Kinase inhibitors

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

1 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 B is a monocyclic heteroaromatic ring, a 6,6 bicyclic heteroaromatic ring, or a 6,5 bicyclic heteroaromatic ring wherein B is optionally and independently substituted with R 12 ′ and independently optionally and independently substituted with one or more R 12  groups in addition to R 3 , and the point of attachment to —C(Z)— of the 6,5 bicyclic ring is on the 6 membered ring; 
 Z is O or S; 
 R 1  is —H, halogen, —CN, —NO 2 , or -T1-Q1; 
 T1 is absent or C1-10 aliphatic, wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 4 )—, or —C(O)—; T1 is optionally and independently substituted with one or more JT1; 
 Q1 is absent, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Q1 is optionally and independently substituted with J1 and independently optionally and independently substituted with one or more R 13  groups; 
 J1 is —Y1-M1; 
 Y1 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —N(R $ )—, —O—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —, Y1 is optionally and independently substituted with one or more JT1; 
 M1 is C1-6 aliphatic, C3-8 cycloaliphatic, halo C1-4 aliphatic, —O(halo C1-4 aliphatic), 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, —OR $ , —SR $ , —N(R $ ) 2 , —C(O)R $ , —C(O) 2 R $ , —C(O)N(R $ ) 2 , —OC(O)R $ , —OC(O)N(R $ ) 2 , —NR $ C(O)R $ , —NR $ C(O) 2 R $ , —NR $ C(O)N(R $ ) 2 , —SO 2 N(R $ ) 2 , —NR $ S(O) 2 R $ , —S(O)R $ , —S(O) 2 R $ , —P(O)R $ , —P(O) 2 R $ , —P(O)(R $ ) 2 , or —PO(OR $ ) 2 ; M1 is optionally and independently substituted with one or more J; or M1 is absent, halogen, —N(O) 2 , or —CN; 
 R 2  is —H, halogen, —CN, —N(O) 2 , or optionally and independently substituted C1-C6 alkyl; 
 R 3  is halogen, —CN, —NO 2 , or -T2-Q2; 
 T2 is absent or C1-10 aliphatic, wherein up to three methylene units of T2 are optionally and independently replaced by G′ wherein G′ is —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 4 )—, or —C(O)—; T2 is optionally and independently substituted with one or more JT2; 
 Q2 is absent, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Q2 is optionally and independently substituted with J2 and independently optionally and independently substituted with one or more R 13  groups; wherein when R 1  and R 2  are —H, R 12  is absent, R 12′  is absent, Z is O, R 3  is -T2-Q2 then -T2-Q2 is not absent, —NHCH 2 CH(OH)CH 2 OH, or 
 
       
         
           
           
               
               
           
         
