Claims
- 1. A method of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof at least one compound having the formula (I):
- 2. The method of claim 1 comprising administering to the patient at least one compound having the formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
R3 is methyl, —CF3, or —OCH3; X is selected from —C(═O)—, —CO2—, —NR10—, —NR10C(═O)—, —NR10CO2—, —NR10SO2—, —SO2NR10—, and —C(═O)NR10—, or X is absent; Z is N; R2 is hydrogen, C2-6alkyl, C1-4alkyl substituted with up to four R26, pentafluoroalkyl, or aryl or heteroaryl optionally substituted with up to two R27; R4 is phenyl substituted with one R12 and zero to three R13; R5 and R10 independently are selected from hydrogen and lower alkyl; R12 is carbamyl, sulfonamido, arylsulfonylamine, or ureido, each of which is optionally substituted with up to two of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, and aralkyl, or alkylsulfonylamine; R13 at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, —OR14, —C(═O)alkyl, —OC(═O)alkyl, —NR15R16, —SR15, —NO2, —CN, —CO2R15, —CONH2, —SO3H, —S(═O)alkyl, —S(═O)aryl, —NHSO2-aryl-R17, —NHSO2-alkyl, —SO2NHR17, —CONHR17, and —NHC(═O)NHR17; R14 is hydrogen, alkyl, or aryl; R15 is hydrogen or alkyl; R16 is hydrogen, alkyl, aralkyl, or alkanoyl; and R17 is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl.
- 3. A method of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof at least one compound having the formula (I):
- 4. The method of claim 3 comprising administering to the patient at least one compound of formula (I), in which R4 and R5 taken together with Z form:
- 5. The method of claim 3 comprising administering to the patient at least one compound having the formula (II):
- 6. The method of claim 3, comprising administering to the patient at least one compound having the formula (Ia), (Ib), or (Ic):
- 7. A compound having the formula (II):
- 8. A compound according to claim 7, having the formula (IIa) or (IIb),
- 9. A compound according to claim 7, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein
X is —C(═O)—, —CO2—, —NR10C(═O)—, or —C(═O)NR10—; Y is —C(═O)NH—, —NHC(═O)NH—, or —NHSO2—; R5 and R10 are hydrogen or —CH3; R13 and R19 at each occurrence are independently selected from lower alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, C1-4alkoxy, nitro, and cyano; R7, R8, R21, R24, and R25 are independently selected from hydrogen and lower alkyl; R22 is lower alkyl; and n is 0 or 1.
- 10. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which X-R2 are:
- 11. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which:
R2a is selected from:
a) straight or branched C2-6alkyl; b) phenyl optionally substituted with up to two of halogen, C1-4alkoxy, and trifluoromethyl; c) C3-6cycloalkyl optionally substituted with up to two C1-4alkyl and/or hydroxy; d) straight or branched C1-4alkyl substituted with up to three of
i) halogen, ii) trifluoromethyl, iii) cyano, iv) C1-4alkoxy, v) phenyloxy, vi) benzyloxy, vii) NH2, NH(C1-4alkyl), and/or N(C1-4alkyl)2, viii) phenyl in turn optionally substituted with up to two of halogen and/or methoxy, ix) heterocycle selected from pyridinyl, indolyl, thiophenyl, furanyl, thiazolyl, thienyl, morpholinyl, tetrahydrofuranyl, triazinyl, piperazinyl, indenyl, and piperadinyl; said heterocycle optionally substituted with one to two C1-4alkyl, x) C3-6cycloalkyl; and R2b is a five to seven membered monocyclic heterocycle selected from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle optionally substituted with C1-4alkyl, phenyl, and/or benzyl.
- 12. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which R1 and R10 are independently hydrogen or CH3.
- 13. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which R6 is hydrogen.
- 14. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which Y is —NHC(═O)NH—or —NHSO2—; R18 is aryl or aryl substituted with alkyl, OCH3, CF3, cyano, or halogen.
- 15. A compound according to claim 7 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which Y is —C(═O)NR23—, R23 is hydrogen or lower alkyl, and R18 is C1-4alkoxy or aryl optionally substituted with alkyl, OCH3, CF3, cyano or halogen.
- 16. A compound according to claim 7, having the formula:
- 17. A compound according to claim 16 or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which R3 and R33 are methyl, R1 and R6 are hydrogen, and R2 is a straight or branched C2-6alkyl or optionally-substituted benzyl.
