ASK 1 inhibiting pyrrolopyrimidine derivatives

1. A compound of formula (I)

where

X is (CH 2 ) m or CH 2 O, where m is 1 or 2;

p is 0 or 1;

R 1 is phenyl or a 5 or 6 membered heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, pyridazinyl or pyrimidinyl, which phenyl or heteroaryl group is optionally substituted with 1 or 2 substituents selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halo, (CH 2 ) n NR 5 R 6 where R 5 and R 6 are independently H or (C 1-4 )alkyl and n is 0 or 1, pyrrolidinyl, morpholinyl, piperidinyl, pyrrolidin(C 1-4 )alkyl, morpholin(C 1-4 )alkyl, piperidin(C 1-4 )alkyl, pyrrolidin(C 1-4 )alkoxy, morpholin(C 1-4 )alkoxy, piperidin(C 1-4 )alkoxy wherein said pyrrolidinyl, morpholinyl or piperidinyl groups are optionally substituted with halo or (C 1-4 )alkyl, with the proviso that when R 1 is phenyl or a 6 membered heteroaryl group, which phenyl or 6 membered heteroaryl group has a substitutent on the atom at the para position, said substituent is selected from the group consisting of methyl, ethyl, isopropyl, methoxy, halo or (CH 2 ) n NR 5 R 6 where R 5 and R 6 are methyl;

R 2 is H, methoxy, ethoxy or CH 2 OCH 3 ;

R 3 is H, (C 1-4 )alkyl, (C 2-4 )alkenyl, halo, cyano, furanyl or pyrazolyl, which pyrazolyl is optionally substituted with 1 methyl group;

R 4 is H or (C 1-4 )alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 where p is 0, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 where p is 1, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 where X is methyl or methoxy, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 where R 2 is H, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 where R 3 is methyl, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 where R 4 is H, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 where R 1 is unsubstituted phenyl or an unsubstituted 5 or 6 membered heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, pyridazinyl or pyrimidinyl, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8 where R 1 is unsubstituted phenyl.

10. A compound according to claim 1 where R 1 is phenyl substituted with (C 1-4 )alkyl or (C 1-4 )alkoxy.

11. A compound according claim 1 where R 1 is pyridinyl substituted with (C 1-4 )alkyl or (C 1-4 )alkoxy, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 where R 1 is isoxazolyl substituted with 1 or 2 (C 1-4 )alkyl groups, or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 where R 1 is imidazolyl substituted with 1 or 2 (C 1-4 )alkyl groups, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1 which is selected from the group consisting of:

N-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-(Methyloxy)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

4-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

2-(Dimethylamino)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-[(Dimethylamino)methyl]-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-(1-Pyrrolidinyl)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-(4-Morpholinyl)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-2-pyridinecarboxamide;

N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-pyridinecarboxamide;

N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

2-Methyl-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridazinecarboxamide;

N-[1-(1H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-5-pyrimidinecarboxamide;

2-(Methyloxy)-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

5-Methyl-N-[1-(1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-isoxazolecarboxamide;

N-[1-(5-Methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(5-Ethyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-{1-[5-(1-Methylethenyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide;

N-{1-[5-(1-Methylethyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide;

N-[1-(5-Methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-2-pyridinecarboxamide;

6-Methyl-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-pyridinecarboxamide;

2-(Methyloxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

3-(Methyloxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

2-Methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

2-Methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

3,5-dimethyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-isoxazolecarboxamide;

N-[1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-methyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

2,6-dimethyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

1-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-1H-imidazole-5-carboxamide;

N-[3-(methyloxy)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-methyl-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-4-pyridinecarboxamide;

N-[1-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-N-methyl-4-pyridinecarboxamide;

N-{1-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide;

N-{1-[5-(3-furanyl)-1H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide;

N-[3-[(methyloxy)methyl]-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzamide;

N-[1-(5-chloro-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(5-cyano-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]-3-{[2-(4-morpholinyl)ethyl]oxy}benzamide;

3-({2-[(3R)-3-fluoro-1-pyrrolidinyl]ethyl}oxy)-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-{[2-(3,3-difluoro-1-pyrrolidinyl)ethyl]oxy}-N-[1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

3-({2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}oxy)-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide;

2-(phenyloxy)-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]acetamide; and

2-phenyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]acetamide,

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 which is N-[1-(5-Methyl-1H -pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]benzamide or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a) the compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable carrier.

17. A method of treating rheumatoid arthritis, which comprises administering to a subject in need thereof an effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.