US2011105430A1PendingUtilityA1
Pyrrolo [2,3-c] pyridine derivatives as p38 kinease inhibiting agents
Est. expiryJun 13, 2028(~1.9 yrs left)· nominal 20-yr term from priority
Inventors:Soumya P. SahooMeng-Hsin ChenKevin D. DykstraHiroo KoyamaPeter T. MeinkeStephen J. O'KeefeGinger Xu-Qiang Yang
A61P 43/00A61P 37/08A61P 25/00A61P 29/00A61P 19/06A61P 19/02C07D 519/00A61P 19/00A61P 11/06A61P 11/00
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Claims
Abstract
Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (A) are inhibitors N of p38 and are useful in the treatment of inflammation such as in the treatment of asthma, 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.
Claims
exact text as granted — not AI-modified1 . 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 (l) 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
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 , 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;
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, and
R 1 and R 2 are independently selected from the group consisting of
(a) hydrogen, and
(b)
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-7 H-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-c]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-trifluoro ethyl)-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-c]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-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one, 6-{[6-(3,5-dimethylisoxazol-4-yl)-1-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 method for treating or preventing asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, or gouty arthritis in a patient in need thereof comprising administering to said patient a therapeutically effective amount, or a prophylactically effective amount, of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.Cited by (0)
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