Qc NH 2 HC: -' ' NHBoc COOH K2 M CO COOEt 1 EDCI, HOBt, DIPEA, DCM

7A I 7B 2IHCiEtOAc

H COOH . N NCO2Et

N COOIt NHNo,

H DCIHOBt, DIPEA, DCM 77E 7C

0IN- H H N C H O CHN- N O

Grubbs2nd cat. N,." --- '. NK

7F 7G

8,-,-sepraion 9 ,N"+ - 0 HN N

NN H

7Z 7E

H0 0- I-N-_ N DMP / o0<N H

, DCM 0 \ IC ~TFA, 'y. H N / CM

--------- ---- 7E7

OMP H 0 \, H-1-YNH NH A.Y -Na---KC ----------- o--4 ~

/ H.7

8 SA

H Pd/rCTHF ~O ayN-K 'N'

100 N"

H HN0 a H.,N N *~ -'. DMP -"'ak---------- 0 ~ HH

N... H

7Z 1

0 0 HN N ', O H Pd/C, MC IF HN--k,,, ~'OH~ - iy OH

N,;' H

7G 11A 0 H DIMPDCM /V H

0HN

H.2

7F 12 ICI

\0-H 1 /L 1-1

K2 CO 3 , dioyxane,H2 0' THF

H H \N, N

DMP H cPENC 2 / DCM / TFA, Py.DCM 121 12

H HH HN H OH H \ OHN- N A DMPH

13A - DGiv 13

[003771 Step 1: Synthesis of compound 7A To a solution of (S)-2-((tert-butoxvcarbonyl)amino)pent-4-enoic acid (50 g, 23.23 mmol) in DMF (60 mL) was added K2C(3 (6.42 g, 46.46 mmol) and EtI (5.43 g, 34.85 mmol). The mixture was stirred at 20 °C for 16 hrs. The reaction mixture was quenched by addition H120 (300 mL) at 0 °C, and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO4 , filtered and concentrated under reduced pressure to give compound 7A (5.5 g, yield: 97.31%) as a yellow oil. iH NMR (400MHz, CDCl 3) 5 5.81- 560 (in, 1H), 5.19 - 4.98 (in, 31-1), 4.35 (d, J= 6.2 Hz, 11-1), 4.26 - 409 (m, 21), 2.63 - 2.39 (in,21-), 1.43 (s, 91-1), 1.32 - 1. 19 (m, 31H)

[003781 Step 2: Synthesis of coiound 7B To a solution of compound 7A (1.0 g, 4.11 mmol) in EtOAc (5 mL) was added HCI/EtOAc (4M, 5.1 iL) at 15 °C. The mixture was stirred at 15 °C for 2 hrs. The reaction was concentrated to give compound 7B (730 mg, yield: 98.9%, HCisalt) as a white solid. 1H NMR (400MHz, CDCl 3 ) 6 8.76 (br. s., 3H), 5.93 - 5.76 (m, 1H), 5.38 - 5.18 (m, 2H), 4.35 4.13 (m, 3H), 2.89 - 2.78 (m, 2H), 1.38 - 1.22 (m, 3H).

[003791 Step 3: Synthesis of coupled product 7B-1 To a solution of (tert-butoxcarbonyl)-L-leucine (900 mg, 3.89 mmol) in DCM (10 mL) was added EDCI (1.12 g, 5.84 mmol) and HOBT (525.78 mg, 3.89 mmol) and DIEA (1.51 g, 11.67 mmol). The mixture was stirred at 20 °C for 15 min, then added compound 7B (699 mg, 3.89 mmol). The mixture was stirred at 20 Cfor 16 hrs. 1-H0 (20 mL) was added, and the mixture was extracted with DCM (10 mL x 3), the organic phase was washed with brine (20 mnL), dried over Na2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate

= 5/1 to 2/1) to afford the coupled product 711-1 (750 mg, yield: 75.2%) as a white solid. 1H NMR (400MHz, CDC 3) o 6.54 (d, J= 7.5 Hz, 1H), 5.74- 5.59 (I 1H), 5.11 (d, J= 12.3 Hz, 2H), 4.84 (br. s., 1H), 4.69 - 4.55 (in, 1H), 4.26 - 4.02 (in, 3H), 2.65 - 2.40 (in, 2H), 1.75 1.63 (in, 2H), 1.52 - 1.37 (in, 10H), 1.27 (t,,J= 7.1 Hz, 3H), 0.93 (t,J=5.3 Hz, 6H).

[003801 Step4: Svithesis of compound 7C The mixture of coupled product 7B-1 (330 ing, 925.77 umol) in EtOAc (5 mL) and HC/EtOAc (4M, 4.6 mL) was stirred at 18 C for 2 hrs. The solution was concentrated to give compound 7C (270 ing, yield: 99.6%, ICI salt) as a white solid, which was used to the next step without purification. 1H NMR (400MHz, CDCl 3 ) ) 8.38 (br. s., 3H), 7.90 (br. s., 11), 5.89 - 5.73 (in, 1H), 5.28 - 5.01 (in, 2), 4.56 (br. s., 1H), 4.35 - 4.02 (in, 314), 2.62 (br. s., 2H), 1.84 (br. s., 31), 1.25 (t, J:= 6.8 Hz, 311), 0.98 (d, J= 8.4 H z, 6H).

[003811 Step 5: Synthesis of compound 7D To a solution of (S)-2-((tert-butoxvcarbonvl)amino)non-8-enoic acid (1.85 g, 6.83 mmol) in DCM (40 mL) was added EDCI (1.96 g, 10.25 mol) and HOBT(922.87 mg, 6.83 mmol) and DIEA (265 g, 20.49 mmol, 3.6 mL), then added compound 7C (2.00 g, 6.83 mmol, HCI salt). The mixture was stirred at 20 °C for 16 hrs. The reaction mixture was added H 2 0 (50 mL), extracted with DCM (20 mL x 3), the organic phase was washed with brine (50 mL), dried over Na2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate = 5/1 to 3/1). Compound 7D (2.8 g, yield: 80.4%) was obtained as a white solid. 'H NMR (400MHz, CDCI) 659 (d, J= 6.2 Hz, 11-1), 6.49 (d, J= 7.9 Hz, 111), 5.86 - 5.58 (in, 2H), 5.09 (d, J= 12.3 Hz, 2H), 5.01 - 4.87 (in, 3H), 4.63 - 4.53 (in, 1H), 4.49 - 4.37 (in, 1H), 4.24 - 4.10 (in, 2), 4.02 (d, J= 6.2 Hz, 1H), 2.60 - 2.44 (in, 2), 2.05 - 1.97 (in, 2H), 1.84 1.76 (in, 1H), 1.69 - 1.48 (in, 4H), 1.42 (s, 9H), 1.37 - 1.18 (in, 8H), 0.99 - 0.84 (in, 6H).

[003821 Stepfi6 Sythesis of compound 7F To a solution of compound 7D (700 mg, 1.37 mmol) in DCM (300 mL) was added Grubbs catalyst 2" generation (58.2 mig,68.5 umol). The mixture was stirred at 40 °C for 16 hrs under N 2 . The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate:= 5/1 to 2/1) to give compound 7F (520 mg, yield: 78.8%) as a white solid. 1H NMR (400MHz, CDCl) 6 6.51 (d, = 7.5 Hz, 1H), 6.24 (d, J= 8.8 Hz, 1H), 5.49 - 5.35 (in, 1H), 5.28 - 5.18 (in, 1H), 5.16 (d, J= 7.9

Hz, 11), 4.65 - 4.46 (m, 2H), 4.21 (q, J= 7.1 Hz, 21), 4.05 (t, J= 7.3Hz, 11), 2.71 - 2.57 (m, 1-), 2.41 - 2.34 (in, 111), 2.05 - 1.99 (in. 311), 174 - 1.35 (m, 16H), 1.33 - 109 (in, 611), 0.90 (dd, J= 6.2, 10.6 Hz, 61). MS (ESI) z (M+H)482.3.

[003831 Step 7: Synthesis of compound 7G and separation to afford 7Z and 7E To a solution of compound 7F (900 mg, 1.87 mmol) in THF (15 mL) was added LiBH4 (122.1 mg, 5.61 mnol). The mixture was stirred at 15 °C for 16 hrs. The excess lithium borohydride was quenched by addition of aqueous saturated ammonium chloride solution (I mL) at 0 °C. The mixture was partitioned between ethyl acetate (20 mL) and aqueous saturated NaHCO 3 (30 mL). The aqueous layer was back extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over Na2 SO 4, filtered and concentrated under reduced pressure to give a residue 7G. The residue was purified by prep HPLC (HCl condition) and then separated by SFC ((Column: IC(250mm*30mm,10um)), Mobile phase: A: CO 2 B: MeOH (0.05% NH 3 .H20) Gradient: 15% of B Flow rate: 60 mL/min Column temperature: 35°C)) to give compound 7E (400 mg, yield: 48.7%) and compound 7Z (40 mg, yield: 4.9%) both as white solid. Compound 7E: H NMR (400MHz, DMSO-d) 6 8.07 (d, J= 8.8 Hz, 1H), 7.67 (d,.J = 8.4 Hz, 1H), 6.32 (d, J= 7.1 Hz, 1H), 5.37 - 5.22 (m, 2H), 4.66 (t, J= 5.5 Hz, 1H), 4.45 433 (in, IH), 4.00 (br. s., IfH), 3.74 (br. s., 1H), 3.30 - 3.24 (in,1), 3.19 - 3.08 (minH), 2.33 - 221 (in, 11), 2.01 - 180 (in, 31), 1.72 - 1.61 (in, 111), 1.57 - 0.91 (in, 191), 0.83 dd,,J= 64, 143 Hz, 61). MS (ESI) wz (M+H)+440.2. Compound 7Z: 1H NMR (400MHz, Methanol-d 4) a 5.37 (br. s., 2H), 4.53 - 4.43 (in, 1H), 4.08 - 3.88 (m, 2H), 3.60 -_3.48 (m, 2H), 2.33- 2.20 (m, 2H), 2.14 - 1.93 (m, 2H), 1.88 1.17 (m, 20H), 1.00 - 0.75 (in, 61).

[003841 Step 8: Synthesis of compound 7: Tert-butyl ((3S,6S,15SE)-15-formvl-3-isobuty1-2,5-dioxo-1,4-diazaevelopentadec-12-en 6-1carbamate To a solution of compound 7E (150 mg, 341.23 umol) in DMSO (100 uL) and DCM (8 mL) was added DMP (289.5 mg, 682.45 umol). The mixture was stirred at 15 °C for 16 hrs. The reaction mixture was quenched by additionsat. NaHC 3 (10mL)andsatNa 2 S 2 O 3

(10 mL) at 15 °C, and then the mixture was stirred until the solution was clear, and extracted with DCM (10 mL x 2). The combined organic layers were washed with H20(20 mL x 2) and brine (20 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 7 (140 mg, yield: 89.1%) as a white solid. 1HNMR (400MHz, DMSO-d6) o 9.39 (s, 1H), 8.18 - 8.02 (m, 2H), 6.54 (d, J= 7.5 Hz,1H), 5.42 - 5.32 (m,1H), 5.29 - 5.20 (m, 1H), 4.49 - 4.39 (m, 1H), 4.23 (br. s., 11), 3.98 (br. s., 1H), 2.17 - 2.05 (m, 1H), 2.01 1.85 (m, 2H), 1.77 - 1.54 (m, 3H), 1.49 - 1.08 (m, 1711), 0.99 (br. s., 1H), 0.92 - 0.74 (m, 6H). IS (E SO)iz M+H)-438.3.

[003851 Step 9: Synthesis of compound 8A To a stirred solution of compound 7 (180 mg, 411.36 umol) in DCM (10 mL) was added isocyanoethane (27.2 mg, 493.63 umol) (2 drops) and Py (130.2 mg, 1.65 mmol) at 0 °C, then TFA (93.8 mg 822.72 umol) was added slowly dropwise. The reaction mixture was stirred for 30 min at 0C Then the reaction temperature was allowed to 16 °Cand stirred for 16 hrs. The mixture was diluted with DCM (10 mL), washed with IN HCi(20 mL x 2), saturated NaHC3 (20 mL x 2). dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by preparatory-HPLC (HCI condition) to give compound 8A (100 mg, yield: 47.6%) as a white solid. 'H NMR (400MHz, MeOD) 6 5.42 - 5.31 (m, 2H), 4.61 - 4.48 (m, I H), 4.33 (br. s., 11-1), 4.24 (d,J=: 11.0 lz, I H), 4.11 - 3.94 (m, 2H), 3.26 - 3.08 (m, 21-1), 2.23 (br. s., 11-1), 2.04 (br. s., 11-1), 1.96 (br. s., 11-1), 187 - 1.73 (m, IH), 1.71 - 1.50 (n, 51), 1.42 (br. s., 91-1), 1.34 - 1.19 (in, 5-1), 1 12 (t,J= 7.1 Hz, 31-1), 0.98 - 0.83 (m, 61-1). MS (ESI) nz (M+H 511.4.

[003861 Step 10: Synthesis of compond 8: Tert-butvl ((3S,6S,1-5S,E)-15-(2-(ethylamino)-2-oxoacetyl)-3-isobiutvl-2,5-dioxo-,i4 diazacloentadec-12-en-6-I1carbaniate Compound 8 was prepared from compound 8A following the procedure of copound 7. Compound 8 (80 mg, yield 75.5 %) was obtained as a white solid. 1H NMR (400MHz, DMSO-d) 6 8.71 (br. s., 1H), 8.18 - 8.02 (m, 2H), 6.52 (d, J= 7.1 Hz, 1H), 5.47 - 5.37 (m, 1I), 5.30 - 5.24 (m, 1H) 5.00 (br. s., fI), 4.50 - 4.40 (m 11), 4.00 (br. s., 11), 3,20 - 3.05 (m, 21H), 244 - 2.38 (m, 1iH), 2.13 (br. s., 1-), 1.95 (br. s., 21-1), 1.69 (br. s, 11-1), 1.62 - 1.09 (n, 191). 1.03(t,J= 7.1 Hz, 31-1), 091 - 0.67 (in, 61). MS (ESI) iz (M+H) 509.4. 3.

1003871 Step 11: Synthesis of compound 9: Tert-butyl ((3S,6S,15S)-15-(2-(ethiylanino)-2-oxoacetyl)-3-isobutyl-2,5-dioxo-1,4 diazacyclopentadecan-6-vi)carbamate

To a solution of compound 8 (50 mg, 98.30 umol) in THF (5 mL) was added Pd/C (10 mg) under N 2 . The mixture was stirred at 15 °C for 2 hrs under H2 balloon. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparatory-HPLC (HCI condition) to afford compound 9 (15.5 mg, yield: 30.9%) as a white solid. 11-H NNIR(400MHz, DMSO-d) 8.39 (br. s., 111), 8.05 (d, J=: 7.5 Hz, 111), 7.87 (d, J= 8.5 Hz, 11). 6.03 (br. s., 1H), 5.17 - 5.08 (in, 11), 457 - 4.49 (m, 1-I), 4.11 - 4.03 (m, ), 3.21 - 3.15 (i,21-1), 1.85 - 1.75 (m, 11-1), 172 - 1.59 (in, 211), 1.55 - 1.42 (m, 4H), 1.41 - 1.17 (in, 21H), 1.09 (t, J= 7.3 Hz, 3H), 0.93 - 0.87 (m, 6H). MS (ESI) m/z (M-H) 511.2.

[003881 Step 12:_Svnthesis of compound 10: Tert-butyl ((3S,6S,5SZ)-15-forinvl-3-isobutyi-2,5-dioxo-1,4-diazaceoipeitadec-12-en 6-yl)carbamate Compound 10 was prepared from compound 7Z following the procedure of compound 7. Compound 10 (16.2 mg, yield'27 %) was obtained as a white solid. 1H NNIR (400M1-lz, DMSO-d )6 6 9.40 (s, FI), 8.24 (d,,J= 8.8 Hz, 1-), 7.91 (d, J= 7.1 Hz, FI), 6.62 (d,,J= 7.5 Hz, 1H), 5.39 - 5.26(m 1H11), 5.24 - 5.12 (m, 111), 4.52 - 4.41 (in, 11-1), 4.26 (d, J= 3.5 Hz, 11). 3.94 (br. s., 111), 2.41 (br. s., IH), 2.31 - 2.20 (in, 11), 2.03 - 188 (in, 21), 1.70 - 1.50 (m, 2H), 1.51 - 1.08 (in, 18H), 0.91 - 0.73 (in, 6H). MS (ESI) n (M1H)+438.3.

[003891 Step 13: Synthesis of compoundI1 A To a solution of compound 7G (100 mg, 227.48 umol) in MeOH (5 inL) was added Pd/C (30 mg) under N 2 . The mixture was stirred at 15'C for 16 hrs under 12 balloon. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 11A (70 mg, yield: 69.7%) was obtained as a white solid. 'H NMR (400MHz, CDCl) 6 7.77 (d, J= 8.8 Hz, 1H4), 712 (d, J= 7.9 Hz, 11), 554 (d, J= 7.9 Hz, IH) 4.48 4.40 (n, 111), 4.30 (br. s., 11-1), 397 (br. s., 11-1), 3.55 - 3.42 m, 21-), 1.85 - 1.75 (in, 11-1), 1.69 - 1.50 (in, 511). 1.45 - 1.02 (m, 221-1),0.89 (t, J= 6.2 Hz, 61-1). MS (ESI) w: (M+-H)442.2.

[003901 Step 14: Synthesis of compound 11: Tert-butvl ((3S,6S,15S)-15-formyl-3-isobut1-2,5-dioxo-1,4-diazaevelopentadecan-6 vll~carbamate Compound 11 was prepared from compound 11A following the procedure of compound 7. Compound 11 (29 mg, yield 38.3 %) was obtained as a white solid. 1 H NMR

(400MHz, DMSO-d) 5 9.39 (s,111), 8.36 (d, J= 7.5 Hz, 1H), 8.13 (d, J= 8.8 Hz, 1H), 6.41 (d, J 7.1 Hz, 11-1), 4.48 (d, J= 7.5 Hz, 11), 430 (br. s., 11), 4.03 (br. s., 11), 176 (br. s., 11), 1.65 - 1.55 (in. 2H), 1.48 - 1.05 (m, 25H), 0.89 -0.82 (i, 61). MS(ESI) nz(M+H) 440.3.

[00391] Step 15: Synthesis of compound 12A To a solution of compound 7F (800 mg, 1.66 minol) in EtOAc (10 mL) was added dropwise -ICI/EtAc (4M, 10 mL) at 0°C. Then the mixture was stirred at 15 °C for 4 hrs. The reaction mixture was concentrated under reduced pressure to give compound 12A (700 mg, crude, HCl) was obtained as a white solid. The crude product was directly used without further purification. 'I-I NMR (400MHz, CDCLs) 8.66 (d, J= 9.3 Hz, 11), 8.52 (d, J= 8.8 Hz, 11), 8,24 (br. s, 31), 5.45 - 5.24 (m, 21-), 4.54 d, J= 7.9 Hz, IH), 4.36 t, J=: 9.3 lz, 11), 4.07 (d, J= 5.7 Hz, 211), 3.80 (br. s., 11). 226 - 2.11 (in, 11), 1.96 (br. s., 2H), 1.76 143 (m, 4H), 1.41 - 0.99 (in, 101), 0.90 (dd.,J= 6.0, 16.5 Hz, 61). MS (ESI) nz(M+H) 382.0.

[003921 Step 16: Synthesis of compound 12B To a solution of 2,5-dioxopyrrolidin--yl (2-(2-methoxyethoxy)ethl) carbonate (750 mg, 2.87 inmol), compound 12A (600 mg, 1.44 mmol, HC) in dioxane (10 mL) and 1120(5 mL) was added K 2CO3 (298 mg, 2.15 mmol) at 0 °C. The mixture was stirred at 20 °C for 3 hrs. This solution was added with H 20(100 mL), filtered and the cake was dissolved with DCM (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product compound 12B (450 mg, yield: 42%) as a grey solid was used into the next step without further purification. 1- NMR (400MHz, CDCl 3)6 6.51 - 6.37 (in, 11), 6.24 (d, J= 8.8 Hz, 11), 5.63 - 5.51 (in, 111), 5.44 - 538 (in, 1H), 5.30 - 5.17 (in, 11), 4.64 - 4.45 (m, 2H), 4.27 - 4.12 (m, 4H), 3.74 - 3.59 (m, 4H), 3.58 - 3.50 (m, 2H), 3.38 (s, 3H), 2.73 - 2.60 (in, iH), 2.33 - 2.25 (m, IH), 2.11 - 1.90 (in, 3H), 1.71 - 1.46 (in, SH), 1.42 1.14 (in, 9H), 0.98 - 0.78 (m, 6H). MS (ESI) inz (M+H)+ 528.2.

[003931 Step-17: Synthesis of com ound 12C To a mixture of LiAlH 4 (108 mg, 2.84 mmol) in THF (10 mL) was degassed and purged with N 2 for 3 times at 0 °C, and the solution of compound 12B (500 mg, 947.60 umol) in THF (10 mL) was added dropwise, and then the mixture was stirred at 0 °C for2 hrs under N 2 atmosphere. The reaction was quenched with H20 (0.1 mL), 15% NaOH (0.1 mL), then added H20 (0.3 mL) and then diluted with TI-F (20 niL). The mixture was dried over Na 2 SO 4 and stirred for 30 min, then filtered the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparatory-HPLC (1HC condition) to give compound 12C (150 mg, yield: 32%) as a white solid. 'H NMR (400MHz, CDCIl) o 7.59 (d, J= 9.0 Hz, IH), 6.42 (d, J= 8.2 Hz, IH), 6.01 (d, J= 7.8 Hz, 1H), 5.44 - 5.32 (m, 2), 4.68 - 4.56 (mi, H), 4.50 (br. s., 1H), 4.26 - 413 (in, 211), 4.04 (br. s, 111), 368 - 3.62 (n,411), 3.58 - 3.46 (n, 311), 3.38 (s, 31), 252 -2.42 (i, iH 2.12 - 1.91 (m, 411), 1.76 1.49 (m, 611), 140 - 1 10 (in, 6H), 0.98 - 0.86 (m, 611). MS (ESI) mz (M+NH)486.2.

1003941 Step 18: Synthesis of compound 12: 2-(2-methoxvethoxy)ethyl ((3S,6S,15S,E)-15-formyl-3-isobutvl-2,5-dioxo-1,4 diazacyclopentadec-12-en-6-vI)carbanate Compound 12 was prepared from compound 12C following the procedure of compound 7. Compound 12 (130 mg, yield 77.5 %)was obtained as a white solid. 1H NMR (400MHz, CDCl 3)69.56 (s, IH), 6.65 (d, J= 7.0 Hz, IH), 6.53 (d, J= 7.8 Hz, IH), 5.58 (d, J = 7.4Hz, iH), 5.45 - 5.40 (in, 1H), 5.28 - 5.16 (m, 1H), 4.62 - 4.50 (m, 2H), 4.27 - 4.10 (m, 3H), 3.75 - 3.59 (in, 411), 3.55 (d,J= 4.3 Hz, 2), 3.38 (s, 311), 2.75 - 2.65 (m, IH), 2.33 2.20 (n, 1H), 2.09 - 1.91 (n,3H), 1.70 - 1.47 (in, 4H), 1.41 - 1.10 (m, 6H), 0.92 (dd,J=: 6.3, 13.7 Hz, 611) MS (ESI) mz(M1H) 484.2.

1003951 Step 19: Synthesis of compound 13A Compound 13A was prepared from compound 12 and isocyanocyclopropane following the procedure of compound 8A. Compound 13A (40 mg, yield 40.9 %) was obtained as a white solid. 'H NMIR (400M z, CDCls) 6 8.50 (br. s., 1i), 7.19 (br. s., IH), 6.87 - 6.59 (m, IH), 6.13 (d, J= 7.4 Hz, 1), 5.47 - 5.21 (m, 2H), 5.01 - 4.50 (in, 3H), 4.38 4.08 (m, 4H), 3.76 - 3.45 (m, 6H), 3.38 (s, 3H), 2.76 - 2.60 (m, 1H), 2.39 (d, J= 13.3 Hz, 1H), 2.16 - 1.77 (m, 4H), 1.76 - 1.45 (in, 6H), 1.38 -1.20 (m, 4H), 1.15 -1.06 (m, 1H), 0.99 0.88 (m,511),0.82 - 0.62 (m,2H),0.55- 0.35(m,21). MS(ESI)mz (M+H[) 569.1.

[003961 Step 20: Sythesis of compound 13: 2-(2-methoxvethoxv)ethyl ((3S,6S,15S,E)-15-(2-(cyclopropilamino)-2-oxoacetyl)-3 isobutyli-2.5-dioxo-1,4-diazaeveloIentadec-12-en-6-vI)carbamate Compound 13 was prepared from compound 13A following the procedure of compound 7. Compound 13 (15 mg, yield 28.6 %) was obtained as a white solid. 'H NMR

(4(X)1HIz,DM-i,,) 6 8.73 (br. s., IH), 8.13 (hr. s,,21-1),6.94 (hrs,, 11-1), 5.40 (hr.s.,11-1), 530 (hr. s., 11-1), 5.00 (hr.s., 111), 4.45 (hr" ., 111), 4.00 (hr s.,311).3.60 - 3.34 (mn,61-1), 3.21 (hr.s., 311),2172(hr. s.,111), 2.42-2129 (in, 111),2108 (hr.s.1, 11,1.95 (hr.s., 2141).1.67 (br. s.,111), 1.57 - 1.09(mn,91), 1.01 (hr. s.,111), 0.95 - 0.71(mn,611), 0.70 - 0.45(in4H). MS (ESI) inz' (M+Hj-'567.3. EXA MPLE 7

Compounids 14417

Bod-IN ELt 2 HN CO2 HE Bo c c CHViOOeH.41 HIdoxane - HH OE E61c. EOG, H0Et,,CAPP.CM 0 t-A 11 14A

I-I E C(D2 H " /00

1CEDC. HO~t, D!FEA.0CM 14D

Hoveyda-C-rubbs' lst H" C) tL I',TH Generation catalyst - 0 '' L'HTF

DCM, <0.0IM, 5'"C,,48h ""~

H

15'C 1611/

~HN-- I H 0 H N , 0 HYN- N"'

N"'K"'~ E.'C, TFFA:Py N"" ________________ H

14 // ISA

0~

N"

15

I H 00 o NqN / HHOH 0 C O~N~~N\-k / C'- H

H~~gips.), THF. 0-- C DM', DCIM H 14FN DMP-C WIkinson's cat. I-I 16

16A

H O N OH 0 HN

1. H2 (15psI), Pd/C, MeOH H'M DCNH 14F ----- ----------- * 17A 2.P-HL 17A 1

[003971 Step 1: Synthesis of compound 14A To a solution of ethyl (IR,2S)-1-((tert-butoxycarbonyl)amino)-2 vinylcyclopropane-1-carboxylatecompound (7.0 g, 27.42 mmol) in EtOAc (50 mL) was added HCL/dioxane (4M, 40 mL). Then the reaction was stirred at 15 °C for 3 hours. Then PE (200 mL) was slowly added to the reaction. The white solid was filtered, collected and dried in vacuum to give compound 14A (5.26 g, crude, HCisalt), which was used directly for the next step without further purification. 1 HNMR(DMSO-d 6 , 400M-z) 9.21 (br. s., 31-1), 5.71 - 5.55 (in. 11) 5.35 (d, J= 17.2 Hz, 111), 5 18 (d, J= 10.6 IHz, I) 4.27 - 4.10(, 21-1), 2.58 - 2.51 (m, 1H), 1.93 - 1.82 (in, 1H), 1.67 - 1.57 (m, 1H), 1.21 (t, J=7.1 Hz, 3H).

[003981 Step 2: Synthesis of compound 141B To a solution of (tert-butoxycarbonyl)-L-Ieucine (6.3 g, 27.4 miol), compound 14A (5.3 g, 27.4 minol) and HOBt (3.7 g,27.4 miol) in DCM (150 mL) was added EDCI

(7.9 g, 41.1 minol) and DIPEA (10.6 g, 82.2 minol, 14.4 mL). The reaction was stirred at 15 °C for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and then washed with HCl (80 mL, 0.5M), sat. NaHCO3 (70 mL x 2) and brine (80 mL). The organics layers were dried over Na2SO4, filtered and concentrated to afford compound 14B (10 g, yield: 85.7%) as off white solid, which was used directly for next step without further purification. 1H- NMR (DMSO-d ,6400MHz) 6 8.64 (s, 1H), 6.71 (d, J= 8.4 Hz, 1H), 5.70 - 5.53 (in, 1H), 5.33 - 5.20 (in, IH), 5.15 - 5.00 (m, 1H), 4.04 - 4.00 (in, 2H), 3.97 - 3.88 (m, 1H), 2.12 (q, J= 8.7 Hz, 111), 1.65 - 1.50 (in, 2H), 1.46 1.29 (m, 11H), 1.23 - 120 (in, 111), 1.13 (t,J= 7.3 Hz, 3H), 0.91 - 0.79 (m, 6H). MS (ESI) wz(M+Na) 3911.

[003991 Step 3:_Svnthesis of coupled product 14C To a solution of compound 14B (9.9 g, 26.9 mmol) in EtOAc (50 mL) was added HCI/dioxane (4M, 75 mL). The reaction was stirred at 15°C for 6 hours. The reaction mixture was concentrated and then PE (700 mL) was added. The solid was collected by filtered and dried in vacuum to afford compound 14C (795 g, yield: 97.1%, HCl salt) as white solid, which was used directly for the next step without further purification. 11 NMR (DMSO-d, 400MHz) 6 9.35 (s, 1H). 8.32 (br. s., 3H), 5.81 - 5.62 (m, 1H), 5.27 (dd, J= 1.3, 17.2 Hz, 1H), 5.11 (dd,,J= 1.3, 10.1 Hz, iH), 4.13 - 3.99 (in, 2H), 3.68 (br. s., IH), 2.21 (q,,J = 8.8 Hz, iH), 1.75 - 1.48 (in, 4H), 1.43 - 1.31 (m, 1H), 1.16 (t, J= 7.1 Hz, 3H), 0.99 - 0.81 (m, 6H).

[004001 Step 4:_Svnthesis of compound-14D To a solution of compound 14C (2.0 g, 6.56 mmol), (S)-2-((tert butoxycarbonyl)amino)non-8-enoic acid (1.78 g, 6.56 mmol) and HOBt (887 ing, 6.56 mmol) in DCM (80 mL) was added EDCI (1.90 g, 9.91 mmol) and DfPEA (2.54 g, 19.68 mmol,3.44 mL). Then the reaction was stirred at I5°C for 18 hrs. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL), and the solution was washed with H (0.5M, 40 mL), sat. NaFICO (40 mL x 3) and brine (50 mL). The organics were collected, dried over Na 2 SO 4 , filtered and concentrated to afford compound 14D (3.1 g, yield: 90.6%) as off-white solid, which was used directly for next step without further purification. H NMR (DMSO-d, 400MHz) 6 8.69 (s, 1H), 7.70 (d,J= 8.4 Hz, 1H), 6.92 (d, J= 7.9 Hz, 1H), 5.84 - 5.72 (m, 1H), 5.67 - 5.55 (m, 1H), 5.24 (dd, J= 1.5, 17.0 Hz, IH), 5.12 - 5.05 (m, 11), 5.03 - 4.89 (m, 21), 4.32 - 4.22 (m, 11-), 4.06 - 3.93 (m, 211), 391 - 3.79 (m, IH), 2.12 - 2.04 (m, 11), 203 - 195 (in, 211), 1.65 - 1.48 (m, 4H), 1.47 - 1.39 (in, 31), 139 - 1.32 (in, 911), 1.31 - 1.17 (m, 6H), 1.12 (t, J 7.1 Hz, 3H), 0.92 - 0.78( 61). MS (ESI) mz (M+H)7 522.2.

