P38 kinase inhibiting agents
View Patent ↗Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
1. A compound represented by chemical formula (A)
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of:
(a) —C(O)—,
(b) —CH(OH)—,
(c) —CH(NR 3 R 4 )—,
(d) —C(═NOR 3 )—,
(e) —CH 2 —, and
(f) —S(O) n —, wherein n is 0, 1 or 2;
Ar 1 is an optionally mono, di- or tri-substituted aromatic or heteroaromatic ring of 6 atoms, wherein the heteroaromatic ring may contain 1, 2 or 3 heteroatoms selected from N, S and O, wherein the substituents are independently selected from the group consisting of:
(a) halo,
(b) —C 1-4 alkyl,
(c) —O—C 1-4 alkyl,
(d) —CF 3 ,
(e) —NH 2 ,
(f) —NH—CH 3 ,
(g) —CN,
(h) —C(O)NH 2 , and
(i) —S(O) n —CH 3 ;
Ar 2 is an optionally mono, di- or tri-substituted fused 5,6 bi-cyclic heterocyclic ring selected from the group consisting of
or N-oxide thereof, wherein the substituents are independently selected from the group consisting of
(a) halo,
(b) —C 1-4 alkyl,
(c) —O—C 1-4 alkyl,
(d) —CF 3 ,
(e) —NH 2 , and
(f) —NH 2 —CH 3 ,
(g) —NH 2 —CH 2 CF 3 ,
(h) —C(O)-morpholinyl,
(i) —C(O)—NR 1 R 2 ,
(j) —C(O)OH,
(k) —CN,
(l) a 5 or 6 membered heteroaromatic or heterocyclic ring containing 1, 2 or 3 hetero atoms selected from the group consisting of S, O and N;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of
(a) hydrogen, and
(b) C 1-4 alkyl,
or R 1 and R 2 or R 3 and R 4 may be joined together to form a 5 or 6 membered saturated ring, said ring optionally containing a heteroatom selected from S, N and O.
2. The compound according to claim 1 , wherein
L is selected from the group consisting of:
(a) —C(O)—, and
(b) —CH 2 —.
3. The compound according to claim 2 , wherein
L is —C(O)—.
4. The compound according to claim 1 , wherein
Ar 1 is an optionally mono, di- or tri-substituted aromatic or heteroaromatic ring of 6 atoms, wherein the heteroaromatic ring may contain 1, 2 or 3 heteroatoms selected from N, S and O, wherein the substituents are independently selected from the group consisting of:
(a) halo,
(b) —C 1-4 alkyl, and
(c) —O—C 1-4 alkyl.
5. The compound according to claim 4 , wherein
Ar 1 is an optionally mono, di- or tri-substituted phenyl or pyridyl, wherein the substituents are independently selected from the group consisting of
(a) fluoro,
(b) chloro, and
(c) —CH 3 .
6. The compound according to claim 1 wherein in choice (1) of Ar 2 , the 5 or 6 membered heteroaromatic or heterocyclic ring containing 1, 2 or 3 hetero atoms selected from the group consisting of S, O and N is selected from the group consisting of:
(a) pyridinyl,
(b) pyridazinyl,
(c) pyrimidinyl,
(d) pyrazinyl,
(e) thiazolyl,
(f) thiophenyl,
(g) pyrrolyl,
(h) oxazolyl,
(i) pyrrolidinyl,
(j) piperidinyl,
(k) piperazinyl, and
(l) morpholinyl.
7. The compound according to claim 1 wherein
Ar 2 is an optionally mono, di- or tri-substituted fused 5,6 bi-cyclic heterocyclic ring selected from the group consisting of:
or N-oxide thereof wherein the substituents are independently selected from the group consisting of:
(a) halo,
(b) —C 1-4 alkyl,
(c) —O—C 1-4 alkyl,
(d) —CF 3 ,
(e) —C(O)-morpholinyl,
(f) —C(O)—NR 1 R 2 , and
(g) —C(O)OH.
8. The compound according to claim 7 wherein
A 2 is an optionally mono, di- or tri-substituted fused 5,6 bi-cyclic heterocyclic ring selected from the group consisting of:
or N-oxide thereof, wherein the substituents are independently selected from the group consisting of:
(a) halo,
(b) —CH 3 ,
(c) —O—CH 3 , and
(d) —CF 3 .
9. The compound according to claim 1 wherein
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of
(a) hydrogen, and
(b) methyl,
or R 1 and R 2 or R 3 and R 4 may be joined together to from a 5 or 6 membered saturated ring, said ring optionally containing a heteroatom selected from S, N and O.
10. A compound according to claim 1 of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
Ar 1 is an optionally mono, di- or tri-substituted aromatic or heteroaromatic ring of 6 atoms, wherein the heteroaromatic ring may contain 1, 2 or 3 heteroatoms selected from N, S and O, wherein the substituents are independently selected from the group consisting of:
(a) halo,
(b) —C 1-4 alkyl, and
(c) —O—C 1-4 alkyl;
A 2 is an optionally mono, di- or tri-substituted fused 5,6 bi-cyclic heterocyclic ring selected from the group consisting of
or N-oxide thereof, wherein the substituents are independently selected from the group consisting of
(a) halo,
(b) —C 1-4 alkyl,
(c) —O—C 1-4 alkyl,
(d) —CF 3 ,
(e) —C(O)-morpholinyl,
(f) —C(O)—NR 1 R 2 , and
(g) —C(O)OH; and
R 1 and R 2 are independently selected from the group consisting of
(a) hydrogen, and
(b) C 1-4 alkyl,
or R 1 and R 2 may be joined together to from a 5 or 6 membered saturated ring, said ring optionally containing a heteroatom selected from S, N and O.
11. A compound according to claim 10 wherein
Ar 1 is an optionally mono, di- or tri-substituted phenyl or pyridyl, wherein the substituents are independently selected from the group consisting of
(a) fluoro
(b) chloro, and
(c) —CH 3 ;
Ar 2 is an optionally mono, di- or tri-substituted fused 5,6 bi-cyclic heterocyclic ring selected from the group consisting of:
or N-oxide thereof, wherein the substituents are independently selected from the group consisting of
(a) halo,
(b) —CH 3 ,
(c) —O—CH 3 ,
(d) —C(O)—NR 1 R 2 , and
(e) —CF 3 , and
R 1 and R 2 are independently selected from the group consisting of
(a) hydrogen, and
(b) methyl,
or R 1 and R 2 may be joined together to from a 5 or 6 membered saturated ring, said ring optionally containing a heteroatom selected from S, N and O.
12. The compound according to claim 1 , selected from the group consisting of:
6-(1H-benzimidazol-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
6-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-[(4,5-difluoro-1H-benzimidazol-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
methyl 2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}-1H-benzimidazole-6-carboxylate,
6-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-difluorobenzoyl)-6-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-[(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-difluorobenzoyl)-6-[(6-methylimidazo[1,2-b]pyridazin-2-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-(1,3-benzoxazol-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-[(6-methyl-3H -imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H -pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-difluorobenzoyl)-6-[(6-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(3,5-difluoroisonicotinoyl)-6-(pyrazolo[1,5-a]pyridin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-difluoro-4-methylbenzoyl)-6-(pyrazolo[1,5-a]pyridin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}-N-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide,
6-{[6-(morpholin-4-ylcarbonyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-(3H-imidazo[4,5-c]pyridin-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,4,6-trifluorobenzoyl)-6-{[(7-trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,4,6-trifluorobenzoyl)-6-{[6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,4-difluorobenzoyl)-6-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-difluorobenzoyl)-6-{[6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}imidazo[1,2-a]pyridine-7-carboxamide,
2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}imidazo[1,2-a]pyridine-7-carboxylic acid,
N,N-dimethyl-2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}imidazo[1,2-a]pyridine-7-carboxamide,
N-methyl-2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo-[2,3-c]pyridin-6-yl]methyl}-imidazo[1,2-a]pyridine-7-carboxamide,
2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}-1H-benzimidazole-5-carboxylic acid,
N-methyl-2-{[7-oxo-3-(2,4,6-trifluorobenzoyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl]methyl}-1H-benzimidazole-5-carboxamide,
3-[(2,4-difluorophenyl)(hydroxy)methyl]-6-(imidazo[1,2-a]pyridin-2-ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one, and
6-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-3-(2,4,6-trifluorobenzyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 , selected from the group consisting of:
Structure
or a Pharmaceutically acceptable slat thereof.
14. The compound according to claim 1 , selected from the group consisting of:
6-{[6-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzolyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-{[6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-{[6-(1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-[(6-methyl-1H -imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-{[6-(1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-{[6-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,
6-{[6-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one
3-(2,6-Difluoro-4-methyl-benzoyl)-6-[6-(3,5-dimethyl-isoxazol-4-yl)-3-H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-Difluoro-benzoyl)-6-[6-(3,5-dimethyl-isoxazol-4-yl)-3-H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-Difluoro-4-methyl-benzoyl)-6-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-Difluoro-benzoyl)-6-[6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one,
3-(2,6-Difluoro-4-methyl-benzoyl)-6-[6-(1-H-pyrazol-4-yl)-3-H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one, and
3-(2,6-Difluoro-benzoyl)-6-[6-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one,
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 which is:
16. A compound according to claim 1 which is
TABLE I
Example
Ar1
Het
83
84
85
86
87
88
89
90
91
92
93
94
17. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .
18. A compound which is
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 18 .