Substituted indole/indazole-pyrimidinyl compounds
The present disclosure provides indole/indazole-pyrimidinyl compounds useful in the treatment of p38 kinase mediated diseases, such as lymphoma and auto-inflammatory disease, having the structure of Formula (I): wherein W, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the detailed description; pharmaceutical compositions comprising at least one of the compounds; and methods for treating p38 kinase mediated diseases using the compound.
1. A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula I:
wherein:
W and X are independently selected from the group consisting of CH and N;
R 1 is selected from the group consisting of cycloalkyl, aryl, heterocyclyl and heteroaryl; wherein the heterocyclyl and heteroaryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of cyano and alkyl; and wherein the cycloalkyl and aryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, alkyl and alkoxy;
R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo;
R 3 and R 4 are independently selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl and hydroxy; and
R 6 is selected from the group consisting of hydrogen and alkyl.
2. A compound according to claim 1 , wherein:
R 1 is selected from the group consisting of heterocyclyl and heteroaryl; wherein the heterocyclyl and heteroaryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of cyano and (C 1 -C 3 )-alkyl;
R 2 is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy and halo; and
R 3 and R 4 are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl.
3. A compound according to claim 2 , wherein:
R 1 is (C 5 -C 6 )-heteroaryl; wherein the (C 5 -C 6 )-heteroaryl substituents may be optionally substituted with one or more substituents independently selected from (C 1 -C 3 )-alkyl;
R 2 is selected from the group consisting of (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy and halo; and
R 3 and R 4 are independently selected from the group consisting of hydrogen and methyl.
4. A compound according to claim 3 , wherein R 1 is C 5- heteroaryl, comprising one or more heteroatoms selected from the group consisting of O, N and S; and wherein the C 5 -heteroaryl may be optionally substituted with one or more substituents independently selected from (C 1 -C 3 )-alkyl.
5. A compound according to claim 4 , wherein the compound has the structure of Formula II:
wherein:
W and X are independently selected from the group consisting of CH and N;
Y is selected from the group consisting of N and C;
Z is selected from the group consisting of O, S and CH;
R 2 is selected from the group consisting of methyl, chloro and methoxy;
R 3 and R 4 are independently selected from the group consisting of hydrogen and methyl; and
R 5 is selected from the group consisting of methyl and hydroxy;
R 10 is (C 1 -C 3 )-alkyl.
6. A compound according to claim 5 , selected from the group consisting of:
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl) (4-((2-methylthiazol-4-yl)methyl)piperidin-1-yl)methan one;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl) (4-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl)(4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl)(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)methanone;
(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-6-methoxy-1-methyl-1H-indazol-5-yl)(4-((1-methyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)methanone;
((2R,5S)-2,5-dimethyl-4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)methanone; and
((2R,5S)-2,5-dimethyl-4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)methanone;
(3-(2-(tert-butyl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl) ((2R,5S)-2,5-dimethyl-4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone; and
(3-(2-(tert-butyl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)((2R,5S)-2,5-dimethyl-4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)methanone.
7. A compound according to claim 3 , wherein R 1 is pyridine.
8. A compound according to claim 7 , wherein the compound has the structure of Formula III:
wherein:
W and X are independently selected from the group consisting of CH and N;
R 2 is selected from the group consisting of methyl, chloro and methoxy;
R 3 and R 4 are independently selected from the group consisting of hydrogen and methyl; and
R 5 is selected from the group consisting of methyl and hydroxy.
9. A compound according to claim 8 , selected from the group consisting of:
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(pyridin-2-ylmethyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(pyridin-2-ylmethyl)piperazin-1-yl)methanone;
((2R,5S)-2,5-dimethyl-4-(pyridin-2-ylmethyl)piperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)methanone; and
((2R,5S)-2,5-dimethyl-4-(pyridin-2-ylmethyl)piperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)methanone.
10. A compound according to claim 1 , wherein:
R 1 is selected from the group consisting of cycloalkyl and aryl; wherein the cycloalkyl and aryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 3 )-alkyl and halo;
R 2 is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy and halo; and
R 3 and R 4 are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl.
11. A compound according to claim 10 , wherein:
R 1 is (C 5 -C 6 )-aryl; wherein the (C 5 -C 6 )-aryl substituents may be optionally substituted with one or more halo substituents;
R 2 is selected from the group consisting of (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy and halo; and
R 3 and R 4 are independently selected from the group consisting of hydrogen and methyl.
12. A compound according to claim 11 , wherein R 1 is C 6 -aryl; wherein the C 6 -aryl may be optionally substituted with one or more fluoro substituents.
13. A compound according to claim 12 , wherein the compound has the structure of Formula IV:
wherein:
W and X are independently selected from the group consisting of CH and N;
R 2 is selected from the group consisting of methyl, chloro and methoxy;
R 3 and R 4 are independently selected from the group consisting of hydrogen and methyl;
R 5 is selected from the group consisting of methyl and hydroxy;
R 6 is selected from the group consisting of hydrogen and methyl; and
R 11 and R 12 are independently selected from the group consisting of hydrogen and fluoro.
14. A compound according to claim 13 , selected from the group consisting of:
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(4-fluorobenzyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(2,4-difluorobenzyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indol-5-yl)(4-(2,4-difluorobenzyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(4-fluorobenzyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(2,4-difluorobenzyl)piperidin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone;
(6-chloro-3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1-methyl-1H-indazol-5-yl)(4-(2,4-difluorobenzyl)piperazin-1-yl)methanone;
((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indol-5-yl)methanone;
((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)(3-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-1,6-dimethyl-1H-indazol-5-yl)methanone; and
(3-(2-tert-Butyl-pyrimidin-4-yl)-6-chloro-1H-indol-5-yl)-(4-(4-fluorobenzyl)-piperidin-1-yl)-methanone.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 , further comprising a therapeutically effective amount of one or more compounds selected from the group consisting of anti-inflammatory drugs, anti-atherosclerotic drugs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules.