Claims
- 1. A compound selected from the group of compounds represented by Formula (I): wherein:R1 is hydrogen or acyl; R2 is hydrogen or alkyl; A is an aryl ring; B is a heteroaryl ring; R3 is selected from the group consisting of: (c) optionally substituted heterocyclyl; (d) optionally substituted aryl or heteroaryl; (f) heteroalkenyl; (g) heteroalkynyl; (h) heteroalkoxy; (i) heteroalkylamino; (j) optionally substituted heterocyclylalkyl; (k) optionally substituted heterocyclylalkenyl; (l) optionally substituted heterocyclylalkynyl; (m) optionally substituted cycloalkoxy, cycloalkylalkyloxy, heterocyclylalkoxy, or heterocyclyloxy; (n) optionally substituted heterocyclylalkylamino; (o) optionally substituted heterocyclylalkylcarbonyl; (p) heteroalkylcarbonyl; (q) optionally substituted cycloalkylamino; (t) —Y-(alkylene)-R9 where: Y is a single bond, —O—, —NH— or —S(O)n— (where n is an integer from 0 to 2); and R9 is cyano, optionally substituted heteroaryl, —COOH, —COR10, —COOR11, —CONR12R13, —SO2R14, —SO2NR15, R16, —NHSO2R17 or —NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl; (u) —C(═NR20)(NR21R22) where R20, R21 and R22 independently represented hydrogen, alkyl or hydroxy, or R20 and R21 (together are —(CH2)n— where n is 2 or 3 and R22 is hydrogen or alkyl; (v) —NHC(X)NR23R24 where X is —O— or —S—, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl; (w) —CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; (y) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (z) arylaminoalkylene or geteroarylaminoalkylene; (aa) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is —NH—, —N(alkyl)- or —O—, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl; (bb) —OC(O)-alkylene-CO2H or —OC(O)—NR′R″ (where R′ and R″ are independently hydrogen or alkyl; (cc) heteroarylalkenylene or heteroarylalkynylene; (dd) X-(alkylene)CH[(CR′R″)mOR40][(CR′R″)nOR40] where: X is —O—, —NH—, —NR— (where R is alkyl), —S(O)p— (where p is an integer from 0 to 2); R40 is acyl, C(O)OR41 (where R41 is hydrogen, alkyl, or cycloalkyl); C(O)ONR41R42 (where R41 is as defined above and R42 are as is hydrogen or alkyl); or C(O)NR41R42 (where R41 and R42 aredefined above); R′ and R″, independently, are hydrogen or alkyl; and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero; (ee) X-(alkylene)-CH(OH)CH2NHR50 where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2); and R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl); and (ff) X-(alkylene)-CH(NR50)—CH2OH where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2); and R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl); and R4 is selected from the group consisting of: (a) hydrogen; (a) halo; (b) alkyl; (c) alkoxy; and (d) hydroxy; R5 is selected from the group consisting of: (a) hydrogen; (b) halo; (c) alkyl; (d) haloalkyl; (e) thioalkyl; (f) hydroxy; (g) amino; (h) alkylamino; (i) dialkylamino; (j) heteroalkyl; (k) optionally substituted heterocyclo; (l) optionally substituted heterocyclylalkyl; (m) optionally substituted heterocyclylalkoxy; (n) alkylsulfonyl; (o) aminosulfonyl, mono-alkylaminosulfonyl or dialkylaminosulfonyl; (p) heteroalkyl; and (q) carboxy; R6 is selected from the group consisting of: (a) hydrogen; (b) halo; (c) alkyl; and (d) alkoxy; and prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
- 2. The compound of claim 1 wherein R3 is:(a) optionally substituted heterocyclyl; (b) aryl or hreteroaryl both optionally substituted with a substituent selected from halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO2R′ (where R′ is alkyl) or SO2NHR′R″ (where R′ and R″ are independently hydrogen or alkyl); (d) heteroalkenyl; (e) heteroalkylamino; (f) heteroalkoxy; (g) optionally substituted heterocyclylalkyl, heterocyclyloxy cycloalkoxy, or cycloalkylalkoxy; (h) optionally substituted heterocyclylalkenyl; (i) optionally substituted heterocyclylalkynyl; (j) optionally substituted heterocyclylalkoxy; (k) optionally substituted heterocyclylalkylamino or cycloalkylamino; (l) optionally substituted heterocyclylalkylcarbonyl; (k) —Y-(alkylene)-R9 where Y is a single bond, —O— or —NH— and R9 is optionally substituted heteroaryl, —CONR12R13, SO2R14, —SO2NR15R16 —NHSO2R17 or —NHSO2R18R19 where R12, R13, R14, R15, R16, R17, R18, and R19 are independently of each other hydrogen, alkyl or heteroalkyl; (l) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (m) arylaminoalkylene or heteroarylaminoalkylene; or (n) Z-alkylene-NR30R31 where Z is —NH—, —N(alkyl)- or —O—, and R30 and R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
- 3. The compound of claim 2, wherein R1 and R2 are hydrogen.
- 4. The compound of claim 3 wherein A is phenyl.
- 5. The compound of claim 4 wherein R4 is hydrogen; and R5 is halo or alkyl.
- 6. The compound of claim 5, wherein R3 is optionally substituted heteroaryl.
- 7. The compound of claim 6, wherein R3 is pyridin-2-yl, pyridin-3-yl, pyridin4-yl, N-oxidopyridin-2-yl, N-oxidopyridin-3-yl, N-oxidopyridin-4-yl or pyridon-2-yl, all optionally substituted.
- 8. The compound of claim 7, wherein R3 is at the 3-position.
- 9. The compound of claim 5, wherein R3 is optionally substituted phenyl.
- 10. The compound of claim 9, wherein R3 is 3-sulfamoylphenyl, 3-methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl.
- 11. The compound of claim 10, wherein R3 is at the 3-position.
- 12. The compound of claim 5, wherein R3 is:(b) heteroalkoxy; (c) heteroalkylamino; (d) optionally substituted heterocyclylalkyl; (e) optionally substituted heterocyclylalkoxy; cycloalkoxy; or cycloalkylalkoxy; (f) optionally substituted heterocyclylalkylamino; (g) —Y-(alkylene)-R9 where Y is a single bond, —O— or —NH— and R9 is optionally substituted heteroaryl, —CONR12R13, SO2R14, —SO2NR15R16 —NHSO2R17 or —NHSO2NR18R19 where R12, R13, R14, R15 R16, R17, R18, and R19 are independently of each other hydrogen, alkyl or heteroalkyl; or (h) Z-alkylene-NR30R31 where Z is —NH—, —N(alkyl)- or —O—, and R30 and R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
- 13. The compound of claim 12, wherein R3 is heteroalkoxy or heteroalkylamino.
- 14. The compound of claim 13, wherein R3 is at the 3-position and is selected from the group consisting of 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 2,2-(dihydroxymethyl)ethoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.
- 15. The compound of claim 12, wherein R3 is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted heterocyclylalkylamino.
- 16. The compound of claim 15, wherein R3 is at the 3-position and is selected from the group consisting of 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy, 2-(2-oxo-pyrrolidin-1-yl)ethoxy, 3-(morpholin-4-yl)propyl, 2-(morpholin-4-yl)ethyl, 4-(morpholin-4-yl)-butyl, 3-(morpholin-4-yl)propylamino, 2-(morpholin-4-yl)ethylamino, 4-hydroxypiperidinylmethyl, 2-(S,S-dioxo-thiamorpholin-4-yl)ethyl, 3-(S,S-dioxo-thiamorpholin-4-yl)propyl, N-methylpiperazinylmethyl, (2,2-dimethyl-1,3-dioxolan-4(S)-yl)m ethoxy, (1,3-dioxolan-2-on-4(R)-yl)methoxy, (2-thioxo-1,3-dioxolan-4-yl)methoxy, (2,2-diethyl-1,3-dioxolan-4(S)yl)methoxy, (2,2-diethyl-1,3-dioxolan-4(S)-yl)methylamino and (2-methyl-2-ethyl-1,3-dioxolan-4(S)-yl)methoxy.
- 17. The compound of claim 12 wherein R3 is —Y-(alkylene)-R9 where Y is a single bond, —O— or —NH— and R9 is optionally substituted heteroaryl, —CONR12R13, SO2 R14, —SO2NR15R16—NHSO2R17 or —NHSO2NR18R19 where R12, R13, R14, R15, R16 R17, R18 and R19 are independently of each other hydrogen, alkyl or heteroalkyl.
- 18. The compound of claim 17, wherein Y is a single bond and R9 is SO2R14 or —SO2NR15R16.
- 19. The compound of claim 18 wherein R3 is methylsulfonylethyl or sulfamoylethyl.
- 20. The compound of claim 1 wherein R3 is selected from the group consisting of:(b) X-(alkylene)CH[(CR′R″)mOR40][(CR′R″)nOR40] where: X is —O—, —NH—, —NR— (where R is alkyl), —S(O)p— (where p is an integer from 0 to 2); R40 is acyl, C(O)OR41 (where R41 is hydrogen, alkyl, or cycloalkyl); C(O)ONR41R42 (where R41 is a defined above and R42 is hydrogen or alkyl); or C(O)NR41R42 (where R41 and R42 are as defined above); R′ and R″, independently, are hydrogen or alkyl; and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero; (c) X-(alkylene)-CH(OH)CH2NHR50 where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2); and R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl); and (d) X-(alkylene)-CH(NR50)—CH2OH where: X is —O—, —NH—, —NR— (where R is alkyl), or —S(O)n— (where n is an integer from 0 to 2); and R50 is C(O)OR51 and C(O)NR51R52 (where R51 is hydrogen, alkyl, or cycloalkyl and R52 is hydrogen or alkyl).