         J2 is —Y2-M2; 
         Y2 is absent, oxo, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G1′ wherein G1′ is —N(R $ )—, —O—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —, Y2 is optionally and independently substituted with one or more JT2; 
         M2 is C1-6 aliphatic, C3-8 cycloaliphatic, halo C1-4 aliphatic, —O(halo C1-4 aliphatic), 3-8 membered heterocyclyl, heteroaryl, aryl, —OR $ , —SR $ , —N(R $ ) 2 , —C(O) 2 R $ , —C(O) 2 R $ , —C(O)N(R $ ) 2 , —OC(O)R $ , —OC(O)N(R $ ) 2 , —NR $ C(O)R $ , —NR $ C(O) 2 R $ , —NR $ C(O)N(R $ ) 2 , —SO 2 N(R $ ) 2 , —NR $ S(O) 2 R $ , —S(O)R $ , —S(O) 2 R $ , —P(O)R $ , —P(O) 2 R $ , —P(O)(OR $ ) 2 , or —PO(OR $ ) 2 ; wherein M2 is optionally and independently substituted with one or more J; or M2 is absent, halogen, —N(O) 2 , or —CN; 
         each J is independently halogen, C1-6 aliphatic, C3-6 cycloaliphatic, —NO 2 , —CN, —N(R $ ) 2 , —OR $ , —C(O)R $ , —C(O)N(R $ ) 2 , —C(O) 2 R $ , oxo, —O(haloC1-4 aliphatic), or halo C1-4 aliphatic; 
         R 4  is —H or an optionally and independently substituted C1-C6 alkyl; 
         each JT1 is independently halogen, —CN, —N(O) 2 , or hydroxy; 
         each JT2 is independently halogen, —CN, —N(O) 2 , or hydroxy; 
         each R $  is independently —H or C1-C6 alkyl; 
         each R 12  is independently halogen, amino, aminoalkyl, alkylaminoalkyl, alkoxy, hydroxy, —CN, —NO 2 , or optionally and independently substituted C1-C6 alkyl; 
         each R 12 ′ is independently halogen, amino, aminoalkyl, alkylaminoalkyl, alkoxy, hydroxy, —CN, —NO 2 , or optionally and independently substituted C1-C10 aliphatic wherein up to three methylene units are optionally and independently replaced by G′ wherein G′ is —O—, —S(O) p —, —N(R 4 )—, or —C(O)—, and each methylene unit is optionally and independently substituted with one or more JT3; or each R 12′  is cycloaliphatic, phenyl, heteroaryl, each independently and optionally substituted with one or more JT4; 
         each JT3 is independently halogen, —CN, —NO 2 , cycloaliphatic, or phenyl; 
         each JT4 is independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; 
         each R 13  is independently halogen, amino, aminoalkyl, alkylaminoalkyl, alkoxy, hydroxy, —CN, —NO 2 , oxo or optionally and independently substituted C1-C6 alkyl; and 
         p is 0, 1 or 2; 
         with the proviso the compound is not (2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)(6-aminopyridin-3-yl)methanone, (2-amino-5-bromopyridin-3-yl)(6-(2-methoxyethylamino)pyridin-3-yl)methanone, (2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)(6-(2-methoxyethylamino)pyridin-3-yl)methanone, (2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)(6-(isobutylamino)pyridin-3-yl)methanone, (2-amino-5-bromopyridin-3-yl)(6-fluoropyridin-3-yl)methanone, methanone (2-amino-5-chloro-3-pyridinyl)-4-pyridinyl-, benzenesulfonamide, N-[2-[(2-amino-3pyridinyl)carbonyl]-5-chloro-3-pyridinyl]-4-chloro-(trifluoromethyl) or methanone, (2-amino-5-chloro-3-pyridinyl)-4-pyridinyl-. 
       
     
     
         2 . The compound of  claim 1  wherein:
 Z is O. 
 
     
     
         3 . The compound of either  claim 2  wherein:
 R 2  is —H, halogen, —CN, —N(O) 2 , or C1-C6 alkyl optionally and independently substituted with one or more R 13 . 
 
     
     
         4 . The compound of  claim 3  wherein:
 R 2  is —H. 
 
     
     
         5 . The compound of  claim 4  wherein:
 R 1  is —H, halogen, or -T1-Q1; 
 T1 is absent or C1-10 aliphatic, wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —N(R 4 )—, or —C(O)—; T1 is optionally and independently substituted with one or more JT1; 
 Q1 is absent, or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Q1 is independently optionally and independently substituted with J1; 
 J1 is —Y1-M1; 
 Y1 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —N(0-, —O—, —C(O)—, or —S(O) 2 —, Y1 is optionally and independently substituted with one or more JT1; and 
 M1 is C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, —OR $ , —SR $ , —N(R $ ) 2 , —P(O) R $ , —P(O) 2 R $ , P(O)(R $ ) 2 , or PO(OR $ ) 2 , wherein M1 is optionally and independently substituted with one or more J; or M1 is absent, —CN, —NO 2 , or halogen. 
 
     
     
         6 . The compound of  claim 5  wherein:
 T1 is absent or C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, or —N(R 4 )—; T1 is optionally and independently substituted with one or more JT1; 
 Y1 is absent or C1-10 aliphatic wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —N(R $ )—, —O—, —C(O)—, or —S(O) 2 ; Y1 is optionally and independently substituted with one or more JT1; and 
 M1 is C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, —N(R $ ) 2 , or —OR $ ; wherein M1 is optionally and independently substituted with one or more J; or M1 is absent, —CN, or halogen. 
 
     
     
         7 . The compound of  claim 6  wherein:
 each J is independently halogen, C1-6 aliphatic, —NO 2 , —CN, —N(R $ ) 2 , —OR $ , —C(O)R $ , —C(O)N(R $ ) 2 , —C(O) 2 R $ , oxo, or halo C1-4 aliphatic. 
 
