Patent EA-002855-B1 (EA)
Title: Substituted nitrogen containing heterocycles as inhibitors of p38 protein kinase
Inventor: BEMIS GUY W
IPC: C07D409/04
Filed: 1997-12-17
Abstract: 1. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein: each of Q1 and Q2 are independently selected from 5-6 membered aromatic carbocyclic or heterocyclic ring systems, or 8-10 membered bicyclic ring systems consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an-aromatic carbocyclic ring and an aromatic heterocyclic ring; wherein: Q1 is substituted with 1 to 4 substituents, independently selected from halo; C1-C3 alkyl optionally substituted with NR'2, OR', CO2R' or CONR'2; O-(C1-C3)-alkyl optionally substituted with NR'2, OR', CO2R' or CONR'2; NR'2; OCF3; CF3; NO2; CO2R'; CONR'; SR'; S(O2)N(R')2; SCF3; CN; N(R')C(O)R<4>; N(R')C(O)OR<4>; N(R')C(O)C(O)R<4>; N(R')S(O2)R<4>; N(R')R<4>; N(R<4>)2; OR<4>; OC(O)R<4>; OP(O)3 H2; or N=C-N(R')2; and Q2 is optionally substituted with up to 4 substituents, independently selected from halo; C1-C3 straight or branched alkyl optionally substituted with NR'2, OR', CO2R', S(O2)N(R')2, N=C-N(R')2, R<3>, or CONR'2; O-(C1-C3)-alkyl optionally substituted with NR'2, OR', CO2R', S(O2)N(R')2, N=C-N(R')2, R<3>, or CONR'2; NR'2; OCF3; CF3; NO2; CO2R'; CONR'; R<3>; OR<3>; NR<3>; SR<3>; C(O)R<3>; C(O)N(R')R<3>; C(O)OR<3>; SR'; S(O2)N(R')2; SCF3; N=C-N(R')2; or CN; wherein R' is selected from hydrogen, (C1-C3)-alkyl; (C2-C3)-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; R<3> is selected from a 5-6 membered aromatic carbocyclic or heterocyclic ring system; and R<4> is (C1-C4)-alkyl optionally substituted with N(R')2, OR', CO2R', CON(R')2, or SO2N(R<2>)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R')2, OR', CO2R', CON(R')2, or SO2N(R<2>)2; X is selected from -S-, -O-, -S(O2)-, -S(O)-, -S(O2)-N(R<2>)-, -N(R<2>)-S(O2)-, -N(R<2>)-C(O)O-, -O-C(O)-N(R<2>), -C(O)-, -C(O)O-, -O-C(O)-, -C(O)-N(R<2>)-, -N(R<2>)-C(O)-, -N(R<2>)-, -C(R<2>)2-, -C(OR<2>)2-; each R is independently selected from hydrogen, -R<2>, -N(R<2>)2, -OR<2>, SR<2>, -C(O)-N(R<2>)2, -S(O2)-N(R<2>)2, or -C(O)-OR<2>, wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring; R<2> is selected from hydrogen, (C1-C3) -alkyl, or (C1-C3)-alkenyl; each optionally substituted with -N(R')2, -OR', SR', -C(O)-N(R')2, -S(O2)-N(R')2, -C(O)-OR', or R<3>. Y is selected from N or C; A, if present, is selected from N or CR'; n is 0 or 1; and R<1> is selected from hydrogen, (C1-C3) -alkyl, OH, or O-(C1-C3)-alkyl. 2. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein Q1, Q2, R1 R and Y are as defined in Claim 1. 3. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein A, Q1, Q2, R, R', X, Y and n are as defined in the same manner as set forth for compounds of formulae Ia and Ib; and R5 is selected from hydrogen, -CR'2OH, -C(O)R<4>, -C(O)OR<4>, -CR'2OPO3H2, and -PO3H2. 4. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein A, Q1, Q2, R, R', R<5>, X, Y and n are as defined in Claim 3. 5. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein  Q3 is a 5-6 membered aromatic carbocyclic or heterocyclic ring system; or an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring; wherein Q3 is substituted with 1 to 4 substituents, each of which is independently selected from halo; (C1-C3) alkyl optionally substituted with NR'2, OR', CO2R' or CONR'2; O-(C1-C3)-alkyl optionally substituted with NR'2, OR', CO2R' or CONR'2; NR'2; OCF3; CF3; NO2; CO2R'; CONR'; SR'; S(O2)N(R')2; SCF3; CN; N(R')C(O)R<4>; N(R')C(O)OR<4>; N(R')C(O)C(O)R<4>; N(R')S(O2)R<4>; N(R')R<4>; N(R<4>)2; OR<4>; OC(O)R<4>; OP(O)3H2; or N=C-N(R')2; and A, Q1, Q2, R, R', X, Y and n are as defined as in Claim 1. 6. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein A, Q1, Q2, R, X, Y and n are as defined in Claim 1. 7. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein Q1, Q3, R, Y and n are as defined in Claim 5. 8. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein Q1, Q2, R, Y, X, A and n are as defined in Claim 6. 9. The compound according to any one of Claims 1 to 8, wherein Q1 is selected from phenyl or pyridyl containing 1 to 3 substituents independently selected from chloro, fluoro, bromo, -CH3, -OCH3, -OH, -CF3, -OCF3, -O(CH2)2CH3, NH2, 3,4-methylenedioxy, -N(CH3)2, -NH-S(O)2-phenyl, -NH-C(O)O-CH2-4-pyridine, -NH-C(O)CH2-morpholine, -NH-C(O)CH2-N(CH3)2, -NH-C(O)CH2-piperazine, -NH-C(O)CH2-pyrrolidine, -NH-C(O)C(O)-morpholine, -NH-C(O)C(O)-piperazine, -NH-C(O)C(O)-pyrrolidine, -O-C(O)CH2-N(CH3)2, or -O-(CH2)2-N(CH3)2 and wherein at least one of said substituents is in the ortho position. 