- 21. The compound of claim 20, wherein R3 is at the 3-position and is X-(alkylene)-CH[(CR′R″)mOR40][(CR′R″)nOR40] where:X is —O—, —NH—, —NR— (where R is alkyl), —S(O)p— (where p is an integer from 0 to 2); R40 is acyl, C(O)OR41 (where R41 is hydrogen, alkyl, or cycloalkyl); C(O)ONR41R42 (where R41 is as defined above and R42 is hydrogen or alkyl); or C(O)NR41R42 (where R41 and R42 are as defined above); R′ and R″, independently, are hydrogen or alkyl; and m and n, independently, are an integer from 0 to 3 provided that m and n are not both zero.
- 22. The compound of claim 21, wherein R3 is at the 3-position and is selected from the group consisting of (diacetoxy)propoxy, (diisobutanoyloxy)propoxy, and (dipivaloyloxy)propoxy, (dimethoxycarbonyloxy)propoxy.
- 23. The compound of claim 22, wherein R4 is hydrogen.
- 24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
- 25. A method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration to the mammal a therapeutically effective amount of a compound of claim 1.
- 26. The method of claim 25, wherein the disease is an inflammatory disease.
- 27. The method of claim 26, wherein the disease is arthritis.
- 28. A process for preparing a compound of Formula (I) selected from compounds of claim 1, which process comprises:(i) reacting a 2-keto-3-phenylaminoacrylonitrile of Formula 1: with a hydrazine of Formula 2: where B, R3, R4 R5 and R6 are as defined in claim 1 to provide a compound of Formula (I) where R1 is hydrogen; or(ii) reacting a 2-keto-3-phenylaminoacrylonitrile of formula 3: where Z is either hydroxy, nitro or halo group and R4 are as defined in claim 1 with a hydrazine of formula 2 to provide a compound of formula 4: followed by conversion of the Z group to the desired R3 group to provide a compound of Formula (I) where R1 is hydrogen;(iii) optionally modifying any of the R1, R3, R4, R5 or R6 groups; (iv) optionally converting the compound of Formula (I) prepared in Steps (i), (ii) or (iii) above, to the corresponding acid addition salt by treatment with an acid; (v) optionally converting the compound of Formula (I) prepared in Steps (i), (ii) or (iii) above, to the corresponding free base by treatment with a base; and(vi) optionally separating a mixture of stereoisomers of a compound of Formula (I) prepared in Steps (i)-(v) above, to give a single stereoisomer.
- 29. A process for preparing a compound of Formula (I) selected from compounds of claim 1, which process comprises reacting a compound of Formula 5: where L is a leaving group under organometallic displacement reaction conditions with an organometallic reagent of formula where M is a metallic moiety to provide a compound of Formula (I) where R1 is hydrogen;(ii) optionally modifying any of the R1, R3, R4, R5 or R6 groups; (iii) optionally converting the compound of Formula (I) prepared in Steps (i) or (ii) above, to the corresponding acid addition salt by treatment with an acid; (iv) optionally converting the compound of Formula (I) prepared in Steps (i) or (ii) above, to the corresponding free base by treatment with a base; and (v) optionally separating a mixture of stereoisomers of a compound of Formula (I) prepared in Steps (i) or (iv) above, to give a single stereoisomer.
Parent Case Info
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of U.S. application Ser. No. 09/401,141, filed Sep. 22, 1999 now U.S. Pat. No. 6,316,466, which is a continuation-in-part of U.S. patent application Ser. No. 09/305,737, filed May 5, 1999 and claims the benefit under 35 U.S.C. 119 (e) of U.S. Provisional Application Ser. No. 60/084,250, filed May 5, 1998, U.S. Provisional Application Ser. No. 60/122,140, filed Mar. 2, 1999, and U.S. Provisional Application Ser. No. 60/130,369, filed Apr. 21, 1999, all of which are incorporated herein by reference in their entirety.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5712303 |
Faraci et al. |
Jan 1998 |
A |
Provisional Applications (3)
|
Number |
Date |
Country |
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60/084250 |
May 1998 |
US |
|
60/122140 |
Mar 1999 |
US |
|
60/130369 |
Apr 1999 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
09/305737 |
May 1999 |
US |
Child |
09/401141 |
|
US |