[004011 Step 5: Synthesis of compound 14E To a solution of compound 14D (500 ing, 0.96 mmol) in DCM (150 mL) was added Hoveyda-Grubbs st Generation catalyst (75 mg, 0.12 ininol). The reaction was stirred at 51 °C for 48 hours. The solvent was removed in vacuum. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate = 4/1 to 3/1) to afford compound 14E (340 mg, yield: 69.0%) as off-white solid. 1H NMR (DMSO-d, 400MHz) 6

855 (br. s., IH), 8.16 (d, J= 7.1 Hz, Il), 6.44 (d, J= 7.1 Hz, 1H), 5.59 - 5.44 (m, 1H), 5.33 (t, J= 9.5 1z, 1H), 4.20 - 4.09 (m, 1H), 4.07 - 3.91 (i, 3),2.27 (br. s., 1-). 1.97 - 1.84 (in, 21), 1.77 - 1.65 (i, 1H), 1.63 - 1.29 (m, 161-1), 1.28 - 1.06 (m, 8H), 0.98 - 0.79 (m, 6H). MS (ESI) inz (M+H) 4494.4.

[004021 Step 6: Synthesis of compound 14F To a mixture of LiAl-4 (53 mg 1.40 mmol) in THF 4mL) was added a solution of compound 14E (230 mg, 0.47 mmol) in THF (8 mL) at 0°C. The resulting mixture was stirred at 0°C for 1.5 hrs. Then the mixture was diluted with THF (30 mL) and then quenched with H2 0 (0.1 mL), NaOH (15%, 0.1 mL) and H2 0 (0.3 mL). After being stirred at room temperature for 40 mins, the mixture was dried over Na 2 SO 4 . The solid was removed by filtration, and the filtrate was concentrated to give a residue, which was purified by re crystallization from EtOAc (6 mL) to afford compound 14F (130 mg, yield: 59.3%) as white solid. 1 H NMR (DMSO-d, 400MHz) 6 8.29 (br. s., 11-1), 8.10 (d, J:=7.5 Hz, 1H), 649 - 6.34 (m, iH), 5.52 - 5.39 (in, IH), 5.04 (t, J= 9.7 Hz, IH), 4.67 (br. s., 1H), 4.23 - 4.11 (in, iH), 4.07 - 3.95 (m, IH), 3.68 - 3.58 (in,iH), 3.28 (br. s.,IH), 2.30 - 2.19 (m,1H), 1.98 - 1.87 (in, 1H), 1.72 - 1.41 (m, 7H), 1.35 (s, 9H), 1.30 - 1.06 (m, 6H), 0.97 - 0.79 (m, 6H), 0.78 - 0.72 (I 1H). MS (ESI) inz (M+Na)- 474.2.

[004031 Step 7: Synthesis of compound 14: Tert-butyl ((R,4S,7S,15S,Z)-1-formyl-4-isobutyl-3,6-dioxo-2,5 diazabicyclo[13.1.0]hexadee-13-en-7-yl)carbamate Compound 14 was prepared from compound 14F following the procedure of compound 7. Compound 14 (63 mg, yield 61.4 %) was obtained as a white solid. 1i NMR (DMSO-d, 400MHz) 9.17 (s, 1H), 8.76 (br. s., 1H), 8.23 (d,J= 7.1 Hz, 111), 6.47 (d, J= 7.1 Hz, IH), 5.59 - 5.48 (in, 1H), 5.33 (t, J= 9.5 Hz, IH), 4.29 - 4.18 (in, iH), 4.05 - 3.94 (in, IH), 2.22 (br. s., IH), 2.08 - 1.99 (in, iH), 1.97 - 1.86 (m, iH), 1.79 - 1.41 (m, 8H), 1.35 (s, 9H), 1.27 - 1.07 (m, 5H), 1.03 - 0.79 (m, 6H). MIS (ESI) mz (M±+H)450.3.

[004041 Step-8: Synthesis of compound 15A Compound 15A was prepared from compound 14 and isocyanoethane following the procedure of compound 8A. Compound 15A (55 mg, yield 19.5 %) was obtained as a white solid. MS(ESI)inz(M-L)523.2.

[004051 Step 9: Synthesis of compound 15:

Tert-butyl ((R,4S,7S,5S,Z)-I-(2-(ethylanino)-2-oxoacetyl)-4-isobutyl-3,6-dioxo- 2,5 diazabicyclo[13.1.0]hexadec-13-en-7-yl)carbamate Compound 15 was prepared from compound 15A following the procedure of compound 7. Compound 15 (16 mg, yield 35.7 %) was obtained as a white solid. H NMR (DMSO-d, 400MHz) 6 8.74 (br. s. 11), 8.31 (br. s., IH), 8.19 (br. s., 1H), 6.41 (d, J= 6.6 Hz, 111), 5.54 - 5.45 (in, 111), 5.43- 5.36 (in, 11) 4.16 (br. s., 1H), 4.04 (br. s., IH), 3.09 3.00 (m, 2H), 2.17 (br. s., 111), 2.07 - 200 (in, 111), 1.95 (br. s., 1 184 (br. s., 111). 1.70 1.51 (in, 5H), 1.45 - 1.39 (in, 2H), 1.35 (br. s., 9H), 1.28 - 1.13 (m, 511), 1.00 (t, J= 7.1 Hz, 3H), 0.93 - 0.79 (in, 6H). MS (ESI) mlz (M+H)v 521.5.

[004061 Step 10: Synthesis of compound 16A To a solution of compound 14F (103 ing, 0.23 mol) in TF (15 mL) was added Wilkinson's cat. (100 mg, 0.11 mmol). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 15°C for 72 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 4/1 to 3/1) to afford crude product (85 mg), which was further purified with preparatory-HPLC (HCI) to afford compound 16A (50 ing, yield: 48.3%) as white solid. 11 NMR (DMSO-d4, 400MHz) 6 8.26 (br. s., 1H), 8.02 (d, J= 7.9 Hz, 111), 6.28 (d, J= 7.5 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.21 - 4.11 (in, 1H), 4.07 (br. s., 1H), 3.67 - 3.59 (in, 1H), 3.45 - 3.38 (in, 1H), 1.74 - 1.02 (in, 26H), 1.00 - 0.72 (in, 8H), 0.45 - 0.35 (m, 1H). NIS (ESI) iz (M+H)-454.2.

[004071 Step 11: Synthesis of compound 16: Tert-butL1 11?4S7S15R-1-formy-4-isobutvl-3,6-dioxo-2,5

diazabicvclo[13.1.01hexadecan-7-vl)carbamate Compound 16 was prepared from compound 16A following the procedure of compound 7. Compound 16 (21 mg, yield 42.7 %) was obtained as a white solid. 'H NMR (DMSO-dr, 400MHz) 3 9.35 (s, 11-), 8.58 (br. s., IH), 8.17 (d, J= 7.9 Hz, 11-1), 632 (d, J= 7.1 -z, I H), 4.27 - 4.17 (in, 11-1), 408 (br. s., 11-), 1.80 - 1.42 (m,IOH), 1.35 (s, 131-1), 124 1.05 (m, 61-1), 098 - 0.80 (in, 6H). MS (ESI) miz (M+Na)' 474.2.

1004081 Step 12: Synthesis of compound 17A To a solution of compound 14F (200 mg442.87 umol) in MeOI-L (20 mL) was added Pd/C (40 ing, 10%wt). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under -2 (15 psi) at 15 °C for16 hours. The reaction mixture was filtered through elite and the filtrate was concentrated. The crude product was purified with preparatory-HPLC (HClcondition) to give compound 17A (85 mg, yield 42.12%) as white solid. H NMR (400MHz, DMSO-d) ( 7.91 (d, J= 9.3 Hz,1H), 7.33 (br. s., 1H), 6.64 (d, J= 7.1 Hz,1H), 4.41 (br. s., 1-1), 3.98 (br. s.,1H), 3.49 - 3.40 (m, 2H), 1.97 (br. s., 111), 1.73 - 1.49 (m, 3H), 1.48 - 1.08 (m, 2411), 105 (br. s., 31), 0.94 - 0.76 (m, 6H). MS (ES )nzM 1 1-1) 456.3.

[004091 Step 13 Synthesis of compound 17: Tert-butvl ((3S,6S.15R)-15-forml-3-isobutvl-15-methvl-2,5-dioxo-1,4 diazaevelopentadecan-6-yI)carbamate Compound 17 was prepared from compound 17A following the procedure of compound 7. Compound 17 (45 mg, yield 52.4 %) was obtained as a white solid. 1H NMR (400MHz, DMSO-d) 9.26 (s, 1H), 8.60 (br. s., 111), 8.09 (d,IJ= 8.8 Hz, MH), 6.58 (d, J= 7.5 Hz, IH), 4.60 - 4.49 (m, iH), 4.00 (d, J= 3.1 Hz, 111), 1.95 - 1.84 (m, IH), 1.64 - 1.53 (m, 2H), 1.52 - 1.32 (m, 13H), 1.32 - 1.10 (m, 12H), 1.03 (s, 3H), 0.93 - 0.80 (m, 6H). MS (ESI) m (M-55)7 398.3.

EXAMPLE 8 Compounds 18-19

M H 0H, 3_OC00OMvAP, _ Na'BH, ,'~ M,,OH CEoCC' b - oa2 N~O CHC 0A

H H '8A 8 18c

- C) L;OH C PddbINAP, THF 0TH'H10 OH

COH

N C02EtI 18E 5-, N.C~ ED ECIHOBt DYEA.CD CM -X I L 7C NH,

0 H

GCoEs 2nd cpt NNTF I~ ~~~N<,'"O 1W N

H

0- " '-'--I Ii1 I.- OE

HH

H ""'N9

H O

C 9E IC l

<NP 0H

251F

15 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 18A (52 g, yield: 98.1%) was obtained as red oil, which was used into the next step without further purification. H NMR (400MHz, CDCl 3) ( 6.89 (br. s., 1H), 5.08 - 4.95 (m, 1H), 4.21 - 4.11 (m, 1H), 2.49 - 2.22 (m, 3H), 2.19 - 2.06 (m, I1H), 1.27 - 1.17

(m, 6H). MS (ESI) inz (M+H)+ 171.8.

[004111 Step 2: Synthesis of compound 18B To a solution of compound 18A (79.5 g, 364.5 mmol) in CH 3CN (300 mL) was added DMA (1.86 g, 15.19 mmol). The mixture was stirred at 10 °C for I h. The reaction mixture was concentrated and diluted with MTBE (200 mL), the organic layer was washed with IN HC (150 mL) and brine (200 mL), dried over Na2 S04, filtered and concentrated under reduced pressure to give compound 18B (80 g, yield97%)salightyellowoil,which

was used in the next step without further purification. H NMR (400-MHz, CDCl 3) 6 5.16 4.99 (m, 1H), 4.59 - 4.49 (m, 1H), 2.65 - 2.25 (in, 3H), 2.06 - 1.92 (m, 1H), 1.61 - 1.34 (m, 9H), 1.31 - 1.19 (m, 6H).

[004121 Step-3: Sithesis of compound 18C To a solution of compound 18B (40 g, 147.4 mmol) in MeOH (300 mL) was added NaBH4 (8.37 g, 221.1 mmol) slowly. The mixture was stirred at 18 °C for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with MTBE (500 mL). The organic layers were washed with brine (500 mL), dried over Na2SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1 to 2:1) to afford compound 18C (26.8 g, yield 52.8%) as a light yellow oil. H N.R (400MHz, CDCl 3) a 5.25 - 5.17 (m, 1H), 5.08 - 4.99 (in, 1), 4.31 - 4.21 (in, 1H), 3.66 (t, J= 6.2 Hz, 2H), 1.98 - 1.79 (in, 2H), 1.76 1.68 (m, 1H), 1.65 - 1.57 (m, 2H), 1.43 (s, 9H), 1.28 - 1.21 (m, 6H).

[004131 Step4: Svithesis of compound 18D A mixture of compound 18C (10 g, 36.3 mmol), allyl methyl carbonate (14.04 g, 120.95 mmol), Pd2 (dba) 3 (997.7 mg, 1.09 mmol), [1-(2-diphenylphosphanyl-1-naphthyl)-2 naphthyl] -diphenyl-phosphane (2.71 g, 4.36 mmol) in THF (150 mL) was degassed and purged with N2 for 3 times. And then the mixture was stirred at 80 °C for 10 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with MTBE (200 mL), filtered through celite and evaporated to give a dark brown syrup. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=9/1 to 5:1) to afford compound 18D (7.80 g, yield 68.1%) as a light yellow oil. 'H NMR (400MHz, CDCI) 6 5.94 - 5.79 (m, 11-1), 5.28 - 5.19 (in, 1H), 5.18 - 5.09 (m,2H), 5.06 - 4.97 (m, i1H), 4.26 - 4.15

(in, 1H), 3.93 (d, J 5.7 Hz, 21), 3.46 - 3.37 (m, 2), 1.91 - 1.78 (in, 11-1), 1.73 - 1.55 (m, 3H), 1.41 (s, 9H), 1.27 - 1.16 (in, 61-1).

1004141 Step 5: Synthesis of compound 18E To a mixture of compound 18D in THF (50 mL) and water (20 mL) was added LiO1H (1.33 g, 55.5 mmol,), and then the mixture was stirred at 10 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with MTBE (70 mL. x 3). The aqueous layer was adjusted to pH ~ 4 with IN HCi and extracted with EA (80 mnL x 3). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4,filtered and concentrated under reduced pressure to give compound 18E (3.4 g, yield 78.5%) was obtained as a colorless oil. The crude product was used in the next step without further purification. 1H NMR (400MHZ, CDC) 10.27- 9.64(m,2H),5.95- 5.83(m, 1H), 5.29 - 5.22 (in, 11-1), 5.20 - 5.14 (m, 11-1), 4.35 - 4.26 (m, 1-), 3.96 (d,J::= 53 Hz, 21-1), 3.50 3.43 (i, 21), 197 - 1.88 (m, 1H), 1.86 - 1.75 (i, 11-1), 1.74 - 1.64 (m, 2H), 1.43 (s, 9H)..

1004151 Step 6: Synthesis of compound 18G A mixture of compound 1E (3.4 g 12.44 mmol), compound 7C (3.64 g, 12.44 mmol, HICI), EDCI (3.58 g, 18.6 mmol), HBt (1.68 g, 12.44 mmol) and D1EA (4.82 g, 37.32 mmol) in DCM (100 iL) was stirred at 10 °C for 48 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (100 mL) and washed with IN HC1 (100 mL), sat. NaHCO 3 (70 mL x 3), dried over Na2 SO4 ,

filtered and concentrated under reduced pressure to give compound 18G (4.1 g, yield 64.4%) as a light yellow solid. 'H NMR (400MHz, CDCl3 ) 6.83- 6.76(m, lH),6.72- 662(m,

1H), 5.96 - 5.84 (m, 1H), 5.72 - 5.60 (m, 1H), 5.41 - 5.33 (i, 1H), 5.30 - 5.22 (i, 11-1), 520 5.14 (m, 1H), 5.13 - 5.05 (m, 2H), 4.62 - 4.54 (in, 1H), 4.46 - 4.38 (m, 1H), 3.99 - 3.93 (in, 2H), 3.53 - 3.42 (in, 2H), 2.62 - 2.43 (m, 3H), 1.92 - 1.57 (m, 8H), 1.56 - 1.49 (in, 1H), 1.42 (s,9H), 1.28 - 1.23 (m, 3H), 0.94 - 0.86 (in,6H).

[004161 Stej 7:_Svnthesis of compound1811 To a solution of compound 18G (1.9 g, 3.71 mmol) in DCM (600 mL) was added Grubbs 2nd cat. (157.6 mg, 185.67uimol), the mixture was degassed and purged with N2 for 3 times, then stirred at 40 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=4/1 to 1:1) to afford compound 18H (2.8 g, yield: 78%) as an off-white solid. H NMR (400MHz,CDCl 3) 6 6.80 - 6.69 (m, 1-1), 6.54 - 6.44 (m, 11-), 5.65 - 5.45 (m,21H), 5.34 - 5.25 (in, 11-), 4.69 - 4.60 (m, 1H), 4.59 - 4.51 (in, 11-1), 3.92 - 3.83 (in, 21-), 3.51 - 3.36(m, IH), 335 - 3.24 (m, 211), 2.73 - 2.61 (m, 1-), 2.58 - 2.47 (m, 111), 2.43 - 2.30 (m, 1[H), 2.15 (s, ILH), 1.91 - 1.79 (m, ILH), 1.75 - 1.48 (m, 611), 1.41 (s, 911), 1.27 - 1.23 (i, 31-1), 0.94 - 0.83 (m, 611) MS (ESI) mnz (M+H)* 4843.

1004171 Step 8: Synthesis of compound 18J Compound 18J was prepared from compound 1811 following the procedure of compound 14F. Compound 18J (300 mg, yield 32.8 %) was obtained as a white solid. MS (ESI) inz (M+H)442.3.

[00418] Step 9: Synthesis of compound 18: Tert-butyl ((5S,8S,11S)-I -formyl-8-isobutyl-6,9-dioxo-I-oxa-7,10-diazacy clopentadec 13-en-5-yl)carbamate Compound 18 was prepared from compound 18J following the procedure of compound 7. Compound 18 (25 ng, yield 12.7 %)was obtained as a white solid. 1H NMR

(400MHz, DMSO-d6 ) 9.45 - 9.37m, 1 H). 8.33 - 8.22 (m, lH),8.22- 8.121(m, 1H), 6.77 6.56 (m, 11), 5.62 - 5.41 (in, 21-1), 4.53 - 432 (in, 21-), 4.06 - 3.96(m, IH), 3.96 - 3.86 (in, 11-1), 3.82 - 3.72 (i, 111), 325 - 3.14 (i, 111), 313 - 3.02 (in,1-1), 2.69- 254 (in,21), 2.20 206 (i, 11-1), 1.78 - 155 (i, 31-), 1.54 - 1.31 (i, 12H), 0.98 - 0.74 (m, 6H). MS (ESI) mz (M-1H)- 440.5.

[00419] Step 10: Synthesis of compounds 19Z and 19E Compound 1811 (1.0 g) was purified by prep-HIPLC (HCI condition) to give two isomers: compound 19Z (200 mg, yield 20%) and compound 19E (480 mg, yield 48/) was obtained both as white solid. Compound 19Z: 1- NMR (400MHz, CDCI;) 3 6.76 - 6.67 (in, 11-1), 6.48 - 6.39 (in, 1H), 5.67 - 5.57 (m, 111), 5.56 - 545 (in, I H, 5.32 - 5.23 (m, 111), 4.71 4.61 (m, 1H), 4.61 - 4.50 (i, 11-1), 427 - 413 (m, 3H), 3.94 - 3.83 (i, 211), 338 - 325 (in, 21-), 2.74 - 2.62 (m, iH), 2.45 - 2.32 (i, 11-1), 2.09 - 1.97 (m, 1H), 1.75 - 1.53 (i, 61-1), 1.42 (s, 9H), 1.31 - 1.22 (m, 311), 0.98 - 0.82 (in, 6H). MS (ESI) n (M+H) 484.2.

Compound 19E: 1 H NMR (400MHz, CDCl 3) 6 6.07- 5.97 (m, 11-1), 5.94 - 5.83 (m, 1H), 5.66 - 5.55 (m, 1H), 5.03 - 4.95 (m, 1H), 4.71 - 4.61 (m, 1K), 4.43 - 4.33 (m, 1H), 4.25 4.10 (m, 3H), 3.96 - 3.84 (m, 2H), 3.72 - 3.64 (m, 1K), 3.48 - 3.37 (m, 1H), 2.60 - 2.48 (m, 2H), 2.16 - 2.03 (m, 1H), 1.92 - 1.82 (m, iH), 1.79 - 1.47 (m, 6H), 1.45 - 1.38 (m, 9H), 1.29

1.23 (m, 3H), 0.92 - 0.84 (m, 6H). MS (ESI) inz (M+H) 484.2.

[004201 Step 11: Synthesis of compound 19F Compound 19F was prepared from compound 19E following the procedure of compound 14F. Compound 19F (390 mg, yield 69.41 %) was obtained as a white solid. 'H NMR (400M z, CDClI) 6 8.17 - 8.05 (m, IFl), 7.87 - 7.67 (m, 1H), 6.49 - 6.34 (m, 1H), 5.65 - 5.33 (in, 21), 480 - 4.65 (m, li), 4.48 - 431 (m, 1K), 4.09 - 3.97 (i, 111), 3.96 - 3.68 (m, 31), 3.65 - 3.55 (m, 1H), 323 - 2.96 (m, 3H),239 - 2.23 (m, 1K), 2.02 - 1.85 (in, 1). 1.81 1.13 (m, 16H), 0.97 - 0.67 (m, 6H). MS (ESI) nz (1+H) 442.1..

[004211 Step 12: Synthesis of compound 19: Tert-butyl ((5S,8S,I1S,E)-i1-fornvl-8-isobutyl-6,9-dioxo-1-oxa-7,10 diazacyclopentadec-13-en-5-yl)carbamate Compound 19 was prepared from compound 19F following the procedure of compound 7. Compound 19 (45 mg, yield 31 %) was obtained as a white solid. 'H NMR (400MHz, DMSOI-d) 5 9.43 (s, 1H), 8.27 (d, J= 7.9 lz, H), 8.18 (d, J= 93 Hz, 1H), 6.60 (d, J=: 75 Hz, 1H , 5.60 - 5.43 (in, 2H), 4.53 - 4.42 (m, 11), 4.36 (t,,J= 8.2 Hz, 11), 4.00 (br. s., 1H), 3.96 - 3.86 (m, 111), 3.82 - 3.71 (m, 11), 3.24 - 3.14 (m, 111), 3.13 - 3.02 (m, 11), 2.68 - 2.53 (i, 21), 2.19 - 2.05 (in, 1), 1.80 - 1.54 (m, 3H), 1.49 - 133 (m, 12H), 0.97 0.77 (m, 6H). MS (ESI) w(M+KH) 440.5. EXAMPLE 9 Tert-butyl ((3S,6S,9S,E)-9-formyl-6-isobutvl-4;7-dioxo-1-oxa-5,8-diazacvlopentadec 11-en-3-y)carbamate (20)

H 7CO2 H N CO2Et

- - - - - --NN . 1 A, Et SFC separat on H Gr DCMA

HNN 2Et o LO HA NH 2 O

THF

20~20C

DMP, DCM NH

20 0 [j

[004221 Step1: Synthesis of compound 20A To a solution of N-(tert-btoxycarbonyl)-O-(pent-4-en-1-yl)-L-serine (960 mg, 3.51 mmol) in THF (10 rnL) was added N-methylmorpholine (533 mg, 5.27 mmol, 580 uL), isobutyl chloroformate (480 mg, 3.51 mmol, 460 uL) at -40 °C. The mixture was stirred at 40 °C for 30 min. A solution of compound 7C (900 mg, 3.51 mmol) in THF (3 mL) and DMF (3 mL) was added at -40 °C. The mixture was stirred at -40 °Cfor another 1.5 hrs. The reaction mixture was quenched withH 20 (1 mL) and partitioned between DCM (50 mL) and 220 (50 mL). The organic phase was separated, washed with sat. NaHCO3 (50 mL), dried over Na2SO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=5/1) to give compound 20A (1.7 g, yield: 77%) as a white semisolid. 1H NMR (400MHz, CDCI;) 5 6.82 (d,J= 7.9 Hz, 11), 6.58 (br. s., 111). 5.84 - 5.73 (i, 11-1), 571 - 5.55 (in, 111). 5.43 - 5.27 (i, 11-1), 5 19 4.91 (m, 411), 4.65 - 4.52 (i, 111), 4.46 - 4.42 (m., IH), 4.28 - 4.07 (m, 31). 3.82 (dd, J= 4.0, 9.3 Hz, IH), 3.56 - 3.38 (in, 3H), 2.63 - 2.42 (in, 2H), 2.14 - 2.01 (in, 2H), 1.73 - 1.58 (in, 4H), 1.56 - 1.48 (m, 1H), 1.45 (s, 9H), 1.26 (t,,J= 7.1 Hz, 3H), 0.92 (dd, J= 6.2,8.8 Hz, 6H). MS (ESI) m z (M-H) 512.1. The product was further separated by SFC to give pure compound 20A SFC method: Column:AD (250mm*30mm,um), Mobile phase: A: CO2 B: EtOH (0.05% NH3 H20) Gradient: 20% of B Flow rate: 65 mL/in Column temperature: 35°C). The was separated by SFC to give compound 20A (Rt = 2.191 min, 400 mg) as a yellow oil.

Compound 20A: 11 NMR (400MHz, Methanol-d 4) 6 5.89 - 5.70 (in, 211), 5.16 - 4.93 (m, 4H), 4.55 - 4.39 (in, 2H), 4.26 - 4.09 (in, 3H), 3.62 - 3.58 (in, 2H), 3.54 - 3.41 (in, 2H), 2.60 - 2.42 (in, 2H), 2.13 - 2.08 (in, 2H), 1.74- 1.57 (in, 5H), 1.45 (s, 9H), 1.18 (t, J= 7.1 Hz, 3H), 0.94 (dd,,J= 6.6, 10.6 Hz, 6H).

[004231 Step 2: Synthesis of compound 20B Compound 20B was prepared from compound 20A following the procedure of compound 18H. Compound 20B (250 mg, yield 66 %) was obtained as a grey solid. 'H

NMR (40MHz, CDC) 6.64 (d, 1= 7.9 Iz, 11), 6.30 (d, J= 8.8 Hz, I l), 5.53 (d, J= 6.6 Hz, H), 5.43- 539 (in, 11), 5.24 - 5.18 (i, lH), 4.75 - 4.65 (m, 1H), 4.58 - 4.50 (m, 1H), 4.22 - 4.17 (m, 311), 3.75 - 3.58 (i, 311), 3.48 - 3.40 (i, 11-1), 2.52 - 2.36 (m, 211), 223 - 2.09 (m, 11-1), 2.05 - 192 (in, 111), 1.84 - 1.80 (in,211), 171 - 1.60 (i, 211), 1.54 - 140 (in, 101), 1.28 (t,J=7.1Hz,3H),0.94 (dd,J= 6.6,9.7Hz,6H). MS(ESI)nm z(M+H) 484.1.

[004241 Step 3: Synthesis of compound 20C Compound 20C was prepared from compound 20B following the procedure of compound 14F. Compound 20C (80 mg, yield 32 %) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6 ) 6 8.22 (d,,!= 9.0 Hz, 1H), 7.72 (d,,= 9.0 Hz, 111), 5.85 (d, J= 8.2 Hz, 1H), 5.36 - 5.20 (in, 2H), 4.65 (t, J= 5.5 Hz, 1H), 4.47 - 4.31 (in, 1H), 4.09 (q,,!= 5.5 Hz,2H ), 3.77(b. s., 111), 3.68 - 3.60 (m, I l), 3.53 - 3.48 (in, 11), 336 - 3.19 (i, 51), 2.25 (d, J= 13.7 Hz, 111), 2.07 - 1.96 (m, 11), 1.90 - 1.75 (in, 21), 1.60 - 126 (m, 121), 0.86 (dd, J= 6.3, 12.9 Hz, 611). M S (ESI) mz (M+H) 442. 1.

[004251 Step 4: Synthesis of compound 20 Compound 20 was prepared from compound 20C following the procedure of compound 7. Compound 20 (24.4 mg, yield 30 %) was obtained as a white solid. 11 NMR

(400MV)z DMSO-6) 9.43 (s, 1H), 8.35 - 8.18 (in, 2H), 6.00 (d, J= 7.8 Hz, 1H), 5.42 5.21 (in, 2H), 4.51 - 4.42 (in, 1H), 4.38 - 4.33 (in, 1H), 4.11 (br. s., 1H), 3.68 - 3.64 (in, 1H), 3.53 - 3.45 (in, 111), 3.27 - 3.13 (m, 2H), 2.48 -2.45 (in, 1H), 2.08 - 2.03 (m,2H), 1.89 (br. s., 111), 1.74 - 1.20 (m, 14H), 0.89 (dd,,1= 6.5, 19.8 Hz, 6H). MS (ESI)inz (M+H)440.2. EXAMPLE 10 Benzyl ((5S,8S,11SlE)-11-formyl-8-isobutvl-6,9-dioxo-1-oxa-7,10-diazacvclopentadec-13 en-5-Ilcarbamate J21)

O HN -- ----- N N IEtO~cCO2Et

H OH H LAH HN IN jPh rN N

N-H 21c 7 21 J=88HI) 2d / 1-82

[00426] Step 1: Synthesis of compound 21A Compound 21A was prepared from compound 18H1 following the procedure of compound 12A. Compound 21A (420 mg, yield 98.4 %/)was obtained as a brown solid. 1H NMIR (400OMHz, DMSO-ds) (5 8.73 - 8.64 (m, 1H), 8.57 d1 =88H,1) .1-82 m

3H), 5.61 - 5.43 (m, 2H), 4.54 - 4.30 (m, 2H), 4.10 - 3.71 (m, SH), 3.16 - 2.97 ( 2 2.18 (m, 1H), 1.86 - 1.44 (m, 6H), 1.38 - 1.25 (m, 0H), - 1.12 (m, 3H), 0.94 - 0.80 1.20

6H). 210 21

[00427] Step 2: Synthesis of compound 21B Compound 21B was prepared from compound 21A following the procedure of compound 41, Compound 21 (50 mg, yield 96 %) was obtained as a brown solid. H

NMR, (400MI-z, DMSO-ds6) 6 8.31 - 8.23 (m, 1H-), 8,23 - 8.15 (m, 1H-), 7.37 - 7.21 (m, 5H-), 7.18 - 7.08 (mi, 1H-), 5.64 - 5.42 (ml, 2H-), 5.05 - 4.93 (ml, 2H-), 4.54 - 4.31 (mi, 2H-), 4. 18 - 3.73

(mi, 5H), 3.23 - 2.99 (M, 2H)0, 1.77 - 1. 61 (mn, 1H-), 1.76 - 1.59 (mi, 1H), 1.58 - 1.38 (mn, 5H-), 1.37 - 1.24 (m, 1H), 1.21 - 1. 10 (m, 3H1), 0.93 - 0.7 3 (m, 6H). MS (ESI) wlh' (MI+H)'- 518. 1.

