Claims
- 1. A method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by cytokine activity or in which cytokine activity is implicated, comprising administering a compound of formula (I):
- 2. The method of claim 1, wherein the cytokine activity is modulated by p38 kinase.
- 3. The method of claim 1, wherein the p38 kinase is p38 α, p38β, p38 γ or p38 δ.
- 4. The method of claim 1, wherein the disease or disorder is selected from inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, angiogenic disorder, infectious disease, neurodegenerative disease and viral disease.
- 5. The method of claim 4, wherein the inflammatory disease is selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.
- 6. The method of claim 4, wherein the autoimmune disease is selected from glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis and graft vs. host disease.
- 7. The method of claim 4, wherein the destructive bone disorder is selected from osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.
- 8. The method of claim 4, wherein the proliferative disorder is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma.
- 9. The method of claim 4, wherein the infectious disease is selected from sepsis, septic shock, and Shigellosis.
- 10. The method of claim 4, wherein the viral disease is selected from acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis.
- 11. The method of claim 4, wherein the degenerative disease is selected from acute Alzheimer's disease, Parkinson's disease, cerebral ischemia, and other neurodegenerative diseases.
- 12. The method of claim 1, wherein the disease or disorder is modulated or otherwise affected by the activity of cytokine IL-1, TNF, IL-6 or IL-8.
- 13. The method of claim 12, wherein the disease or disorder is modulated or otherwise affected by the activity of cytokine IL-1.
- 14. The method of claim 12, wherein the cytokine IL-1 modulated disease or disorder is selected from rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, inflammatory reaction induced by endotoxin, inflammatory bowel disease, tuberculosis, atherosclerosis, muscel degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, diabetes, pancreatic .beta.-cell disease and Alzheimer's disease.
- 15. The method of claim 12, wherein the cytokine TNFa modulated disease or disorder is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, malignancy, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis.
- 16. The method of claim 12, wherein the cytokine TNFα modulated disease or disorder is associated with a viral infection.
- 17. The method of claim 16, wherein the viral infection is selected from HIV, CMV, influenza and herpes.
- 18. The method of claim 16, wherein the viral infection is a veterinary virus infection caused by equine infectious anaemia virus, caprine arthritis virus, visna virus; maede virus, retrovirus infections.
- 19. The method of claim 12, wherein the cytokine IL-8 modulated disease or disorder is selected from psoriasis, inflammatory bowel disease, asthma, cardiac reperfusion injury, renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.
- 20. A method of reducing the expression of inducible pro-inflammatory proteins, comprising administering a compound of formula (I):
- 21. The method of claim 20, wherein the pro-inflammatory protein is prostaglandin endoperoxide synthase-2 (PGHS-2).
- 22. A method of treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with inducible pro-inflammatory proteins, comprising administering a compound of formula (I):
- 23. The method of claim 22, wherein the disease or disorder is selected from edema, analgesia, fever, pain, neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain.
- 24. A method of inhibiting p38 kinase activity, comprising administering a compound of formula (I):
- 25. The method of claim 24, wherein the p38 kinase is selected from p38α kinase, p38β kinase, p38γ kinase and p38δ kinase.
- 26. The method of claim 24, wherein the p38 kinase is selected from p38α kinase and p38β kinase.
- 27. The method of claim 1, wherein the disease or disorder is selected from pancreatitis, asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic O-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, meloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders, solid tumors, ocular neovasculization, infantile haemangiomas; viral diseases, acute hepatitis infection, hepatitis A, hepatitis B, hepatitis C, HIV infection, CMV retinitis, AIDS, SARS, ARC, malignancy, herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase synthase-2.
- 28. The method of claim 1, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2 or —NR4R5.
- 29. The method of claim 1, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and R3 is selected from alkyl, —OR4, substituted alkyl, cycloalkyl, —CR4cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
- 30. The method of claim 1, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and Y is-C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO2NH—, —NHSO2— or —C(═O)—.
- 31. A compound of formula (I):
- 32. A compound of formula (I):
- 33. A compound of formula (I):
- 34. The compound of claim 31, wherein R1 is lower alkyl.
- 35. The compound of claim 31, wherein R1 is methyl.
- 36. The compound of claim 31, wherein R2 is hydrogen or alkyl.
- 37. The compound of claim 31, wherein R2 is hydrogen or lower alkyl.
- 38. The compound of claim 31, wherein R2 is hydrogen.
- 39. The compound of claim 31, wherein R3 is selected from alkyl, —OR4, substituted alkyl, cycloalkyl, —CR4cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
- 40. The compound of claim 31, wherein R3 is cycloalkyl, cycloalkylalkyl, alkoxyalkyl or heteroaryl.
- 41. The compound of claim 31, wherein R3 is methyl, isopropyl, ethyl, cyclopropyl, cyclopropylmethyl, methoxymethyl, oxazolyl or thiazolyl.
- 42. The compound of claim 31, wherein Y is —C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO2NH—, —NHSO2— or —C(═O)—.
- 43. The compound of claim 31, wherein Y is a single bond, —C(═O)NH— or —SO2NH.
- 44. The compound of claim 31, wherein B is a thiazolyl, oxazolyl, dithiazolyl, thiadiazolyl, oxadiazolyl or triazinyl ring optionally substituted with one or two R13.
- 45. The compound of claim 31, wherein B is a thiazolyl ring optionally substituted with one or two R13.
- 46. The compound of claim 31, wherein B is a thiazolyl ring optionally substituted with one R13.
- 47. The compound of claim 31, wherein Q is a single bond, —CO(O)—, —C(O)— or —C(O)NH—(C0-4alkyl)-.
- 48. The compound of claim 31, wherein Q is a single bond.
- 49. The compound of claim 31, wherein Q is —C(O)—.
- 50. The compound of claim 31, wherein Q is —CO(O)—.
- 51. The compound of claim 31, wherein Q is —C(O)NH—(C0-4alkyl)-.
- 52. The compound of claim 31, wherein Q is —C(O)NH— or —C(O)NHCH2CH2—.
- 53. The compound of claim 31, wherein Q is —C(O)NH—.
- 54. The compound of claim 31, wherein D is a monocyclic or bicyclic ring system optionally containing up to four heteroatoms selected from N, O, and S or D is C1-6alkyl and wherein D is optionally substituted by one to four (CR9R10)wE groups.
- 55. The compound of claim 31, wherein D is C1-6alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl ring, wherein the heteroatoms are selected from O, N and S and D is optionally substituted with one to four (CR9R10)wE groups.
- 56. The compound of claim 31, wherein D is selected from methyl, ethyl, propyl, ethoxy cyclopropyl, phenyl, benzyl, benzimidazolyl, piperazinyl, piperidinyl, diazaoxazolyl or pyrimidinyl and D is optionally substituted with one to four (CR9R10)wE groups.
- 57. The compound of claim 31, wherein D is selected from 1-piperazinyl, 4-piperidinyl, 4-pyridinyl, 1,3,4-diazaoxazolyl or 3-pyridinyl, and D is optionally substituted with one or two (CR9R10)wE groups.
- 58. The compound of claim 31, wherein D is phenyl and D is optionally substituted with one or two (CR9R10)wE groups.
- 59. The compound of claim 31, wherein w is 1.
- 60. The compound of claim 31, wherein w is 0.
- 61. The compound of claim 31, wherein D is substituted with one to four substituents selected from halo, alkyl, nitro, alkoxy, alkoxycarbonylalkoxy, alkoxyamidoalkylamido, hydroxycarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, aryl, heteroaryl containing 1 to 3 heteroatoms and optionally substituted with one or two alkyl groups, and heterocyclyl containing 1 to 3 heteroatoms and optionally substituted with two or more alkyl or alkoxycarbonyl groups.
- 62. The compound of claim 31, wherein D is substituted with one to four substituents selected from chloro, fluoro, methyl, methoxy, ethoxy, methylaminocarbonyl, methoxycarbonylamino, tertbutyloxyamidoethylamido, methoxycarbonyl or phenyl.
- 63. The compound of claim 31, wherein D is substituted with a heterocyclyl ring selected from morpholinyl or piperidinyl, where the heterocyclyl ring is further substituted with one or two methyl or methoxycarbonyl groups.
- 64. The compound of claim 31, wherein D is substituted with heteroaryl ring selected from isoxazolyl, furyl, benzimidazolyl and thiazolyl, where the heteroaryl ring is further substituted with one or two methyl groups.
- 65. The compound of claim 31, wherein D is substituted with N-morpholinyl, piperidin-4-yl or 1-methoxycarbonylpiperidin-4-yl.
- 66. The compound of claim 31, wherein D is substituted with 2-benzimidazolyl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-yl or 2-methylthiazol-5-yl.
- 67. The compound of claim 31, wherein D is selected from methyl, ethyl, propyl, isopropyl, hydroxycarbonylmethyl, methylaminocarbonylmethyl, ethoxycarbonylpropyl, ethoxycarbonylmethyl, phenyl, fluorophenyl, tolyl, methoxyphenyl, methoxycarbonylmethoxy, ethoxy, benzimidazolyl, methylpiperazinyl, piperidinyl, 1,3,4-diazaoxazolyl, morpholin-1-ylphenyl, piperidin-4-ylphenyl, 1-methoxycarbonylpiperidin-4-ylphenyl, benzyl, chlorophenyl, methylcarbonylaminophenyl, bromophenyl, carboxymethyl, tertbutyloxyamidoethylamidophenyl, methylaminocarbonylmethyl, N-methoxycarbonylpiperidinyl, piperidinyl, pyridinyl, cyclopropyl, dimethylisoxazolylmethyl, methylisoxazolylmethyl and methylthiazolylmethyl.
- 68. The compound of claim 31, wherein D is selected from methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, hydroxycarbonylmethyl, ethoxycarbonylpropyl, methylaminocarbonylmethyl, ethoxycarbonylmethyl, phenyl, 4-fluorophenyl, p-tolyl, 4-methoxyphenyl, 4-methoxycarbonylmethoxyphenyl, ethoxy, 2-benzimidazolylmethyl, 4-methylpiperazin-1-yl, 1,3,4-diazaoxazolyl, 4-piperidinyl, benzyl, 4-chlorophenyl, 4-morpholin-1-ylphenyl, 4-(piperidin-4-yl)phenyl. 4-(1-methoxycarbonylpiperidin-4-yl)phenyl, 4-ethoxycarbonylmethoxyphenyl, 4-methylamidophenyl, and 4-tertbutyloxyamidoethylam idophenyl.
- 69. The compound of claim 31, wherein R13 is selected from methyl, trifluoromethyl, tert-butyl, amido, methoxycarbonyl, carboxyl, ethoxycarbonyl, cyclopropylmethylaminocarbonyl, thienyl, methylenedioxybenzyl, ethylenedioxybenzyl, pyridinyl, and phenyl; and R13 is optionally substituted with one or more R14, where R14 is hydrogen, chloro, fluoro, hydroxy, methyl, cyano, amino, aminoethyl, N-morpholinyl, methylsulfonylamino, tertbutoxyamidomethylamido, tertbutoxyamidoethylamidophenyl, aminomethylamido, methoxycarbonylpiperazinyl, methylcarbonyl, methoxy, ethoxy, methoxycarbonyl, trifluoromethyl, hydroxymethyl, amido, aminomethyl, carboxy, tertbutoxyamidoethylamido, aminoethylamido, methylsulfonyl, N-morpholinocarbonyl, cyclopropylamido, ethylthio, carboxymethoxy, N-morpholinoethoxy, aminoethoxy, ethylamido, n-butoxy, aminopropyloxy or carboxymethoxy.
- 70. The compound of claim 31, wherein R13 is selected from methyl, trifluoromethyl, tert-butyl, amido, methoxycarbonyl, carboxyl, ethoxycarbonyl, cyclopropylmethylaminocarbonyl, thienyl, methylenedioxybenzyl, ethylenedioxybenzyl, 4-cyanomethylphenyl, 4-cyanophenyl, 2-chlorophenyl, 4-hydroxyphenyl, m-tolyl, 3-fluorophenyl, p-tolyl, 3-cyanophenyl, 5-methylcarbonylthien-2-yl, 5-cyanothien-2-yl, 4-methoxyphenyl, 4-methoxycarbonylphenyl, 4-fluorophenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-aminocarbonylphenyl, 4-aminocarbonylphenyl, 3-aminomethylphenyl, 3-carboxyphenyl, 4-carboxyphenyl, o-tolyl, 2,4-difluorophenyl, 3-aminoethylaminocarbonylphenyl, 4-aminoethylaminocarbonylphenyl, 3-aminomethylaminocarbonylphenyl, 4-aminomethylaminocarbonylphenyl, 4-methylsulfonylphenyl, 4-(N-morpholino)carbonylphenyl, 4-ethoxy-3-fluorophenyl, 3-cyclopropylamidophenyl, 3-ethoxyphenyl, 4-ethylthiophenyl, 4-methoxy-3-fluorophenyl, 4-fluoro-3-methylphenyl, 3,4-difluorophenyl, 3-methyl-4-methoxyphenyl, 3-hydroxycarbonylmethoxyphenyl, 4-(N-morpholino)ethoxyphenyl, 4-hydroxyphenyl, phenyl, 3-aminoethoxyphenyl, 4-ethylaminocarbonylphenyl, 4-n-butoxyphenyl, 3-methyl-4-methoxyphenyl, 3-aminopropyloxyphenyl 4-cyanomethylphenyl, 4-aminophenyl, 3-aminophenyl, 4-aminoethylphenyl, 4-morpholin-1-ylphenyl, 4-methylsulfonylaminophenyl, 3-tertbutoxyamidomethylamidophenyl, 4-tertbutoxyamidomethylamidophenyl, 3-tertbutoxyamidoethylamidophenyl, 4-tertbutoxyamidoethylamidophenyl, 3-aminomethylamidophenyl, 4-(methoxycarbonylpiperazin-1-yl)phenyl and 2-methoxypyrimidin-3-yl.
- 71. The compound of claim 31 that has formula (I-1):
- 72. The compound of claim 31 that has formula (I-2):
- 73. The compound of claim 31 that has formula (I-3):
- 74. The compound of claim 31 that has formula (I-4):
- 75. The compound of claim 31 that has formula (I-5):
- 76. The compound of claim 31 that has formula (I-6):
- 77. The compound of claim 31 that has formula (I-7):
- 78. The compound of claim 31 that has formula (I-8):
- 79. The compound of claim 31 that has formula (I-9):
- 80. The compound of claim 31 that has any of formulae (I-10):
- 81. A compound selected from:
N-methoxy-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide; N-methoxy-4-methyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; 3-[4-(4-Cyano-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benzamide; N-Cyclopropyl-3-[4-(4-fluoro-phenyl)-thiazol-2-yl amino]-4-methyl-benzamide; N-Cyclopropyl-3-[4-(4-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; N-Cyclopropyl-3-[4-(3-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; N-Cyclopropyl-3-[4-(2-methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-benzamide; N-Cyclopropyl-4-methyl-3-(5-methyl-4-phenyl-thiazol-2-ylamino)-benzamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid phenylamide; N-Isopropyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; N-Ethyl-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; N-(2-Methoxy-ethyl)-4-methyl-3-(4-phenyl-thiazol-2-ylamino)-benzamide; [4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-phenyl]-morpholin-4-yl-methanone; 4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-1-thiazol-2-yl-benzamide; 4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-N-[1,2,4]triazol-4-yl-benzamide; 4-Methyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-3-(4-phenyl-thiazol-2-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(5-phenyl-oxazol-2-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,2,4] oxadiazol-3-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-ylamino)-benzamide; N-Cyclopropyl-4-methyl-3-(3-phenyl-[1,2,4]thiadiazol-5-ylamino)-benzamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carboxylic acid benzyl ester; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-methyl-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester; 5-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-nitro-phenyl)-thiazole-5-carboxylic acid ethyl ester; N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-thiazol-2-ylamino]-benzamide; 3-[5-Bromo-4-(4-nitro-phenyl)-thiazol-2-ylamino]-N-cyclopropyl-4-methyl-benzamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-morpholin-4-yl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid methyl ester; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-phenyl-thiazole-5-carboxylic acid cyclopropylmethyl-amide; 4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-methoxycarbonyl-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl ester; 4-{3-[2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-5-(cyclopropylmethyl-carbamoyl)-thiazol-4-yl]-phenyl}-piperidine-1-carboxylic acid methyl ester; 