Indazole derivatives as modulators of interleukin-1 receptor-associated kinase

1. A compound of Formula (I)

wherein:

R 1 is an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

R 2 is H, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

each of a, a′, b, and c is independently N or C(R 3 );

each of R 3 , R 5 , and R 6 is independently H, an optionally substituted aliphatic, an optionally substituted alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, sulfanyl, sulfinyl, sulfonyl, sulfonamide, amido, sulfamide, urea, thiourea, carbamoyl, cycloaliphatic, cycloalkyloxy, heterocycloaliphatic, heterocycloalkyloxy, aryl, aralkyl, aryloxy, aroyl, heteroaryl, heteroaralkyl, heteroaryloxy, or heteroaroyl;

R 4 is H;

K is —N(R X′ )—;

J is a bond, —O—, —S(O) i —, —N(R X′ )—, alkylene, —C(O)—, —C(O)—O—, —C(O)—N(R X′ )—, —(CH 2 ) p N(R X′ )—, or —N(R X′ )—C(O)—;

R X′ is independently H or an optionally substituted aliphatic;

n is 0, 1, 2, or 3;

i is 0, 1, or 2;

p is 1, 2, 3, or 4; and

provided that when R 1 is an unsubstituted alkyl and J is —O—, then R 2 is H, an optionally substituted aliphatic, an optionally substituted aryl, or an unsubstituted heteroaryl.

2. The compound of claim 1 , wherein R X′ is H.

3. The compound of claim 1 , wherein R 1 is an optionally substituted aliphatic, or an optionally substituted cycloaliphatic.

4. The compound of claim 3 , wherein R 1 is alkyl optionally substituted with halo, amino, amido, hydroxyl, or alkoxy; or R 1 is a cycloalkyl optionally substituted with: hydroxyl, halo, amido, amino, alkoxy, cyano, carboxy, optionally substituted aliphatic, optionally substituted cycloaliphatic, or optionally substituted heterocycloaliphatic.

5. The compound of claim 4 , wherein R 1 is an optionally substituted bicycloaliphatic.

6. The compound of claim 1 , wherein R 1 is an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.

7. The compound of claim 1 , wherein J is a bond, —O—, —N(R X′ )—, alkylene, —C(O)—, —C(O)—O—, —C(O)—N(R X′ )—, —(CH 2 ) p —N(R X′ )—, or —N(R X′ )—C(O)—.

8. The compound of claim 7 , wherein J is —C(O)—, —CH 2 —, a bond, or an alkylene.

9. The compound of claim 1 , wherein R 2 -J- is H, HO—CH 2 —, ((((pyridin-4-yl)ethyl)piperazin-1-yl)methyl)-, CH 3 CH 2 O—C(O)—, morpholinomethyl, cyclopentylaminocarbonyl, isopentylaminocarbonyl, piperidinylmethyl, or pyrolidinecarbonyl.

10. The compound of claim 1 , wherein R 5 is an optionally substituted aryl or an optionally substituted heteroaryl.

11. The compound of claim 10 , wherein R 5 is a heteroaryl optionally substituted with 1 to 3 alkyl, alkoxy, amino, carboxy, amido, halo or cyano; or R 5 is an aryl optionally substituted with alkyl, alkoxy, amino, halo, or cyano.

12. The compound of claim 11 , wherein R 5 is pyridyl optionally substituted with alkyl, alkoxy, amino, amido, halo, or cyano; or R 5 is phenyl optionally substituted with alkyl, alkoxy, amino, halo, or cyano.

13. The compound of claim 12 , wherein R 5 is (4-methoxy)pyridin-3-yl, 3-methoxymethylphenyl, 2-methoxyphenyl, or 2-trifluoromethoxyphenyl.

14. The compound of claim 1 , wherein R 5 is bromo, H, or phenyl substituted with —N(R X′ )( R Y′ ), —N(R X′ )—C(O)—R Y′ , or —N(R X′ )—S(O) 2 —R Y′ , wherein R Y′ is independently H or an optionally substituted aliphatic.

