Apoptosis signal-regulating kinase 1 inhibitors

1. A method for treating a disease in a subject, the method comprising administering to the subject a compound of the formula:

a stereoisomer thereof or a pharmaceutically acceptable salt of the compound or stereoisomer, wherein

m is 0, 1 , or 2;

R 0 is selected from the group consisting of

in which * represents a point of attachment;

each R is independently selected from the group consisting of hydroxy, nitro, halo, cyano, (C 1-6 )alkoxy, (C 1-6 )alkyl, amino(C 1-6 )alkyl, and halo(C 1-6 )alkyl, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, (C 1-6 )alkoxy, halo(C 1-6 )alkoxy, amino, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, halo(C 1-6 )alkyl, perhalo(C 1-6 )alkyl, amino(C 1-6 )alkyl, hydroxy(C 1-6 )alkoxy, halo(C 1-6 )alkoxy, perhalo(C 1-6 )alkoxy, R 9 -carbonyl(C 1-6 )alkyl, R 9 -sulfonyl(C 1-6 )alkyl, R 9 -carbonyl, and R 9 -sulfonyl;

R 1 is selected from the group consisting of cyano, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 3-6 )cycloalkyl, and sulfonyl, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, cyano, amino, carbonylamino, sulfonylamino, (C 3-6 )cycloalkyl, oxycarbonyl, hydroxycarbonyl, aminocarbonyl, sulfonyl, aminosulfonyl, wherein the amino, carbonylamino, sulfonylamino, oxycarbonyl, aminocarbonyl, sulfonyl, and aminosulfonyl are each unsubstituted or further substituted with 1-2 substituents independently selected from the group consisting of (C 1-6 )alkyl, halo(C 1-6 )alkyl, perhalo(C 1-6 )alkyl, and (C 3-6 )cycloalkyl;

R 2 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C 1-6 )alkoxy, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl, (C 1-6 )alkyl, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, carbonyl(C 1-6 )alkyl, thiocarbonyl(C 1-6 )alkyl, sulfonyl(C 1-6 )alkyl, and sulfinyl(C 1-6 )alkyl, each unsubstituted or substituted with 1-3substituents independently selected from the group consisting of hydroxy, unsubstituted amino, mono-substituted amino, di-substituted amino, (C 1-6 )alkyl, and halo(C 1-6 )alkyl;

R 3 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C 1-6 )alkoxy, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl, (C 1-6 )alkyl, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, carbonyl(C 1-6 )alkyl, thiocarbonyl(C 1-6 )alkyl, sulfonyl(C 1-6 )alkyl, and sulfinyl(C 1-6 )alkyl, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, (C 1-6 )alkyl, halo(C 1-6 )alkyl, and perhalo(C 1-6 )alkyl;

R 4 is selected from the group consisting of hydroxy, unsubstituted amino, (C 1-6 )alkylamino, (di-(C 1-6 )alkyl)amino, (C 1-6 )alkoxy, and (C 1-6 )alkyl;

R 8 is —(CR 23 R 23 ′) p OH;

R 9 is selected from the group consisting of hydroxy, unsubstituted amino, (C 1-6 )alkylamino, (di-(C 1-6 )alkyl)amino, (C 1-6 )alkoxy, and (C 1-6 )alkyl;

R 10 is selected from the group consisting of hydroxy, unsubstituted amino, (C 1-6 )alkylamino, (di-(C 1-6 )alkyl)amino, (C 1-6 )alkoxy, and (C 1-6 )alkyl;

R 21 is selected from the group consisting of —C(R 23 ) 3 , —(CR 23 R 23′ ) p —C(R 23 ) 3 , —(CR 23 R 23′ ) p OH, —(CR 23 R 23′ ) p C(O)R 10 , —(CR 23 R 23′ ) p S(O) 2 R 10 , and —O(CR 23 R 23′ ) p OH;

R 22 is selected from the group consisting of hydrogen, (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl and halo(C 1-6 )alkyl;

R 23 and R 23′ are each independently selected from the group consisting of hydrogen, halo, hydroxy, and (C 1-6 )alkyl;

k is 1, 2, 3, or 4;

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

q is 1, 2, 3 or 4;

wherein the disease is congestive heart failure.