10. The compound according to Claim 4, wherein Q1 contains at least two substituents, both of which are in the ortho position. 11. The compound according to Claim 4, wherein Q1 is selected from:         12. The compound according to Claim 6, wherein Q1 is selected from 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-3-aminophenyl, 2,6-dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-dichloro-4-pyridyl, 2chloro-4,5 methylenedioxy phenyl, or 2-chloro-4-(N-2-morpholino-acetamido)phenyl. 13. The compound according to any one of Claims 1 to 8, wherein Q2 is selected from phenyl or pyridyl and wherein Q2 optionally contains up to 3 substituents, each of which is independently selected from chloro, fluoro, bromo, methyl, ethyl, isopropyl, -OCH3, -OH, -NH2, -CF3, -OCF3, -SCH3, -OCH3, -C(O)OH, -C(O)OCH3, -CH2NH2, -N(CH3)2, -CH2-pyrrolidine and -CH2OH. 14. The compound according to Claim 13, wherein, Q2 is selected from       unsubstituted 2-pyridyl or unsubstituted phenyl. 15. The compound according to Claim 14, wherein Q2 is selected from phenyl, 2-isopropylphenyl, 3,4-dimethylphenyl, 2-ethylphenyl, 3-fluorophenyl, 2-methylphenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 2-carbomethoxylphenyl, 2-carboxyphenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-pyridyl, 2-methylenehydroxyphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-chloro-4-fluorphenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorphenyl or 2-methylenehydroxy-4-fluorophenyl. 16. The compound according to any one of Claims 1 to 8, wherein X is selected from -S-, -O-, -S(O2)-, -S(O)-, -NR-, -C(R<2>)- or -C(O)-. 17. The compound according to Claim 15, wherein X is S. 18. The compound according to any one of Claims 1 to 8, wherein n is 1 and A is N. 19. The compound according to any one of Claims 1 to 8, wherein each Y is C. 20. The compound according to Claim 19, wherein each R attached to Y is independently selected from hydrogen or methyl. 21. The compound according to Claim 1, wherein said compound is selected from any one of compounds 2 to 3, or 5 to 53, set forth in Table 1. 22. The compound according to Claim 3, wherein said compound is selected from any one of compounds 101 to 145 set forth in Table 2. 23. The compound according to any of Claims 5 to 7, wherein Q3 substituted with 2 to 4 substituents, wherein at least one of said substituents is present in the ortho position relative to the point of attachment of Q3 to the rest of the inhibitor. 24. The compound according to Claim 23, wherein both ortho positions are occupied by one of said independently selected substituents. 25. The compound according to Claim 24, wherein Q3 is a monocyclic carbocyclic ring; and each of said ortho substituents on Q3 are independently selected from halo or methyl. 26. The compound according to Claim 24, wherein Q3 contains 1 to 2 substituents in addition to said ortho substituents, said additional substituents being independently selected from NR'2, OR', CO2R' CN, N (R')C(O)R<4>; N(R')C(O)OR<4>; N(R')C(O)C(O)R<4>; N(R')S(O2)R<4>; N(R')R<4>; N(R<4>)2; OR<4>; OC(O)R<4>; OP(O)3H2; or N=C-N(R')2. 27. The compound according to Claim 5, wherein said compound is a compound of formula Ie and is selected from any one of compounds 201 or 203 to 209, set forth in Table 3. 28. The compound according to Claim 7, wherein said compound is a compound of formula Ig and is selected from any one of compounds 202/301, 302 to 399, or 1301, set forth in Table 4. 29. The compound according to Claim 8, wherein said compound is a compound of formula Ih and is selected from any one of compounds 401 to 412, set forth in Table 5. 30. A pharmaceutical composition comprising an amount of a compound according to any one of Claims 1 to 8 effective to inhibit p38, and a pharmaceutically acceptable carrier. 31. A method of treating or preventing inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation or conditions associated with prostaglandin endoperoxidase synthase-2 in a patient, said method comprising administering to said patient a composition according to Claim 30. 32. The method according to Claim 31, wherein said method is used to treat or prevent an inflammatory disease selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, or adult respiratory distress syndrome. 33. The method according to Claim 31, wherein said method is used to treat or prevent an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastr