Apoptosis signal-regulating kinase 1 inhibitors
The present invention relates to apoptosis signal-regulating kinase 1 (“ASK1”) inhibiting compounds of the formula wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
N a denotes a nitrogen atom;
ring A is selected from the group consisting of (C 3-12 )alicyclyl, hetero(C 3-12 )alicyclyl, (C 7-12 )bicycloalicyclyl, hetero(C 3-11 )bicycloalicyclyl, (C 4-12 )aryl, hetero(C 1-11 )aryl, (C 7-12 )bicycloaryl, and hetero(C 1-11 )bicycloaryl, each unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of hydroxyl, oxo, halo, cyano, (C 1-6 )alkyl, (C 1-6 )alkenyl, (C 1-6 )alkynyl, halo(C 1-6 )alkyl, (C 1-6 )alkylcarbonylamino, (C 1-6 )alkylaminocarbonyl, (C 1-6 )alkoxy, amino, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkylcarbonyl, aminocarbonyl, hydroxylcarbonyl, and (C 1-6 )alkylsulfonyl, each unsubstituted or substituted;
X is selected from the group consisting of CR 3 and N;
R 1 is —C(O)-ring B; wherein
ring B is selected from the group consisting of phenyl, a five-membered heteroaryl which contains up to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and a six-membered heteroaryl which contains up to four nitrogen atoms, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halo, nitro, cyano, thio, mercapto, oxy, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido, carbamoyl, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, sulfamoyl, (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 1-10 )alkynyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, (C 1-10 )oxaalkyl, (C 1-10 )oxoalkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )alicyclyl, hetero(C 3-12 )alicyclyl, (C 8-12 )bicycloalicyclyl, hetero(C 3-11 )bicycloalicyclyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl, and hetero(C 4-12 )bicycloaryl, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen, (C 1-6 )alkoxy, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, (C 1-6 )alkyl, (C 1-6 )alkenyl, (C 1-6 )alkynyl, hetero(C 1-6 )alkyl, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, carbonyl(C 1-6 )alkyl, (C 3-6 )cycloalkyl(C 1-3 )alkyl, hetero(C 1-5 )cycloalkyl(C 1-3 )alkyl, (C 3-6 )alicyclyl, hetero(C 1-5 )alicyclyl, each substituted or unsubstituted; and
R 3 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, carbonylamino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 1-10 )alkynyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, (C 1-10 )oxaalkyl, (C 1-10 )oxoalkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )alicyclyl, hetero(C 3-12 )alicyclyl, (C 8-12 )bicycloalicyclyl, hetero(C 3-11 )bicycloalicyclyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.
2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is a five-membered heteroaryl containing up to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and where the heteroaryl is unsubstituted or substituted with said 1-3 substituents of ring B.
3. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, each unsubstituted or substituted with said 1-3 substituents of ring B.
4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is a thienyl, unsubstituted or substituted with said 1-3 substituents of ring B.
5. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is a six-membered heteroaryl, which contains up to four nitrogen atoms, and is unsubstituted or substituted with said 1-3 substituents of ring B.
6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, each unsubstituted or substituted with said 1-3 substituents of ring B.
7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is phenyl, unsubstituted or substituted with said 1-3 substituents of ring B.
8. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is pyridinyl, unsubstituted or substituted with said 1-3 substituents of ring B.
9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-3 substituents of ring B is independently selected from the group consisting of halo, nitro, oxy, hydroxy, (C 1-6 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, (C 1-6 )alkyl, (C 1-6 )alkenyl, (C 1-6 )alkynyl, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, aza(C 1-6 )alkyl, oxa(C 1-6 )alkyl, oxo(C 1-6 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-6 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-5 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 3-7 )alicyclyl, hetero(C 3-7 )alicyclyl, (C 4-12 )aryl, and hetero(C 1-10 )aryl, each unsubstituted or substituted.
10. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-3 substituents of ring B is independently selected from the group consisting of halo, hydroxyl, nitro, thio, cyano, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, halo(C 1-6 )alkyl, (C 1-6 )alkoxy, hydroxyl(C 1-6 )alkyl, mercapto, sulfinyl, sulfonyl, sulfamoyl, amino, amido, carboxyamido, carbamoyl, carbonyl and carbonyloxy, each unsubstituted or substituted.
11. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-3 substituents of ring B is independently selected from the group consisting of hydroxyl, halo, cyano, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, halo(C 1-6 )alkyl, —C(CH 3 )(OH)CF 3 , (C 1-6 )alkoxy,
where
k is 1, 2, 3, or 4; and
R 21 is selected from the group consisting of hydroxyl, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 2-4 )alkynyl, halo(C 1-4 )alkyl, alkyloxy, —(CH 2 ) n OH, —CF 3 , —(CH 2 ) n CN, —(CH 2 ) n COOH, —(CH 2 ) n CONH 2 , —(CH 2 ) n heteroaryl, and —(CH 2 ) n O(CH 2 ) n heteroaryl, where n is 0, 1, 2, 3, or 4.
12. The compound or pharmaceutically acceptable salt according to claim 11 , wherein R 21 is selected from the group consisting of methyl, perfluoromethyl, hydroxyl, hydroxyl(C 1-4 alkyl, and cyano(C 1-4 )alkyl.
13. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is an unsubstituted or substituted phenyl of the formula
where
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, cyano, thio, (C 1-6 )alkyl, halo(C 1-6 )alkyl, (C 1-6 )alkoxy, hydroxyl(C 1-6 )alkyl, mercapto, sulfinyl, sulfonyl, sulfamoyl, amino, amido, carboxyamido, carbamoyl, carbonyl and carboxyl, each unsubstituted or substituted; provided that at least two of R 7 , R 8 , R 9 , R 10 , and R 11 are hydrogen.
14. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is an unsubstituted or substituted phenyl of the formula
wherein R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, hydroxyl, (C 1-6 )alkyl, halo(C 1-6 )alkyl, —C(CH 3 )(OH)CF 3 , (C 1-6 )alkoxy, halo, cyano,
provided that at least two of R 7 , R 8 , R 9 , R 10 , and R 11 are hydrogen,
where
k is 1, 2, 3, or 4; and
R 21 is selected from the group consisting of hydroxyl, (C 1-4 )alkyl, halo(C 1-4 )alkyl, alkyloxy, —(CH 2 ) n OH, —CF 3 , —(CH 2 ) n CN, —(CH 2 ) n COOH, —(CH 2 ) n CONH 2 , —(CH 2 ) n heteroaryl, and —(CH 2 ) n O(CH 2 ) n heteroaryl, where n is 0, 1, 2, 3, or 4.
15. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 21 is selected from the group consisting of methyl, perfluoromethyl, hydroxyl, hydroxyl(C 1-4 alkyl, and cyano(C 1-4 )alkyl.
16. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 9 is independently selected from the group consisting of hydrogen, t-butyl, —C(CH 3 )(OH)CF 3 , —C(OH)(CH 3 ) 2 , and —C(CH 2 OH)(CH 3 ) 2 ; and R 7 , R 8 , R 10 , and R 11 are each hydrogen.
17. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is selected from the group consisting of
18. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring B is selected from the group consisting of
19. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of (C 5-7 )alicyclyl, hetero(C 1-6 )alicyclyl, (C 8-11 )bicycloalicyclyl, hetero(C 4-10 )bicycloalicyclyl, (C 6 )aryl, hetero(C 1-5 )aryl, (C 8-10 )bicycloaryl, and hetero(C 4-10 )bicycloaryl, each unsubstituted or substituted with said 1-5 substituents of ring A,
where
each hetero(C 1-6 )alicyclyl, hetero(C 4-10 )bicycloalicyclyl, hetero(C 1-5 )aryl, and hetero(C 4-10 )bicycloaryl contains 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and
each (C 8-11 )bicycloalicyclyl, hetero(C 4-10 )bicycloalicyclyl, (C 8-10 )bicycloaryl, and hetero(C 4-10 )bicycloaryl comprises of a first ring fused to a second ring, where the first ring attaches directly to the ring containing N a , and where the second ring is selected from a group consisting of five, six and seven membered cyclyls.