2. The method according to claim 1 , wherein the compound has the formula:

is a stereoisomer thereof or a pharmaceutically acceptable salt of the compound or stereoisomer.

3. The method according to claim 1 , wherein

each R is independently selected from the group consisting of hydroxy, nitro, halo, cyano, (C 1-6 )alkoxy, —OCHF 2 , —OCF 3 , (C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, —CHF 2 , —CF 3 , —C(CH 3 )(OH)CF 3 , —CH 2 OCH 2 CF 3 , —C(O)OCH 3 , —OCH(CH 3 ) 2 , amino(C 1-6 )alkyl, hydroxycarbonylamino(C 1-6 )alkyl, (C 1-6 )alkoxycarbonylamino(C 1-6 )alkyl, and (C 1-6 )alkylcarbonylamino(C 1-6 )alkyl.

4. The method according to claim 1 , wherein R 1 is selected from the group consisting of (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-6 )alkyl, and (C 1-6 )alkylsulfonyl(C 1-6 )alkyl, each unsubstituted or mono- or di-(C 1-6 )alkyl substituted.

5. The method according to claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclopropylmethyl, and methylsulfonylmethyl.

6. The method according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, hydroxy, halo, cyano, (C 1-6 )alkyl, (C 2-6 )alkenyl, hydroxy(C 1-6 )alkyl, hydroxy(C 2-6 )alkenyl, dihydroxy(C 1-6 )alkyl, (C 1-6 )alkylsulfonyl, hydroxycarbonyl(C 1-6 )alkyl, aminocarbonyl(C 1-6 )alkyl, hydroxysulfonyl(C 1-6 )alkyl, and aminosulfonyl(C 1-6 )alkyl, wherein the amino of aminocarbonyl(C 1-6 )alkyl and aminosulfonyl(C 1-6 )alkyl are each unsubstituted, or mono- or di-(C 1-6 )alkyl substituted.

7. The method according to claim 1 , wherein R 2 is halo or hydrogen.

8. The method according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, halo, and (C 1-6 )alkyl.

9. The method according to claim 1 , wherein R 3 is selected from the group consisting of chloro, bromo, and methyl.

10. The method according to claim 1 , wherein R 4 is selected from the group consisting of hydroxy, (C 1-6 )alkyl, unsubstituted amino, (C 1-6 )alkylamino, and (di-(C 1-6 )alkyl)amino.

11. The method according to claim 1 , wherein R 21 is selected from the group consisting of (C 1-6 )alkyl and hydroxy(C 1-6 )alkyl.

12. The method according to claim 1 , wherein R 21 is selected from the group consisting of methyl, —CH 2 OH, and —CH 2 CH 2 OH.

13. The method according to claim 1 , wherein R 21 is hydroxymethyl.

14. The method according to claim 1 , wherein R 22 is selected from the group consisting of (C 1-3 )alkyl and hydroxy(C 1-3 )alkyl.

15. The method according to claim 1 , wherein R 22 is selected from the group consisting of hydrogen, methyl, and CF 3 .

16. The method according to claim 1 , wherein R 21 is selected from the group consisting of methyl, —CH 2 OH, and —CH 2 CH 2 OH, and R 22 is selected from the group consisting of hydrogen, methyl, and CF 3 .

17. The method to claim 1 , wherein the compound is selected from the group of compounds consisting of:

N-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(3-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide;

(R)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

N-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(R)-N-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide;

N-(1,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(R)-N-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide;

(R)-N-(3-bromo-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-N-(3-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(2,3-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(S)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-3-methylbenzamide;

N-(3-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;

(S)-N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(S)-N-(2,3-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-N-(2,3-dichloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide;

(R)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)-3-methylbenzamide;

a stereoisomer of any one of the aforementioned compounds; and

a pharmaceutically acceptable salt of any one of the aforementioned compounds or stereoisomer.

18. The method according to claim 1 , wherein the compound is a single stereoisomer.

19. The method according to claim 1 , wherein the compound is N-(3-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

20. The method according to claim 1 , wherein the compound is N-(1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

21. The method according to claim 1 , wherein the compound is (R)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

22. The method according to claim 1 , wherein the compound is (R)-N-(3-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

23. The method according to claim 1 , wherein the compound is (S)-N-(3-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

24. The method according to claim 1 , wherein the compound is N-(3-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.