[004281 Step 3: Synthesis of compound 21C Compound 21C was prepared from compound 21B following the procedure of compound 14F. Compound 21C (125 mg, yield 27.2 %) was obtained as a white solid. 'H NMR (400MHz, DMSO-d) 6 8.15 - 8.09 (m, 1H), 7.80 - 7.74 (m, 1H), 7.35 - 7.27 (m, 5H), 7.08 - 7.02 (m, 1H), 5.63 - 5-.32 (m, 2H), 4.1.69 (br s, 1-2), 4.41 - 4.34 (m, 3), 4.09 (br s, 1H), 3.91 - 3.69 (m, 3H-), 3.22 - 3.09 (m, 2H-), 3.09 - 2. 96 (m, U-H0, 2.40 - 2227 (m, 1), 1.97 - 186 (m, 1H), 1.71 - 1.60 (8, I H), 1.53 - 1.31 (m, 7H), 0.91 - 0.78 ( 6H).8, MS (ESI) m z (M+H)-'476.3.

[004291 Step 4:-Svnthesis of conound-21 Compound 21 was prepared from compound 21C following the procedure of compound 7. Compound 21 (20 mg, yield 14.14%) was obtained as a white solid. 'H NMR (400MHz,CDCl3) 5 9.55 (s, 11-), 7.34 (br s, 5H), 7.08 - 6.85 (m, 211), 5.94 - 5.84 (in, 1-1), 5.67 - 5.38 (m, 2H), 5.22 - 4.96 (m, 2 )4.63 (br s, 211), 4.39 (hr s, 1H), 3.88 (hrs,2),3.28 (br s, 211), 2.69 (br s, IH), 2.30 - 1 98 (n, 21). 1.72 - 147 (in, 611), 0.98 - 0.86 (In, 61). MS (ESI) mlz (M-1-1) 4742 EXAMPLE II

Compounds 22-23

O K20sO 4 2H0 NaBH 4 , MeOH Nai04 THFH20 N O H 22A H

0 N 0~ ~~127 NK:-Kt 0 t-BuOK, THF

22B H 22C

H N_. C0 2 Et H o cii H0 HN-'- , coOt OHNCN CO2E O OH '' " ~ -. '---,.----------------- - --------------------- ------ N2 N EOCJ-03 H 22E H DIPEA DCM

00NH- _. CO2Et

- .0.1eq AGubbs 2s* separate on

.DCM HH

22F

0C0

A-NH NH CHEt 0 N CO2Et

H

22G -- 2 25H

HNLiAIH 4 OHN-N OH

H DMP0 CM ' -O HN- N O

H H 0ON- N CO2 Et THFI-~ - O N .N

H H

22H 23A

H DMP, DCM OHN N

23

[00430] Step 1: Synthesis of compound 22A 'To a solution of ethyl (S)-2-((tert-butoxycarbonyl)amino)non-8-enoate (4 g, 13.36 mmol) and K2 0s() 4 .2H10 (246 mg, 668.00 umol) in THF (100 mL) and -120 (50 mL) was added NalO4 (5.72 g, 26.72 mmol) at 0 °C. After addition, the reaction mixture was stirred at 10 °C for I h. The reaction mixture was filtered and the filtrate was diluted with 200 mL of sat. Na 2S203 , then the mixture was extracted with EtOAc (100 mL x 2) and the organic layers were washed with 50 mL of sat. Na2 S20 3 , and brine (50 mL x 2). The organic layer was dried over Na2 SO 4 and concentrated to give compound 22A (3.9gyield: 96.9%) as colorless oil, which was used to next step without furtherpurification. MS(ESf)iz (M-1Boc-H[)201.9.

[004311 Step 2: Synthesis of compound 22B To a solution of compound 22A (2.9 g, 9.62 mmol) in MeOH (50 mL) was added NaBH4 (473 mg, 12.51 mmol) as portions. After addition, the reaction mixture was stirred at 10 °C for 2 hrs. 50 nL of water was added into the reaction mixture and concentrated to remove MeOH, then the mixture was extracted with EtOAc (50 mL x 2), the combined extracts were washed with brine (40 mL x 2). The mixture was dried over Na 2SO4 and concentrated in vacuo to afford crude compound 22B (2.5 g, yield: 85.7%) as colorless oil, which was used to next step without further purification. 1H NMR (400MHz, CDCl 3)65.04 - 4.97 (in, 1H), 4.30 - 4.23 (m, 1H), 4.22 - 4.15 (in, 2H), 3.64 (t, J= 6.5 Hz, 2H), 1.47 - 1.28 (in, 22H).

[004321 Step-3: Synthesis of compound 22C To a solution of PPh 3 (2.59 g, 9.89 mmol) in DCM (30 mL) was added12 (2.51 g, 9.89 mmol), then the mixture was stirred for 6min and DIEA (1 28 g, 9.89 mmol, 1.73 mL), compound 22B (2.5 g, 8.24 mmol) in DCM (10 mL) was added. After addition, the reaction mixture was stirred at 10 °C for 15 hrs. 200 mL of Petroleum ether was added into the reaction mixture and stirred for 5 min. The mixture was filtered and the filtrate was washed with Na 2 S 2 O 3 (100 mL x 2) and brine (100 mL) Then the mixture was dried over Na2SO4 and concentrated to afford compound 22C (1.2g, yield: 35.2%) as colorless oil. 1H NMR (400MHz, CDCl) o 5.03 - 4.95 (m, IH), 4.31 - 4.24 (m, 1H), 4.23 - 4.17 (in, 2H), 3.18 (t, J 7.0 Hz,2'H), 1.86 - 1.77 (m, 3H), 1.66 - 1.59 (in, 1H), 1.45 (s, 9H), 1.42 - 1.32 (in, 6H), 1.29 (t, J= 7.2 Hz, 3 H).

[004331 Step 4: Synthesis of compound 22D To a solution of compound 22C in THF (40 mL) was added t-BuOK (1 M, 6.5 mL), then the reaction mixture was stirred at 10 °C for 12 hrs. The reaction mixture was poured into 50 mL of water and the mixture was extracted with MTBE (50 mL x2), then the aqueous layer was acidified by IN[C to pH ~ 3, then extracted with EtOAc (50 mL x 2) and the combined extracts were washed with brine (50 nL), the organic layer was dried over Na2SO and concentrated in vacuo to afford compound 22D (450 mg, yield: 80.2%) as colorless oil. H NMR (DMSO-d 400 MHz): o 12.37 (br. s, 1H), 7.04 - 6.94 (m, 1H), 5.86 - 5.73 (in, 1H),

5.05 - 4.90 (m, 2H), 3.90 - 3.80 (m, 1H), 2.05 - 1.98 (m, 2H), 1.73 - 1.20 (m, 15H).

[004341 Stepj5: Synthesis of compound 22E Compound 22E was prepared from compound 22D following the procedure of compound7D. Compound 22E (1.2 g, yield 44.34%) was obtained as an off-white solid. 'H NMR (400M1-lz, CDC): 6.56 - 6.34 (m, 1K), 5.81 - 5.62 (in, 2H), 5.12 (d, J= 13.2 Hz, 21-1), 5.01 - 4.92 (m, 2H), 4.61 - 4.42 (in, 2), 4.22 - 411 (in, 21), 2.59 - 2.48 (in, 2H ), 2.05 2.01 (in, 2), 1.66 (br s, 3H) 1.57 (s, 311), 1.44 (s, 91-1), 1.29 - 1.25 (m, 3H), 0.93 (d, J= 5.3 Hz. 61) MS (ESI) mlz (M-56)j 440.]1

[004351 Step 6:_Synthesis of comnound_22F and searation-to obtain 22G and 2211 Compound 22F was prepared from compound 22E following the procedure of compound 7F. Compound 22F was purified by preparatory-HPLC (HCl condition) to give compound 22G (120 mg, yield: 21.2%) as white solid and compound 2211 (100 mg, yield: 13.5%) as white solid. Compound 22G: 1H NMR (DMSO-d, 400MHz): 6 8.19 (d,J= 5.7 Hz,1H), 7.27 (br. s., 1), 7.04 (br. s., IH), 5.23 - 5.38 (m, 1H), 5.12 - 5.21 (m, 1H), 4.47 - 4.25 (in, 2H), 4.15 3.98 (in, 2H), 3.87-3.74 (m, 11), 2,27 - 2.14 (in, 1[H), 2.07 (d,J=: 10.6 Hz, 1H), 1.88 - 1.71 (m, 11), 1.59 - 1.40 (m, 5H), 1.36 (s, 10H), 1.23 (d, J= 7.5 Hz, 211), 1.15 (t, J= 73 Hz, 41), 0.84 (dd, J= 17.0, 6.4 Hz,71-1). MS (ESI) miz (M-56)42. Compound 22H: H NMR (400MHz, DMSO-d6 ): 6 8.41 - 8.13 (in, IH), 7.90 (d, J= 7.9 Hz, IH), 6.76 - 6.51 (m, 1H), 5.34 (dd, J= 6.8, 14.3 Hz, 1H),5.21 -5.06 (m, IH), 4.55 4.29 (m, 21), 4.05 (q,J= 7.1 Hz, 2H), 3.92 (br. s., 1H), 1.95 (br. s., 2H), 1.68 - 1.43 (m, 5H), 1.34 (s, 13H). 1.15 (t,J=: 7.1 Hz, 41-1),088 - 0.79 (m, 7H). MS (ESI) mX (M-56)_4121.

[004361 Step 7: Synthesis of compound 22J Compound 22J was prepared from compound 22G following the procedure of compound 14F. Compound 22J (120 mg, yield 21.2%) was obtained as a white solid. 'H NMR (400M1z, DMSO-dl): 6 7.74 (d, J= 7.8 Hz, 11-1), 7.13 (br. s., 11-1), 7.01 (br. s., 1H), 5.16 (br. s., 2H), 4.63 (t, J= 5.1 Hz, 111), 4.34 (d, J= 7.8 Hz, 1-), 3.77 (br. s., 2), 3.22 3.10 (m, IH), 2.30 (d, J= 13.7 Hz, iH), 1.94 - 1.65 (m, 2H), 1.48 (d, J= 5.1 Hz, 4H), 1.35 (br. s., I lH), 1.23 - 1.03 (in, 4H), 0.84 - 0.80 (in, iH), 0.82 (br. s., 6H). MS (ESI) n z(M 56)-370.0.

[004371 Step-8: Synthesis of compound 22: Tert-butl (( 3S,14S,E)-14-forml-3-isobutvl-2,5-dioxo-L4-diazacyclotetrade-11-en-6 y1)carbamate Compound 22 was prepared from compound 22J following the procedure of compound 7. Compound 22 (25 mg, yield 25.1 %) was obtained as a white solid. JH NMR (400M1iz, CDC): 9.54 (s, 1N). 6.84 (br. s., 11), 6.61 (d, J: 82 Hz, 11-1), 5.41 - 5 22 (in, 21-1), 4.83 (br.s., 1), 4.66 - 4.38 (i, 2H), 4.15 (br. s., 1-1), 2.71 (d, J= 14.9 Hz, 1-1), 2.25 2.06 (m, 2H), 1.95 (d, J= 7.4 Hz, 2H), 1.72 - 1.56 (in, 5H), 1.45 (s, 9H), 1.34 - 1.23 (in, IH), 1.22 - 1.09 (m, 2H), 0.96 - 0.90 (m, 6H). MS (ESI) nz (M+H)-424.2.

[004381 Sten 9:-Svnthesis of comnound-23A: Compound 23A was prepared from compound 22H following the procedure of compound 14F. Compound 23A (120 mg, yield 21.2 %) was obtained as a white solid. lH NMR (400MHz, DMSO-d6): . 8.09 (d, J= 9.0 Hz, 11), 7.57 (d,J: 8.6 Hz, 11), 6.47 (d, J 7.0Hz,1H),5.20(br.s.,2H),4.63 (t,J= 53 Hz, IH), 4.35 (q, J= 7.8 Hz, 11), 3.97 - 3.78 (in, 211), 330 - 3.23 (in, 21), 317 - 3.07 (in, 11), 227 (d, J= 14.1 Hz, 1H). 2.05 - 1.77(m, 3H), 1.57 - 1.38 (i, 4H), 1.33 (s, 1011), 1.23 - 1.09 (in, 2H), 0.94 (d, J:= 4.3 Hz, 1H). 0.86 0.79 (in, 6H). IS (ESI) mz (M-56) 370.1. 1004391 Step 10: Synthesis of compound 23: Tert-butvl ((3S,14S,E)-14-fornvl-3-isobutyl-2,5-dioxo-1,4-diazaeelotetradec-11-en-6 vllcarbamate Compound 23 was prepared from compound 23A following the procedure of compound 7. Compound 23 (10 mg, yield 11.2 %) was obtained as a white solid. H NMJR (400MHz, CDCl 3): 6 9.69 - 9.48 (in, 1H), 6.90 (br. s., 1H), 6.74 (d,,J= 7.0 Hz, 1H), 5.44 5.23 (m, 3H), 4.67 (br. s., 2H), 4.16 (br. s., 1H), 2.72 (d, J= 13.3 Hz, iH), 2.21 (br. s., iH), 2.02 (br. s., 211), 1.82 (br. s., 211), 1.73 - 1.62 (in, 41-1), 1,42 (br. s., 9H) 1.28 - 1.10 (m, 31), 0.97 - 0.90 (m, 61). MS (ESI) mlz (M-56)368.2. EXAMPLE 12

Compounds 24-25

OH

0 NH NH LiAIH4 COEt '2 PdICIMe..H

NH- separaion

24A 22F

OH / -. N H ON

- N x - N H

24B 24C

H OH H0 _H N DMP,DCM 0 HN

H J

24B 24

N ) HN- H. DMP, DC 0 HN

24C 25

[004401 Step 1: Synthesis of compound 24A Compound 24A was prepared from compound 22F following the procedure of 1 compound 14F. Compound 24A (260 mg, yield 77.21 %) was obtained as a white solid. H

NMR (400M z, Methanol-d4) : c 5.44 - 5.19 (in, 2H), 4.53 (q,,J=7.1 Hz, IH), 4.18 - 3.78 :(m, 2H), 3.51 - 3.38 (in, 2H),2.44 - 2.27 (in, lH), 2.21 - 1.89 (in, 3H), 1.70 - 1.50 (m, 5H), 1.44 - 1.39 (m, 9H), 1.29 - 1.11 (m, 3H)0.96 - 0.89 (m, 6H). MS (ESI) ml (M-56) 370.1.

[004411 Step 2: Synthesis of compounds 24B and 24C To a solution of compound 24A (260 mg, 610.96 umol) in MeOH (30 mL) was added Pd/C (80 mg, 10% under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 10 °C for 2 hrs. The mixture was filtered. The filtrate was concentrated. The residue was purified by preparatory--IPLC (HC condition) to give compound 24B (80 mg, yield: 18.7%) as a white solid and compound 24C (80 mg, yield: 18.1%) as a white solid. Compound24B.H NR (400Mz, DMSO-d)): 6 7.79 (d,,J= 88 Hz, 11), 7.19 (d, J= 7.9 Hz, 1H), 7.05 (br. s., 1H), 4.53 (t.,J= 5.7 lz, 1H), 4.45 - 4.30 (m, 11-1), 378 (d, J= 5.7IHz, 21H), 3.27 - 3.09(m, 21), 1.60 - 1.46 (m, 4H), 1.41 - 132 (n, 111-1), 124 (br. s., 51-1), 1.17 - 1.01 (m, 6H), 0.83 (dd,,J= 6.4, 10.8 Hz, 6H). MS (ESI) nz (M-56) 372.1. Compound 24C: 'H NMR (400MHz, DMSO-d): 6 8.14 (d, J= 9.3 Hz, 1H), 7.75 (d, J= 9.3 Hz, IH), 6.41 d,,J= 7.5 lz, 1H), 4.52 (t,J= 5.7 Hz, 11-1), 4.43 (q, J= 7.9 Hz, 1H), 3.96 (br. s., 1H), 3.79 (br. s., 1-1), 3.27 - 3.09 (m, ) 162 - 1.47 (m, 3H), 1.43 - 1.37 (m,

31-1), 1.33 (s, 9H), 1.28 - 1.17 (m, 611), 1.13 - 1.03 (m, 41-), 088 - 0.80 (m, 6H). MS (ESI) m z (M-56)Y 3720.

[004421 Step 3: Synthesis of compound 24: Tert-butvl ((3S,14S)14-formyl-3-isobutl1-2,5-dioxo-1,4-diazacvclotetradecan-6 Ilcarbamate Compound 24 was prepared from compound 241 following the procedure of compound 7. Compound 24 (11 imgyield 13.8 %) was obtained as a white solid. 'H NMR (400M1Hz, DMSO-d): 6 9.39 (s, 1H), 8.40 (d, J= 7.4 Hz, 111), 7.40 (d, J= 8.2 Hz, 1H), 6.98 (br. s., 1H), 4.44 (d, J= 6.3 Hz, 1H), 4.26 (br. s., 1H), 3.81 (br. s., 111), 1.55 (br. s., 3H), 1.44 (br. s., 311), 1.36 (br. s., 10H), 1.25 (br. s., 5H), 1.12 (br. s., 511), 0.89 - 0.81 (m, 611). MS (E SI) m (M+H) 426.3.

[004431 Step 4:_Synthesis of compound-25: Tert-butvl ((3S,14S-I14-formvl-3-isobutyl-2,5-dioxo-1,4-diazaevelotetradecai-6

vl)carbamate Compound 25 was prepared from compound 24C following the procedure of compound 7. Compound 25 (10 mg, yield 12.6 %) was obtained as a white solid. I H NMR (400MHz, CDCIs): 6 9.56 (s, IH), 6.89 (dJ:: 7.0 Hz, 1iH ) 6.64 (d, J=: 7.4 lz, 11), 5.33 (d, J= 8.2 Hz, 111), 4.65 (br. s., 2H), 4.12 (br. s., 11), 2.04 (br. s., 111), 179 (br. s., 1H), 1.66 (d, J= 6.7 Hz, 61), 1.43 (br. s., 12H), 1.26 (br. s., 61-1), 093 (d,J:: 14.5 Hz, 61). MS (ESI) nz (M-56) 370.0. EXAMPLE 13 Benzyl ((3S,6S,1-6S)-16-formyl-3-isobutyl-2,5,9,13-tetraoxo-1,,8,12 tetraazacyclohexadecaii-6-vI)carbamate (26)

H- Ho M(OMe)2 H LiB.H, THF ) 0 H HO [0H ISI MeOH IN3 Bc PTSA DCM 2 OH2Boc2 ,,,EtN I'Iuc. 28B

0 0B0 Boc 0 0 Boc

PhI(OAc)2,TEMPO HO A x N /--- LOH.HO N ACN, H2 O 26D t ED C,HOBT 26E H THF H O H 28F DIEA, DCM

0N Oo N O - N bzHN O. HCI/EtOM OFzHN N O 26F -O HOB N|H N EDCI, HOBt DIPA, DCM NH DIPEA, DCM oc 26G 26H

CbzHN. OH [Bc | CbzHN, Nk DbzHN "B H cc ~ LiOH.THF/H 2O NH" 22K!2NL N CIdi H , H2 N OH H- D|EA DMF H MNH DH NNHH

- bzH NH CCzH

02 2H CbzHN,,_I ObzHN,, I

00 HN

26M 28

[004441 Sten 1:_Synthesis of conound-26A To a solution of TMSCl (200 mL, 1.60 mol) in MeOH (500 mL) was added L glutamic acid (47 g, 319 mmol) as portions at 0 C. After addition, the reaction mixture was stirred at 10 °C for 15hrs. The reaction mixture was concentrated to afford dimethyl (2S)-2 aminopentanedioate (67 g, yield 99.1%) as colorless oil, which was used to next directly without further purification. To a solution of dimethyl (2S)-2-aminopentanedioate (67 g, 316.58 mmol) in MeOH (500 mL) was added'TEA (132 mL, 949.74 mmol) and (Boc)2 O (90 g, 411.55 mmol) at 0 °C slowly. After addition, the reaction mixture was stirred at 10 °C for 14 hrs. Themixture was concentrated and the residue was dissolved in Et)Ac (500 mL), the mixture was washed with 0.5 N HC (300 mL.), sat. NaHCO 3 (300 mL), and brine (300 mL). The organic layers was dried over Na 2SO4 and concentrated in vacuo to afford compound 26A (75 g, yield 86.05%) as colorless oil. 'H NMR (400 MHz, CDC 3 ): 6 5.17 - 5.05 (in, 1H), 4.40 - 4.28 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.49 - 2.33 (m, 2H), 2.25 - 2.13 (in, 1H), 2.02 - 1.89 (m, 1H), 1.44 (s, 9H). MS (ESI) mz (M+23)-297.9.

[004451 Step 2: Synthesis of compound 26B

To a solution of LiBH4 (30 g, 136 mol) inT-F(500 mL) was added dropwise a solution of compound 26A (75 g, 272.43 mmol) in THF (150 mL) at 0°C. After addition, the reaction mixture was stirred at 0 °C for I h, then warmed to 10 °C and stirred for 16 hrs. Then MeOH (300 mL) was added into the reaction mixture slowly and stirred for 30 min followed by added NHCl (30 mL) dropwise into the mixture slowly. The mixture was filtered, and the solid collected was washed with ItOAc (IL). The filtrate was concentrated and the residue was dissolved in water (800 mL) and EtOAc (800 mL), the mixture was separated and the aqueous was extracted with EtOAc (800 nL x 2). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was diluted with MTBE and filtered to afford compound 26B (35 g, yield 58.6%) as white solid. 'H NMR (400MHz, CDCl 3): 6 4.95 - 4.84 (m, 1H), 3.75 - 3.50 (m, 5H), 3.01 (br. s., IH), 2.49 (br. s., 1H), 1.67 1,41 (n, 13H).

[004461 Step 3: Synthesis of compound 26C To a solution of compound 26B (15 g, 68.41 mmol) in DCM (60 mL) was added2,2 dimethoxypropane (126 mL, 1.03 mol) and PTSA (1.2 g, 6.84 mmol). After addition, the reaction mixture was stirred at 15 °C for 2 hrs. Then the reaction mixture was quenched with sat.NaHCO3 (100 mL) and extracted with EtOAc (200 mL. x 2), the combined extracts were washed with brine (100 mL) and dried over Na2 SO 4, then concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate:= 3/1 to 2/1) to afford compound 26C (9 g, yield 50.7%) as colorless oil. 'H NMR (400MHz, CDCI3 ): 6 4.02 - 3.64 (in, 5H), 1.91 - 1.68 (m, 1H), 1.66 - 1.52 (in,6H), 1.52 - 1.43 (m, 13H).

[004471 Step 4: Synthesis of compound 26D To a solution of compound 26C (9 g, 34.70 mmol) in ACN (100 mL) and H20 (100 mL) was added PhI(OAc)2 (25 g, 76.34 mmol), TEMPO (1.1 g, 6.94 mmol) at 0 °C under N 2 atmosphere. After that, the reaction mixture was stirred at 15 °C for 2 hrs. Then Na 2 S20 3 (200 mL) was added into the reaction mixture and the mixture was stirred for 5 min. and extracted with EtOAc (300 mL x 2), the combined extracts were diluted with sat. Na-I) 3

(300 rnL) and separated, the aqueous layer was acidified by IN HC to p-I 3, then the mixture was extracted with EtOAc (300 mL x 2). the combined extracts were washed with brine (150 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford compound 5 (4 g, yield 38.3%) as colorless oil. H NMR (400M1-1z, DMSO-cl6):.12.02 (br s., 111), 3.90 - 3.67 (m, 311), 228 - 212(, 2H), 1.87 - 1.77 (m, 111), 174 - 1.63 (in, I), 1.58 - 1.27 (m, 1511).

[004481 Step 5: Synthesis of compound 26E Compound 26E was prepared from compound 26D and ethyl 3-aminopropanoate following the procedure of compound 7D. Compound 26E (5 g, yield 452 %) was obtained as a colorless oil. 'H NIR (400MHz, CDCIs): 4.20 - 4.11 (m, 2H), 3.99 - 3.83 (m, 2H), 3.77 - 3.67 (in, 1H), 3.57 - 3.47 (in, 2H), 2.60 - 2.49 (in, 2H), 2.28 - 2.12 (in, 21H), 2.03 - 1.83

(m,2H), 1.62 - 1.40 (m, 15H), 1.27 (t,J=6.6 Hz, 3H.

[004491 Step 6:_Svnthesis of compound-26F To a solution of compound 26E (5.0 g, 13.42 mmol) in THF (100 mL) was added a solution of LiOH.H 20 (1.7 g, 40.26 mmol) in H20 (100 mL) at 0 °C. After addition, the reaction mixture was stirred at 10 °C for 2 hrs. The reaction mixture was acidified to pH- 8 and extracted with EtOAc (200 mL), the aqueous layer was acidified by IN HCl to pH ~ 3 and extracted with EtOAc (200 mL x2), the combined extracts were washed with brine (100 mL x 2) and dried over Na 2 SO4, then concentrated in vacuo to afford compound 26F (4.5 g, yield 77.9%) as colorless oil. 1H NMR (400M1Hz, DMSO-d): 6 12.15 (br. s., 1H), 3.88 - 3.80 (in, 111), 3.78 - 3.65 (m, 2H), 3.24 - 3.15 (in, 2H), 2.38 - 2.31 (in, 2H), 2.06 - 1.98 (m, 2H),

1.84 - 1.74 (m, 1H), 1.68 - 1.57 (in, 1H), 1.52 - 1.32 (m, 15H). MS (ESI) mz(M+23)366.9.

[004501 Sten 7:_Svnthesis of compound-26G Compound 26G was prepared from (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert butoxycarbonyl)amino)propanoic acid and methyl L-leucinate following the procedure of compound 7D. Compound 26G (9 g, yield 84.1 %) was obtained as a white solid. 11NMR (400MHz, CDC-): 6 7.41 - 7.29 (in, 51), 705 (br. s, 111), 6.25 - 6.15 (n, 1H), 5.22 (br. s., 111), 5.16 - 5 10 (m, 2H), 4.60 - 4.52 (m, 111), 4.34 - 4.27 (m, 111), 3.72 (br. s., 31), 3.58 3.44 (in, 211), 1.67 - 1.56 (in, 31), 1.43 (s, 91), 0.96 - 0.90 (in, 61). MS (ESI) n (M Boc-H)' 365.9.

[004511 Step 8: Synthesis of compound 2611 To a solution of compound 26G (9.0 g, 19.33 mnmol) in EtOAc (20 mnL) was added HC1/EtOAc (4M, 128 mL) at 0 °C. After addition, the reaction mixture was stirred at 15 °C for2 hrs. The reaction mixture was concentrated in vacuo to afford compound 26H (7.0 g, yield 90.1%, HCI salt) as white solid, which was used to next without further purification. 1H

NMR (400MHz, DMSO-d6 ): 6 8.62 - 8.52 (in, 11), 8,26 - 8.09 (m, 3H), 7.71 - 7.63 (m, 11), 743 - 7.25 (in, 51), 5.05 (s, 211), 4.40 - 422 (i, 21), 3.60 (s, 31), 3.24 - 3.10 (in, 11), 3.02 2.88 (m, 1H), 1.65 - 1.55 (m, 211), 1.53 - 1.45 (m, I1i), 0.90 - 0.79 (m, 61).

[004521 Step 9: Synthesis of compound 26J. Compound 26J was prepared from compound 261- and 26F following the procedure of compound 7D. Compound 26J (7.0 g, yield 61.9 %) was obtained as a white solid. 1H N.M (400MHz, DMSO-d): 6 8.34 - 8.27 (in, 1H), 7.85 - 7.73 (in, 2H), 7.38 - 7.29(m,6H),

5.03 (s, 2H), 4.35 - 4.26 (m, 1H), 4.20 - 4.11 (m, 1H), 3.89 - 3.80 (in, 1H), 3.78 - 3.67 (in, 2H), 3.65 - 3.60 (in, 3H), 3.32 - 3.15 (in, 4H), 2.27 - 2.18 (in,2H), 2.10 - 1.94 (m, 2H), 1.86 1.80 (in, 111), 1.70 - 1.53 (m, 41), 152 - 1.32 (m, 16H), 0.91 - 0.87 (m, 3H), 0.85 - 0.82 (in, 311).

[004531 Step 10: Synthesis of compound 26K Compound 26K was prepared from compound 26J following the procedure of compound 26F. Compound26(6.0g,yield 70.0%) was obtained as a colorless oil. 11 NMR (400MHz, DMSO-d): 6 12.52 (s, 11), 8.16 - 8.10 (m, 1). 7.85 - 7.73 (in, 211), 737 7.27 (in, 6H), 5.01 (s, 2H), 4.24 - 4.17 (in, 1H), 4.15 - 4.08 (m, 1H), 3.88 - 3.79 (in, 1H), 3.77 - 3.64 (in, 2H), 3.26 - 3.12 (m, 4H), 2.25 - 2.16 (in, 2H), 2.08 - 1.98 (in, 2H), 1.68 - 1.48 (in, 5H), 1.46 - 1.33 (m, 12H), 0.92 - 0.71 (m, 9H).

[004541 Step 11: Synthesis of compound 26L Compound 26L was prepared from compound 26K following the procedure of compound 26K. Compound 26L (4.5 g, yield 75.3 %, HCI) was obtained as a light yellow solid. 'I- NMR (400MHz, DMSO-6): 12.52 (s, 11), 816 - 810 (in, 111), 7.85 - 7.73 (m, 2H), 7.37 - 7.27 (m, 611), 5.01 (s, 211), 4.24 - 417 (m, 1-), 4.15 - 4.08 (m, 11), 388 - 3.79 (m,111), 3.77 - 364 (in, 21), 3.26 - 3.12 (i, 41). 25 - 2.16 (in, 211), 2.08 - 1.98 (m, 2H), 1.68 - 1.48 (m, 511), 146 - 1.33 (in, 1211), 0.92 - 0.71 (i,911).

[004551 Step 12: Synthesis of compound 26M To a solution of compound 26L (10 g, 1.74 mmol, HC) and DIEA (0.9 mL, 5.23 mol,) in dry DMF (250 mL) was added HATU (728 ig, 1.92 mmol). After addition, the reaction mixture was stirred at 10 °C for 1 h. The reaction mixture was concentrated in vacuo to remove DMF. The residue was purified by preparatory-lPLC (HCI) to afford compound 26M (180 mg, yield 19.5%) as white solid. 'H NMR (400MHz, DMSO-d6 ): 6

8.20 - 8.14 (m, 111), 7.90 - 7.82 (m, 11-), 7.62 - 7.53 (m, 11-), 7.40 - 7.25 (m, 6H), 7.00 - 6.93 (i, 11), 5.08 - 4.98 (m, 211), 437 - 428 (in, 111), 4.08 - 4.00 (i, 1H), 3.81 - 3.73 (in, 21), 372 - 3.62 (i, 111), 3.54 - 3.44 (i, 111), 3.30 - 3.23 (i, 211), 2.91 - 2.81 (i, 111), 239 - 2.28 (i, 1H), 2.11 - 1.99 (, 3H), 1.97 - 1.87 (m, 1H), 1.79 - 1.68 (m, 1H), 1.56 - 1.46 (in, 1H), 1.42 - 1.24 (in, 2H), 0.97 - 0.79 (i, 6H). MS (ESI) nz (M +1H)- 520.1.).

