P-38 inhibitors

• US 20040254236A1
• Filed: 06/02/2004
• Published: 12/16/2004
• Est. Priority Date: 06/03/2003
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Dong, Qing, Pierre, Fabrice, Wang, Jianqiang
• Granted Patent: US 7,652,044 B2
• Time in Patent Office: Days
• US Class Current: 514/426
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 249/14 : Nitrogen atoms
• CPC Class Codes: C07D 263/48 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 271/07 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/08 : 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Provided are 5-membered heterocycle-based p38 kinase, including p38α and p38β kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

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.

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)—

.

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).

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)—

.

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.

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.

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)—

.

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.

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)—

.

31. 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—

(C_0-4alkyl)-.

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—

(C_0-4alkyl)-.

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 C_1-6alkyl and wherein D is optionally substituted by one to four (CR⁹R¹⁰)_wE groups.

55. The compound of claim 31, wherein D is C_1-6alkyl, 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):

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.

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.

32. A compound of formula (I):

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.

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.

33. A compound of formula (I):

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.

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.

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.