- 18. A compound according to claim 7, which is selected from (i) N-(2,2-Dimethylpropyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-N,5-dimethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;
3-[[6-[(Hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl]-5-methylpyrrolo [2,1-f][1,2,4]triazin-4-yl]amino]-N-methoxy-4-methylbenzamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-methylpropyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(2,2-Dimethylpropyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(1,1-Dimethylethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-N-(2-methoxyethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Methoxy-4-methyl-3-[[5-methyl-6-(4-morpholinylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide; N-Cyclohexyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1R)-1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1S)-1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(4-Fluorophenyl)methyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-N-[(2-methoxyphenyl)methyl]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(4-pyridinylmethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[2-(4-pyridinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[2-( 1-piperidinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[2-(4-morpholinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(1R,2S)-2,3-Dihydro-1H-inden-1-yl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo [2,1-f][1,2,4]triazine-6-carboxamide; N-[(1S,2R)-2,3-Dihydro-1H-inden-1-yl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Methoxy-4-methyl-3-[[5-methyl-6-[[4-(phenylmethyl)-1-piperidinyl]carbonyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide; N-Cyclopropyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Cyclopentyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[2-(4-Fluorophenyl)ethyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(Cyclohexylmethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(tetrahydro-2-furanyl)methyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(2-1H-Indol-3-ylethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Butyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo [2,1-f][1,2,4]triazine-6-carboxamide; N-(Cyclopropylmethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-methylbutyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(2-Furanylmethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-thienylmethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-phenoxyethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-methylcyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Ethyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-N,5-dimethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(2-Fluoroethyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(2,3-Dihydro-1H-inden-2-yl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Ethyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2,2,3,3,3-pentafluoropropyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5,7-dimethyl-N-( 1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-(4-Fluorophenyl)-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo [2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-N-(2-methoxyphenyl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-N-[(3-methoxyphenyl)methyl]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[3-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(2,6-Dichlorophenyl)methyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(1S)-1-Cyano-2-phenylethyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-phenylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-Methoxy-4-methyl-3-[[5-methyl-6-(1-pyrrolidinylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(2-pyridinylmethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(phenylmethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(4-methyl-2-thiazolyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1R)-1-methylpropyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1S)-1-methylpropyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(3-Fluorophenyl)methyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[1-(4-Fluorophenyl)ethyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; N-[(2,4-Difluorophenyl)methyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; and N-[(2,6-Difluorophenyl)methyl]-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[[(4-Cyanophenyl)amino]carbonyl]-2-methylphenyl]amino]-N-ethyl-5-methyl pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[[(4-Cyano-phenyl)amino]carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1S)-1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[[[(4-Cyanophenyl)amino]carbonyl]amino]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; or is (ii) a pharmaceutically-acceptable salt, hydrate, or prodrug thereof.
- 19. A compound according to claim 7 which is selected from N-Ethyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(1-methylethyl)pyrrolo [2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; and 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[1-methylpropyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; and a pharmaceutically-acceptable salt thereof.
- 20. A compound having the formula (II):
- 21. A compound according to claim 20, having the formula:
- 22. A compound according to claim 20 having the formula:
- 23. A compound according to claim 20 which is N-Ethyl-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; or a pharmaceutically acceptale salt comprising a methanesulfonic salt thereof.
- 24. A compound according to claim 20 which is 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-(l-methylethyl)pyrrolo [2,1-f][1,2,4]triazine-6-carboxamide; or a pharmaceutically acceptale salt thereof.
- 25. A compound according to claim 20 which is 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; or a pharmaceutically acceptale salt thereof.
- 26. A compound according to claim 20 which is 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[1-phenylethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; or a pharmaceutically acceptale salt thereof.
- 27. A compound according to claim 20 which is 4-[[5-[(Methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[1-methylpropyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; or a pharmaceutically-acceptable salt thereof.
- 28. A pharmaceutical composition comprising at least one compound according to claim 7 and a pharmaceutically-acceptable carrier or diluent.
- 29. A pharmaceutical composition comprising at least one compound according to claim 20 and a pharmaceutically-acceptable carrier or diluent.
- 30. A method of treating an inflammatory disorder comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 28.
- 31. The method of claim 30 in which the inflammatory disorder is selected from asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, and arthritis including rhematoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis.
RELATED INVENTIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/249,877, filed Nov. 17, 2000, and U.S. Provisional Application No. 60/310,561, filed Aug. 7, 2001, both of which are incorporated herein by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60249877 |
Nov 2000 |
US |
|
60310561 |
Aug 2001 |
US |