[004561 Step13: Sy-ithesis of comound 26 Compound 26 was prepared from compound 26M following the procedure of compound 7. Compound 26 (18 mg, yield 10.5 %, HCl) was obtained as a white solid. 'H NMR (400MHz, DMSO-d6). 9.49 (s, 1H), 8.34 - 8.20 (in, 2H), 7.54 - 7.28 (in, 7H), 7.23 7.17 (m, 1H), 5.10 - 4.99 (m, 211), 4.43 - 4.28 (in, 21-), 4.15 - 4.04 (m, IH), 3.73 - 3.46 (in, 311),2.98 - 2.83 (m, 111), 235 - 2.04 (in, 511), 1.85 - 1.68 (in, 11-1), 1.61 - 1.40 (m, 3H), 0.98 0.91 (in. 31), 0.91 - 0.86 (i, 311). MS (ESI) mz (M+H)518.1 EXAMPLE 14 Compounds 27-29 N-((3S,6Sj5SE)-3-((S)-sec-butvli)-15-formvl-2,5-dioxo-1,4-diazacyclopentade-12-en-6 VI)-4-fluorobenzenesulfoiamide (27)

soc BO N' H CC, THF H

27A H H NH Et 27 N ~YOEt 2-M-HOI/'EtO)Ac IC

7B A C7 .1 G b27C NHN NC CO2EtN N N,.. CO2E OHr" 27. N N -/!EAH.o ME I H H N H 0C HN ' N, N .C0,Et 0 H cO2Bt UG ~(\/3I y- CO,\

H ji H EDCI; HO~tDIEA; DCMD0.1 eq Grubb's2nd--0 27D ---- DMv 27E

270

O HNI N, H 0E 2M C 12 O HNr[ DIEA, DCM OEt H 2N. -H'I F

27F 27G

H O HN N H 0 yOH O O HN N L;I C '. UA-H44 7.0 eq DMP F THF, 1.5h F - H DCM DGM H 27H 27

[004571 Step-1: Synthesis of compound 27A A solution of DCC (178 g, 8.65 mnol) in anhydrous THF (20 mL) was added to a solution of (tert-butoxycarbonyl)-L-isoleucine (2.00 g, 8.65 mmol) and N-hydroxysuccinimide

(1.0 g, 8.65 mmol) in anhydrous THF(20 mL). The resultant mixture was stirred at 15 °C for 12 hrs. The insoluble substance was filtered off The filtrate was concentrated to afford compound 27A (2.90 g, crude) as colorless gum, which was used for next step without further purification.

[004581 Step 2: Synthesis of compound 27B DIEA (0.97 mL, 5.57 mmol) was added to a mixture of compound 7B (1.0 g, 5.57 mmol) and compound 27A (1.83 g, 5.57 nmol) in DME (20.00 mL). The resultant mixture was stirred at 15 °C for 12 hrs. The mixture was concentrated and the residue was treated with DCM (50 mL) and H 2 0 (30 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 15 mL). The combined organic layer was washed with saturated NaHCO- (15 mL), IN HCI (15 mL), brine (15 mL), dried over anhydrous MgSO4 ,

filtered and concentrated. The residue was triturated with PE/i-Pr2 O (v/v= 5/1, 10 mL) to afford compound 27B (1.15 g, yield 57.9%) aswhite solid. MS(ESI) imz(M--H)357.1. 'H NMR (400MHz, DMSO-d) 6 8 20 (d, J= 7.6 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 5.84 - 5.69 (in, 1H), 5.15 - 5.07 (in, 1H), 5.05 - 5.03 (in, 1H), 4.36 - 4.25 (in, 1H), 4.10 - 4.06 (in, 2H), 3.85 - 3.83 (in, 1H), 2.47 - 2.31 (in, 2H), 1.68 - 1.66 (in, 1H), 1.40 - 1.38 (m,1H), 1.38 (s, 9H), 1.17 (t,J=7.2Hz, 3H), 1.11 - 1.06 (m, 1H), 0.89 - 0.75 (in, 6H).

[004591 Step-3: Synthesis of compound 27C Compound 27C was prepared from compound 27B following the procedure of compound 12A. Compound 27C (0.8 g, yield 97.2 %) was obtained as a white solid. 'H

NMR (400MHz, DMSO-d) 6 8.95 (d, J= 6.8 Hz, 1), 8.32 (br.s., 311), 5.89 - 5.77 (in, 1), 517- 5.12 (i, 111), 5.09 - 5.08 (m, 111), 4.34 - 4.32 (m, 11-1), 4.09 - 4.06 (i, 2H), 3.73 - 3.72 (i, 11), 2.47 - 2.46 (M, 211), 1.87 - 185 (in, 111), 1.52 - 1.48 (i, 1H), 1.20 - 1.15 (in, 41), 0.92 (d, J= 6.8 Hz, 3H), 0.88 - 0.84 (in, 3H).

[00460] Step 4: Synthesis of compound 27D Compound 27D was prepared from compound 27C and (S)-2-((tert butoxycarbonyl)amino)non-8-enoic acid following the procedure of compound 7D. Compound271) (1.4 g, crude) was obtained as a pale yellow solid and used for next step directly. MS (ESI) nz (M-+Na)Y 532.2. 'H NMR (400MHz, DMSO-d) ( 8.40 (d, J= 6.8 Hz, 11), 759 (d, J= 8.8 Hz, 11-1), 6.98 (d, J= 8.0 Hz, 11-1), 5.79 - 5.71 (i, 211), 5.12 - 4.92 (i, 41), 4.27 - 4.23 (m, 21), 4.08 - 4.05 (in, 2H), 3.92 - 3.89 (m, IH), 2.43 - 2.39 (n, 21), 2.01 - 1.99 (in, 2H), 1.59 - 1.14 (in, 23H), 0.85 - 0.79 (in, 6H).

[004611 Step 5: Synthesis of compound 27E Compound 27E was prepared from compound 27D and ethyl 3-aminopropanoate following the procedure of compound 18H. Compound 27E (0.8 g, yield 84.7 %) was obtained as a pale yellow solid. MS (ESI) mz (M+Na) 504.2. H NMR (400MHz, CDCl 3)6 6.40 - 6.20 (in, 2H), 5.41 - 5.30 (in, iH), 5.23 - 5.15 (in, iH), 4.56 - 4.54 (in, 1H), 4.28 - 4.10 (m, 3H), 4.08 - 3.97 (m, 11), 267 - 244 (in, 111), 2.37 - 2.12 (m, IFH), .02 - 1.78 (in, 411), 160 (s, 211), 1.47 - 1.40 (in, 2H), 1.40 - 1.19 (m, 1611), 1,18 - 1.02 (in, 311), 090 - 0.76 (in, 611).

[004621 Step 6: Synthesis of compound 27F Compound 27F was prepared from compound 27E following the procedure of compound 12A. Compound 27F (0.73 g, yield 99.2 %) was obtained as an off-white solid

which was used directly. H NMR (400MHz, DMSO-d 6 ) 6 8.58 - 856 (in, 211), 8.18 (br. s., 3H), 5.46 - 5.29 (in, 2H), 4.40 - 4.36 (in, IH), 4.31 - 4.27 (m, 1H), 4.11 -4.07 (in, 2H), 3.89 3.88 (in, iH), 2.23 - 2.12 (in, 1H), 2.03 - 1.93 (m, 2H), 1.84 -1.82 (in, 1H), 1.68 -1.64 (in, 3H), 1.57 - 1.44 (in, IH), 1.27 -1.22 (in, 3H), 1.21 -1.18 (m, 4H), 1.14 - 0.97 (in, 3H), 0.89 (d, J= 6.4 Hz, 3H ), 0.87 - 0.81 (m, 3H).

[004631 Step 7: Synthesis of compound 27G DIEA (0.92 mL, 5.25 mmol) was added to a mixture of compound 27F (730.00 mg, 1.75 mmol) in DCM (30 inL). The suspension turned clear solution. Then 4 fluorobenzenesulfony chloride (374.62 mg, 1.93 mmol) was added. The resultant mixture was stirred at 10 'C for 12 hrs. The mixture was turned thick slurry. The mixture was diluted with DCM (100 mL) and THF (30 mL), washed with1H20 (20 mL), saturated NaHCO 3 (20 mL), IN HCI (20 mL), brine (15 mL x 2), dried over anhydrous MgSO4 , filtered and concentrated. The residue was triturated with EA (15 mL) as off-white solid, which was re purified by triturating withEA/MeOI (v/v= 10/1, 15 mL) to afford to afford compound 27G (490 mg yield 51.9%) as white solid. MS (ESI) iz (M+Na) 562. L.

1004641 Step 8: Synthesis of compound 27H Compound 2711 was prepared from compound 27G following the procedure of compound 14F. Compound 2711 (110 mg, yield 26.5 %) was obtained as a white solid. MS (ESI) inz (M+Na)_ 520.0. 'H NMR (400M1Hz, DMSO-d) 6 8.03 (d,J= 9.6 Hz, 11H), 7.86 7.83 (m, 2H), 7.76 (d,,J= 9.2 Hz, IH), 7.68 (d, J= 8.8 Hz, IH), 7.38 - 7.33 (m, IH), 5.27 (br. s., 2H), 4.68 -4.65 (m, IH), 4.01 - 3.93 (m, 2H), 3.79 - 3.68 (m, IH), 3.32 - 3.25 (m, IH), 3.14 - 3.06 (m, 1H), 2.33 - 2.25 (m, 1H), 2.01 - 1.76 (m, 3H), 1.65 - 1.54 (m, 1H), 1.43 (d, J=6.8 Hz, 2H), 1.23 - 1.04 (m, 7H), 0.96 - 0.85 (m, 1H), 0.71 -0.68 (m, 7H).

[004651 Step 9: Synthesis of compound 27 Compound 27 was prepared from compound 27H following the procedure of compound 7. Compound27 (25 mg, yield 50.2 %) was obtained as a white solid. MS (ESI) inz (M+Na+H20) 536.1. 'H NMR (400MHz, DMSO-d6) 6 9.41 (s, 11-), 827 (dJ::8.4 H z,

11), 8.10 (d, J= 9.2 Hz, 11), 7.86 - 7.83 (m, 2H), 7.75 (d, J= 8.4 Hz, 111), 7.39 - 7.34(m, 2H), 5.37 - 5.24 (i, 21), 435 - 4.08 (m, 11-1), 4.08 - 3.97 (m, 2H), 2.02 -1.94 (m, 3H), 1.61 0.71 (m, 18H). 4-fluoro-N-((3S,6S,15SE)-15-formvl-3-isopropyl-2,5-dioxo-1,4-diazaevelopentadee-12 en-6-vI)benzenesulfonamide (28)

H 0

0 HN- N H F 0

H/ 28 ---

[004661 Synthesis of compound 28 Compound 28 was prepared using the same synthetic steps as for compound 27, except that in Step 1'(tert-butoxycarbonyl)-L-valine was used as the starting amino acid.

Compound 28 (15 mg, yield 37.7 %) was obtained as a white solid. MS (ESI) nz (M+H)v 482.1. N-(3S,6S.15S,E)-3-benzyl-15-formivl-2,5-dioxo-1,4-diazaevelopentadee-12-en-6-i)-4 fluorobenzenesulfonamide (29)

H 0 0OHN N

HF

29

[004671 Synthesis of ompound 29 Compound 29 was prepared using the same synthetic steps as for compound 27, except that in Step 2, compound 7B was coupled with (tert-butoxycarbonyl)-L-phenylalanine. Compound 29 (40 mg, yield 57 %) was obtained as a white solid. 1H NMR (400MHz, DMSO-d) 6 9.13- 893 (m, H), 844 (d, J=9.0 Hz 1H), 8.19 (d, J= 83 lz, IH). 7.87 7.66 (m, 3H), 7.38 - 7.08 (m, 7H), 5.37 - 5.26 (m, 1H), 5.26 - 5.14 (m, 111), 4.48 - 4.36 (in, 1H), 4.30 - 4.16 (m, 1H), 3.99 - 3.86 (m, 1H), 2.87 - 2.76 (in, 1H), 2.62 - 2.52 (in, 1H), 2.43 2.36 (m, 1H), 2.02 - 1.81 (m, 3H), 1.65 - 1.52 (m, IH), 1.47 - 1.34 (m, 1H), 1.31 - 1.15 (in, 3H), 1.09 - 0.97 (m, 2H), 0.95 - 0.78 (m, I1H). MS (ESI) mz (M+Na) 530.1.

EXAMPLE 15 Benzvl ((6S,9S,12S)-6-formyl-9-isobutyl-8,11-dioxo-1-oxa-7,10-diazaevelohexadec-14 yn-12-V)carbamate J30) CbzHN, CO 2Me CbzH-N, ,CO 2Me 12im dazle/PPh, OHI DM 30A HO HO 0o >= = TMSCI MeOH BOC2LiH 4,HI Me2C(Oe)2

HN PTSA, DCM N H 2N H2 F22N30B Yboc 'c 3E/)\ 30C 30D

H I Cbz-N A

Br a t/30A NIS, AgNO3 I 1ZMS I,Si CF2C1EBr / Z NnA~Q ----- ------ -- - --- -

NaH, TIF 30G 2) CuCN-2Li, THF BocN-- 30F

O' 0 CbzH O..)N.M CbzHN.)k, 1 N. Boc c LiIHTHF/H2C)

30H ' 30J

H2J -hH, Cr NLN < NCH CbzHIN H2 N CbzHN -- i HCI, /dioxane NH2 Y B ---- ------ oc ----------- EDC!, > 0'- a HOEt, 30K 30L. DIPEA, DCM

O OH CbzHN H CbzHN N N 'OH TFA/DCM H 2 HATiPr2NEt,DMF H

30N 30P

CbzHN N H1N DMvlP, DCM, DMv4SO ,

30

[004681 Step 1: Synthesis of compound 30A To a solution of PPh3 (4.53 g, 17.28 mmol) and imidazole (1.18 g, 17.28 mmol) in DCM (150 mL) at 0 °C was added12 (4.38 g, 17.28 mmol) in three portions. The solution was warmed to 10 °C and stirred for 10 min, and re-cooled to 0 °C. Methyl ((benzyloxy)carbonyl)-L-serinate (3.50 g, 13.82 mmol) in DCM ('25 nL) was then added dropwise. The solution was stirred at 0 °C for 1 hr and 10 °C for 1.5 hrs. The reaction mixture was then filtered through silica gel using PE/EA = 50/50 as eluent, concentrated. The residue was purified by column chromatography (Si02, petroleum ether : ethyl acetate= 1:0 to 10:1) to afford the desired compound 30A (4.00 g, yield: 79.70%) as colorless oil. 1H NMR (400MHz, CDCl 3) 6 7.42 - 7.27 (in, 5H), 5.63 (m, 1H), 5.22 - 5.05 (in, 2H), 4.60 (m, 11-1), 3.82 (s, 31-1), 3.69 - 3.49 (m, 2 H).

[004691 Step 2: Synthesis of compound 30B To a solution of TMSC (11.76 mL 93.1 miol) in MeOH (25 mL) was added(2S)-2 aininohexanedioic acid (3 g, 18.62 mmol) at 0 °C. The mixture was stirred at 10 °C for 16 hrs. The mixture was concentrated to afford compound 30B (6 g, crude) as colorless oil, which was used to next step without further purification.

[004701 Step 3: Synthesis of compound 30C To a solution of dimethyl (2S)-2-aminohexanedioate 30B (6 g, 31.71 mmol) in MeOH (100 mL) was added TEA (13.19 ml, 95.13 mmol) and (Boc)2 0 (9 g, 41.22 mmol) at 0 °C. The mixture was stirred at 10 °C for 16 hrs. The mixture was concentrated and the residue was dissolved into EtOAc (100 mL), the mixture was washed with HCI (0.5 N, 20 mL), saturated NaHCO3 (20 mL x 2), and brine (30 mL). The organic layers was dried over Na 2 SO 4 and concentrated in vacuo to afford compound 30C (8.7 g, crude) as colorless oil. H NMR (400MHz, CDC 3 ) 6 5 17 - 4.95 (in, 11), 439 - 4.22 (in, 111), 3.75 (s, 31-1), 3.67 (s, 31-1),2.41 - 227 (in. 2), 1.90 - 1.79 (i, 11-1), 1.77 - 1.57 (in. 311), 1.47 - 1.37 (i, 91-).

[004711 Step 4: Synthesis of compound 30D Compound 30) was prepared from compound 30C following the procedure of compound 26B. Compound 30D (7.9 g, yield 63.2 %) was obtained as a colorless oil. 1H

NT (400 MHz, CDCI 3 ): 5.08 - 4.44 (in, 2H), 3.75 - 3.52 (m, 5H), 3.15 - 2.62 (in, 1H), 2.41 - 1.78 (in, 1H), 1.65 - 1.40 (in, 14H).

[004721 Step 5:-Svnthesis of conound-30E Compound 30E was prepared from compound 30D following the procedure of

compound26C. Compound 30E (310 mg, yield 39.51 %)was obtained as a colorless oil. IH NMR (400MHz, CDC 3 ): 5 3.95 - 3.89 (in, 1H), 3.81 - 3.69 (in, 2H), 369 - 3.61 (in, 2), 1.64 - 1.53 (m, 611), 152 - 1.41 (in,131-1), 1.41 - 1.29 m, 21-1)

1004731 Step 6: Synthesis of compound 30F To a solution of compound 30E (310 mg, 1.13 mmol) and 3-bromoprop-1-yne (161.31 mg, 1.36 mmol) in DMF (5 mL) was added NaH (54.24 mg, 1.36 mmol, 60% purity) at 0 °C. After addition the mixture was stirred at 0 °C for 2 hrs, then stirred at 5 °C for 14 hrs. To the reaction mixture was added water (15 mL) and extracted with EA (30 rnL x 2), the combined extracts were washed with IN HC (10 nL), sat. Na-CO3 (10 mL), dried over Na 2 SO 4 , and then concentrated in vacuo. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate = 3/1 to 2/1) to afford compound 30F (164 mg, yield 46.6%) as colorless oil. Hl NNIR (400MHz, CDC 3 ): 6 4.14 - 4.09 (in, 21-1),

3.93 - 3.86 (in, 11-1), 3.80 - 3.67 (i, 2H), 3.55 - 3.46 (in, 211), 2.41 (t, J=2.3 Hz, 111), 1.65 1.51 (in. 6H), 1.50 - 1.40 (m, 131-1), 139 - 129 (in,21).

[004741 Step 7: Synthesis of compound 30G To a solution of compound 30F (250 ing, 802.77 umol) in DCM (10 mL) was added NIS (198.6 mg, 883.05 umol) and AgNO 3 (163.64 ig, 963.33 umol). The mixture was stirred at 8 °C for 4 hrs. The mixture was concentrated. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=3/1 to 2/1) to afford compound 30G (293 mg, yield 83.46%) as yellow oil. 'H NMR (400MHz, CDCl 3): 6 4.28 (s, 2H), 3.96 3.85 (in, IH), 3.81 - 3.69 (m, 2H), 3.57 - 3.44 (m, 2H), 1.67 - 1.51 (m, 7H), 1.50 - 1.43 (m, 121-1), 140 - 1,26 (m, 2H).

[004751 Step 8: Svnthesis of compound 30H To a solution of pre-active Zn powder (154.49 mg, 2.36 mmol) in THIF (6 mL, fresh distilled) was added 1,2-dibromoethane (22.9 mg, 121.88 umol). The reaction mixture was stirred at 70 °C then cooled back to 8 °C, this cycle was repeated three times. Freshly distilled TMSC (8.15 mg, 75.00 umol) was added and the reaction was stirred at 8 °C for 0.1 h. A solution of compound 30A (425.59 mg, 1.17 mmol) in anhydrous THF (5 mL) was added at 8 °C. The reaction was stirred at 8°C for 0.75 h. Meanwhile, a round bottomed flask, equipped with a stirrer bar, was charged with LiC1 (101.34 mg, 2.39 mmol), which was subsequently dried under vacuum at high timeperature with hot gun. To this flask was added CuCN (104.96 mg, 1.17 mmol) and anhydrousTHF (5 mL), the mixture was stirred at 8 °C until a yellow solution was obtained that was then cooled to -10 °C. The previously prepared solution of the organozine iodide was decanted from the excess zinc via syringe and added dropwise to the solution of the copper complex. The reaction mixture was stirred at -10 °C for 0.2 h and then cooled to - 78 °C and a solution of compound 30G (410 mg, 937.55 umol) in anhydrous THF (5 mL) was added. The reaction was stirred at -20 °C for 4 h and then at 8 °C for 16 hrs. The mixture was quenched with 10% NH 4 Cl (40 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over Na2 SO4 and concentrated. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=10:1 to 5:1) to afford compound 30H (260 mg, yield 23.08%) as yellow oil. 1H NMR (400M1-Hz, CDCl3): 7.38 - 7.35 (in, 5H), 5.70 - 5.51 (m, IH), 5.13 - 5.10 (m, 2H), 4.10 - 4.05 (m, 1H),

3.96 - 3.84 (m, 211), 3.83 - 3.68 (n, 611), 3.48 - 3.42 (n, 11-), 2.87 - 2.72 (m, 211), 1.61 - 1.32 (m, 2111).

[004761 Step 9: Synthesis of compound 30J Compound 30J was prepared from compound 30H following the procedure of compound 26K. Compound 30J (220 mg, crude) was obtained as a yellow oil and used for next step directly. MS (ESI) wNz(M+Na) 555.0.

[004771 Step 10: Synthesis of compound 30K Compound 30K was prepared from compound 30J and ieri-butyl L-leucinate following the procedure of compound 26J. Compound 30K (60 mg, yield 20.7 %) was obtained as a colorless oil. MS (ESI) m (M+Na)724.4.

[004781 Step11: Synithesis of comound 30L Compound 30L was prepared from compound 30K following the procedure of compound 26L. Compound 30L (60 mg, crude, H.) was obtained as a yellow oil and used for next step directly. MS (ESI) m, (M-Na) 562.1.

[004791 Step 12: Svnthesis of compound 30M To a solution of compound 30L (60 mg, 100.31 umol, HCl) in DCM (3 mL) was addedTFA (3 mL, 40.52 mmol). The mixture was stirred at 15 °C for 30 min. The reaction mixture was concentrated to afford compound 30M (60 mg, crude, TFA) as yellow oil, which was used to next step without further purification. MS (ESI) n (M +H1) 5061.

[004801 Step 13: Synthesis of compound 30N Compound 30N was prepared from compound 30M following the procedure of compound 26M. Compound 30N (13 mg, yield 22.44 %) was obtained as a white solid. MS (ESI) wx (M +H) 488. 1 H NMR (400MHz, DMSO-d) 68.19 - 8.05 (m, 1H), 8.18 - 8.03 (in, 1H), 7.80 - 7.73 (m, 1H), 7.40 - 7.29 (m, 5H), 7.18 - 7.04 (m, 11H), 5.09 - 4.98 (m, 1H), 5.09 4.96 (m, 1H), 5.10 - 4.96 (m, IH), 5.08 - 4.94 (m, IH), 4.64 - 4.56 (in, 1H), 4.66 - 4.52 (m, 11),4.43 - 4.34 (in, HIF), 4.31 - 4.15 (in, IH), 4.04 - 3.93 (i, 211),3.88 - 3.73 (m, 11-1), 330 3.15 (i, 3H), 2.70 - 2.59 (m, 11-), 2.56 - 2.45 (in, 43), 1.63 - 1.47 (m, 31-1), 146 - 1.33 (n, 311), 1.33 - 1.15 (m, 51-1), 0.93 - 0.77 (in, 611).

1004811 Step 14: Synthesis of compound 30

Compound 30 was prepared from compound 30N following the procedure of compound 26. Compound 30 (3.2 mg, yield 21.42 %) was obtained as a white solid. MS (ESI) iz (M ±H) 486.2. 'H NMR (400MHz, DMSO-d6): 9.43 (s, 1H), 8.38 - 8.30 (m, lH), 8.25 - 8.15 (im, IH), 7.39 -7.27 (m, 5H), 7.19 - 7.07 (m, 1-H), 5.06 - 4.96 (m, 211),4.46 4.35 (in, 211), 4.27 - 4.18 (m, IH), 4.02 - 3.90 (m,H2H), 274 - 255 (in, 211), 1.64 - 1.25 (m, 911),0.96 - 0.86 (i, 31), 0.85 - 0.75 (m, 311). EXAMPLE 16 (4R,7S)-4-isobutvl-1-methyl-2.5-dioxo-1,6-diazacvclotetradee-9-eiie-7-arbaidehyde (31)

C<- O C Br -' CI ~ -BuLi THF -60C - r.' / ---------------------- ------------ LiHMDS. THF~ -. ------- J-

Bu ); D,

31A

BCH_ TFPDCMH BULTH ---------- - EDC HORBt DPEA, DCM F

31C 31D\

3

NN

3C0 1-------

/ 31F 31G

01OH N NN LiCH THF/H CN-., , N

K, I E"DCI,-HOBt DCM

31H 31 K

H~ L

31

[004821 Sten1: Snthesis of comound 31A (S)-4-benzyoxazolidin-2-one (70 g,39503inmmol) was dissolved in T-F(700nmL) andcooledto-65CundeN n-BuLi (190m, 474.04 mmo 2.5M inhexane)was added

during 1h and theresultant mixture was stirred forI1 hat -65°C to -60°C. Then 4 methylpentanoyl chloride (66.2 mL, 493.79inmmol) was added and the resulting mixture was stirred at -60°C to -65°C forih before warming to 0- 5°C and stirred at 0- 5°C for 16 hours. The reaction was quenched with saturated NH 4 C (500imL),.the THF was removed under vacuum, and the aqueous phase was washed with EtOAc (500nmL x2). The organic phase was then washed with IN NaOH (200 mL) and brine (200 mL), after which it was dried over anhydrous Na2 SO. The product was isolated following filtration and removal of the solvent under vacuum to give compound 31A (115.20 g, 79% yield) as a yellow solid. 1H NMR (CDCl 3 400 MHz) 6 7.43 - 7.21 (m, 5H), 4.76 - 4.68 (m, 1H), 4.28 - 4.18 (in, 2H), 3.35 (dd, J=3.3, 13.3 Hz, 1H), 3.09 - 2.91 (m, 2H), 2.82 (dd, J=9.7, 13.4 Hz, IH), 1.76 - 1.58 (in, 3H), 1.02 - 0.90 (m, 711). MS (ESI) m (M-Na) 412.2.

[004831 Step 2: Synthesis of compound 31B The solution consisting of compound 31A (80 g, 290.55 mmol) and THF (800 mL) was added to LiHMDS (323 mL, 322.83 mmol, IM in THF) at - 60°C to -65°C under N 2

. The mixture was stirred at -65°C for 1 hour and then tert-butyl 2-bromoacetate (1193 mL, 807.08 mmol,) was added at - 60°C to -65°C dropwise. The mixture was stirred at -65°Cfor 1I h and then warmed to 5°C - 10 °C slowly, and stirred for 16 hours before quenching with saturated NI-14 C1(500 ml). THF was removed under vacuum, and the aqueous phase was washed with EtOAc (500 mL x 2). The combined organic phase was then washed with I N NaOH (200 mL) and brine (200 mL), the organic phase was dried over anhydrous Na2 SO4 and concentrated. Much solid was precipitated out, filtered and the filter cake was washed with PE: EA (10:1, 15 mL x 2), then the filter cake was dried under reduced pressure to give the pure compound 31A (30g) as a white solid. The filtrate was concentrated and purified by FCC (PE: EA=1:0 to 1:1) to afford compound 31B (14 g) as a white solid.1 H NM R (CDClI 400 MHz) 6 7.39 - 7.19 (m, 5H), 4.70 - 4.59 (m, IH), 4.31 - 4.20 (m, 1H), 4.19 - 4.10 (in, 2H), 3.38 --3.30 (in, 1H), 2.81 - 2.67 (m, 2H),2.53 - 2.43 (in, 1H), 1.68 - 1.49 (in, 3H), 1.42 (s,9HI),1.38-1.28(i,1[H),0.92 (t, J=6.8lz,6[H). MS(ESI)mnz:(M+Na_)412.2.

[004841 Step 3: Synthesis of compound 31C BnOH (16.66 g, 154.06 mmol, 16 mL) was dissolved in THE (300 mL) and cooled to 0°C. n-BuLi (2.5M, 37 mL) was added dropwise and the reaction mixture was stirred for 0.5 h under N 2 atmosphere. A solution of 31B (30.0 g, 77.03 mmol) in THIF (100 mL.) was added and the reaction mixture was stirred at 0 °C for 4 hrs. The reaction mixture was quenched with sat. NI- 4 C (200 mL), and then extracted with EA (200 mL x 3). The combined organic layers were dried over Na 2 SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate = 20/1 to 10:1). Compound 31C (23.00 g, yield: 93.19%) was obtained as a colorless oil. 'H NMR (400MHz, CDC1 3) 6 7.43 - 7.28 (m, 5H), 5.20 - 5.08 (m, 2H),296 - 2.84(m, 11), 2.67 - 2.57 (m, 111), 2.41 - 2.32 (m, 111), 164 - 1.51 (in, 211), 1.41 (s, 91-1), 1.33 - 1.29 (m, 111), 0.93 - 0.85 (in,6H).

[004851 Step 4: Synthesis of compound 31D To a solution of 31C (23.0 g, 71.78 mmol) in DCM (100 mL) was added TFA (154 g, 1.35 mol, 100 mL) slowly. The mixture was stirred at 18 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 31D (18.50 g, yield: 97.51%) was obtained as a yellow oil. The product was used in the next step without further purification. 'H NIMR (400MHz, CDCl3) 6 10.39 (br s, 1H), 7.45 - 7.29 (m, 5H), 5.22 - 5.11 (m, 21-1), 3.03- 2.90 (m, 1H), 2.8 5 - 273 (in, 111), 259 - 2.49 (i, I H), 1.69 - L 52 (in, 21-), 143 - 127 (in, 1H), 0.99 - 0.83 (m, 61-1).

[004861 Step 5: Synthesis of compound 31E Compound 31E was prepared from compound 31D and N-methylhex-5-en-1-amine following the procedure of compound 7D. Compound 31E (880 g, yield 82.27 %) was obtained as a colorless oil. MS (ESI) n (M-H) 360.1. 11H NMR (400MHz, CDCl 3) 6 7.45 - 7.23 (m, 5H), 5.85 - 5.70 (m, 1H), 5.22 - 5.14 (m, 1H), 5.12 - 5.06 (in, 1H), 5.05 - 4.91 (m, 2H), 3.46 - 3.34 (m, 1H), 3.32 - 3.20 (m, 1H), 3.13 - 3.02 (m, 1H), 2.97-2.85 (m, 3H), 2.78 2.67 (in, 1H), 2.41 - 2.30 (m, 1H), 2.11 -2.05 (in, 2H), 1.63 - 1.44 (m, 4H), 1.43 - 1.29 (in, 3H), 0.97 - 0.81 (m, 6H).