15. The compound of claim 14 , wherein R 5 is 3-aminophenyl.

16. The compound of claim 1 , wherein n is 0 or n is 1.

17. The compound of claim 1 , wherein each of a, a′, b, and c is independently CR 3 .

18. The compound of claim 17 , wherein R 3 is H.

19. The compound of claim 1 , wherein one or two of a, a′, b, and c are N.

20. The compound of claim 1 , wherein R 1 is a cycloaliphatic optionally substituted with hydroxy; J is —CH 2 —, —C(O)—, or —CH 2 —N(R X′ )—; R 5 is optionally substituted phenyl or pyridyl; each of a, a′, b, and c is independently CH; and n is 0.

21. The compound of claim 20 , wherein J is —CH 2 —; and R 2 is an optionally substituted heterocycle containing at least one N attached to J.

22. The compound of claim 1 , wherein R 1 is aliphatic optionally substituted with hydroxy; R 2 J- is H; R 5 is H or halo; each of a, a′, b, and c is independently CH; and n is 0.

23. The compound of claim 1 , wherein K is —NH—; R 1 is an alkyl or cyclohexyl, optionally substituted with hydroxy; J is a bond or —CH 2 —; R 2 is alkyl, cycloalkyl, or heterocycloalkyl; R 5 is heteroaryl or amino phenyl; and n is 0.

24. The compound of claim 1 , wherein the compound is:

(2-(5-(3-aminophenyl)-1H-indazol-3-ylamino)-1-cyclohexyl-1H-benzo[d]imidazol-6-yl)methanol;

(1-cyclohexyl-2-(5-(3-(methoxymethyl)phenyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-5-yl)methanol;

4-(2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-5((4-(2-(pyridin-4-yl)ethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanol;

ethyl 1-((2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylate;

(2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1-phenyl-1H-benzo[d]imidazol-5-yl)methanol;

N-(1-cyclohexyl-5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(4-methoxypyridin-3-yl)-1H-indazol-3-amine;

2-(5-(2-methoxyphenyl)-1H-indazol-3-ylamino)-N-cyclopentyl-1-(4-hydroxycyclohexyl)-1H-benzo[d]imidazole-5-carboxamide;

1-(4-hydroxycyclohexyl)-N-isopentyl-2-(5-(2-methoxyphenyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carboxamide;

(1-(4-hydroxycyclohexyl)-2-(5-(2-methoxyphenyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-5-yl)(pyrrolidin-1-yl)methanone;

N-cyclopentyl-1-(4-hydroxycyclohexyl)-2-(5-(2-(trifluoromethoxy)phenyl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carboxamide;

2-(5-(2-(trifluoromethoxy)phenyl)-1H-indazol-3-ylamino)-1-(4-hydroxycyclohexyl)-N-isopentyl-1H-benzo[d]imidazole-5-carboxamide;

ethyl 1-(4-hydroxycyclohexyl)-2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazole-5-carboxylate;

4-(5-(hydroxymethyl)-2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-1-yl)cyclohexanol;

(1-cyclohexyl-2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-5-yl)methanol;

N-(1-cyclohexyl-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-5-(4-methoxypyridin-3-yl)-1H-indazol-3-amine;

3-(2-(5-(4-methoxypyridin-3-yl)-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-1-yl)propan-1-ol; or

3-(2-(5-bromo-1H-indazol-3-ylamino)-1H-benzo[d]imidazol-1-yl)propan-1-ol.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 .

26. A method of treating rheumatoid arthritis or osteoarthritis in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of claim 1 .

27. The method of claim 26 , wherein said compound is administered in combination with a therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, a COX-2 inhibitor, hydroxychloroquine, cyclosporine A, D-penicillamine, infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazine analogs, mesalamine, corticosteroids, corticosteroid analogs, 6-mercaptopurine, cyclosporine A, methotrextate and infliximab, interferon beta-1 beta, interferon beta-1 alpha, azathioprine, glatiramer acetate, a glucocorticoid, and cyclophosphamide.