P-38 INHIBITORS

• US 20100004298A1
• Filed: 09/11/2009
• Published: 01/07/2010
• Est. Priority Date: 06/03/2003
• Status: Abandoned Application

• Current Assignee: Fabrice Pierre, Jianqiang Wang, Qing Dong
• Original Assignee: Fabrice Pierre, Jianqiang Wang, Qing Dong
• Inventors: Dong, Qing, Pierre, Fabrice, Wang, Jianqiang
• Application Number:
  US12/557,835
• Publication Number:
  US 20100004298A1
• Time in Patent Office: Days
• US Class Current: 514/363
• 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

1-109. -109. (canceled)

110. A compound of formula (I):

or pharmaceutically acceptable derivatives thereof, wherein;

R¹ is methyl, halo, hydroxyl, lower alkyl, lower cycloalkyl, lower alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —

NH₂ or —

NR⁴R⁵;

R² is attached to any available carbon atom of the phenyl ring A and at each occurrence is independently selected from alkyl, substituted alkyl, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —

OR⁴, —

CN, —

NR⁴R⁵;

—

S(═

O)alkyl, —

S(═

O)aryl, —

NHSO₂-arylene-R⁴, —

NHSO₂alkyl, —

CO₂R⁴, —

CONH₂, —

SO₃H, —

S(O)alkyl, —

S(O)aryl, —

SO₂NHR⁴, and —

NHC(═

O)NHR⁴;

n is 0, 1 or 2;

R³ is selected from hydrogen, alkyl, —

OR⁴, substituted alkyl, cycloalkyl, —

CR⁴cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle;

Y is a single bond, —

C(═

O)NH—

, —

NH(C═

O)—

, —

NH(C═

O)NH—

, —

SO₂NH—

, —

NHSO₂—

, —

C(═

O)—

;

Z is NR⁴, S or O;

B is a 5-membered heterocyclic ring system optionally substituted with up to two R¹³;

Q is independently selected from a single bond, —

O—

, —

S—

, —

NR⁴—

, —

S(O)—

, —

SO₂—

, —

C(O)—

, —

CO(O)—

, —

C(O)NH—

(C_0-4alkyl)- or —

CH₂—

;

D is a monocyclic or bicyclic ring system optionally containing up to four heteroatoms selected from N, O, and S, and wherein a CH₂ adjacent to any of the said N, O or S heteroatoms is optionally substituted with oxo (═

O) or D is C_1-6alkyl, and wherein D is optionally substituted by one to four (CR⁹R¹⁰)_wE groups;

w is an integer having a value from 0-4;

R¹⁰ is selected from H, C₁-C₄ alkylhydroxy, C₁-C₄alkylaryl and C₁-C₄alkylheteroaryl, wherein said aryl or heteroaryl group is unsubstituted or substituted with 1-3 groups independently selected from halo, NO₂, C₁-C₄alkyl, C₃-C₁₀cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloalkyl, haloalkoxy, OH, C₁-C₄alkoxy, C₁-C₄alkylcarbonyl, CN, NH₂, NR⁶R⁷, SR⁶, S(O)R⁶, SO₂R⁶, SO₃R⁶, SO₂NR⁶, CO₂H, CO₂R⁶, and CONR⁶R⁷;

E is selected from H, halogen, NO₂, C₁-C₄alkyl, C₃-C₁₀cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloalkyl, haloalkoxy, OH, OR⁶, CN, CHO, CO₂R⁶, CONR⁶R⁷, OCOR₆, OC(═

O)OR⁶, OC(═

O)NR⁶R⁷, OCH₂CO₂R⁶, C(═

O)R⁶, NH₂, NHR⁶, NR⁶R⁷, NR⁷C(═

O)R⁶, NR⁷C(═

O)OR⁶, NR⁷C(═

O)C(═

O)OR⁶, NR⁷C(═

O)C(═

O)NR⁶R⁷, NR⁷C(═

O)C(═

O)(C₁-C₆alkyl), NR⁷C(═

NCN)OR⁶, NR⁷C(═

O)NR⁶R⁷, NR⁷C(═

NCN)NR⁶R⁷, NR⁷C(═

NR⁶)NR⁷R⁸, NR⁶SO₂NR⁶R⁷, NR⁷SO₂R⁶, SR⁶, S(═

O)R⁶, SO₂R⁶, SO₃R⁷, SO₂NR⁶R⁷, NHOH, NHOR⁶, NR⁶NR⁷NR⁸, N(COR⁶)OH, N(CO₂R⁶)OH, CONR⁷(CR⁹R¹⁰)_rR⁶, CO(CR⁹R¹⁰)_pO(CHR⁹)_qCO₂R⁶, CO(CR⁹CR¹⁰)_rR⁶, CO(CR⁹R¹⁰)_pO(CR⁹R¹⁰)_pO(CHR⁹)_qCO²R₆, CO(CR⁹CR¹⁰)_rOR⁶, CO(CR⁹R¹⁰)_pO(CR⁹R¹⁰)_qR⁶, CO(CR⁶CR¹⁰)_rNR⁶R⁷, OC(O)O(CR⁹R¹⁰)_mNR⁶R⁷, O(CO)_n(CR⁹R¹⁰)R⁶, O(CR⁹R¹⁰)_mNR⁶R⁷_mNR⁷C(O)(CR⁹R¹⁰)_rOR⁶, NR⁷C(═

NC)(CR⁹R¹⁰)_rR⁶, NR⁷CO(CR⁹R¹⁰)_rNR⁶R⁷, NR⁷(CR⁹R¹⁰)_mOR⁶, NR⁷(CR⁹R¹⁰)_rCO₂R⁶, NR⁷(CR⁹R¹⁰)_mNR⁶R⁷, NR⁷, NR³(CR⁹R¹⁰)_nSO₂(CR⁹R¹⁰)_rCO₂R⁶, NR⁷(CR⁹R¹⁰)_mNR⁶R⁷, NR⁷(CR⁹R¹⁰)_nSO₂(CR⁹R¹⁰)_qR⁶, CONR⁷(CR⁹R¹⁰)_nSO₂(CR⁹R¹⁰)_qR⁶, SO₂NR⁷(CR⁹R¹⁰)_qR⁶, SO₂NR⁶(CR⁹R¹⁰)_mOR⁶, C₂-C₆alkenyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkylmethyl, aryl, heterocyclic optionally substituted with one or two alkyl groups, heteroaryl optionally substituted with one or two alkyl groups and alkylaryl, wherein said aryl groups are unsubstituted or substituted with 1 or 2 substituents each independently selected from R¹²;

m is an integer having a value from 2-6;

p is an integer having a value from 1-3;

q is an integer having a value from 0-3;

r is an integer having a value from 0-6;

R¹² at each occurrence is independently selected from halo, NO₂, C₁-C₄alkyl, C₃-C₁₀cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloalkyl, haloalkoxy, OH, oxo, C₁-C₄alkoxy, OR⁶, O(CR⁹R¹⁰)CO₂R⁶, O(CR⁹R¹⁰)_mNR⁶R⁷, O(CR⁹R¹⁰)_pCN, O(CR⁹R¹⁰)_rC(═

O)NR⁶R⁷, C₁-C₄alkylcarbonyl, CN, NH₂, NHR⁶, NR⁶R⁷, NR⁷(CR⁹R¹⁰)CO₂R⁶, NR⁷OR⁶, NR⁷(CR⁹R¹⁰)_mOR⁶, NR⁷CH((CR⁹R¹⁰)_pOR⁶)₂, NR⁷C((CR⁹R¹⁰)_pOR⁶)₃, NR⁷C(═

O)R⁶, NR⁷(CR⁹R¹⁰)_mNR⁶R⁷, NR⁷(CR⁹R¹⁰)_qR⁶, SR⁷, S(O)R⁷, S₂R⁷, SO₂NR⁶, SO₃R⁷, CO₂H, CO₂R⁶, and CONR⁶R⁷;

R⁴ is hydrogen, lower alkyl and lower cycloalkyl;

R⁵ is hydrogen, lower alkyl and lower cycloalkyl;

R⁶, R⁷ and R⁸ are independently selected as follows;

i) R⁶, R⁷ and R⁸ are independently selected from H, C₁-C₆alkyl, C₃-C₁₀cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkylcarbonyl, C₃-C₇cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆alkoxycarbonyl, aryl(C₀-C₅alkyl)carbonyl, aryl(C₁-C₅alkoxy)carbonyl, heterocyclic(C₀-C₅alkyl)carbonyl, heterocyclic(C₁-C₅alkoxy)carbonyl, C₁-C₆alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C₀-C₄alkylaryl, C₀-C₄alkylheterocyclic, wherein said cycloalkyl, aryl, or heterocyclic groups are unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of C₁-C₄alkyl, hydroxyl, C₁-C₄alkoxy, F, Cl, Br, haloalkyl, NO₂ and CN;

or,

ii) R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸ when both substituents are on the same nitrogen atom (as in (—

NR⁶R⁷) or (—

NR⁷R⁸)), can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo(3,2,2)nonan-3yl, and 1-tetrazolyl, the said heterocycle being optionally substituted with 1-3 groups each independently selected from oxo, C₀-C₄alkylOH, C₀-C₄alkylOC₁-C₄alkyl, C₀-C₄alkylCONH₂, C₀-C₄alkylCO₂C₀-C₄alkyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₀-C₆alkylcarbonyl, C₃-C₇cycloalkylcarbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇cycloalkoxycarbonyl, —

NHCOalkyl, aryl, heteroaryl, arylalkoxycarbonyl, heteroarylalkoxycarbonyl, C₁-C₆alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl;

R⁹ is hydrogen or C₁-C₄alkyl; and

R¹³ is hydrogen, alkyl, haloalkyl, aminocarbonyl, hydroxycarbonyl, alkoxycarbonyl, cycloalkylalkylaminocarbonyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, alkylthio, alkylaminocarbonyl or lower cycloalkyl;

where the substituents on alkyl group are selected from one to four substituents selected from halo, hydroxy, alkoxy, oxo (═

O), alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl;

alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, CONHaryl, CONHaralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl;

alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted or unsubstituted heterocycles, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the substituents on aryl group are selected from one to four substituents selected from alkyl, substituted alkyl, haloalkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, hydroxyalkyl, aminoalkyl, alkoxy, alkanoyl, alkanoyloxy, amino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, cyanoalkyl, heterocyclyl, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, aminocarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, aryloxy and CONR^aR^b, where R^a and R^b are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonylaminoalkyl and alkylamino;

or R^a and R^b together with the nitrogen on which they are substituted, form a 3-6 membered heterocyclic or heteroaryl ring;

the substituent may be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

111. The compound of claim 110, wherein R¹ is lower alkyl.

112. The compound of claim 110, wherein R³ is selected from alkyl, —

OR⁴, substituted alkyl, cycloalkyl, —

CR⁴cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.

113. The compound of claim 110, wherein R³ is cycloalkyl, cycloalkylalkyl, alkoxyalkyl or heteroaryl.

114. The compound of claim 110, wherein R³ is methyl, isopropyl, ethyl, cyclopropyl, cyclopropylmethyl, methoxymethyl, oxazolyl or thiazolyl.

115. The compound of claim 110, wherein Y is a single bond, —

C(═

O)NH—

or —

SO₂NH.

116. The compound of claim 110, wherein B is a thiazolyl, oxazolyl, dithiazolyl, thiadiazolyl, oxadiazolyl or triazinyl ring optionally substituted with one or two R¹³.

117. The compound of claim 110, wherein Q is a single bond, —

CO(O)—

, —

C(O)—

or —

C(O)NH—

(C_0-4alkyl)-.

118. The compound of claim 110, 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.

119. The compound of claim 110, 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.

120. The compound of claim 110 that has formula (I-1):

where B is selected from 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, oxazole and thiazole.

121. The compound of claim 110 that has formula (I-2):

where X¹ is selected from O, S and optionally substituted N, where the substituent on the N when present is selected from hydrogen, alkyl, substituted alkyl, alkenyl or alkynyl and X² is S or O.

122. The compound of claim 110 that has formula (I-3):

123. The compound of claim 110 that has formula (I-5):

where n₁ is 0-5.

124. The compound of claim 110 that has formula (I-6):

where n₃ is 1-4.

125. The compound of claim 110 that has formula (I-7):

where n₂ is 0-4.

126. A compound of claim 110 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-ylamino]-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-M ethyl-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-methyl phenylamino)-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-hydroxymethylphenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-m-tolyl-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluorophenyl)thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-p-tolyl-thiazole-5-carboxylic acid benzylamide;

4-(3-Cyanophenyl)-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazole-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-cyclopropylcarbamoyl-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-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]benzoic acid ethyl ester;

3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-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-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxymethyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

4-(3-Carbamoylphenyl)-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-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-thiazole-5-carboxylic acid benzylamide;

4-(3-Aminomethyl-phenyl)-2-(5-cyclo-propylcarbamoyl-2-methylphenylamino)-thiazole-5-carboxylic acid benzylamide;

3-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)-thiazol-4-yl]-benzoic acid;

4-[5-Benzylcarbamoyl-2-(5-cyclopropyl-carbamoyl-2-methyl-phenylamino)thiazol-4-yl]-benzoic acid;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-o-tolyl-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methanesulfonyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-[4-(morpholine-4-carbonyl)-phenyl]-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-3-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylsulfanyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3-fluoro-4-methoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-fluoro-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(3,4-difluoro-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(2-fluoro-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(1H-indol-5-yl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-methoxy-3-methyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-ethylcarbamoyl-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-hydroxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-2-methyl-phenylamino)-4-(4-propoxy-phenyl)-thiazole-5-carboxylic acid benzylamide;

4-[3-(3-Amino-propoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methyl-phenylamino)-thiazole-5-carboxylic acid benzylamide;

4-[3-(2-Amino-ethoxy)-phenyl]-2-(5-cyclopropylcarbamoyl-2-methylphenyl-amino)-thiazole-5-carboxylic acid benzylamide;

2-(5-Cyclopropylcarbamoyl-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.

127. A pharmaceutical composition, comprising a compound of claim 110 and a pharmaceutically acceptable carrier.

128. A method of inhibiting p38 kinase activity, comprising administering a compound of claim 110.

129. The method of claim 128, 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.