[004871 Step 6: Synthesis of compound 31F To a solution of 31E (8.80 g, 24.48 mmol) in MeOH (100 mL) was added NaOH (4.90 g, 122.40 mmol) and H20(20 mL). The mixture was stirred at 30 °C for 24 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with water (100 mL) and extracted with MTBE (100 nLx 3). Tothe water layer was added IN HC until pH -- 4, then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 ml.), dried over Na2 S04, filtered and concentrated under reduced pressure to give a residue. Compound 31F (4.90 g, yield: 61.67%) was obtained as a colorless oil. The product was used in the next step without further purification. 'H NIMR (400MHz, CDCl3) 6 10.51 (br s, 1H), 5.84 - 5.71 (m, 11), 5.07 - 4.90 (m, 21-1), 346 - 3.19 m, 2H), 3.03 - 2.90 (in, 41-1), 275 - 2.61 (i, IH), 2.51 - 2.40 (in,

11), 2.14 - 2.05 (m, 2H), 1.74 - 1.48 (in, 41), 1.46 - 1.33 (in, 2), 1.32 - 1.26 (m, IF), 0.97 0.86 (m. 6H). MS (ESI) iz (M+H)v 270 1).

[004881 Step 7: Synthesis of compound 31G Compound 31G was prepared from compound 31F and ethyl (S)-2-aminopent-4 enoate following the procedure of compound 7D. Compound 31G (4.60 g, yield 70.66 %) was obtained as a yellow oil. 'H NMR (400IflIz, CDCl3)6 6.59 - 6.41 (m, 1H), 5.82 - 5.59 (m, 2H), 5.16 - 4.85 (m, 4H), 4.63- 4.50 (m, 1H), 4.12 - 4.05 (m, 1H), 3.41 - 3.10 (m, 3H), 2.98 - 2.79 (m, 4H), 2.73 - 2.60 (m, 1H), 2.57 - 2.38 (m, 2H), 2.32 - 2.18 (m, 1), 2.03 - 1.96 (m,1K), 1.70 - 1.42 (m, 5K), 1.41 -1.28 (m,2K), 1.23 (t, J=7.2 Hz, 3H), 1.20 - 1.10 (m, 1H), 0.94 - 0.82 (m, 6H). MS (ESI) iz (M1+)-396.2.

[004891 Step 8: Snthesis of compound 31H Compound 31H was prepared from compound 31G following the procedure of compound 1811. Compound 31H (700 mg yield 35.7 %) was obtained as brown oil. 1K NMR (400MHz, CDC;) 6 6.57 (br d,J=7.8 Hz, 0.77H), 6.19 (br d, J=9 21z, 0 161), 5.56 5.43 (m, 111), 537 - 5.23 (m, 11), 4.84 - 4.73 (m, 0.17H), 4.62 - 4.50 (in,1), 4.29 - 4.09(m, 3H), 3.67 - 3.54 (m, 0.18H), 3.12 - 3.01 (m, 1K), 2.98 (s, 3K), 2.79 - 2.62 (m, 2H), 2.54- 2.42 (m, 1H), 2.27 - 2.09 (m, 2K), 2.08 - 1.85 (m, 2H), 1.84 - 1.54 (m, 4H), 1.52 - 1.41 (m, 1H), 1.40 - 1.30 (m, 1), 1.29 - 1.23 (m, 3H), 1.23 - 1.22 (m, 1H), 1.19 - 1.09 (m, 1H), 0.93 (d, J=6.5 Hz, 3K), 0.89 (d,.J=6.7 Hz,3'H). MS (ESI) nz (M-) -367.2.

[004901 Step 9: Synthesis of compound 31J Compound 31J was prepared from compound 31H following the procedure of compound 26K. Compound31J (330 mg, yield 87.55 %) was obtained as white foam and used for next step directly. MS (ESI) inz (M+Na) 339.2.

1004911 Step 10: Synthesis of compound 31K Compound 31K was prepared from compound 31J and N-methoxymethanamine following the procedure of compound 26J. Compound 31K (150 mg, yield 38.31 %) was obtained as a white solid. 14NMR (400MHz, CDCI3) 6 6.50 (br d, J=8.5 Hz, 0.69H), 6.31 (br d, J=9.3 Hz, 0.19H), 5.56 - 5.47 (m, 1), 5.44 - 5.33 (m, 1), 4.97 (br s, 1H), 4.32 - 4.19 (m, 1H), 3.77 (s, 3H), 3.20 (s, 3K), 3.07 - 2.95 (m, 3K), 2.84 - 2.72 (m, 1K), 2.63 - 2.41 (m, 2H), 2.24 -2.06 (m, 2H), 2.05- 1.90 (m, 2H), 1.82 - 1.68 (m, 1H), 1.61 - 1.31 (m, 4H), 1.29 1.14 (m, 2K), 0.95 - 0.84 (m, 6H). MS (ESI) mz (M+H) 382.2.

[004921 Sten11j:Snthesis of compound-31 Compound 31 was prepared from compound 31K following the procedure of compound 14F. Compound 31 (90 mg, yield 76.06 %) was obtained as a white solid. lH NMR (400M1-lz, CDCl) 9.61 - 9.56 (m, 0151-1), 952 (s, 0.7211), 675 (br d, J=6.4 lz, 1H), -5.44 (m, I H), 5.34 - 5,23 (m, 11), 4.54 - 445 (m, 11-1), 4.24 - 4.15 (m, lH), 3.18 - 3.09 (n, 11-1), 3.02 - 2.96 (m, 311), 2.77 - 2.64 (i, 21), 255 - 2.46 (in, 111), 2.25 - 1.94 (m, 4H), 1.85 - 1.74 (n, 21), 1.57 - 142 (in, 211), 1.39 - 128 (in, 1H). 1.27 - 1.12 (n, 2H), 0.98 - 0.88 (m, 6H). MS (ESI) m(M+H)* 323.2. EXAMPLE 17 Tert-butyl ((4S,7S,1OS,E)-10-formi-7-isobutvl-5,8-dioxo-1-oxa-6,9-diazacvclopentadec 12-en-4-VA)carbamate (32) 0 0 oc 2 O HO 1) NaC/H 2 0 ,EOH HO 1 HO H H1 OH 5 C 6h NaOH,MeCN 2)DMF 25 C,24h 0- 25°C, 12h Soc . 32B 32A 0

MsCi MsO I r A K0 HO

0 -10 °C 1 hH Acetone H 1. NaH, THF Bo' 50 °C, 2 h 2 aq. NaOH 32C 32D 0 C. 3.5h

C02Ft 0 CO 2 Et 0~N

H Grubb's2nd

HH EDCI, HOBT DIEA, DCM 32F KO- 40, 160 32E 15°C, 12 h

.HN-\ I CO2Et

H.

H 0 C 15h H/

32G 32H

HC 0O HN DMPDCM -HH 10 - 20 °C, 1

32

[004931 Step 1: Synthesis of compound 32A To a solution of L-homoserine (120 g, 1.01 mol, 1.00 eq) in MeCN (212 mL) was added NaOH (1M, 1.01 L, 1.00 eq). The mixture was cooled to 0 °C and then Boc 2 0 (233 g, 1.07 mol, 245.32 mL, 1.06 eq) in MeCN (50 mL) was slowly added to the mixture. The reaction was stirred at 25 °C for 12 hours. The organic solvent was removed and added the aqueous to pH- 5 with HCl(2N, 200 mL). Then NaCl was added until the solution reached saturation. The mixture was filtered. The filter cake was dried under reduced pressure to give compound 32A (480 g, crude) as a white solid. H NMR (DMSO-d, 400MHz) 6 7.05 6.98 (m, 1H), 4.05 - 3.95 (m, IH), 3.50 - 3.37 (m, 21-1), 1.83 - 1.60 (in, 21-1), 1.45 - 1.30 (m, 9H) MS (ESI)inz(M+Na')241.8.

[004941 Step 2: Synthesis of compound 32B To a solution of compound 32A (240 g, 1.09 mol, 1.00 eq) in EtOH (800 mL) was added the solution of NaOH (45.78 g, 1.14 mol, 1.05 eq) in H-.0 (400 mL). The mixture was stirred at 25 °C for 16 hours. The solvent was removed and the residue was dissolved in DMF(100mL). Then Mel (16 mL, 255.04 mimol, 3.35 eq) was added tothe above solution. The mixture was stirred at 25 °C for 24 hours. Then the mixture was extracted with EA (800 ml x 3). The organic phase were collected, washed with brine (1000 mL x 5), dried with Na2 SO 4, filtered and concentrated to afford compound 32B (116 g, yield: 45.62%) as yellow oil. 1H NMR (DMSO-d, 400MHz) 6 7.20 - 7.15 (m, 1H), 4.15 - 4.05 (m, IH), 3.65 - 3.60 (m, 3H) 3.50 - 3.40 (m, 2H), 1.82 - 1.63 (in, 21-1), 1.45 - 130 (m, 9H)

[004951 Step 3: Synthesis of compound 32C To a solution of compound 32B (162 g, 694.50 mmol, 1.00 eq) and TEA (290 mL, 2.08 mol,, 3.00 eq) in DCM (500 mL), MsCl (99 mL, 1.27 mol, 1.83 eq) was dropwise added at 0 °C. The reaction was stirred at 10 °C for 12 hours before diluted with water (100 ml), extracted with DCM (300 mL x 2). The organic layers were combined and dired over Na2 SO 4. Filtered and the filtrate was concentrated in vaccuo to give compound 32C (200 g, crude) as black brown oil. 1H NM R (DMSO-d, 40011z) 7.42 - 7.32 (m, 1H), 4.30 - 4.10 (m, 2H), 3.65 (s, 3H), 3.16 (s, 3H), 2.15 - 1.90 (m, 2-1), 1.45 - 1.30 (m, 9H).

[004961 Step-4: Synthesis of compound 32D To a solution of compound 32C (25 g, 80.30 mmol, 1.00 eq) in acetone (400 mL) was added LiBr (21 g, 241 mmol, 3.00 eq). The mixture was stirred at 50 °C for 2 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by FCC (PE/EA = 4:1)to give compound 32D (145 g, crude) was obtained as yellow oil. H NMR (DMSO-d, 400M-lz) 6 7.40 - 7.32 (m, 11-1), 4.20 - 4.10 (m, IH), 3.65 (s., 311), 3.60 3.45 (s, 21-1), 220 - 205 (in,2-), 1.50 - 1.30 (m, 91-1).

[004971 Step 5:-Svnthesis of conound-32E But-3-en-1-ol (8.7 mL, 101.30 mmol, 1.50 eq) was added to a solution of NaH (6.75 g, 168.83 mmol, 60% purity, 2.50 eq) in THF (50 ml) at 0 °C under N2. The reaction was stirred at 0 °C for 30 min under N 2 . The solution of compound 32D (20 g, 67.53 mmol, 1.00 eq) inTIHF (50 mL) was added dropwise at 0 °C under N 2 and stirred at 0 °C for2 hours. H0 (50 mL) was added and the mixture was stirred at 0 °C for I h. The mixture was extracted with ethyl acetate (100 mL x 2). The combined aqueous layers were acidified with2N H C1 to p1 3 and extracted with ethyl acetate (200 mL x 2). The organic layers were combined and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give compound 32E (4.3 g, crude) as yellow solid.

[004981 Step 6:-Svnthesis of conound-32F Compound 32F was prepared from compound 32E and 7C following the procedure of compound 7D. Compound 32F (250 mg, yield 13%) was obtained as a white solid. 'H NMR (DMSO-dr, 400MHz) 6 8.27(br d, J= 7.3 Hz, 11-), 7.70(br d,J:: 8.3 Hz,1H), 6.93 (br d, J= 8.3 Hz,H),5.85 - 5.67 (m, 21-1), 5.14 - 4.95 (m, 4H) , 4.43 - 4.20 (in, 2 H), 4.11 - 3.90 (m, 311), 3.45 - 3.33 (in ,4H), 2.47- 2.31 (m,3iH), 2.23(q, J= 6.7 Hz, 2H), 1.88 - 175 (m, 11-1), 1.73 - 1.55(m, 2H), 1.43 (br t, J= 7.2 Hz, 21-), 1.39 -1.29 (in, 91), 1.15 (t, J= 7.0Hz, 31-1), 0.85(dd,J=6.5, 14.8 Hz, 6H). IS (ESI) inz (M+H)511.6.

[004991 Step 7: Synthesis of compound 32G Compound 32G was prepared from compound 32F following the procedure of compound 18H. Compound 32G (260 mg, yield 76.33 %) was obtained as a white solid. 1 H NMR (DMSO-d , 400MHz) 6 6 8.12 (br d, J= 9.3 Hz, 1H), 7.53 (br d, J= 7.5 Hz, 1H), 6.95 6.86 (in, 1H), 5.75 - 5.64 (in, 1H), 5.37 - 5.24 (m, IH), 4.45 - 4.21 (in, 2H), 4.13 - 3.99 (m, 3H), 3.34 - 3.19 (in, 411), 2.45- 2.30 (in, 21-1), 2.12 (br d, J= 5.0 Hz, 2H), 1.93 - 181(, 1H), 1.73 - 1.39 (in, 4H), 136 (s, 9H), 116 (t, J= 7.0 Iz, 3-), 0.91 - 0.75 (i, 611). MS (ESI) inz (M-H) 484.2.

1005001 Step 8: Synthesis of compound 32H Compound 32H was prepared from compound 32G following the procedure of compound 14F. Compound 32H (100 mg, yield 52 %) was obtained as white solid. 1jHNMR (CDCl3, 400MHz) ( 6.82 (br d, J= 8.3 Hz, 1H), 6.43 (br d, J= 7.0 Hz, 1H), 5.67- 5.56 (in, IH), 5.55 - 5.44 (m, 1H), 5.17 (br d, J= 7.5 Hz, IH), 4.57 - 4.47 (m, IH), 4.38 -4.29 (in,

11), 4.06 (br d, J= 4.8 Hz, lH), 72 - 3.56 (m, 4H), 3.52 (td, J= 4.9, 9.51z, 1H), 3.44 335 (in, 1H), 2.97 (brt,J= 5.4 Hz, 1H), 2.47 - 2.37 (m, I1H), 2.34 - 2.18 (m, 311), 2.10 (dq, J = 4.4, 9.4 Hz, 1H), 1.95 - 1.81 (n, 211), 1.66 - 1.61 (m, 111), 1.53 - 1.38 (n, 1011), 0.92 (dd, J = 3.9, 6.4 Hz, 6H). MS (ESI) m (M-i H442.1.

[005011 Step 9: Synthesis of compound 32 Compound 32 was prepared from compound 3211 following the procedure of compound 7. Compound 32 (25 mg, yield 50 %) was obtained as white solid. 1H NMR (CDC3, 400MHz) 6 9.57 (s, 1H), 7.02 - 6.90 (m, 1H), 6.74 (br d,,J= 7.3 Hz, 1H), 5.61 - 5.48 (m, 1H), 5.31 (br d,,J= 7.3 Hz, IH), 5.24 - 5.17 (m, 1H), 4.68 - 4.54 (m, 2H), 4.36 - 4.27 (m, 11), 373 - 3.59 (m, 211), 359 - 3.50 (in, 11-1), 348 - 3.38 (in, 114),2.77- 2.60 (in, II), 2.40 2.50 (m, 1H), 2.37 - 2.25 (in, 11), 2.24 - 212 (in, 21-), 1.98 - 1.82 (m, 2H), 1.67 - 1.61 (m, 11), 1.51 - 136 (m, 101), 0.97 - 0.85 (m, 611). MS (ESI) m z(M+H)- 440.2. EXAMPLE 18 Tert-butyl ((4S.7S,10S)-10-formyl-7-isobutvl1-5,8-dioxo-1-oxa-6,9-diazaevelopentadecan 4-1v)carbamate (33)

H O

0/Pd/C 2 , 210%) 0 H- CH,-H I1 20-25 (),2 h 0, 0-'

32H 33A

/ 0 0 HN H - i \ '. AH

DMP/DCM N'

15 - 25 °C, 24 h

[005021 Step 1: Synthesis of compound 33A The mixture of compound 32H (46 mg, 104.18 umol, 1.00 eq) and Pd/C (20 mg) in MeOH (10 mL) was stirred at 20 - 25 "C for 2 hours under H 2 atmospheres. Filtered and the filtration was concentrated under reduced pressure to give compound 33A (40.00 mg, yield: 86.5%) as a white solid. 11H NMR (DMSO-d, 400MHz) 7.92 (d, J= 9.0 Hz, 111), 7.75 (br d, J= 8.8 Hz, IH), 6.60 (br d, J= 7.5 Hz, IH), 4.59 (br s, IH), 4.46 - 4.33 (mI, IH), 4.10 3.93 (in, IH), 3.72 (br s, IH), 3.29 - 3.20 (m, 3H), 3.19 - 3.10 (in, IH), 1.93 - 1.79 (in. IH),

1.72 (qd, J= 6.7, 11.2 Hz, 1I), 1.62 - 1.45 (m, 2H), 1.44 - 1.08 (m, 15H), 0.85 (br dd, J 6.4, 129 Hz, 61-). MS (ESI) m z (M+H) 444.2.

[005031 Step 2: Synthesis of compound 33 Compound 33 was prepared from compound 33A following the procedure of compound 7. Compound 33 (20 mg, yield 45 %) was obtained as white solid. J-H NMR (CDCl3, 400MHz) o 9.55 (s, IH), 6.84 (br d,,J=7.0 Hz, 1H), 6.70 (br d,,J=8.5 Hz,1H), 5.17 (br d, J=8.0 Hz, 111), 4.61 - 4.51 (m, 2H), 4.30 - 4.21 (m, iH), 3.62 - 3.54 (m, iH), 3.53 3.43 (m, 2H), 3.41 - 3.34 (m, 1H), 2.30 - 2.20 (m, iH), 2.06 - 1.95 (m, 1H), 1.88 - 1.79 (in, IH), 1.78 - 1.68 (m, 2H), 1.67 - 1.65 (m, 1H), 1.63 - 1.58 (m, 2H), 1.55 - 1.49 (m, 2H), 1.45 (s,9-),1.34-1.30(i,2H),0.92 (dd,J=:6.3,10.3Hz,611). MS(ESI)mn:(M+Hj)442.3. EXAMPLE 19 Tert-buty1 ((3S,6S,15S)-15-forml-3-isobutvl-15-meth1-2,5-dioxo-1,4 diazacyclopentadecan-6-vl)carbamate (34)

NH N1 Bcc B'cN NH SSOC 2 , MeOH 34 EDCI HOBt, DCM 34A 34B

H Y NH N CO2H

HCI/EtOAc H2 NH NBoo NH ---------- --- ------------------------------ /

34C EDC!, HOBt, DCMI 34D

H O / 0 0 ,Y Nk NH- N' #- ~ O~<H. H

0.05 eq Gru 2H N H' N 4, THF NH PdC H DCM 34F J

/ \\0NH ,N C, Nc

NH NH>N NH DMP, DCM N 34G 34

[005041 Step 1: Synthesis of compound 34A

To a mixture of (S)-2-amino-2-methylpent-4-enoic acid (110 mg. 851,66 umol) in MeOH (10 mL) was slowly added SOCl 2 (307 mg, 2.58 mmol) at 0 °C, the mixture was warmed to 20 °C (room temperature) and stirring for 30min at 20 °C. The solution was then refluxed at 66 °C for 20hrs. The mixture was directly concentrated under vacuum to give compound 34A (152 mg, 99.35% yield, HCI salt) as colorless oil. The crude was used directly for the next step. HNMR(400M11Hz,CDOD) 5.81 - 5.68 (m, I H), 5.33 - 5.25 (m, 2 H), 3.83 (s, 3 H) 2.76 - 2.63 (m, I1 -), 2.62 - 2.52 (m, I1H), 1.56 (s, 3 H).

1005051 Step 2: Synthesis of compound 34B Compound 34B was prepared from compound 34A and(tert-butoxycarbonyl)-L leucine following the procedure of compound 7D. Compound 34B (230 mg, yield 74.78%) was obtained as an off-white solid. 1H NMR (400MHz, CDCi)O 6.74 (br. s., 1 H). 5.71 5.54 (in, I H), 5.13 - 5.05 (m, 2 H), 4.82 (br. s., I H), 4.11 - 3.98 (m, I H), 3.78 - 3.70 (in, 3 H), 2.94 - 2.83 (m, I H), 2.62 - 2.53 (m, I H), 1.74 - 1.60 (m, 3 H), 1.51 - 1.37 (in, 12 H), 0.93 (dd,,J= 4.5, 6.1 Hz, 6 H).

[005061 Step-3: Synthesis of compound 34C Compound 34C was prepared from compound 34B following the procedure of compound 12A. Compound 34C (188 mg, yield 99.51%, HCI salt) was obtained as a colorless oil ans used directly for the next step.

[005071 Step 4: Synthesis of compound 34D Compound 34D was prepared from compound 34C and (S)-2(tert bitoxycarbonyl)amino)non-8-enoic acid following the procedure of compound 71) Compound 34D (160 mg, yield 37.0%) was obtained as a colorless oil. MS (ESI) m/z ('M+Na) 532.1.

[005081 Step 5:_Svnthesis of compound-34E Compound 34E was prepared from compound 34D following the procedure of compound 18H. Compound 34E (250 mg, yield 66.1 %) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) 6 6.80 (s, 1H), 6.33 (br d, J=8.4 Hz, 1H), 5.43 - 5.32 (m, 111), 5.10 (br d, .=7.7 Hz, 2H), 4.55 - 4.44 (in, H), 4.05 - 3.95 (m, 11), 3.82 - 3.76 (m, 311), 3.00 2.89 (m, 111), 2.58 - 248 (m, 1H), 2.12 - 1.90 (m, 41), 171 - 1.59 (in, 611), 1.55 - 1.48 (m, 2H), 1.46 - 1.31 (m, 101), 1.24 - 1 15 (m, 311), 0.97 - 0.84 (m, 6H). MS (ESI) m z (M+H) 482. 2.

[005091 Step 6:_Svnthesis of compound-34F Compound 34F was prepared from compound 34E following the procedure of compound 14F. Compound 34F (160 mg, yield 59.46 %) was obtained as white solid. 1H

NMR (400M1-lz, CDC 3) 654 - 6.42 (m, 111), 630 - 6.19 (in, 111), 5.47 - 5.31 (in, 21), 5.04 (br d, =7.7 Hz, 111), 4.53 - 442 (in, H), 4.12 - 4.02 (in, 1H), 3.76 - 3.66 (in, 11), 3.63 3.54 (in, 11), 2.55 - 2.43 (m, 111), 2.16 - 2.05 (in, 41), 1.83 - 1.72 (in, 1), 1.56 - 1.40(m, 13H), 1.31 - 1.19 (m, 711), 095 - 085 (in, 61). MS (ESI) miz (M+H)454.2.

[005101 Step 7: Synthesis of compound 34G To a solution of compound 34F (90 ing, 198.41 umol) in MeOH (20 mL) was added Pd-C (10%, 20 mg) under N2 . The suspension was degassed under vacuum and purged with 12 several times. The mixture was stirred under H2 (15 psi) at 20°C for 16 hours. The reaction mixture was filtered through Celite pad and the filtrate was concentrated to give compound 34G (72 mg, 77.23% yield) as white solid. The crude product was used directly for the next step. MS (ESi) mz (M4H)456.3.

[005111 Step 8: Synthesis of compound 34 Compound 34 was prepared from compound 34G following the procedure of compound 7. Compound 34 (41 mg. yield 65.41 %) was obtained as white solid. - NMR (400MHz, CDCl 3) ( 9.18 (s, 11), 6.72 (s, 11-1), 6.32 (br d, :=73 Hz, 111).5 17 (br d, J=7.9 Hz, IH), 4.56 - 445 (in, 11). 4.07 (br s, 111), 2.48 - 2.38 (in, 111), 190 (br s, 111), 173 - 1.65 (m, 2H), 1.55 (br d, 1=7.9 Hz, 2H), 1.50 (s, 3H), 1.43 (s, 9H), 1.23 (br s, 11H), 0.98 (br s, 2H), 0.94 (br d, J=6.2 Hz, 6H). MS (ESI) mz (M+H)Y 454.3. EXAMPLE 20 Tert-butyl ((3S,6S,15SN)-5-fornvl-3-isobutyl-15-methyl-2,5-dioxo-1,4 diazaceloLentadec-12-en-6-vi)carbanate-(35)

J H X °Y NH OH O O NH

NH` DMP, DCM NH'

34F

[005121 Step 1: Synthesis of compound 35 Compound 35 was prepared from compound 34F following the procedure of compound 7. Compound 35 (55 mg. yield 85.96 %) was obtained as white solid. -INMR

(400MHz, DMSO-6) 6 9.37 - 9.23 (m, 111), 8.03 br d, J=9.5 Hz, IH), 7.63 (s, 11), 7.16 703 (m, 111), 5.52 - 5.39 (i, 11). 5.23 (td, J=7.6, 14.9 Hz, 111), 4.38 - 4.24 (in, 111), 4.01 389 (i, 1H), 2.47 - 2.40 (i, 1H), 2.20 (br dd, J=8.4, 139 Hz, 1H), 1.98 (br d, J=4.4 Hz, 2H), 1.90 - 1.78 (m, iH), 1.65 (br dd, J=6.2, 10.6 Hz, IH), 1.51 (br s, iH), 1.47 - 1.41 (in, 2H), 1.41 - 1.33 (m, 12H), 1.26 - 1.17 (m, 3H), 1.14 (s, 4H), 0.88 - 0.76 (m, 6H). MS (ESI) m z(M+H) 452.3. EXAMPLE 21 Benzyl ((3S,6S15S)-15-formyl-3-isobutvl-15-_methyl-2,5-dioxo-14 diazaeeloeitadecai6-vi)carbanate-(36)

H S/ NH N

O NH' I-I H O 0

34E 36A

HN

CBzOSu, NJH

368 .. /K 2 CO.

H N NO H c NCN H2,

36D 3 6

[00513] Sten 1: Synthesis of compound 36A To solution of compond 34E (310.0img, 643.66 umol) inMeOHI(15 mL) was added Pd-C (10%, 30img) underN2. The suspensions degassed under vacuum andpurged with H2 several times. The mixture was stirred under1H2 (15 pi) at20°C for 45 hours. The reaction mixture was filtered through Celite pad and the filtratevwasconcentrted. Compound 36A (300.0 mg, yield:96.4%) was obtained as colorless oil. The crude product was used directly for the next step.

[005141 Stp2 ytei fcmon 6

To a mixture of compound 36A (300.0 mg, 620.30 umol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 7.00 mL, 45.14 eq) and the reaction was stirred at 20 °C for ih. The reaction mixture was directly concentrated. Compound 36B (260.0 mg, yield: 79.8%, HCl) was obtained as colorless oil and used as such without purification.

[005151 Step 3: Synthesis of compound 36C To a mixture of compound 36B (260.0 mg, 619.06 umol, HCl) in dioxane (4 mL) and H 2 0 (4 mL) was added K2 CO (216.0 mg, 1.56 mmol) and CbzOSu (215.99 mg, 866.68 umol), and then the mixture was stirred at 25 °C for 2 hours under N 2 atmosphere. The reaction mixture was quenched with H20 (20 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2SO4 . The solid was removed by filtration and the filtrate was concentrated to give the residue. The residue was purified by flash silica gel chromatography (Eluent of 0~20% EA/PE). Compound 36C (250 mg, yield: 78.0%) was obtained as white solid.

[005161 Step 4: Synthesis of compound 36D Compound 36D was prepared from compound 36C following the procedure of compound 14F. Compound 361) (105 mg, yield 37.7%) was obtained as a white solid. H NMR (400MHz, DMSO-d) 5 8.08 (br d, J=9.0 H4z, 1), 7.40 - 7.26 (m, 51), 7.22 (br d, J=7.7 Hz, 1), 7.17(s, iF), 5.11 - 4.89 (m, 2H), 4.70 (br t, J=5.8 Hz, 1H), 4.43 - 4.27 (in, 1H), 4.12 - 4.02 (n, 111), 3.33 (br s, 1H), 3.19 (br dd, J=6.5, 10.7 Hz, 1H), 2.03 - 1.82 (in, 1H), 1.70 - 1.44 (m, 3H), 1.43 - 1.08 (m, 18H), 0.94 - 0.70 (m, 6H). MS (ESI) mz (M+H) 490.2.

[005171 Step 5: Synthesis of compound 36 Compound 36 was prepared from compound 36D following the procedure of compound 7. Compound 36 (31 mg, yield 33.3 %) was obtained as a white solid. 'H NMR (400MHz, DMSO-dc) 6 9.30 (br s, 1H), 8.06 (br d,,=9.0 Hz, 1H), 7.80 (br s, 1H), 7.58 (br d, J=7.5 Hz, 1H), 7.34 (br s, 5K), 513 - 4.91 (in, 2H), 4.34 (br s, IH), 4.02 (br d,,:=6.4 Hz, 1H), 1.82 - 1.40 (m, 4H), 1.39 - 1.08 (m, 18-), 0.89 - 0.76 (in,61). MS (ESI) iz (MH) 488.3. EXAMPLE 22 Tert-butyl ((IS,4S,7S,15R,Z)-1-forml-4-isobutvl-3,6-dioxo-2,5 diazabicyclo[13.1.01hexadec-13-en-7-v1)carbamate (37)

Ph

PhA1-N'COEt tBIiCOK, THF Ph- Ph NH, .HCI 1) IN HG! + ---------------- - ~ c E t 00N+ / OE2) NaHC D3 V B, B, -C02-3) 4NHOidioxane37 37A

NHBoc C)H2_ BO&2 /OOEI SFC separation ZZN, 8 Y DMPI.H F 37C//

370 .- '37E

BocHN (k.2 Et

4N HIC1/EtOAG- CIHH z' N CO 2 Et -AN'2 BOC N N 'iK-n OEt HC

EtCDAc EDO, HOBt, DIPEA,0DCM

37E 37F 37G

/ H

4N HCI/dioxane C)' N

rtOA EDCC.HOB[, DIPEA.DCM. H 37H 37J / 4

HN- 0 0ys N ',C2 E1

Hoveyda-Grubbs'131 N" LiAIH N'

(ienmtloi / THF DCM 37K --- -137L

IMP, DOM 0 o HN- NJN

N" H

37

[005181 St.1-:-vntesisof coynpund-37A To amixture of t-BuOK (6,9g,6172no) in T-IF (45ml-) at78'CWas added ethyl 2'-((dipenyietyjien)arnino)aceta(15 g, 56.11mrmo) in THF (30rn) The reaction mixture was warmed to0 0'C, and strired at this temperature for 45min.The mixture was then cooled back to-78 'C,forthe addition of E)-4-dibromobut-2-ene (12 g,56.11 mmrol) in THE(3 0mLnQand then striped at 0'Cfor45min and cooled back to -78 'C, for the addition of t-BuOK (6.9 g,61.72mmol) inTHF (45rnL). 'The reaction mixture was finally strired for2 hat) 0 `C. The mixturewas removed underreduced pressure togive compound 37A (15 g. cude), which wasused direlyfor thenext stpithout furtherpurification. 1i1

2 92

NOR (400MHzCDC3) ) 7.82 (d, J= 7.2 Hz, 11), 7.64 - 7.58 (mi, I H), 750 (t, J= 7.0Hz, 11), 7.42 - 7.29 (in, 511), 7.16 - 7.11 (m, 2H), 5.93 - 5.81 (m, 11-1), 5.06 - 4.96 (m, 1H), 4.29 (d, J= 7.3 Hz, 1H), 3.78 - 3.73 (m, 2H), 1.49 - 1.40(m, 11), 1.37- 1.21 (m, 3H), 1.13 (t, J= 7.2 Hz, 2H).