20. The compound or pharmaceutically acceptable salt according to claim 19 , wherein ring A is selected from the group consisting of phenyl, hetero(C 2-5 )aryl, (C 9-10 )bicycloaryl, and hetero(C 5-10 )bicycloaryl, each unsubstituted or substituted with said 1-5 substituents of ring A,
wherein
the hetero(C 2-5 )aryl is a six-membered heteroaryl;
the (C 9-10 )bicycloaryl comprises a first ring that is a phenyl, and a second ring that is a five membered heteroaryl or a phenyl;
the hetero(C 5-10 )bicycloaryl comprises a first ring that is a six-membered heteroaryl, and a second ring that is selected from the group consisting of phenyl, five-membered heteroaryl and six-membered heteroaryl;
each hetero(C 2-5 )aryl and hetero(C 5-10 )bicycloaryl contains 1-4 heteroatoms each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur.
21. The compound or pharmaceutically acceptable salt according to claim 20 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
22. The compound or pharmaceutically acceptable salt according to claim 20 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
23. The compound or pharmaceutically acceptable salt according to claim 19 , wherein ring A is selected from the group consisting of hetero(C 1-4 )aryl and hetero(C 4-9 )bicycloaryl, each unsubstituted or substituted with said 1-5 substituents, where
the hetero(C 1-4 )aryl is a five-membered heteroaryl;
the hetero(C 4-9 )bicycloaryl comprises of a first ring that is a five-membered heteroaryl, and a second ring that is selected from the group of phenyl, and five, six and seven membered heteroaryl; and
each hetero(C 1-4 )aryl and hetero(C 4-9 )bicycloaryl contains 1-4 heteroatoms each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur.
24. The compound or pharmaceutically acceptable salt according to claim 23 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
25. The compound or pharmaceutically acceptable salt according to claim 23 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
26. The compound or pharmaceutically acceptable salt according to claim 19 , wherein ring A is selected from the group consisting of (C 6 )alicyclyl, hetero(C 1-5 )alicyclyl, (C 9-11 )bicycloalicyclyl, and hetero(C 5-10 )bicycloalicyclyl, each unsubstituted or substituted with said 1-5 substituents of ring A, wherein
the hetero(C 1-5 )alicyclyl is a six-membered heteroalicyclyl;
the (C 9-11 )bicycloalicyclyl comprises a first ring that is a six-membered alicyclyl, and a second ring that is selected from the group consisting of five, six and seven membered cyclyl;
the hetero(C 5-10 )bicycloalicyclyl comprises a first ring that is a six-membered heteroalicyclyl, and a second ring that is a five, six or seven membered cyclyl;
each hetero(C 1-5 )alicyclyl and hetero(C 5-10 )bicycloalicyclyl contains 1-4 heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur.
27. The compound or pharmaceutically acceptable salt according to claim 26 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
28. The compound or pharmaceutically acceptable salt according to claim 19 , wherein ring A is selected from the group consisting of (C 5 )alicyclyl, hetero(C 1-4 ) alicyclyl, (C 8-10 )bicycloalicyclyl, and hetero(C 4-9 )bicycloalicyclyl, each unsubstituted or substituted with said 1-5 substituents, wherein
the hetero(C 1-4 )alicyclyl is a five-membered heteroalicyclyl,
the (C 8-10 )bicycloalicyclyl comprises a first ring that is a five-membered alicyclyl, and a second ring that is selected from the group consisting of five, six and seven membered cyclyl;
the hetero(C 4-9 )bicycloalicyclyl comprises a first ring that is a five-membered heterocycloalicyclyl, and a second ring that is selected from the group consisting of five, six and seven membered cyclyl; and
each hetero(C 1-4 )alicyclyl and hetero(C 4-9 )bicycloalicyclyl contains 1-4 heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur.
29. The compound or pharmaceutically acceptable salt according to claim 28 , wherein ring A is of the formula
unsubstituted or substituted with said 1-5 substituents of ring A.
30. The compound or pharmaceutically acceptable salt according to claim 19 , wherein ring A is selected from the group consisting of (C 7 )alicyclyl, hetero(C 3-6 )alicyclyl, (C 10-11 )bicycloalicyclyl, and hetero(C 6-10 )bicycloalicyclyl, each unsubstituted or substituted with said 1-5 substituents,
wherein
the hetero(C 3-6 )alicyclyl is a seven-membered heterocycloalkyl;
the (C 10-11 )bicycloalicyclyl comprises a first ring that is a seven-membered alicyclyl, and a second ring that is selected from the group consisting of five, six and seven membered cyclyl;
the hetero(C 6-10 )bicycloalicyclyl comprises a first ring that is a seven-membered heteroalicyclyl and a second ring that is selected from the group consisting of five, six and seven membered cyclyl; and
each hetero(C 3-6 )alicyclyl and hetero(C 6-10 )bicycloalicyclyl contains 1-4 heteroatoms, each of which is independently selected from the group consisting of nitrogen, oxygen and sulfur.
31. The compound or pharmaceutically acceptable salt according to claim 30 , wherein ring A is of the formula
unsubstituted or substituted with said 1-5 substituents of ring A.
32. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-5 substituents of ring A is independently selected from the group consisting of halo, cyano, hydroxy, oxy, oxo, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, carbonylamino, (C 1-10 )alkylamino, sulfonamido, sulfonyl, (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 1-10 )alkynyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, (C 3-12 )cyclo alkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )alicyclic, hetero(C 3-12 )alicyclic, (C 4-12 )aryl, and hetero(C 1-10 )aryl, each unsubstituted or substituted.
33. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-5 substituents of ring A is independently selected from the group consisting of hydroxyl, oxo, halo, cyano, (C 1-6 )alkyl, (C 1-6 )alkenyl, (C 1-6 )alkynyl, halo(C 1-6 )alkyl, (C 1-6 )alkylcarbonylamino, (C 1-6 )alkylaminocarbonyl, (C 1-6 )alkoxy, amino, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkylcarbonyl, aminocarbonyl, hydroxylcarbonyl, and (C 1-6 )alkylsulfonyl, each unsubstituted or substituted.
34. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of said 1-5 substituents of ring A is independently selected from the group consisting of hydroxyl, fluoro, chloro, cyano, oxo, methoxy, methyl, ethyl, hydroxymethyl, perfluoromethyl, methoxymethyl, methylcarbonylamino, methylaminocarbonylamino, aminocarbonyl, methylcarbonyl, hydroxycarbonyl, and methylsulfonyl.
35. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of
36. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of
37. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of
38. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of
39. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is of the formula
40. The compound or pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from the group consisting of
41. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, (C 1-6 )alkyl, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, (C 3-6 )cycloalkyl(C 1-3 )alkyl, hetero(C 1-5 )cycloalkyl(C 1-3 )alkyl, (C 3-6 )cycloalkyl, and hetero(C 1-5 )cycloalkyl, each substituted or unsubstituted.
42. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is hydrogen.
43. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, hydroxyl, amino, thio, oxy, (C 1-6 )alkyl, (C 1-6 )cycloalkyl, and (C 1-6 )alkoxy, each unsubstituted or substituted with 1-2 substituents each of which is independently selected from the group consisting of hydroxyl, halo, halo(C 1-6 )alkyl, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, hetero(C 1-5 )cycloalkyl, phenyl, and hetero(C 1-5 )aryl.
44. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, and methoxy.
45. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is hydrogen.
46. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is methyl.
47. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
ring A is selected from the group consisting of (C 5-7 )alicyclic, hetero(C 1-6 )alicyclic, (C 8-11 )bicycloalicyclic, and hetero(C 4-10 )bicycloalicyclic, (C 6 )aryl, hetero(C 1-5 )aryl, (C 8-10 )bicycloaryl, and hetero(C 4-10 )bicycloaryl, each unsubstituted or substituted with 1-5 substituents that are each independently selected from the group consisting of hydroxyl, oxo, halo, cyano, (C 1-6 )alkyl, (C 1-6 )alkenyl, (C 1-6 )alkynyl, halo(C 1-6 )alkyl, (C 1-6 )alkylcarbonylamino, (C 1-6 )alkylaminocarbonyl, (C 1-6 )alkoxy, amino, hydroxy(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkylcarbonyl, aminocarbonyl, hydroxylcarbonyl, and (C 1-6 )alkylsulfonyl, each unsubstituted or substituted;
R 3 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, and methoxy; and
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, hydroxyl, (C 1-6 )alkyl, halo(C 1-6 )alkyl, —C(CH 3 )(OH)CF 3 , (C 1-6 )alkoxy, halo, cyano,
where
k is 1, 2, 3, or 4; and
R 21 is selected from the group consisting of hydroxyl, (C 1-4 )alkyl, halo(C 1-4 )alkyl, alkyloxy, —(CH 2 ) n OH, —CF 3 , —(CH 2 ) n CN, —(CH 2 ) n COOH, —(CH 2 ) n CONH 2 , —(CH 2 ) n heteroaryl, and —(CH 2 ) n O(CH 2 ) n heteroaryl, where n is 0, 1, 2, 3, or 4.
48. The compound or pharmaceutically acceptable salt according to claim 47 , wherein R 3 is hydrogen.
49. The compound or pharmaceutically acceptable salt according to claim 47 , wherein R 9 is independently selected from the group consisting of hydrogen, t-butyl, —C(CH 3 )(OH)CF 3 , —C(OH)(CH 3 ) 2 , and —C(CH 2 OH)(CH 3 ) 2 ; and R 7 , R 8 , R 10 , and R 11 are each hydrogen.
50. The compound or pharmaceutically acceptable salt according to claim 47 , wherein R 9 is —C(OH)(CH 3 ) 2 , and R 7 , R 8 , R 10 , and R 11 are each hydrogen.
51. The compound or pharmaceutically acceptable salt according to claim 47 , wherein R 9 is —C(CH 2 OH)(CH 3 ) 2 , and R 7 , R 8 , R 10 , and R 11 are each hydrogen.
52. The compound or pharmaceutically acceptable salt according to claim 47 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
53. The compound or pharmaceutically acceptable salt according to claim 47 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
54. The compound or pharmaceutically acceptable salt according to claim 47 , wherein ring A is selected from the group consisting of
each unsubstituted or substituted with said 1-5 substituents of ring A.
55. The compound or pharmaceutically acceptable salt according to claim 47 , wherein ring A is selected from the group consisting of
56. The compound or pharmaceutically acceptable salt according to claim 47 , wherein ring A is selected from the group consisting of
57. The compound according to claim 1 , which is selected from the group of compounds consisting of:
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-cyclopropylbenzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide;
N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;
4-tert-butyl-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;
N-(5-(3,5-dimethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-acetylbenzamide;
N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
methyl 4-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(2-ethyl-1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
methyl 4-(5-(3-ethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate;
4-(2-hydroxypropan-2-yl)-N-(5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(4-(methylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(2-methoxypyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(6-acetamidopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(2-fluoropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;
N-(5-(6-aminopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
(R)-4-(2-hydroxypropan-2-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(3-oxopiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(2-methoxypyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(4-(hydroxymethyl)piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
N-(5-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(4-methoxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
(S)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(4-acetylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
(R)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-(3-cyanopiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
N-(5-(4-hydroxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;
(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;
4-(2-hydroxypropan-2-yl)-N-(5-(4-oxo-3,4,7,8-tetrahydropyrido[4,3-c/]pyrimidin-6(5H)-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;
(S)—N-(5-(2-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylic acid;
(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylic acid;
N-(5-(3-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;
4-(2-hydroxypropan-2-yl)-N-(5-(4-(methylsulfonyl)piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide; and
4-(2-hydroxypropan-2-yl)-N-(5-(1,1-dioxothiomorpholino)thiazolo[5,4-b]pyridin-2-yl)benzamide; and
a pharmaceutically acceptable salt of any one of the aforementioned compounds.
58. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as defined in claim 1 , and a pharmaceutically acceptable carrier.