Calpain modulators and therapeutic uses thereof

1. A compound having the structure of formula:

or a pharmaceutically acceptable salt thereof, wherein:

A 2 is a single bond;

A 4 is a single bond;

A 3 is directly attached to the ring-atom to which A 2 is attached;

A 3 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3-10 carbocyclyl;

A 5 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 1-8 alkyl, —S—, —S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;

A 6 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkenyl, optionally substituted —O—C 1-6 alkyl, optionally substituted —OC 2-6 alkenyl, —OSO 2 CF 3 , and any natural or non-natural amino acid side chain;

A 7 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 1-8 alkyl, —S—, S(═O)—, —SO 2 —, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;

when A 5 and A 7 are single bond, A 6 is directly attached to the carbon to which —COR 1 is attached;

R 1 is selected from the group consisting of H, —COOH, —CH 2 NO 2 , —C(═O)NOR, —CONR 2 R 3 , —CH(CH 3 )═CH 2 , —CH(CF 3 )NR 2 R 3 , —C(F)═CHCH 2 CH 3 ,

R 14 is halo;

each R, R 2 , and R 3 are independently selected from —H, optionally substituted C 1-4 alkyl, optionally substituted C 1-8 alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C 3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aryl(C 1 -C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl;

R 6 is independently selected from —H and optionally substituted C 1-4 alkyl;

X and Z are each independently selected from the group consisting of C(R 4 ) and N;

each R 4 is independently selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), halo, hydroxy, and C 1 -C 6 alkoxy;

Y is selected from the group consisting of NR 5 , O, S, and SO 2 ; and

R 5 is selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy).

2. The compound of claim 1 , wherein:

A 6 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 1-8 alkyl, optionally substituted —O—C 1-6 alkyl, optionally substituted —OC 2-6 alkenyl, and any natural or non-natural amino acid side chain; and

each R, R 2 , and R 3 are independently selected from —H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl.

3. The compound of claim 1 , wherein X and Z are independently selected from the group consisting of CH and N.

4. The compound of claim 1 , wherein X is CH, Z is N, and Y is NR 5 .

5. The compound of claim 1 , wherein X is N, Z is C(R 4 ), and Y is O.

6. The compound of claim 5 , wherein R 4 is selected from —H and C 1-4 alkyl.

7. The compound of claim 1 , wherein X is N, Z is C(R 4 ), and Y is S.

8. The compound of claim 1 , wherein X is N, Z is N, and Y is S.

9. The compound of claim 1 , wherein A 3 is substituted with 18 F.

10. The compound of claim 1 , wherein A 3 is substituted with C 1 -C 6 alkyl containing one or more 11 C.

11. The compound of claim 1 , wherein A 3 is selected from the group consisting of

and

A 9 is selected from the group consisting of H, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 3-10 carbocyclyl, and C 1-4 alkyl;

X 2 , X 1 , and Z are each independently selected from the group consisting of C(R 4 ) and N;

Y 1 is selected from the group consisting of NR 5 , O, and S;

J, L, M 1 and M 2 are each independently selected from the group consisting of C(R 4 ) and N;

R 4 is selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), halo, hydroxy, and C 1 -C 6 alkoxy;

R 5 is selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy).

12. The compound of claim 1 , wherein A 3 is selected from the group consisting of

13. The compound of claim 1 , wherein A 3 is selected from the group consisting of

14. The compound of claim 1 , wherein A 3 is an optionally substituted C 6-10 aryl or an optionally substituted 5-10 membered heteroaryl.

15. The compound of claim 14 , wherein A 3 has the structure:

wherein

J, L, M 1 , M 2 , and M 3 are each independently selected from the group consisting of C(R 4 ) and N; and

each R 4 is independently selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), halo, hydroxy, and C 1 -C 6 alkoxy.

16. The compound of claim 15 , wherein each of J, L, M 1 , M 2 , and M 3 are C(R 4 ).

17. The compound of claim 16 , wherein each R 4 is independently selected from —H and halo.

18. The compound of claim 15 , wherein M 1 is C(R 4 ); R 4 is halo and each of J, L, M 2 , and M 3 are CH.

19. The compound of claim 15 , wherein L is C(R 4 ); R 4 is halo and each of J, M 1 , M 2 , and M 3 are CH.

20. The compound of claim 14 , wherein A 3 has a structure selected from the group consisting of:

wherein

J, L, M 1 , M 2 , M 3 , M 4 , and M 5 are each independently selected from the group consisting of C(R 4 ) and N; and

each R 4 is independently selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), halo, hydroxy, and C 1 -C 6 alkoxy.

21. The compound of claim 14 , wherein A 3 has the structure:

wherein

X is selected from the group consisting of C(R 4 ) and N;

Y is selected from O and S; and

R 4 is selected from the group consisting of —H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), halo, hydroxy, and C 1 -C 6 alkoxy.

22. The compound of claim 1 , wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6 is substituted with 18 F.

23. The compound of claim 1 , wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6 is substituted with C 1 -C 6 alkyl containing one or more 11 C.

24. The compound of claim 1 , wherein A 6 is phenyl.

25. The compound of claim 1 , wherein A 7 is selected from the group consisting of single bond, —CH 2 —, O, —CH═CH—, and —S.

26. The compound of claim 1 , wherein A 7 is selected from the group consisting of single bond, optionally substituted C 6-10 aryl, and phenyl.

27. The compound of claim 1 , wherein A 5 is —CH 2 —.

28. The compound of claim 1 , wherein A 5 is —CH 2 — or —CH 2 CH 2 —; A 7 is a single bond; and A 6 is selected from the group consisting of C 1 -C 4 alkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl.

29. The compound of claim 28 , wherein A 6 is selected from the group consisting of optionally substituted phenyl, phenyl and phenyl optionally substituted with one or more C 1-4 alkyl, C 3-7 carbocyclyl, halo, hydroxy, and C 1 -C 6 alkoxy.

30. The compound of claim 28 , wherein A 6 has the structure:

31. The compound of claim 1 , wherein A 5 is a single bond, A 7 is a single bond; and A 6 is C 1 -C 5 alkyl.

32. The compound of claim 31 , wherein A 6 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2-dimethylpropyl.

33. The compound of claim 1 , wherein R 1 is CONR 2 R 3 .

34. The compound of claim 33 , wherein R 2 is —H and R 3 is optionally substituted C 1-4 alkyl.

35. The compound of claim 33 , wherein R 2 is —H and R 3 is selected from the group consisting of —H, C 1 -C 4 alkyl optionally substituted with C-amido, and C 3 -C 6 cycloalkyl.

36. The compound of claim 35 , wherein R 3 is selected from the group consisting of —H, ethyl, cyclopropyl, and methyl substituted with C-amido.

37. The compound of claim 33 , wherein R 3 is selected from the group consisting of optionally substituted C 1-4 alkyl and benzyl.

38. The compound of claim 1 , wherein R 6 is selected from the group consisting of —H, methyl, and optionally substituted C 1-4 alkyl.

39. A compound having the structure selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

40. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

41. A method of treating fibrotic disease comprising administering to a subject in need thereof, a compound according to claim 1 .

42. The method of claim 41 , 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.

43. A compound having the structure selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

44. A compound having the structure selected from the group consisting of:

and pharmaceutically acceptable salts thereof.