[005191 Step 2: Synthesis of compound 37B Compound 37A (15 g, 46.96 iniol) was taken up in MTBE (150 mL) and treated with HCi(1 M, 100 mLThen the mixture was stirred at 15 °C for 3.5 hrs. The layers were separated and the aqueous layer was extracted with MTBE (2 x 100 mL), the aqueous layer was basified to pH -8-9 with sat NaHCO 3 solution. The desired amine was extracted with MTBE (3 x 100 mL) and the orgainic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was treated with 4N HCI/dioxane (40 mL). Then the mixture was concentrated under reduced pressure to give compound 37B (36 g, crude, HCI salt). 11 NMR (400MHz, DMSO-d) 6 9.09 (br s, 3H). 5.67 - 5.56 (in, IH), 5.35 (d, J= 17.2 Hz, iH), 5.18 (d, J= 10.1 Hz, iH), 4.25 - 4.11 (in, 2H), 2.47 - 2.42 (in, IH), 1.82 (dd, J= 6.0,9.9 Hz, iH), 1.63 (dd,,J= 6.1, 8.0 Hz, IH), 1.21 (t, J= 7.1 Hz, 3H).

[005201 Step-3: Sithesis of compound 37C To a mixture of compound 37B (4.8 g, 25.05 mmol, HCl), Boc20 (5.7 g, 26.30 mmol, 6 mL), DMAP (612 mg, 5.01 mmol) in THF (50 mL) was added DIEA (9.7 g, 75.15 mmol, 13 mL) at 0 °C. The mixture was stirred at 15 °C for 24 hrs. The mixture was concentrated in vacuum. The residue was treated with EtOAc (100 mL), washed with H20 (50 mL). The organic layer was separated and the aqueous layer was extracted with EA (2 x 30 mL). The combined organic layers was washed with 0.5 N 1-C (2 x 30 mL), saturated Na-C)3 (2 x 30 mL), brine (50 mL), dried over anhydrous MgSO 4 , filtered and concentrated. The residue was purified by column chromatography (SiO 2, Petroleum ether: Ethyl acetate = 5: 1) to give compound 37C (2.3 g, yield: 35%). 1H NIR (400MHz, DMSO-d) o6 7.63 (s, iH), 5.68 5.55 (m, IH), 5.21 (br d, J= 17.2 Hz, 1H), 5.04 (dd, J= 1.9, 10.3 Hz, 1H), 4.09 - 3.96 (m, 2H), 2.08 (q, = 8.7 Hz, iH), 1.54 (br dd, J= 5.3, 7.3 Hz, 1H), 1.40 - 1.30 (m, 9H), 1.27 1.23 (m, 111), 1 19 - 111 (in, 3H). MS (ESI) mz (M-100)+ 155.8.

[005211 Step 4: Synthesis of compounds 37D and 37E The compound 37C (1 g) was resolved by SFC to give two isomers.

SFC method: Column: AY(250mm*30mm,10u) Mobile phase: A:C 2 B0.,1%NH-20 1 ETOH; Gradient: 15% of B; Flow rate: 60mL/min. The compound 37C was separated by SFC to give compound 37D (500 mg,yield: 49.9%) (Rt= 1.49 min) and compound 37E (450 mg, yield: 25.9%) (Rt= 2.68 min) both as yellow oil. [1H1NMR (400MHz, DMSO-d ) 367.64 (s, 1H), 5.67 - 5.54 (m, I H), 5.21 (br d, J= 17.2 Hz, 11), 5.07 - 5.01 (i, 11), 4.10 - 394 (m, 211), 2.08 (q, J:= 8.7 Hz, 1H), 157 - 1.44 (m, 11), 1.38 - 1.31 (m, 911), 1 27 - 1.23 (m, 11), 1.18 - 1.10 (m, 311). MS (ESI) mz (M O) 155.8. 'H NMR (100MHz, DMSO-d6) 6 7.64 (s, 1H), 5.67 - 5.54 (in, 1H), 5.21 (br d, J= 17.0 Hz, 1H), 5.04 (dd, J= 1.7, 10.3 Hz, 1H), 4.11 - 3.95 (in, 2H), 2.08 (q, J= 8.8 Hz, IH), 1.54 (br dd, J= 5.4, 7.2 Hz, 1H), 1.38 - 1.31 (in, 9H), 1.27 - 1.23 (in, 1H), 1.19 - 1.10 (in,

31H). MS(ESI)m z(M-100)155.9..

[005221 Step 5: Synthesis of compound 37F Compound 37F was prepared from compound 37E following the procedure of compound 12A. Compound 37F (380 mg, crude, ICisalt) was used directly for the next step. 11NMR (400MHz, DMSO-d) 66 9.12 (br s, 2H), 5.62 (qd, J= 8.7, 10.1 Hz, 111), 5.34 (dd, J= 1.3, 172 Hz, 11), 5 17 (dd , J 1.3, 10.4 Hz, 111), 4.25 - 4.10 (m, 2H), 2.47 - 2.42 (in, IH), 1.83 (dd, J= 6.0, 9.9 Hz, 1H), 1.64 - 1.60 (m, 1H), 1.23 - 1.13 (in, 3H).

[005231 Step 6: Synthesis of compound 37G Compound 37G was prepared from compound 37F and(ert-butoxycarbonyl)-L leucine following the procedure of compound 7D. Compound 37G (800 mg, yield 50.5 %) 1 was obtained as an off-white solid and used directly for next step without purification. H

NMR (400M-Hz, DMSO-d) 66 8.63 (s, 1H), 6.74 (br d, J= 8.4 Hz, 1H), 5.56 (br d,J= 9.5 Hz, 1H), 5.27 (br dd, J= 1.4, 17.1 Hz, 11), 5.11 - 5.03 (in, 11), 4.00 (td, J= 7.0, 13.8 Hz, 21-1), 3.92 - 3.84 (m, 111), 2.13 (br d,J= 8.4 Hz, 111), 1.67 - 1.56 (m, 2H), 1.45 - 128 (in, 11-), 1.20 (br dd, J= 5.2, 9.4 Hz, 111), 1.14 - 1.09 (i, 3H), 0.85 (t, J:: 7.3 Hz, 611). MS (ESI) m/z (M-+Na) 391.1.

[005241 Step 7: Synthesis of compound 3711 Compound 3711 was prepared from compound 37G following the procedure of compound 14A. Compound 37H (700 mg, crude, HCl salt) was obtained as a white solid and used directly for the next step. H NMR (400MHz, DMSO-d) o 9.41 (s, 1H), 8.41 - 8.21 (s,

31), 5.65 - 5.51 (mO,1) 5,29 (dd, J= 1.5, 17.2 Hz, 11-), 5.11 (dd, J= 1.5, 10.4 z, 1H), 4.11 - 3.94 (m, 2H), 3.65 - 3.61 (n, 111). 2.24 (q, J= 8.4 Hz, 11-1), 1.76 - 1.52 (in, 411), 1.40 1.35 (n, 111), 1.14 - 1.10 (i, 3H), 0.94 - 0.87 (n, 6H).

[005251 Step 8: Synthesis of compound 37J Compound 37J was prepared from compound 3711 and (S)-2-((tert butoxycarbonyl)amino)non-8-enoic acid following the procedure of compound 7D. Compound 37J (600 mg, yield 44.8 %) was obtained as an off-white solid. IH NMR (400MHz, CDCl 3 )6.95 (br s,1H), 6.45 (d, J= 8.4 Hz, 1 ), 5.84 - 5.72 (m, 21), 5.31 (dd, J = 1.1, 17.2 lz, 11), 5.13 (dd, J= 1.4, 10.5 Hz, 111), 5.02 - 4.92 (m, 211), 446 - 4.42 (in, 114), 4.19 - 4.07 (i, 211), 4.01 - 3.95 (m, 111), 2.16 - 2.09 (m, 111), 2.06 - 2.01 (m, 211), 1.85 - 1.72 (i, 4H), 166 - 152 (i, 31), 1.46 - 144 (i, 9H), 1.42 - 131 (i, 6H), 1 23 (t, J= 7.1 Hz, 3H), 0.96 - 0.93 (in, 6H). MS (ESI) nz(M+H)+ 522.3.

[005261 Step 9: Synthesis of compound 37K Compound 37K was prepared from compound 37J following the procedure of compound 14E. Compound 37K (100 mg, yield 47.24 %) was obtained as a white flocculus. H NMR (400MHz, CDC ) 63 7.24 (br s, 1H), 6.30 (br d, J= 7.9 Hz, 1H), 5.68 - 5.59 (m, 1H), 5.28 (dd, J= 7.6, 10.5 Hz, 1H), 5.15 (br d, J= 8.2 Hz, 1H), 4.59 - 4.43 (in, 1H), 4.16 (q, J= 72 Hz, 211), 4.09 - 3.95 (m, 111), 243 (br d, J= 8.6 Hz, 11), 2.03 - 1.76 (m, 611), 1.71 1.65 (in, 211), 152 - 1.42 (m, 1111), 1.37 - 1.21 (m, 81), 0.91 (dd, J= 6.4, 18.1 Hz, 61) MS (ESI) mlz (M-Na) 516.3.

[005271 Step 10: Synthesis of compound 37L Compound 37L was prepared from compound 37K following the procedure of compound 14F. Compound 37L (40 mg, yield 43.7 %) was obtained as an off-white solid. H NMR (400MHz, CDCls) 6 6.83 (br s, 1H), 5.82 - 5.58 (in, 1H), 5.49 - 5.46 (m, IH), 5.20 5.00 (in, 1H), 4.40 (br s, 1H), 4.10 (br s, 1H), 3.69 - 3.65 (in, 1H), 3.54 - 3.50 (in, IH), 2.21 (br s, 1H), 2.00 (br s, 111), 1.88 - 1.50 (m, 7H), 1.41 (s, 9H), 1.35 - 1.25 (in, 6H), 0.99 (s, 1H), 0.95-0.84(m,611). MS(ESI)nv (M+H)452.3.

[005281 Step 11: Synthesis of compound 37 Compound 37 was prepared from compound 37L following the procedure of compound 7. Compound 37 (50 mg, yield 50 %) was obtained as an off-white solid. 11

NMR (400MHz, CDCl 3) 6 8.88 (s, 1H), 7.48 (br s, 1H), 6.46 - 6.36 (m, I H), 5.61 - 5.59 (i,

11), 5.41 - 5.23 (m, 211), 4.59 - 4.43 (in, 11), 4.10 - 3.98 (in, 11), 2.52 - 2.48 (in, 11H), 2.32 2.06 (in, 11). 2.01 - 1.91 (in, 1-), 1.80 - 1.58 (i, 811), 1.43 (s, 91-), 1.29 - 1.27 (i, 511), 0.95 - 0.88 (m, 611). MS (ESI) mz (M+H)- 450.3.

EXAMPLE 23: Biological Assay Protocols

[005291 Biochemical inhibition of Calpains 1, 2, and 9

[005301 Calpain 1, 2, and 9 activity and inhibition thereof are assessed by means of a continuous fluorescence assay. The SensoLyte 520 Calpain substrate (Anaspec Inc) is optimized for detecting calpain activity. This substrate contains a novel internally quenched 5-FAM/Q XLTM 520 FRET pair. Calpains 1,2 and 9 cleave the FRET substrate into two separate fragments resulting in an increase of 5-FAM fluorescence that is proportional to calpain activity.

1005311 Assays are typically setup in black 384-well plates using automated liquid handling as follows. Calpain assay base buffer typically contains 50mM Tris, p-I 7.5, 100mM NaCl and 1rM DTT. Inhibitors are serially diluted in DMSO and used to setup 2x mixtures with calpains in the aforementioned buffer. After incubation at ambient temperature (25C), the reaction is initiated by adding a 2x mix of the fluorescent peptide substrate and CaCl 2 (required for in-situ calpain activation) in the same buffer. Reaction progress curve data are typically collected for 10min using excitation/emission wavelengths of 490 nm/520 nm on SpectraMax i3x or the FLIPR-Tetra plate readers (Molecular Devices Inc). Reaction rates were calculated from progress curve slopes typically over 1-5min. Dose response curves (rate vs. log inhibitor concentration) were typically fit to a 4-parameter logistic function to extract

IC5 values.

Inhibition of cellular calpain activity

[005321 Calpain activity in SH-SY5Y cells and inhibition thereof are assessed by means of the Calpain-Glo" platform (Promega, Inc) which is a homogeneous, luminescence assay that uses the cell-permeable and pro-luminescent calpain substrate Suc-LLVY-amino-luciferin. Upon calpain cleavage followed by cell lysis and quenching the luminescence signal developed is proportional to intra-cellular calpain activity.

[005331 Assays are typically setup by seeding SH-SY5Y cells in white 384-well plates at 40k/per well in RPMI-1640 containing 1% serum followed by 37C overnight incubation. Next morning, cells are pre-incubated for ihr with serially diluted compounds followed by addition of 20uM each of Suc-LLVY-aminoluciferin substrate and A23187 (ionophore used to induce Ca flux and calpain activity) diluted in Calpain-Glo buffer. After a 4hr incubation at 37C (calpain reaction), cells are lysed at 37C for ihr using 0.9% Triton X-100 containing PBS with 10OuM MDL-28170 (excess calpain inhibitor to quench calpain activity). After centrifugation at 300rpm, the Calpain-GloTM luciferase detection reagent in Calpain-GloTM buffer is added followed by 10min incubation prior to reading luminescence counts using an EnVision plate reader (Perkin Elmer Ic). Dose response curves (luminescence vs. log inhibitor concentration) were typically fit to a 4-parameter logistic function to extractIC 0 values.

[005341 Calpain Inhibition

[005351 Column A: Human Calpain 1/NS I1C50 (nM)_MEAN

[005361 Column B: Human Calpain 2/NS1 C50 (nM)_MEAN

[005371 Column C: Human Calpain 9/NSI IC50 (nM)_MEAN A:<3uTIM; B: 3-10 utM; C:> 10 UM;

HT 0 HNH

0N' H 0 HN--- HNH 0

H 0 N 2 B A B

H200

.... A a n

4 ad AA A

0OHN N H 4 A A

NO'O

0 HN Ni HH

HH

0HN N H A AA

H

0 H I298

8... A Ca AnB

H

0 HN H 9' 8 0%41,j * A A

H0

HH

/ OHH 0 N 10~ HN6 AN

*~ HO A0 A A

H /

0OHN HO 12 * ~H AA A Hi

....... iA Cal unB (I A rc

H 0

HO

/0OHN N 14 ~ Hc cc

H 0 H 0 O0HN N 1N ~ Now

HH

OHINN N 16 O~~HcB B OA6 H

0OHN 'NH

N!N H

....... iA CatunB C Iunrc

180 K> H0 H AN

i ~ No iH

HO0 0~ H 19 A AA Nil H 1

Hg /

0 H 201 A N"' H

0 HNIN"

N' H

....... d A Cal mn B (I A rC

X\I 0HN-K N0 24 ~A AA

0OH N 24 A A A

-70 0 H- I

261 H 213B C

NH HH

1* _______________________,on__ trn i ... .......... ...... n ...

28... A Ca AnB ........ .... ..... .... .... .... .... . .H.

. O HNP- N,, 298 A A A

H/

H 0 O N NH NH

H0 H 3129~NK A A A3

HH

QON NH 30 A A A

NW

HH ______ 0 _______N tr n i ... .......... ...... n ...

3. ... d CA A An

H 0I OHN N

H

H 0 HN N 0I"

W H

*HO \0 HN-N

NII H

Bleomycin-induced pulmonary fibrosis in mice or rats

[005381 The method for inducing pulmonary fibrosis in mice is described in Current Protocols in Pharmacology: 5.46.1, entitled "Mouse Models of Bleomycin-induced Pulmonary Fibrosis". In order to induce pulmonary fibrosis, 6-8 week old C57B1/6 mice or Wistar rats are instilled once oropharyngeally with-~1.5 U/kg of bleomycin sulfate (Calbiochem, Billerica, MA). Briefly, for oropharyngeal administration of bleomycin, mice or rats are anesthetized with isofluorane and then suspended on its back at a~60 degree angle on an inclined surface with a rubber band running under the upper incisors. The airway is opened while securing the tongue with one arm of padded forceps and bleomycin is administered into the back of the oral cavity with a syringe. The study is terminated on day 14-28 for oropharyngeally administered bleomvcin in mice and rats.

[005391 Alternatively, for systemic bleomycin administration by osmotic pumps in mice, the pumps are loaded with bleomycin and implanted subcutaneously under isofluorane anesthesia as described in Lee, Am JPhysiol Lung CellMolPhysiol, 2014. Briefly, mice are systemically administered -50 U/kgbleomycin (Blenoxane; Teva Pharma. North Wales, PA) via osmotic pumps for 7 days. On day 10, the osmotic pumps are removed, and the study is continued until day 35.

[005401 All animals are euthanized at the termination of the studies by cervical dislocation for gross necropsy, and blood collected by cardiac puncture. The lungs from each animal are dissected from the animal and weighed. The BAL cells and fluid are collected by lavaging the lung twice with 0.5 mllHanks Balanced Salt Solution (RBSS; VWR, Radnor, PA). After collection of BAL cells and fluid, lungs are dissected and removed from each animal. Whole lungs are inflated with 10% NBF and then fixed in 10% NBF for histology. Severity of fibrosis in the lungs is evaluated using a modified Ashcroft score (Hubner, Biotechniques, 2008). Carbon tetrachloride-induced liver fibrosis in mice or rats

[005411 Carbon tetrachloride-induced liver fibrosis is a widely used and accepted model for evaluating novel antifibrotic therapies. The methods for inducing liver fibrosis by carbon tetrachloride administration is described in Lee,J Clin Invest, 1995 and Tsukamoto, Semin Liver Dis, 1990. Briefly, male C57BL/6 mice are challenged with 1mg/kg carbon tetrachloride (Sigma Aldrich, diluted 1:7 in corn or olive oil) administered by intraperitoneal injection twice weekly for a period of 4 weeks. Mice are euthanized on day 28. In an alternative implementation, Wistar rats are administered carbon tetrachloride by intraperitoneal injection three times per week for 8-12 weeks. Rats areeuthanized atthe termination of the experiment, 8-12 after study initiation.

[005421 Blood is collected by cardiac puncture and processed into serum for evaluation of liver enzymes (including ALT, AST, ALP, etc) at several timepoints throughout the study and at termination of the study. The liver tissues from all animals are collected and fixed by immersion in 10% neutral buffered formalin, processed, paraffin embedded, sectioned, mounted, and stained with Masson's Trichrome (Tri) or Picrosirius Red (PSR) using standard histological methods for evaluation of fibrosis severity. Mouse Unilateral Ureteral Obstruction Kidnev Fibrosis Model 1005431 Female C57BL/6 mice (Harlan, 4-6 weeks of age) will be given free access to food and water and allowed to acclimate for at least 7 days prior to test initiation. After acclimation, mice are anesthetized and undergo unilateral ureteral obstruction UUO) surgery or sham to left kidney. Briefly, a longitudinal, upper left incision is performed to expose the left kidney. The renal artery is located and 6/0 silk thread is passed between the artery and the ureter. The thread is looped around the ureter and knotted 3 times insuring full ligation of ureter. The kidney is returned to abdomen, the abdominal muscle is sutured and the skin is stapled closed. All animals are euthanized 4, 8, 14, 21, or 28 days after UUO surgery. Following sacrifice blood is collected via cardiac puncture, the kidneys are harvested and one half of the kidney is frozen at -80 ° C. and the other half is fixed in 10% neutral buffered formalin for histopathological assessment of kidney fibrosis. 131omyin DeralFibrosis Model

[005441 Bleomycin (Calbiochem, Billerica MA) is dissolved in phosphate buffered saline (PBS) at 10 ug/ml, and sterilized by filtration. Bleomycin or PBS control (100 ul) is injected subcutaneously into two locations on the shaved back of C57/BL6 or S129 mice (Charles River/Harlan Labs, 20-25 g) once daily for 28 days while under isoflourane anesthesia (5% in 100%02). After 28 days, mice are euthanized and 6 mm-full thickness punch biopsies are obtained from each injection site. Dermal fibrosis is assessed by standard histopathology and hydroxyproline biochemical assays.

EXAMPLE 25: Targeting Calpains

Targeting calpains as a novel strategy towards inhibition of EpMT

[005451 Calpains are calcium dependent non-lysosomal cysteine proteases that selectively cleavage their target substrates, often leaving behind a functional domain and can be a form of post-translational modification. There are currently 14 known genes encoding for the large calpain subunit in humans: CAPN1 (NCBI Gene ID 823), CAPN2(NCBI Gene ID 824), CAPN3(NCBI Gene ID 825), CAPN5(NCBI Gene ID 726), CAPN6 (NCBI Gene ID 827), CAPN7 (NCBI Gene ID 23473), CAPN8(NCBI( Gene I[ 388743). CAPN9(NCI Gene ID 10753), CAPNI(NCBI Gene ID 11132), CAPNI1(NCBI Gene I) 11131), CAPNl2(NCBI Gene ID 147968), CAPNI3(NCBI Gene ID 92251), CAPN14 (NCBI Gene ID 440854) CAPN15(NCBI Gene ID 6650) and 2 known genes for the small regulatory subunits CAPN4/CAPNSI(NCBI Gene ID 826) and CAPNS2 (NCBI Gene ID 84290) (Goll 2003; Schad 2002) . The majority of research has focused on the ubiquitously expressed CAPNI (aka mu-calpain) and CAPN2 (aka m-calpain), which require micro or millimolar levels of calcium for their activation, respectively. These isoforms, along with CAPN9, have been shown to form a heterodimer with the small regulatory subunit (CAPNSI akaCAPN4) (Ravulapalli 2009). Capainshave been implicated in numerous cellular processes, including cytoskeletal rearrangement (Dourdin 2001), migration (Leloup 2006), signaling (Janossy 2004), and differentiation (Santos 2012).

[005461 For assessment of in vitro EMT, NMuMG cells (ATCC) were grown to confluence in 10% serum (Fetal Bovine Serum) growth media (Dubecco's Modified Eagles Medium supplemented with lOug/mL insulin) and then were followed by 24h starvation in 0.5% serum media -/- drug inhibitors. Cells were then treated with recombinant human TGFbI (R&D Systems 5ng/mL) +-drug inhibitors in 0.5% serum media. For time points greater than 24h, the aforementioned media was refreshed every 24 hours. Cell lysates were analyzed for aSMA protein expression by western blot.

1005471 Miettinen et al. (1994). "TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors." J Cell Biol 127(6 Pt 2):2021-36

[005481 Lamouille et al. (2014). "Molecular mechanisms of epithelial-mesenchymal transition." Nat Rev Mol Cell Biol 15(3):178-96

[005491 For assessment of in vitro FMT, Normal Human Lung Fibroblasts (NHLF) cells (Lonza) were grown in Fibroblast Growth Media-2 (Lonza CC-3131/with CC-4126 bullet kit) and then were followed by 24h starvation in serum/growth factor free Fibroblast Basal Media

2 (Lonza CC-313)+/- drug inhibitors. Cells were then treated with TGFbl (5ng/mL) Fibroblast Basal Media +/- drug inhibitors. Cell lysates were analyzed for aSMA protein expression by western blot.

[005501 Pegorier et al. (2010). "Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentiallyTransforming Growth Factor (TGF)-B Iin normal human lung fibroblasts (NHLF)" Respir Res 11:85

EXAMPLE 26: Human Treatment

[005511 The efficacy of treatment with a compound of a preferred embodiment compared with placebo in patients with idiopathic pulmonary fibrosis (PF) and the safety of treatment with a compound of a preferred embodiment compared with placebo in patients with IPF is assessed. The primary outcome variable is the absolute change in percent predicted forced vital capacity (FVC) from baseline to Week 52. Other possible end-points would include, but are not limited to: mortality, progression free survival, change in rate of FVC decline, change in Sp02, and change in biomarkers (HIRCTimage analysis; molecular and cellular markers of disease activity). Secondaryoutcome measures include: composite outcomes of important IPF-related events; progression-free survival; the rate of death from any cause; the rate of death from IPF; categorical assessment of absolute change in percent predicted FVC from baseline to Week 52; change in Shortness-of-Breath from baseline to Week 52; change in percent predicted hemoglobin (Hb)-corrected carbon monoxide diffusing capacity (DLco) of the lungs from baseline to Week 52; change in oxygen saturation during the 6 minute walk test (6MWT) from baseline to Week 52; change in high-resolution computed tomography (HRCT) assessment from baseline to Week 52; change in distance walked in the 6MWTfrom baseline to Week 52. Patients eligible for this study include, but are not limited to: those patients that satisfy the following inclusion criteria: diagnosis of IPF; 40 to 80 years of age; FVC>50% predicted value; DLcof35% predicted value; either FVC or DLco 90% predicted value; no improvement in past year; a ratio of the forced expiratory volume in 1 second (FEV 1) to the FVC of 0.80 or more; able to walk 150 meters in 6 minutes and maintain saturation?83% while on no more than 6 L/min supplemental oxygen. Patients are excluded from this study if they satisfy anyof the following criteria: unable to undergo pulmonary function testing; evidence of significant obstructive Jung disease or airway hyper responsiveness; in the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 52 weeks of randomization; active infection; liver disease; cancer or other medical condition likely to result in death within 2 years; diabetes; pregnancy or lactation; substance abuse; personal or family history oflong QT syndrome; other IPF treatment; unable to take study medication; withdrawal from other IPF trials. Patients are orally dosed with either placebo or an amount of a compound of a preferred embodiment (1 mg/day-1000 mg/day). The primary outcome variable will be the absolute change in percent predicted FVC from Baseline to Week 52. Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated for 52 weeks. Physical and clinical laboratory assessments will be performed at defined intervals duringthe treatment duration, for example at weeks2, 4, 8, 13, 26, 39, and 52. Pulmonary function, exercise tolerance, and shortness-of-breath will be assessed at defined intervals during the treatment duration, for example at weeks 13, 26, 39, and 52. A Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety. Example Trial in SSc

[00552] The efficacy of treatment with a compound of a preferred embodiment compared with placebo in patients with systemic sclerosis (SSc) and the safety of treatment with a compound of a preferred embodiment compared with placebo in patients with SSc is assessed. The primary outcome variable is the absolute change in Modified Rodnan Skin Score (mRSS) from baseline to Week 48. Other possible end-points would include, but are not limited to: mortality, percentage of patients with treatment-emergent adverse events (AEs) and serious adverse events (SAEs), composite measurement of disease progression, and change in biomarkers (molecular and cellular markers of disease activity, such asC-reactive protein). Secondary outcome measures include, but are not limited to: Scleroderma Health Assessment Questionnaire (SHAQ) score; the Health Assessment Questionnaire Disability Index (HAQ-DI); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT) score; severity of pruritus as measured by a standardized scale, such as the 5-D Itch Scale; St. George's Respiratory Questionnaire (SGRQ) score; Tender Joint Count28 (TCJ28); lung function parameters; standard vital signs (including blood pressure, heart rate, and temperature); electrocardiogram measurements (ECGs); laboratory tests (clinical chemistry, hematology, and urinalysis); pharmacokinetics (PK) measurements. Included in these measurements and in addition, clinical and biomarker samples, such as skin biopsies and blood (or serum and/or plasma), will also be collected prior to initiation of treatment.

Additionally, patients eligible forthis study include, but are not limited to, those patients that satisfy the following criteria: Patients at least 18 years of age; diagnosis of SSc according to the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) Criteria, meeting criteria for active disease and with a total disease duration of less than or equal to 60 months; 10 mRSS ! 35. Patients are excluded from this study if they satisfy any of the following criteria: major surgery within 8 weeks prior to screening; scleroderma limited to area distal to the elbows or knees; rheumatic autoimmune disease other than SSc; use of any investigational, biologic, or immunosuppressive therapies, including intra-articular or parenteral corticosteroids within 4 weeks of screening. Patients are orally dosed with either placebo or an amount of a compound of a preferred embodiment (I mg/day-1000 mg/day).The primaryoutcome variable will be the absolute change in mRSS from Baseline to Week 48. Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated for 48 weeks. Physical and clinical laboratory assessments will be performed at defined intervals during the treatment duration, such as Weeks 2, 4, 8, 12, 24, 36, and 48. Clinical and biomarker samples will also be collected at Week 48. A Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety.

[005531 In some embodiments, patients may be treated with a calpain inhibitor in combination with additional therapies such as anti-inflammatories including glucocorticoids, analgesics (e.g. ibuprofen), aspirin, and agents that modulate a Th2-immune response, immunosuppressants including methotrexate, mycophenolate, cyclophosphamide, cyclosporine, thalidomide, pomalidomide, leflunomide, hydroxychloroquine, azathioprine, soluble bovine cartilage, vasodilators including endothelin receptor antagonists, prostacyclin analogues, nifedipine, and sildenafil, IL-6 receptor antagonists, selective and non-selective tyrosine kinase inhibitors, Wnt-pathwaymodulators, PPAR activators, caspase-3 inhibitors, LPA receptor antagonists, B cell depleting agents, CCR2 antagonists, pirfenidone, cannabinoid receptor agonists, ROCK inhibitors, miRNA-targeting agents, toll-like receptor antagonists, CTGF-targeting agents, NADPH oxidase inhibitors, tryptase inhibitors, TGF [i inhibitors, relaxin receptor agonists, and autologous adipose derived regenerative cells.

[005541 While some embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[005551 The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appendedclaims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[005561 The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use ofsuch terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase "consisting essentially of 'will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any element not specified.

[005571 In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present technology. This includes the generic description of the present technology with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[00558] All publications, patent applications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[00559] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[00560] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[00561] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes

[00562] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

312 17678412_1 (GHMatters) P109779.AU

REFERENCES CITED 1. U.S. PatentNo. 5,145,684

2.Goll et al. (2003). "The calpain system." Physiol Rev 83(3):731-801.

3. Schad et al. (2002). "A novel human small subunit of calpains." Biochem J 362(Pt 2):383-8.

4. Ravulapalli et al. (2009). "Distinguishing between calpain heterodimerization and homodimerization." FEBS J 276(4):973-82.

5.Dourdin et al. (2001). "Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts." J Biol Chem 276(51):48382-8.

6. Leloup et al. (2006). "Involvement of calpains in growth factor-mediated migration." Int J Biochem Cell Biol 38(12):2049-63.

7.Janossy et al. (2004). "Calpain as a multi-site regulator of cell cycle." Biochem Pharmacol 67(8):1513-21.

8. Santos et al. (2012). "Distinct regulatory functions of calpain I and 2 during neural stem cell self-renewal and differentiation." PLoS One 7(3):e33468. 9. Miettinen et al. (1994). "TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors." J Cell Biol 127(6 Pt 2):2021 -36. 10. Lamouille et al. (2014). "Molecular mechanisms of epithelial-mesenchymal transition." Nat Rev Mol Cell Biol 15(3):178-96. 11. Pegorier et al. (2010). "Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-BI in normal human lung fibroblasts (NHLF)" Respir Res 11:85.

Claims

WE CLAIM

1. A compound comprising Formula I:

wn 2 R3 A R2 L4 R2 R2 R4 LN N N R R2 A R2 R R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of:0 and S;

A

NR1

each R4 is R1

each Rland R 3 is independently selected from the group consisting of: hydrogen, C1 C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted C1-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C0 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR2 , SR 2, substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form aC3-C 1 2cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C0 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any

314 17924458_1 (GHMatters) P109779.AU

R 2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2

, 0, NH, NR 2 , C(=O), C(=S), S, S(=), S(=0) 2 , -C-, -CH-, a C3-C1 2 spirocyclic group R2-(R2)m

of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a C3-C 12 cycloalkyl ring structure, a C3-C1 2 fused cycloalkyl ring structure, a C3-C1 2 aryl ring structure, a C3-C 12 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, a C3-C1 2 fused heteroaryl ring structure, a C3-C1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure;

and wherein Wn does not form an (S)-- CH 2CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof.

2.The compound of claim 1, wherein n is 1, Wu is WI, andWi is CHR2 where R2 is a Ci-C8 alkyl or Ci-C8alkenyl.

3.The compound of claim 1 or claim 2, wherein L 4 is -S02-Ar, -CO-0-substituted alkyl, CO-0-C(CH 3) 3 , -CO-0-CH 2Ar, -CO-alkyl, -CO-substituted alkyl, -CO-CH 3, or -CO-Ar.

315 17924458_1 (GHMatters) P109779.AU

4.The compound of any one of claims 1-3, wherein one R2 on the R 2 R carbon atom is a substituted C1-C8 alkyl, a C3-C9 heteroaryl, a substituted C3-C9 heteroaryl, or a naturally or unnaturally occurring amino acid side chain.

5. The compound of claim 4, wherein the C-C8 alkyl is -CH-(CH 3) 2 or -CH 2 -CH-(CH 3 ) 2

. 6.The compound of claim 1, wherein n is 4, W, is -WW 2 W3 W 4 -, WI is CHR2 , and one R2

on the R2 R carbon atom is -CH-(CH 3) 2, and W2 is CHR2 where R 2 is a C1 -C 4 alkyl covalently bonded to the R2 group on Wi and forms a bicyclic ring structure.

7.A compound comprising a formula selected from the group consisting of Formula II, XV, XVI or XVIII:

3 n R2 R 20O , RO

R2 O0R2 RR2 O R1

Formula II

LN N N'R2-R1

R2 A R2 R 2 A R1

Formula XV N N <tN N'R

L4 RO 2-Z-R 1

R2 2 R2 R2R O R1

Formula XVI

316 17924458_1(GHMatters) P109779.AU

/ Wn

,' R3 A 2 NR R-Z-L 4 N A R2R 2 R2 A

Formula XVIII

where:

when the formula is Formula II: n is from 1-11;

when the formula is Formula XV or XVIII: n is from 1-12, and each A is independently selected from the group consisting of 0 and S;

A

k N 11Ra

when the formula is Formula XVI: n is from 1-12;each R4 is R

each R'and R 3 is independently selected from the group consisting of: hydrogen, C1 C8 alkyl, substituted C1-C8 alkyl, Ci-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted C1-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C0 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR2 , SR 2, substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or share another R' substituent to form aC3-C 1 2cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, CI-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C0 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any

317 17924458_1 (GHMatters) P109779.AU

R 2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2

, 0, NH, NR 2 , C(=O), C(=S), S, S(=O), S(=0) 2 , -C-, -CH-, a C3-C1 2 spirocyclic group of R2-(R2)m

where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

Z is selected from the group consisting of: C-C8 alkyl, substituted C1-C8 alkyl, C-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C8 alkynyl, Ci-C8 alkoxy, substituted C-C 8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R 2 ) 2

, CHR 2, 0, NH, NR 2, S, substituted sulfonyl, sulfinyl, substituted sulfinyl , and a covalent bond;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form a C3-C 12 cycloalkyl ring structure, a C3-C1 2 fused cycloalkyl ring structure, a C3-C1 2 aryl ring structure, a C3-C 12 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, a C3-C1 2 fused heteroaryl ring structure, a C3-C1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure;

and wherein Wn does not form an (S)-- CH 2CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide functional group; and wherein ----- is a single bond;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

8.The compound of claim 7, wherein L 4 is selected from the group consisting of acyl, aminoacyl, carboxy ester, -CO-ethylene glycol, -CO-polyethylene glycol, substituted sulfonyl, and formyl.

318 17924458_1 (GHMatters) P109779.AU

9.The compound of claim 8, wherein the carboxy ester is -CO-0-CH 2-Ph or the substituted sulfonyl is -S02-Ar.

10. A compound comprising a formula selected from the group consisting of Formula III XIV:

R2 R2 3 R2 R 2 R2 R2O R3 N -O R3 N O\ R 20RR2

0 NR -R NIN L~ N z z2114 N 'z -z R

FormulaIII FormulaIV Formula V

20 R R 0 R2 0 --R R2 2

R R N' R2N R2 N O R 0 2 0 z

R1 R N L4 1 L4-N zi- z R220R2 -R1 20Ri ,R1 F R1,N

Formula VI Formula VII Formula VIII 14 R2,z2-a4 z 6z',z~ L z3 R3 ziR2R N N0 N-R 1 R2 R 2O L-NR 1 OZ z0 R2O 2

R zeR 2 N N zz 3R.-N Z5 0 ONL 2 4a

L -N zi-z2- L4'N RZ

R2 R2 R

Formula IX Formula X Formula XI

319 179244581 (GHMatters) P109779.AU

R1 1 R"s' R 1 RNs ,R1

0 "10 azz Nt z R0 1 zioR

N Z10 z8 ' z6 R N Z 11 Z9 N z 12 'Z 10 OR 2 z4' R2 O 0 R O Z

N . R3-N 0 z O 0 -'1Y 2z4 2- R2R 23

2z L4 ~' R Lz8 z 2 z 4 Rz RR z

Formula XII Formula XIII Formula XIV

where:

when the formula is Formula III:

Z' is selected from the group consisting of: CH 2 ,C(R) 2 ,CHR', O, NH, NR', C(=O), R2-(R 2)m

C(=S), S, S(=O), andS(=0) 2, aC3-C 12 spirocyclic group of where m is 1-19;

when the formula is Formula IV-XIV:

Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6, Z 7 , Z 8 , Z 10, Z" and Z 12 are each independently selected from the group consisting of:CH 2 , C(R 2 ) 2 ,CHR2, 0, NH, NR 2 , C(=0), C(=S), S, S(=0), S(=0) 2 , -C-, R2-(R2)m

CH-, aC3-C 12 spirocyclic group of where m is 1-19, wherein any two adjacent Z atoms may form CR=CR' or C--C;

each Wand R 3 is independently selected from the group consisting of: hydrogen, CI C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted Ci-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C10 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C 9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR 2 , SR 2 , substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or

320 17924458_1 (GHMatters) P109779.AU share another R' substituent to form a C3-C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C cycloalkyl, substitutedC3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form aC3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl; and wherein when the formula is Formula V-XIV,

any and all Z groups do not form an (S) -+-CH 2CH2C(O)NH group in the ring starting

from the carbon attached to R2 which is adjacent to the keto-amide functional group;

and any two or more Z groups can be bonded together to form a C3-C1 2 cycloalkyl ring structure, a C3-C 12 fused cycloalkyl ring structure, a C3-C 1 2 aryl ring structure, aC3-C 1 2 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, aC3-C 1 2 fused heteroaryl ring structure, a C3-C 1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

11. A compound comprising Formula XVII:

, R 2 A Z R1 LNL41 R\e N 2 N R R R2 A R2 R R2 A

Formula XVII

321 17924458_1 (GHMatters) P109779.AU where: each A is independently selected from the group consisting of:0 and S;

A

Ny R

each R4 is R1

each R1 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-CI1 cycloalkyl, substituted C3-C1O cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH2 , NHR 2, SR2 , substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R 1 substituent to form a C3-CI2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C-C8 alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted C1-C8 alkenyl, C1-C8 alkynyl, substituted C1-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C8 alkoxy, amino, substituted amino, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

L 3 is a group containing 1-8 atoms and is selected from the group consisting of: C1-C8 alkyl, substituted Ci-C8 alkyl, Ci-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C alkynyl, substituted C1-C8 alkynyl, C1-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, sulfonyl, C(R2)2 , CHR 2, 0, NH, NR 2 , S, substituted sulfonyl, sulfinyl, and substituted sulfinyl;

Z is selected from the group consisting of: C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted Ci-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C8 alkynyl, Ci-C8 alkoxy,

322 17924458_1 (GHMatters) P109779.AU substituted Ci-C 8 alkoxy, substituted amino, alkylthio, substituted alkylthio, sulfonyl,C(R 2) 2

, CHR 2, 0, NH, NR 2, S, substituted sulfonyl, sulfinyl, substituted sulfinyl ,and a covalent bond;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

wherein each L 3 and Z are capable of being covalently bonded to the same or other R2 functional groups such that a bicyclic or spirocyclic ring system is formed;

and wherein L 3 and Z do not form an (S)-- CH 2CH 2C(O)NH- group in the ring starting from the carbon atom closest to the keto-amide or thio-keto-amide functional group; and wherein ----- is a single bond;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, having the structure selected from the group consisting of:

HO0 H 0 HO0 O HN N, O HN N 0HN N, O H O O '- H O H -0 I 0 kJ0N" 0 H N" H H 3 1 2

H 0 H HO O IN OHN N, N O H H O HHN N,O 0 0 0

0H 0 H N"H 4 5 6

0 H 0 0H HH 0 H N H H 00 HiN N, 0 M N,. 0N0Hi N, N,.

0A H' W' 0 0" 0 0 H H H

7 8 9

323 17924458_1 (GHMatters) P109779.AU

H 0 HO HO0 00 HiN N, H 00 HN N," H 0N,o 0 0 HIN N, H

H N'H H H1 12 10

HO 0 HN HN" 0 HIN 0~ H HN\N, H N, HO 0 // N, N0 0 HN \-,ON 0 N o 0 Ov XOA\, 0 XOA H NHNH 1314 15

HO HON NHO HN N,H >0ON HN N >/o 0 ~ 0

H H H

16 17 18 0

HO0 HO H 0 0 HN N H 0 N, H N'H.N N XON

0 H 19 020 21 0

H HH 0 0 0HN N,, 0 0 HN H, 0 00 HiN N,

HN 0 N0 H /H/ 227 23 724

OHIN N, I 0 N,, 0H N,,

X0HN 00 0N 0,ISI

NH

0 H

HON, H 0 0 0 0 0 00 N~ HN N,, HN Y/, 0H _,O NHDI N".V F N' 0

28 29 H3

324 17924458_1(GHMatters) P109779.AU

H 0 HN4 0

N, 0 H 0H XAN'" OH 00N HN N H N'H 32 3 00

H

H H 0 0HN N 00 HN N 0 00 0

" H H 34 35

H 0 NH 0 0 0OHN N 0 0 NN

N" 0 H 0 0-

36/ 37

and pharmaceutically acceptable salts thereof.

0 H N.)~ N 00

13. A compound having the structure 31 or pharmaceutically acceptable salts thereof.

14. A compound from Table 1:

Table 1

325 17924458_1 (GHMatters) P109779.AU

1- IF

0 0 H

N N 0

9 10

oH 00

H0 0 HH

ol N N N326 172481H Htr)1079A

0 0

0 0N

0

H0 H327 172481G ttr)1070A

Na 0H

o 00 HH N:N H H1

0 NH2

o 0 0 0 H 0 00 H N N_ N 0 N N NopHN H H 00 0H NH2

0 00 0

IJ ,H 00l H 0 0 \/ N N/ N 0 N N_ N H H 00 0 NH 2 0 NH 2

0328 19451HatesP077.A o 0

H H 0 _1"H H NNNF \pNNN 0 H H 0H 000 NH2 o NH 2

00

0 N H 0 N N H -H -S 0 N HN N NI 00 0 H 0 NH 2 0 o0 NH 2

65 66 00

0 0 o H Nj Ha N- N LN C 0 NN N HH H H 0 o0 NH 2 o0 NH 2

o 0 o 0 o a H 0 H a H H H H 0 0 o NH 2 0 NH 2

73 7 0 0

0 sN H 0 H 0 F H H H 0 0 0 NH 2 0 NH 2

329 179244581 (GHMatters) P109779.AU

E77 78 0 0

0 0N H 0 N o F "N N N \ / 0 H

H0N N

0 NH2

L85 86

o 0 00

H 0 HH 0 0N N HHN 0H 0H 0 NH 2

89 90

H330 1794481GH-ttrsP1077.A

97 1981

101

o 0 0 H N0

0

0 0

H1 112 H

0

H0 H331 17924581GH'atersP10N79.A

113 114

H0 j

117 118

0 0 0 H0 H_ :1 N N:

0

It N 0 0 N N H 0 0 N0

0 NH2

332 17924581GH~ate~sP10979.0

N N 0

H0

0

00

0 333 1792458HGH0ttNs)N09N9.0

00H

00 N H H H H 0 0 0 H HH 0 NH 20

153 154

00 0 0

N 0 NH o, N N 0 N ?H 0

00H 0 NH 2

1571584

0 0

334 19451HatesP0 H709.AU

00H 0 0K 0

N H a H H 0NM 0

0 NH 2 H

- HN F -- / N~ N 0

I~ HIH 0 oH 0 0 NH-I

173 174

0 0

H HN 335 172458(GN)tes)N077.A o 0

00

o 0

189 190

0 0

11F 0 \/

S-_ N N N 0 F-0 -1-336 172458I Iates)H077HA

00

0 H H 0s NN N) N H H 0 0 NH 2

0 0 0 0 - !HH 0 0 N HII 0 N N N HNNH H' H H 0 0 0 NH 20 NH

337

17924581GH~ate~sP10979.0

209 10 0 0 00 110 S- -N HH H- NH H H 0

aN F NN, N H 0 Ha H NH 2 0 NH 2

213 14]

0

0

00

0 i 0 0 H~~~ 0 ,C

aKN N 0 \, / H H N 0 H' 0H0 0 NH2

2172

H 00

H 0 H N 0 0 H 0 H H ~- NN-N H 00 0 N,0 NH 2

7251 P079 22~tes

22526] 0 0

0 o1 S H_ H 0 H F \1 / a) N W-_N N 0N-L N H a: H H 0 N H 0 0 NH 2 0 NH 2

, 0 0 0 0 - ix0 - 11 N N N 0 F/ NN 0 0 H H

0 NH 2 0 NH 2

233 234

4H 0 A)

N 0 0 0~ 0 0 Nt / H H /

O NHH

00 0,7 N 0 ', N N N o

0NN H H

N20 NH 2

33 1794481GHHttrsP1077.A

245 46 00 -_ 0 II1N NH 0 N 0

00 NH2

249 250

0 0

0 0

00

17924581GN 34 S-- NP109N9.N

M72]

0 0 0 0 0 F s H_ N H H C N NN 0 0 N N N 0 HH H H 0 0 0 NH2 0 NH2

6

0 H H 0 0 H 0 0 0 N N N F S-N N N H H 0 H 0 0 0 NH2 0 NH2

269 270

0 0 11 H_- H 0 H 'A, S-N N 0 N N N N 0 H H 0 H 0 0

NH, NH2

273 274

0 0 U H_- H 0 0 H_, H S-N N F__(D S-N '01 N N 0 H 0 H 0 0

0 NH2 0 NH2

341 179244581 (GHMatters) P109779.AU

F 0 N/ 0

11 N 0 0H

0 00H

0 H 0F HF

N N N H342 172451GHHtesP19H9A

H 0

0

00

4H H 343 1794451(0 ater)P1N77.A

-191 20

0 0

H 0

0

0 0

a1 0

s Hj 344 17924581(GNat0e0)P1077H.A

39 40 H 00

0 0 s.-,NNOl N0 -j -)-- "H 0 0 H,0 NH,

0 a HH1 - H H0 a N 0 -N N N o 0 H HH 0 NH 2 00H

0 0 00 0 a-J ,

HH 0N 0 N N 0 N N 0

H NH0 0 NH 2

0 N0

34 172451GHatesP1970A

59 6 a 00 o 0

H 0H 0a 0 N N N 00 N N N H 1 N H H H H

0 NH2 0 NH2

63 64 00

0 0 UH NH H F iiN 0 0 k' o 'IN0 N N N 0N H H 0o NH 0 2 a NH 2

67 68 o" 0

0l 0 - I0 LN H "HH SJ-N N N F / S--N 0 N N N 0

0 0H 0

000 NH 2 o NH,

0

00 o 0 S NN 0:: 11 H H H N S-N H H 0 NH2 o NH 2

75] 76] 0

H0 0 0 H 00 N N -N o0 N HH HH 0 0 0 NH, 0 NH 2

346 179244581 (GHMatters) P109779.AU

07 0o 0 0 0H 0 0 0H 0 H 0 -kN N N 01 N N N 0 H H H 00 NH 2 00 NH 2

0 0 0

"H H H 0 0 H HN 0 H 0H

a NH 2 a-1 NH 2

91 920

0 0

N0

N347 172451GHaHesP1970A

99 100

H 00

0 0

107 108

0 0

111 1 20

F-a- - N0

Al 348 17248(H~tesP077.AU o 0 H 0 N N NH H 0 NH0 0 NH2

119 120

0 0

N< N N 0 N HH HI 00

1349

17924581GH~ate~sP10979.0

0 0 H

139 140

00

0 0

0350 172458(G ates)1077.A

H 0 0 N 00 O0 N N 0H 0H " NH2 0 NH,

000 0 0 o H H 0 N N N--N H)A 0 HY H HH H NH 00 0 NH2 H

155 156

0 0

0351 172458(H0ttrsP0970A

0H 0

N 0 H

0 H H

167 168

00 H 00

00 0 N

M-71 352

17248(H~tesP09770

0 N 0H

0 NH2

1 180l

0 0

00 00

0 0

0 H0 N N1

H H

NH,0 NH 2

187 1353

17248(H~teP09709HA0

191 192

0

0 0

o 0 0 0 0 s H 0 a~~ HH \/ N 2

19 196

'9 0 0 0 NH2 00 NH 2

M354

17924581GH~atersP10979.A

07] 08

0 0 0 0

H 0 0 H 0 0 N N N 0 H N tN H H H 0 H

o NH 2 0 NH 2

11 2q

0 0

H 0 00 o N N H 00 HH 0 NH 0 N N N H 0 0 o NH 2 0 NH 2

215 216

0 0

0 0 - IH 0 H 0 0 F ~- N00 N N H N N H 0 0 0 NH 2 0 NH2

19 20o 0 00 0 N 1. 0- H 7H HIN NN 0 S-N 0 N -N 0 : 0 0H

0 NH2 0 NH 2

355 179244581 (GHMatters) P109779.AU

0

HI o 0 H 0 0H 0 NH 2 0

0 NH,

227 28 0 0 _ C0H a 0

H 0 0 0 0It N N N H H 00 0 NH 2 o NH 2

231 232

0 0 0 0

H 0H 00 o N N N 0 'JN N N H H H 0H 00 0 NH, 0 NH 2

235 236

0 0

H H 0j 0 NN>

0 NH 20 H

239 240

0

0 1 H-356 1794481GHHttrsP1077.A

N 0

0 Ha

00

H0 H357 17924451(GH aters)P1N77N.A

59 60l

0

0 00

H D 0

0 0 HF

358 19451HateP0 N7N9NAN

75] 76]

0 0

0

0 NH,

0\ NH,

2r~l m0

87 88_j H

0 NH0

283 359

17248(H~tesP09770 or atautomer and/or apharmaceutically acceptable salt thereof.

360 17924458_1(GHMatters) P109779.AU

15. Acompound from Table 2:

Table 2

1 2

H 0 0

0

9 10

0 0

0 0

361N 1794481 0 0 H H1077.A

:17 18I

00

0-- N_ H 00 N N0 N H 0 H - 0 NH)2

H H N N H

0 0 0 H~< 0 0 N H N 0 H N H 0 0 NH NH2

25] -362

19451HateP0 779.0

33 34 H N

0 N 0

0NH 0 0'N- N H N N N:N1 H N H H NH 0 0 NH 2 0 0 NH,

37 38 0 0 0 0 H 0 0 H 0 0' N N N 0 N N N H' H H H 00 NH, 0 NH2

:41 42 0 0

o 0 0 H0H 0 o N N N H HHH o 0 0 NH2 0 NH 2

H 0 0

oJL N N N- 0 N N N' H H HH 0 0 0 NH 2 0 N 2

363 179244581 (GHMatters) P109779.AU

491 50

53 54

H ) 0 J

0 0

364,0 H

172451GHa 54P1979A

:65 66

0

H 0

0 N N N H H HH 0 0I

H 0 0 H 0 0 0N N N H l- N N 0 HH H H 000

0 NH, 0 NH 2

73 365

172451GHatesP1979A

81l 82] H H N N O 0

-- " 0 O HN HNN0 HNH H N H

O NH 2 0 H

851 86

0

H 0H 0

0 IN N0 HNH N N HN

NH NH 2

89 94

0 0 H 0 H) 0 H 0 0 H~' N N ON0- N N_ N 0 H H H -- )

O0 NH, 0 H

97 98 0 0 0 0

H 0 H 00 O aN N N H H HH 00 0 NH 2 0 NH2

97] 936 1724510HatesP1909A

T11 :102

0 0 o H 0 H 0 0 N : N'N 0 N N N H 0 H _H- H

0 0 NH NH,

105 106]

H 0 H

00

109 110 N 0 N 0 H 0 N NN) 0 0 NH0H 2

H

0 0 NH

H 1~ 0 00~N

HN "N N* N' H H a ~ ~ NH 20 NH

117 118

No 'o t:Yao H H 0 N HH H 0H

'N00 NH 2 0 NH, 2

367 17924458_1(GHMatters) P109779.AU

121 122

0 00

0 0

00

11 H_368 117H.HU

19451Hates0

141 142

0 0

00

00 0

0 0

H H_ 369 17924451(GHoate s)N--77N.A

161 162 H N N 0

11 H 0 H NH 2 0 0 NH 2

165 16

0 NH 0 0

N ~ 0 - H Ho H V H N s N N 0 3 1 N o HNH 2 0 NH,

169 17

0 0

1- H___H NN N S- N0 1 H H 0

N H 0 00 H

O NH 2 0 NH,

173 17 H N 0

0 0 N_, 0 N N H H

0 0 NH

370 179244581 (GHMatters) P109779.AU

177 178 H N

H 00i" 0 N 0 H H N N 00

0 N, NH,

181 18 H N N H 0 0

0 kN H 0 0 4-~ H N N 0 NH 0 HH H N N 0 0 H 0 NH 2 7 O NH 2

185 18 H NH N

0 0

0K N N N N HH 0 H

0 0 H- NH 2

NH 0 0N 0 H 0 0j o N H 0 H N_ N I 0 k-- H 0 0 N NN 0 H 00 NH 2 0 H 0 NH

371 179244581 (GHMatters) P109779.AU

193 194

0 0 0H 00 NN N 0 0 H 0 NHN 2

197 19 0 0 0H

0 H 0 00 HH0 N N N 0H H

0 NH 2

201 20 0 0 0

H 0 00 o N N, N H 0o HH 0 N N N H H 0 0 o NH 2 0 o NH 2

20520 0 0

0 0 0 0A' H 0 I-,H 00 N N N 0 N N N H H H H 0 0 0 NH 2 0 NH 2

372 179244581 (GHMatters) P109779.AU

209 210

0 0

' 0H 0 0 N H N 0 o~t"N N N 00 N N N H H H H 00 0 NH 2 0 NH 2

213 21

0 0 0

H 0 H_ 0 N 0 0 N H N 0 N' H 0H 0H 0

o NH 2 0 NH

217 218

0 0 00 H 0 0 N N) -N 0-OI NN N 0 H H H0 00 0 NH 2 0 H

221 22

00

0

373 179244581 (GHMatters) P109779.AU

225 226

00

HH N 0 0,

NHN NH N H H HH 00 ~ H 20 NH 2

0 NH00 0H 0 H 0 N N N 0J N N N H H H H 0 00 0 H NH,

7 172481G Nt~)1079A

241 242

00 H0

0 ' H 0 H NN N- N N 0

00 NH 2 0 NH 2

L24524

0

0 0

11 0 H3-5 1792458(GH tte-NP0N)9.A

257 258

0 00

0

00

00 00

00

376 1794451(GNH2 0P1977.A

273 274

00

- H H 0

0 NH

0 0N NH

0 H H 0 NH 20

0 0 H

00H 0 0

0 N NHN

H H

00

0 NH

377NH

172581G~tesP079A

289 290

0 0

L29329

0 0 0

0H N NH

HH

0 11I H 11I H 0 S-N H 0 0 S-N H 0 N N 11N N 0 0H 0 0 0H 00

0 NH 2 0 H

301 30

0 - H NH0

11N H 0

0 0 H

0 NH2 H

378 179244581 (GHMatters) P109779.AU

305 306

0

00

-NN0 NH N N 0N

H 0 0

0 NHN0 2

0 NH 2

313 31

0

H 0 0

H H 0 NH

H N 0 NH 0 H 0 H 0 N N N 0 HH

0 NH2 H

00 0NHr

379 179244581 (GHMatters) P109779.AU

321 322 H N

0

olk HH 0 H H 0 N IN: N 0 0H H

0 NH2

325 32 NH H N

0

0ll N H 0H 0 0i HN N 0 N NC H0 6 0 NH2

o0 NH 2

329 33 H

NH

0 Hi 0 00 N N_ N0 0 N- H 0 H H H N N 0 0 H 0 NH 2 0 NH2

380 179244581 (GHMatters) P109779.AU

333 334

0NH 0

0N-N \ H0 'o/ H N N0H 0 ~ H0 0 NH,

337 33

H N N H H

N.0 NH 2 0 H

34134 0

H 0 07 0 - H 0 l H H 0 N 0 N N N H 0H a NN H

04 5

0. 0 NH 0 NH2

0l 0 0

N N N 0 0 N N N H H H 7_ H 0 0 N20 NH 2

381 179244581 (GHMatters) P109779.AU

349 350 00 00

J H 0 H 0 0 0 N N N 0 0 N N N H- H H H 0 0

o NH 2 0 NH 2

35335

0 00 00 H 0H NN H N H H 0 NNN N H H

0 o NH2 o NH 2

35735

0 0 o;0 0 ol ,H 000 o NN N H NN 0 H H N 0 H 0 0 NH2 0 H

36136 H N -N

- H 11 H sN S-N H0 N H a 'N F \ \ N, N 0 0 H 0 ~~NH 2 0 0 r H

382 179244581 (GHMatters) P109779.AU

365 366

0H NH 0

SNH 0H H0 0 H a N N H k N 00 NH 0 NH2

0 0

0H 7HH_ 1H H 0 N N HNN N H 0 H 0 0 0 H20 NH 2

37337

0 0 0 NH 0 ~ ~ ~ K H N) 0 0 H H H N H 0H0

0 H20 NH 2

377 378

00 H0 0 0-~k N N 0H H NN)

0 NH 20 H

383 179244581 (GHMatters) P109779.AU

381 382

0

N H 0 00

0 H

39339

00 H0 0 H 0 0HH 0 N N N H0 H H 0NNNH 0HH 0 NH 0

3384

17924581GH~ate~sP10979.0

397 398

00

H 0 0 0 0 OJ NNNN N H H H H 0 N H

0 H H 0 NH 2 No NH

405 40 H NH

)-I

N N HH H H

HH 0H 0N'

0

0 H _ H 0 0 H o N H N N HH H

0 NH 2 ~"0 NH

00

00 0 0

H 0 H 0

0 NH 0H HHN

H13 H4H4 0 0

0 NH 2 0 NH 2

385 179244581 (GHMatters) P109779.AU

417 418

0

H H NN N 0 H H 00

0 NH2

421 42

0 0

0 0I

38620 H 172581G tesP079A

437 438

00

0 H H N,

0 0 NHN

N NNH2N 0 0 H NHN

0 00

S-0 NHs NH2 N~ NN

H 1 H

- 0 0 0 H S-N H 0 0

H 00

N N NH H 0

~ H2 0 NH 2

387 Ht~)1079A 172481H

53 454

0 NH - _H 0 S-N H 0 o 0 N 0N H F \ S- ) 7Ho NH 200 H

5745

0 -1 I H- H 0 '- _<_ 1H _ H 0 S N N 0 N N Hi H 0 o 0H _ o NH2 0 NH 2

6

00 00 0 0 11 H- H 0 5 ~H H NN N- i N 0 00 H 0 0 N

0 NH2 0 NH 2

388 17924581GH~ate~sP10979.0

69 470

00

0

NN N 0~'

478

00 00

HH N, N H H 00 -0 0 I N~ N H/0

H 0

H 0 NH 2

0 NH,2 H

38 172481G Nt~)1079A

0NH 0

0 H 00 S N 0 H

0 NH 2 0 NH 2

89 490 00 00

- j H 0 0 S N N 0 F 'N N oH F \ N--S 0 \/ 0 H 0 NH 2 00 NH

9349

o0

S- 1 H H

0 NH 2

390

19451HatesP070A

00

00

H0

_-o 0 0, 0

0 0

00

51391

19451HatesP0 0J "H.0U

E521 2

0 0

HN0

NHN H 0 H -~ 0 N N N N aI H 0 0 N.2 0H a NH2

NH N

0 ~N H N 0 a N

H. 0 H H 0 H a NH 2 0 N.

a NH

39 17924581GH~ate~sP10979.0

E53

0 NH 0

H 01H 0~ ')N N) NH H HH

0

541 54 0

0 0 0 H 0 HN IL 0 0 ~ H 0 N - H N N H H 02 o NH 0 NH 2

54546 0 0

0 0

HN H 0 HH H H 0 H0 0 NH 2 0 NH 2

549 55

00

0 0

393 1794481HH tt- 001077.H

H 0 01

NN0 HH H 0 NH

394 172458(NH2 es)1077.A

1 HN H 1

0- 0 0 N-- N N S- N H 0 N H N H 00 0H 0 NH 20 H

585 58 HH NN

0 NH - N 0 0NNCSII- H HC0 0 -'7-H N-N H 0 0H N NH

H

0~~NNH

00

0 395 1794451(G~S_ H H1 07.A

597 15981

0

H1 0

N N- ~/ 4H H H

It N0N0

0 NH2 0 NH 2

601 60 0 0

0i 0

0 N0 / 0N H__ U H 0 N

o NH2 0 NH 2

605 60

0 HN 11 H HI 01_, H H 0 --

N N N \N N0 F N H 0 H

0 NH 2 0 NH2

613 61 HH

N NH

H S-NHN 00- N 0- H 0N 0 NHH

0 NH 20 H

61396 17924581GH~ate~sP10979.H

0 0 0 1H H 00 F\ / N N_ N F / 1- N N 0,::0 H 0 H 0 H0 0 NH 2 0 NH 2

621 622 0 0

0 0

H\ _f-N H N 0"_H H 0 o H F\ s o H 0 0 NH, 0 NH 2

625 62 0

- H_-H 0 No H N 0

0 HH 00 0

629 63

00

H 0

H_-A 11 _, )397 19451HateS -PN09779.AN

0H 0H 0 0

0 0

L641 L642]