4-{3-[2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-5-[1,3,4]oxadiazol-2-yl-thiazol-4-yl]-phenyl}-piperidinium trifluoroacetate; N-Cyclopropyl-4-methyl-3-[4-(4-nitro-phenyl)-5-[1,3,4]oxadiazol-2-yl-thiazol-2-ylamino]-benzamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 4-Bromo-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 4-(4-Cyanomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 4-(4-Cyano-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-4,5-dihydro-thiazole-5-carboxylic acid benzylamide; 4-(2-Chloro-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(3-hydroxymethylphen-yl)-thiazole-5-carbox-ylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-m-tolyl-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3-fluorophenyl)thia-zole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-p-tolyl-thiazole-5-carboxylic acid benzylamide; 4-(3-Cyano-phenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thia-zole-5-carboxylic acid benzylamide; 4-(5-Acetyl-thiophen-2-yl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 4-Benzo[1,3]dioxol-5-yl-2-(5-cycloprop-ylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 4-(5-Cyano-thiophen-2-yl)-2-(5-cycloprop-ylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 4-[5-Benzylcarbamo-yl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiaz-ol-4-yl]benzoic acid ethyl ester; 3-[5-Benzylcarbamo-yl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiaz-ol-4-yl]-benzoic acid methyl ester; 2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(4-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropyl-carbamoyl-2-methyl-phenylamino)-4-(2-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-hydroxymethyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 4-(3-Carbamoylphen-yl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 4-(4-Carbamoyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(2,3-dihydrobenzo [1,4] di-oxin-6-yl)-thiazole-5-carboxylic acid benzylamide; 4-(3-Aminomethyl-phenyl)-2-(S-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide; 3-[5-Benzylcarbamo-yl-2-(5-cyclopropyl-carbaroyl-2-methyl-phenylamino)-thiaz-ol-4-yl]-benzoic acid; 4-[5-Benzylcarbamo-yl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]-benzoic acid; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-o-tolyl-thiazole-5-car-boxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(2,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-methanesulfonyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-[4-(morpholine-4-carbonyl)-phenyl]-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-ethoxy-3-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-ethylsulfanyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3-fluoro-4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(3,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(2-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(1H-indol-5-yl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-methoxy-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylc ar-b amoyl-2-methyl-phenyl amino)-4-(4-ethylc arb amoyl-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-hydroxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-(4-propoxy-phenyl)-thiazole-5-carboxylic acid benzylamide; 4-[3-(3-Amino-propoxy)-phenyl]-2-(5-cyclopropylcar-bamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 4-[3-(2-Amino-ethoxy)-phenyl]-2-(5-cyclopropylcarbamo-yl-2-methylphenyl-amino)-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcar-bamoyl-2-methyl-phenylamino)-4-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-thiazole-5-carboxylic acid benzylamide; 2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methanesulfonylamino-phenyl)-thiazole-5-carboxylic acid benzylamide; 4-(4-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; 4-(3-Amino-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; ({3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester; (2-{3-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester; ({4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester; (2-{4-[5-Benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester; 4-[3-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 4-[3-(3-Amino-propionylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 4-[4-(2-Amino-acetylamino)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide ditrifluoroacetate; 2-{4-[5-benzylcarbamoyl-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-phenylcarbamoyl}-ethyl-ammonium ditrifluoroacetate; 4-(4-Cyanomethyl-phenyl)-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide; and 4-[4-(2-Amino-ethyl)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide.
- 82. A pharmaceutical composition, comprising a compound of claim 31 and a pharmaceutically acceptable carrier.
- 83. The pharmaceutical composition of claim 82 formulated for single dosage administration.
- 84. The method of claim 22, wherein the disease or disorder is selected from pancreatitis, asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic P-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, meloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders, solid tumors, ocular neovasculization, infantile haemangiomas; viral diseases, acute hepatitis infection, hepatitis A, hepatitis B, hepatitis C, HIV infection, CMV retinitis, AIDS, SARS, ARC, malignancy, herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase synthase-2.
- 85. The method of claim 20, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2 or —NR4R5.
- 86. The method of claim 20, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and R3 is selected from alkyl, —OR4, substituted alkyl, cycloalkyl, —CR4cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
- 87. The method of claim 20, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and Y is-C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO2NH—, —NHSO2— or —C(═O)—.
- 88. The method of claim 22, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2 or —NR4R5.
- 89. The method of claim 22, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and R3 is selected from alkyl, —OR4, substituted alkyl, cycloalkyl, —CR4cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
- 90. The method of claim 22, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and Y is —C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO2NH—, —NHSO2— or —C(═O)—.
- 91. The method of claim 24, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2 or —NR4R5.
- 92. The method of claim 24, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and R3 is selected from alkyl, —OR4, substituted alkyl, cycloalkyl, —CR4cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
- 93. The method of claim 24, wherein R1 is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH2, —NR4R5 or —OR4; and Y is —C(═O)NH—, —NH(C═O)—, —NH(C═O)NH—, —SO2NH—, —NHSO2— or —C(═O)—.
- 94. A method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by cytokine activity or in which cytokine activity is implicated, comprising administering a compound of claim 31.
- 95. A method of reducing the expression of inducible pro-inflammatory proteins, comprising administering a compound of claim 31.
- 96. A method of treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with inducible pro-inflammatory proteins, comprising administering a compound of claim 31.
- 97. A method of inhibiting p38 kinase activity, comprising administering a compound of claim 31.
- 98. A method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by cytokine activity or in which cytokine activity is implicated, comprising administering a compound of claim 32.
- 99. A method of reducing the expression of inducible pro-inflammatory proteins, comprising administering a compound of claim 32.
- 100. A method of treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with inducible pro-inflammatory proteins, comprising administering a compound of claim 32.
- 101. A method of inhibiting p38 kinase activity, comprising administering a compound of claim 32.
- 102. A method of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by cytokine activity or in which cytokine activity is implicated, comprising administering a compound of claim 33.
- 103. A method of reducing the expression of inducible pro-inflammatory proteins, comprising administering a compound of claim 33.
- 104. A method of treating, preventing, or ameliorating one or more symptoms of diseases or disorders associated with inducible pro-inflammatory proteins, comprising administering a compound of claim 33.
- 105. A method of inhibiting p38 kinase activity, comprising administering a compound of claim 33.
- 106. A pharmaceutical composition, comprising a compound of claim 32 and a pharmaceutically acceptable carrier.
- 107. The pharmaceutical composition of claim 106 formulated for single dosage administration.
- 108. A pharmaceutical composition, comprising a compound of claim 33 and a pharmaceutically acceptable carrier.
- 109. The pharmaceutical composition of claim 108 formulated for single dosage administration.
RELATED APPLICATIONS
[0001] Priority is claimed herein under 35 U.S.C. § 119(e) to U.S. provisional patent application Ser. No. 60/475,662, filed Jun. 3, 2003, and No. 60/531,541, filed Dec. 19, 2003, entitled “P-38 INHIBITORS.” The disclosures of the above-referenced provisional applications are incorporated herein by reference in their entirety.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60475662 |
Jun 2003 |
US |
|
60531541 |
Dec 2003 |
US |