0 0

0

0 0 0

0 NH/ 0 H

649 65

00

11 H H 0398 19451Hate S -NPN00911 HAU

0 0 0H 0

H Hk

00 NH 20 H

661 662

00

0 H oN 0 N H N NH

00

0 NHN

oH 0 \/Fl NN N N 0 H

0 NH2

669 67

0 0

0 NH20 N0

673 674

il 399 17248(G~teS)P109H77H9.AU

67 678 HN HN

0 0

H F SN rH 0 F - H H N1 0 F: -N' 0 0 Ne N 10 0H _ 0 NH 2 0 NH 2

68168 H NH N

0 '"H 0 - 1 F i -N H 0 H 0 0 N N F /0 HN0 0H N C o H 0 o NH 2 0 NH 2

685 686 0

0 NH - i--4 0

H_ 0 &CNI N N) H F H 0 0 0 NH 2 O NH 2

689 69 0 0

0 H H 0 F Hl~ H O ll / N N 0 N N 0I HH 0 0 o NH 2 0 NH 2

693 69

0 0 0 11 0 - Hj0 - 4 H 0 NN 01 F \ NN- 0 0- H 0H F->--H 0)0 N; 0 NH 2 0 NH 2

400 179244581 (GHMatters) P109779.AU

697 16981

00

0 0

0 0

l HH N H401 19451HateS)P10979.0

0 0

00

00 00

0402 1724580 Nates)N077NA

729 730

0 0 11

0 0H

73403

19451HatesP09770A

H, H 0 0 N N N 0 11 Hj H 0 H S--N 0 h N 0 0 N C>- H 0 NH2 0

0 NH2

753

0 0 0 11 S- H H 0 it H__ H -N N N 0 0 AN 0-0 H 0 0 NH2 0 NH2

757

0 0 0 "_H H 0 F s N Hj H l N N F 0 H 0 N N) N 0 0 H 0 0 NH2 0 NH2

761 762

H 0 SH F-0 - 1111 N N S__H__ H H 0 N 0 F--C >- Illl N N 0 H 0 N 0 0 0 NH2 0 NH2

404 179244581 (GHMatters) P109779.AU

0 O-- a LIN N 0 NON 00

o ~ ONR 0NyN ONR R 0 0 215'N.S'-~ (15)

405

79248(G3 te )1979

781 782

ONR 00ONR 2 'Nlo (15) R"" (15)

785 78

R NONR ONR

(15)0 (5

789 79

ON

793 79

R. 0, 00 0\-/ %rf CONR 0&.- l.

406 179244581 (GHMatters) P109779.AU

797 798

R2Nl ONR R2-No".N,,CONR

801 80

ONR C1. ONR

00

1) N( 0~~

I I

00

407 179244581 (GHMatters) P109779.AU

809 810 o R, 0 R, N.'kYO 2.'Ni,~ N YQ 0O

N' N CONR IN'NyONR (18~ (18)

0 813 814 o R 0OR, R2*, N f0 0 RN'is N 0 0 N CONR N 1JCONR 0(18)(18)

817 81

02 R2 R2 N { ,IC0NR 2k -N S N-CQNR N s(S) N (S) N e(S) N -')

(19) (19) 0 ,.0

408 179244581 (GHMatters) P109779.AU

821 822

2~ ' 1 NS)ONRON NS N(S)OR Ne.(S

(19) 0 (19) 0 0

o 0 0

2 1-0N NIS) -C0NR N S) - ON N(S) N It ) N(S) (S) (19) 0(19)

0 0 0

172458 (G(S)es (S)77.A

3 4

0 0

7 H 0

00

0 0

00

0-1 NN N 0 N410 172458 H H HsP0979A

19 20

0

H 00

0 HH0 HH 00 00

00 N JH H N) N 0'1)N H 0N 0 H H -N H

0 NH2 00 NH

02NH

N H 0 H N 0 0 N-- H 0' H N N 0 0H 0 N 0 P 0NH 2 00 NH 2

341 17924581GH~ate~sP10979.H

35 36

NH 0 0 0 H 0 0 ,O'KN 0 0 N N N N 0 N -' H-- H H N H 00 0 NH 2 NH,

04

0 0 0 0 0 0 0H 0a H 40 0-1 N N N 0 kN N NHH H 0H H 0

0 H2 0 NH2

4 43 0 0 0 0

H 0 -l HH J HH N N 0H o HC NN0 H N

00 o NH 2 00 NH 2

448

0 0 0 0 HH 0 0H 00 ,H o- N N N! 0 N N N!

0 H0 0 H2H 0r H0 NH 2

412 179244581 (GHMatters) P109779.AU

51 52

0 0

o 0

63 H 640 0 0

O-JI,413 1792458("H r NH, 0P0979.A

67 68

0

00

0 0

H H

00 H 0 N NH0 00 H0NHH H N H 0 0 0 NH2

79

N N H 0 H

H rN 0 H0 0 H N H H N N 0 H 00 0 NH2 0 NH

741 172481G Ht~)1079A

83 84

0 NH 0 NH

0 H 0 N 0 0 N-- H N; 0 o N H N H H 0 N H 00 00 NH 2 0 NH 2

87 8

H 0 0H 0 N N N 00 H 0 H j) H 0 N 0l NH 2 H 0 NH 2

91

0 0

0 H 0 000 0 N N N 0 N N N HH H H 0 0 NH2 0 NH 2

9

o 0 0 H 0 0 0 H 0 o NN N 0 N N N HH H H 00 NH, 0 NH 2

415 179244581 (GHMatters) P109779.AU

99 100 0

0 0 0

H 0 0 H 0 0 0 N N N 0 N N N H H H H

100

0 0 NH 00H

0- N ' H 0 N' H 0 H 0 H H H 0 HH 0N

NH 2 0 NH 2

0 0

N N N 0 H

0-~ 0 H0 0 N NH H0 NH 2

o H

0 H

o 0 0 H 0 0N 0 0 H C N N 0' H N N 0 : H H H

0 0 0

cr0 NH 2 0 NH 2

416 179244581 (GHMatters) P109779.AU

119 120 0

0 00 H 0 H 0

-~0 N N N 0 a N Nj N 0N N H H

0 NH 2 0 NH 2

12312

00

131 011H 132H

0 0

417,0 H

1792458(GHattes)P0T89.A

139 140

0 0

0 0

H 0

o 0

0 0 0

00

H0 0 418 17924581GH~ate~sP10979.I

159 160

00H

0SN H 0 N -e HH 0 0 N0 0 NH2

16316 H H N N 0 H 0 -N H 0 \ 0H N N SN H H H/ 0 N

0 NH 2 0 0 -) NH 2

00

00 00 -1 iH H0 0 / NH H -N- N 0 / -. N N 0 0 \ oN 0 \ i/j N 0

O NH2 0 NH2

0 00

S-N H)001 N 0

H: 0 N 0 NH 2

419 179244581 (GHMatters) P109779.AU

175 176 H N

0 H 0o~ N 0 -JH H N-' H 0H N N

0 NH

17918 H N N H 0 o -HH 0 00 H 0 0 0N NN 0 N rN H H H NH

00 NNH 2 00 NH 2

183U18 H H N

00

lj ,H 0 00 N H 00 N N H N N H H 0 H

00 NH 2 0 NH 2

18718 NH

00H 0 0 H 0 00 N N N H IN N HH H 0 00 NH 2 0 NH

420 179244581 (GHMatters) P109779.AU

191 192

0 NHH 0

0 N H N 070 N 0 H H H

0 NH 2

19519

a 0

H7 0 0

H N H H H N j0 H H 0 o NH, 0 NH2

203[20 0 0 0 0

0 H 00 o N- N 0N H aI 0 HN N 0 H 0H

N20 NH,

20730 00 00 0 0 0 HN H0N N N H N N HH H 0 0 0 NH 0 NHH

20742 8 17924581GH~ate~sP10979.0

211 212

0 0 0 0

o H 0 H 0 N NH0 N N N N H- H H 0 0 0 NH2 0r H

21521

0H 0 0 0 N NNHH H H 0 0 0 NH2

0 NH

0 0

H oI 0

'j422 17248(H -tes0 H7N9.AU

227 228

0

00

0H0 0 H H Hi 0 H N H H N 00 0 NH2

235 3

H N H 0 0HNN N 'NH 0 N1 N N H H H H 00 0 NH2 0 H

23954 0 0

H 00N 0

H 0 N N 0 0a N H N C N 0H H N: - ,H 0 H 0 NH 2

2423 1724810 0t~)1079A

243 244

0 0o 0 00 jN N HH HN)<: 00

0 NH2

24724

0 0

0 0

2424

19451Hates097090A0

259 260

00 00

H 0

0 0

26736

0 0 0 0

00

H 0 425 1794451HG Hte HP1977.H

275 276

00

H H0

0 0H

00

0 H

0 H

00

llH_-,426 1792458(GHattes)P0979.H

291 292

0 00

0 HN S-N H N H/ H NH 00 0 H20 NH 2

29950

H 0 H 0 0 11 H - l H S-N H 0 N 0 H- N N\H . / \0 N: N 0/ 0 H

0 NH 2 0 NH 2

H 0

0 1427 17248(Hat~10H779.AUo

307 308

0

0 0 0I

H H N S- N N N NN N 0/ 00 H 0 0H 0 h NH 2 0 NH,

31131

0

0 0 0

- s-H H N - N 0 - II H H 00 _ N: N 0H 0 0H

O NH 2 0 NH 2

31531

HN

0 0

0 N N H0 HHN NC H H 0 0 H 0 NH 2

31932

NH 0 0 H

N 7HO~k NNH N NN 0 H H HH 00

0 NH 2 0 NH

428 179244581 (GHMatters) P109779.AU

323 324 H N

NH 0

H 0 00 0 N H IN N H 0 H0 0 H 0L- NHH 0 H N, N 0 NH 2 00 H

32732 H N H N

0 0

0oI N H 0 0H 0 0 H N N N N N 0H H H 0 0 NH2 o NH 2

33132

NHN

o N N N H 0HkNH 0 0

0H 0 N H 0 N 2 HH 0 0 NH 2

429 179244581 (GHMatters) P109779.AU

335 336

0

0 0o Ho N N 0N o N H N H 0H H H0 0NH o NH 20 H

33934

00

0 0 0N H 0o N N H H HN N N HH 0 H 00 o NH, 0 NH2

343 4

00

00

o P 00

H 0 0I - N- N N H HH

0 0 NH 0 NH2 H

430 17924581GH~ate~sP10979.0

351 352

0 ~0"

0 0 q H 0 0 H0 N N N HH N N N 0H H 0H0 0 NH 2

0 NH 2

35535

0

00 H 0H 0 H 0 H N 0 N N_ N H H H H 00 o NH2 0 NH 2

359 360

0 HN o 0 IH - H 0 N HN_ J; N 0F 0 / a0 N -N 0 H H H 00 NH 2 0 0 NH 2

36336 H H NN

H 00 N- F 'H NH 0 0 O HH N N

0 NH 2 a NH,

431 179244581 (GHMatters) P109779.AU

367 368 0

00

H H F0 O 0 N N

H0 F NH 2 0 NH 2

- SIN j0 0 H 0 H 0 o NH2

H 0 0

N 0

0 S N NN 0 HH 00

0 NH 2

37958

00 H 00 o NN N H N 0

0 NH 2

3432

17248(H~tesP0 H0H

383 384

0 Ho

0

3433

172458(H~tt~s0979

395 396

H 0 0 0 NN N H H 0 00

H H

0 0 0H

0 0 H

0

H 0 0

H H

N H

HH ~ H 0 -N N

HN o0 N H 0 0 H 0 0 H N 0 N N N H 0 H HH

0 NH ' NH 2

4434 17924581GH~ate~sP10979NH

411 412 0 0 00

H 0 0 H H 0 -0 ' N N N NNN H H 0 0 cf " 0 H20 NH2

415 416j 0 0 0 0 0 H H HN 0 0 H N 0 N N N C HH HN

o NH 2 -. 0 NH 2

41942

00

423 4240H

SN 0 N N

4435

172458(H~tt~s0979

431 432

0 0- :

0 0

4436

19451HatesP0770A

447 448

H N H 0 - H 11I H N- H 0 S-N H 0 0

0 O 0 H 0I 0 H

0 NH 2 0 NH 2

45145

NH N 0 0 01 H 11 H - H H 0 0 / S-N- % H N 0 N 0

/~N) -N 0 H

oI NH 2 0 NH 2

0 0

45956

00 F 0 00 NN

0 H20 NH 2

4437

17248(H~tesP0770

463 464

0

-H H 0- H 0 0

0 11N lk ~ N 0 H 00 H 0 0 o NH 2 0 NH 2

46746 0

0 0 011H_ H 0 -H H N-N H S\1N N N: N

0 ~ H0 o0 0 NH 0 NH2

47147

0 0 _ H 0

1 N0 N-- H H

0~ 0 NH 2

47547

0 0

438 179244581 (GHMatters) P109779.AU

479 480

o HN

N H 0 0 H 0F \0/ N N) N O N N0 N \/ 0 H N 0 H HNH 0 0 H O NH 2

N H

0 iH o 0N

S: -N H 0

0 H --110FN -N

0 : NH 2 0 0 NH 2

L48748

0 0

0IH_- 0 - H -1IJ H 0 N) N SSN H H 0 F--op-N H O NHH O H NH 2

491 492

0 0 JI HH 0 Fk N N0

\2 b- H

0~~ 0H 2 \ 2

439 179244581 (GHMatters) P109779.AU

495 496

0

0 0

_j 0 -N H H 0 0. 0 N2 0 NH 2

50350

00

H 0

H H 0H 0 NH

44 1794481 0 0 0 01077.A

511 512

0 0

0 0

0 0 00

0 0

0441 172458H Hates)0077HA

527 528

O 0

N NH 0 H

HH NN

0 H0 0), 0 0 0 0

H H N N 0NN H 0 H HH

o NH 2 H

53954

00 0 0 0 H K-N N 0o H N H N N NIT H N N H

or NH 20NH

0 0

4H 0

O N N N O N -N N H H H H 0 0 2 NH 0 NH 2

543 44 17924581GH~ate~sP10979.0

547 548

H~K 0 0 0 H- N 0N 0 N0lH

00

55916

0 0

563 564H H

S--H H N 443 17245 1(Hats109779N.AU

567 568

0 0

0 H

57157

N'N N:'

N NH 0 0 H H

57958

0

-_ H 0 I N _ N HH 00 0 kN N) -N H HH H 0 NH 2 0 NH

58358 HNH NHNN

0 0H0

11 HN N 11 H H 0 0k H / S-N N N H %

0 NH2 0 H

0H NH

"_444 19451Hates)PN09H9.0

587 588

0

S-N H 0 0 NN N0 0 H0 H

0 NH,

59159

00

-~ H 0 -1 H_ H0 8 SH N N \/ IIN N0 0N H 0 H 0 0 0 NH2 0 NH 2

59950 00 0 0

11 ~H HN N 0 - - H H 0

0 / N)K~ HH 0 / N N H

0 0 o NH 2 0 NH 2

603 604

0 0 II 0

/ ON N 0 -0 H 0H 00 0 NH 20 H

603 445

172451GHa0 0P1979A

607 608 H N

01- H_- HH S-NN 1 H 0 HH N~~ NNHN H

0 H N N

HH

0 -H 00 H10 F/N N 0 - u CS-N' H 0 0 0 0 :: H F \/N,\_ N

o NH20 H

615 616

H

0 0 NH H 01 00 H-N FN-_ SNH N N) N 00H 0 0 H

0 NH2 0 NH 2

61962 0

00

0 0

oN)HN 0 NH

0 0 - 0 0 0 H 0HH0 H H

0 0

0H NH H H

446 179244581 (GHMatters) P109779.AU

627 628

0

HH

N0

0 NH,

63513

00

OIJI'N

0 0 0 0 NH2

63954

0 0 0 0 H H 0~ 0N -N 00 N N N 0 0 H H H 0 0 NH0 NH,

447c

192451G~tesP079A

643 644

0

HF N/ N

0

0 NH

0 oH

0 00

0 0

0 -0-4 8 1724810 0t~)1079A

663 664

H - -1 j H H 0

66768

H HH F0 000 0 /H 0NFHH

00

00 N 0N 00HH 0 NH2 0 NH 2

6449

19451HatesP09770A

683 684 H N H

- F NQH H

F /~-N H H H ~ 0 H00N / a N:C N 'o

00 NH 2 0 NH 2

68768

- 0-0 0 0 ItH H 0 IlH H \ / N N F / N 0 0H 0 H 0 o o NH 2 0 NH 2

69169 00 00

F -_/ "H H 0 N 0"_H H 0 N0 N N\ 11~ N 0H 0 0 H

o NH 2 0 NH- 2

69569

0450 172458HH Ht HP0979A

703 704

0H 0

H _I 0

0 H

00~

700

0 0

0 0

7451

172458(H~tt~s0979

719 720

H 0 0 0 HiS S N N 11 _H_-- H ki H k N N -N 'o 0

0 NH2 0 0 NH2

723

h 0 ZH 0 0 0 H H 'o 0 N H N N 0 S N N H N 0 0 H 0 0 NH2

0 NHz

727

11 S-_H_ 0 0 H 11 N N N 0 F /s,I I - N H N H N 10 0 H 0 H 0 0 NH 0 NH2

0 0 0 11 0 U H H S-N N 0 S,I--H N H 0 N N H H 0 0 0 l 0 NH2 0 NH2

0 0 0 H_ H 0 H__ H S H F ,!IN N 0 11 N) -N 0 0 H H 0 0 0 0 NH2 0 NH2

452 179244581 (GHMatters) P109779.AU

74 7440

0 0

H 0

0 N N _j453 172458 0 N NsP0979A

0 If 0 s H H li-- N N 0 N if 0 AH -- Hj 0 0 N 00 H 0 NH2

0 NH2

2

0 H 0 0 H 0 N: 0 N H -N H 0 H 0 0

0 NH, 0 NH2

SH

0 0 0 H H 0 F- lt F S,,---N N N 11 N N) -N 0 0 H 0 H 0 0 NH2 0 NH2

767 Ri 0 AH 0 QtN - N-11 CONR Hj 0 N 0 N N 0 R2, 0 H N (12 0 NH2

454 179244581 (GHMatters) P109779.AU

771 772

o NyN CONR 0CONR R2-j (0 R2~N. 0 017 (13

L775]77

O N RR NNR R

0

77978

0ON NC'ANR N~rr (15) (5

78378

R20 ONR R2 5CONR

R2~~N(I Y (15) 0

455 179244581 (GHMatters) P109779.AU

787 788

oONR N

(15)

00

ONR -ICONR

7456 R,077N.0 17924581(G0a0teN

803 804 Ri R

Q NRR t. 0 ,2N ) 1!7)(0R,,N(17)0 1)

0 0,

807 808 0 R. 0 R,

N "C0NR y N-JCN ~~ yr,.2 (N ( 18) (18)

811 1 o R 0 Rl R-'e N N 0 N1, N0 2 bN R'0 C0

(18) (1 8)

457 179244581 (GHMatters) P109779.AU

815 816

o R2 N S) \,--CONR NIS. -~C '(S) N (S)" (S) N(S) (19) 0 (19)

81982

R2 R2N Ne. S) N> ' N ~ ~ -CONR ,-CONR NS (S) (S)

() (19) 0 (19) 0

17248 (ates) PCONR N..(SA

827 828

RN SCONR R ~(S) N(S), Ni.. N S

(19) (S) o (19) 0

or a tautomer and/or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising any one of the compounds of claims 1-15 and a pharmaceutically acceptable excipient.

17. A kit comprising a composition including the compound of any one of claims 1-15 and instructions for use.

18. A method for treating fibrotic disease by decreasing the expression level and/or activity of a calpain, wherein the calpain is CAPN1, CAPN2, or CAPN3, comprising administration of an effective amount of a composition comprising a compound of any one of claims 1-15 to a subject in need thereof, wherein the fibrotic disease is liver fibrosis, lung fibrosis, or a combination thereof.

19. A method of treating a fibrotic disease, wherein the disease is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis,

459 179244581 (GHMatters) P109779.AU wherein the treatment decreases the expression level and/or activity of a calpain, wherein the calpain is CAPN1, CAPN2, or CAPN9, wherein the treatment inhibits myofibroblast differentiation, Fibroblast-to-Myofibroblast Transition (FMT), or Epithelial to Mesenchymal Transition or Endothelial to Mesenchymal Transition or treats a disease associated with myofibroblast differentiation, wherein the myofibroblast differentiation is a TGF-mediated myofibroblast differentiation, wherein the fibrotic disease is stiff skin syndrome (SKS) or a cancer of epithelial origin selected from the group consisting of breast cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, brain, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, prostate cancer, and renal cell carcinoma.

wherein the subject is a mammal or a human,

wherein the route of administration is selected from the group consisting of: enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal.

20. The method of claim 19, wherein the route of administration is intravenous.

21. A method of inhibiting myofibroblast differentiation comprising contacting a cell with a compound of any one of claims 1-15, wherein the cell is in a fibrotic tissue, a cancerous tissue, or a tissue with high TGFP signaling.

22. A method for inhibiting calpain, the method comprising contacting a compound of any one of claims 1-15 with a CAPN1, CAPN2, and/or CAPN9 enzyme residing inside a subject.

23. A method of competitive binding with calpastatin (CAST), the method comprising contacting a compound of any one of claims 1-15 with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject, wherein the compound specifically inhibits one or more of the enzymes selected from the group consisting of: CAPN1, CAPN2, and CAPN9 by at least one of the following values: i) 4-fold, and with at least an IC5 o value of 15 pM; ii) 10-fold, and with at least an IC 5 o value of 15 pM; or ii) 100-fold, and with at least an IC5 o value of 15 pM.

460 17924458_1 (GHMatters) P109779.AU

24. The use of a compound of any one of claims 1-15 for the manufacture of a medicament for treating fibrotic disease.

25. The use of a compound of any one of claims 1-15 for treating fibrotic disease.

26. A pharmaceutical composition comprising a therapeutic compound for treatment, prevention or reduction of a symptom of a fibrotic disease or a fibrotic condition, wherein the therapeutic compound is a calpain modulator present in the composition in an amount effective to alter the fibrotic state of at least one tissue in a human subject to whom the composition is administered and wherein the therapeutic compound is a compound comprising Formula I:

Wn , R3 A 2 L4 R2- R R4 2 N4 R2 A R2 R R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of:0 and S;

A

NR1

each R4 is R1

each Wand R 3 is independently selected from the group consisting of: hydrogen, CI C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted C1-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C10 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C 9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR2 , SR 2, substituted sulfonyl, and substituted sulfinyl, wherein any R' substituent may be covalently bonded to or

461 17924458_1 (GHMatters) P109779.AU share another R' substituent to form a C3-C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C cycloalkyl, substitutedC3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form aC3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2

, 0, NH, NR 2 , C(=O), C(=S), S, S(=), S(=0) 2 , -C-,-CH-, a C3-C1 2 spirocyclic group R2-(R 2)m

of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form aC3-C 12 cycloalkyl ring structure, a C3-C1 2 fused cycloalkyl ring structure, aC3-C 1 2 aryl ring structure, a C3-C 12 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, aC3-C 1 2 fused heteroaryl ring structure, a C3-C 1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure;

and wherein Wn does not form an (S) -- CH 2CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof.

462 17924458_1 (GHMatters) P109779.AU

27. The pharmaceutical composition of claim 26 wherein the therapeutic compound is a selective calpain modulator,

wherein the selective calpain modulator, is selected from a specific calpain-9 modulator, a selective calpain-9 modulator, a selective calpain-9 and calpain-1 modulator, a selective calpain-9 and calpain-2 modulator, or a selective calpain-9, calpain-2 modulator, and calpain 1 modulator,

wherein the calpain modulator decreases the expression level and/or activity of calpain-9 in a fibrotic tissue when administered to the subject.

wherein an alteration of the fibrotic state of at least one tissue comprises one or more of the following: a reduction or reversal of growth of a fibrous tissue, a reduction in fibrogenesis a reduction or halting of a fibroproliferative state, a reduction in a migration of a fibroblasts or a fibroblast precursor, a reduction in extracellular matrix deposition, a reduction infibroblast proliferation, a reduction in fibroblast accumulation, a reduction in mesenchymal transition, a reduction in myofibroblast accumulation, a reduction in migration offibroblasts, a reduction in migration of myofibroblasts, a reduction in cytokine production, a reduction in growth factor production, a preservation of organ function from progressive decline associated with the fibrotic disease or fibrotic condition a reversal of the fibrosis, a restoration of physiological organ function to a pre-fibrotic state, a reduction in accumulation offibrotic matrix in a tumor environment, a reduction in cancer growth or tumor burden, an induction of cancer cell senescence, an induction of apoptosis of cancer cells, an enhancement of cancer cell apoptosis, an induction of cancer cell death, an inhibition of angiogenesis, or an inhibition of metastases,

wherein the fibrotic disease is a disease selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, ischemic-reperfusion injury, interstitial fibrosis, systemic scleroderma, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, macular degeneration, pancreatic fibrosis, fibrosis of organ transplant recipients, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, injection fibrosis,

463 17924458_1 (GHMatters) P109779.AU cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, stiff skin syndrome, and rheumatoid arthritis; or the fibrotic disease is selected from the group consisting of sarcoma, adenoma, breast cancer, basal cell carcinoma, leiomyoma, neurofibroma, fibroadenoma, glioma, astrocytoma, ependymoma meningioma, neuroma, islet cell tumor, gastrinoma, glucagonoma, VIPoma, somatostatinoma, plasma cell tumor, transitional cell tumor, intramedullary and extramedullary tumor, schwannoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, brain, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, skin cancer, prostate cancer, and renal cell carcinoma.

28. A method for the treatment, prevention or reduction of a symptom of a fibrotic, sclerotic or post inflammatory disease or condition comprising the step of administering to a human subject in need thereof a pharmaceutical composition comprising a therapeutic compound, wherein the therapeutic compound is a calpain modulator present in the composition in an amount effective to alter the fibrotic, sclerotic or post-inflammatory state of at least one tissue in the human subject and wherein the therapeutic compound is a compound comprising Formula I:

'' Wn , R3 A 2 4 R R R4 2 N4 R2 A R2 R R2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of:0 and S;

A

NR1

each R4 is R1

464 17924458_1 (GHMatters) P109779.AU each Rand R 3 is independently selected from the group consisting of: hydrogen, C1 C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C alkynyl, substituted C1-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C0 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3 C9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR 2 , SR 2 , substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R1 substituent to form aC3-C 1 2cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, C-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C0 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form aC3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system; each W is independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2

, 0, NH, NR 2 , C(=O), C(=S), S, S(=), S(=0) 2 , -C-,-CH-, a C3-C1 2 spirocyclic group R2-(R2)m

of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form aC3-C 12 cycloalkyl ring structure, a C3-C1 2 fused cycloalkyl ring structure, aC3-C 1 2 aryl ring structure, a C3-C 12 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, aC3-C 1 2 fused heteroaryl

465 17924458_1 (GHMatters) P109779.AU ring structure, a C3-C1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure; and wherein Wn does not form an (S)-- CH 2CH 2 C(O)NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group; and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein the therapeutic compound is a selective calpain modulator selected from a specific calpain-9 modulator, a selective calpain-9 modulator, a selective calpain-9 and calpain-1 modulator, a selective calpain-9 and calpain-2 modulator, or a selective calpain-9, calpain-2 modulator, and calpain-1 modulator.

29. Use of a therapeutic compound comprising Formula I:

'' Wn , R3 A 2 N>N L4R 2 R R4 2 R A R2 RR2 A

Formula I

where:

n is from 1-12;

each A is independently selected from the group consisting of:0 and S;

A

NR1

each R4 is R1

each Wand R 3 is independently selected from the group consisting of: hydrogen, CI C 8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C-C8 alkenyl, C-C alkynyl, substituted C-C8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, C3-Cio cycloalkyl, substituted C3-C10 cycloalkyl, C3-Co heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3

466 17924458_1 (GHMatters) P109779.AU

C9 heteroaryl, substituted C3-C9 heteroaryl, CI-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2 , NH 2 , NHR 2 , SR 2 , substituted sulfonyl, and substituted sulfinyl, wherein any R 1 substituent may be covalently bonded to or share another R1 substituent to form a C3-C 12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each R2 is independently selected from the group consisting of: hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, CI-C8 alkenyl, substituted C1-C8 alkenyl, Ci-C8 alkynyl, substituted Ci-C 8 alkynyl, C3-C 7 aryl, substituted C3-C 7 aryl, cyano, OH, Ci-C8 alkoxy, substituted Ci-C alkoxy, amino, substituted amino, C3-C cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form aC3-C 1 2 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;

each W is independently selected from the group consisting of: CH 2 , C(R 2 ) 2 , CHR 2

, 0, NH, NR 2 , C(=O), C(=S), S, S(=O), S(=0) 2 , -C-,-CH-, a C3-C1 2 spirocyclic group R2-(R2)m

of where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR=CR' or C--C;

L 4 is selected from the group consisting of: R2, acyl, acylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, -CO-ethylene glycol, -CO polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;

and wherein any two or more W groups can be bonded together to form aC3-C 12 cycloalkyl ring structure, a C3-C1 2 fused cycloalkyl ring structure, aC3-C 1 2 aryl ring structure, a C3-C 12 fused aryl ring structure, a C3-C1 2 heteroaryl ring structure, aC3-C 1 2 fused heteroaryl ring structure, a C3-C 1 2 heterocyclic ring structure, and a C3-C1 2 fused heterocyclic ring structure;

and wherein Wn does not form an (S) -- CH 2CH 2 C()NH- group in the ring starting from the carbon attached to R2 which is adjacent to the keto-amide or thioketo-amide functional group;

467 17924458_1 (GHMatters) P109779.AU and wherein ----- is a single bond; or a tautomer and/or a pharmaceutically acceptable salt thereof, wherein the therapeutic compound is a selective calpain modulator selected from a specific calpain-9 modulator, a selective calpain-9 modulator, a selective calpain-9 and calpain-1 modulator, a selective calpain-9 and calpain-2 modulator, or a selective calpain-9, calpain-2 modulator, and calpain-1 modulator, in the manufacture of a medicament for the treatment, prevention or reduction of a symptom of a fibrotic, sclerotic or post inflammatory disease or condition.

468 17924458_1 (GHMatters) P109779.AU