     
     
         8 . The compound of  claim 7  wherein:
 T1 is absent, C1-C10 alkyl, C2-10 alkenyl, or C2-C10 alkynyl wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, or —N(R 4 )—; T1 is optionally and independently substituted with one or more JT1; 
 Q1 is absent, phenyl, indolyl, quinolyl, isoindolyl, isoquinolyl, indazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, benzothienyl, furyl, benzofuryl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, or pyridyl; wherein Q1 is optionally and independently substituted with J1; 
 Y1 is absent or C1-10 alkyl group wherein up to three methylene units of Y1 are optionally and independently replaced with G1 wherein G1 is —O—, Y1 is optionally and independently substituted with one or more JT1; and 
 M1 is phenyl, —N(R $ ) 2 , or —OR $ ; wherein M1 is optionally and independently substituted with one or more J; or M1 is absent, or —CN. 
 
     
     
         9 . The compound of  claim 5  wherein:
 R 1  is —H, or halogen. 
 
     
     
         10 . The compound of  claim 9  wherein ring B is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoquinolyl, cinnolinyl, quinazolinyl, pyridopyridyl, pyridopyrdazinyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl wherein ring B is substituted with R 3  and independently optionally substituted with R 12 ′ and independently and optionally and independently substituted with one or more R 12  groups. 
     
     
         11 . The compound of  claim 10  wherein ring B is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         s is 0, 1 or 2; 
         u is 0 or 1; 
         X is, —O—, —S—, or —NR X —; and 
         R X  is absent or —H. 
       
     
     
         12 . The compound of  claim 11  wherein ring B is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12  wherein ring B is pyridyl substituted with R 3  and independently optionally and independently substituted with R 12 ′ and independently and optionally substituted with R 12 . 
     
     
         14 . The compound of  claim 13  wherein:
 R 3  is -T2-Q2; 
 T2 is absent or C1-10 aliphatic, wherein up to three methylene units of T2 are optionally and independently replaced by G′ wherein G′ is —O—, —S—, —N(R 4 )—, or —C(O)—; T2 is optionally and independently substituted with one or more JT2; 
 J2 is —Y2-M2; 
 Y2 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y2 are independently and optionally replaced with G1′ wherein G1′ is —N(R $ )—, —O—, —C(O)—, or —S(O) 2 —, Y2 is optionally and independently substituted with one or more JT2; 
 M2 is C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, 5-12 membered aryl, —N(R $ ) 2 , —OR $ , —C(O)R $ , —C(O) 2 R $ , —S(O) R $ , or —S(O) 2 R $  wherein M2 is optionally and independently substituted with one or more J; or M2 is absent, —NO 2 , or —CN; and 
 each J is independently halogen, C1-6 aliphatic, —NO 2 , —CN, N(R $ ) 2 , —OR $ , —COR $ , —CON(R $ ) 2 , —CO 2 R $ , oxo or halo C1-4 aliphatic. 
 
     
     
         15 . The compound of  claim 14  wherein:
 T2 is absent or C1-10 aliphatic, wherein up to three methylene units of T2 are optionally and independently replaced by G′ wherein G′ is —N(R 4 )—, —O—, —S—, or —C(O)—; T2 is optionally and independently substituted with one or more JT2; 
 Y2 is absent, oxo, or C1-10 aliphatic wherein up to three methylene units of Y2 are optionally and independently replaced with G1′ wherein G1′ is —O—, —N(R $ )—, —C(O)—, or —SO 2 —, Y2 is optionally and independently substituted with one or more JT2; 
 M2 is —OR $ , —N(R $ ) 2 , —C(O)R $ , —C(O) 2 R $ , —S(O)R $ , or —S(O) 2 R $ , pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyranyl, tetrahydropyranyl, isooxazolyl, piperidinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, cyclopropyl, naphthyl, or phenyl, wherein M2 is optionally and independently substituted with one or more J; or M2 is absent, —N(O) 2 , or —CN; and 
 each J is independently halogen, C1-6 aliphatic, —NO 2 , —CN, —N(R $ ) 2 , —OR $ , oxo, or halo C1-4 aliphatic. 
 
     
     
         16 . The compound of  claim 15  wherein:
 Q2 is selected from the group consisting of absent, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, thiadiazolyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, thiazepanyl, azocanyl, diazocanyl, triazocanyl, indolyl, indazolyl, benzimidazolyl, quinolyl, quinoxalyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, azabicyclopentyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclodecyl, diazabicyclohexyl, diazabicycloheptyl, azetidinyl, isoindolinyl, isoindolyl, dihydroindazolyl, dihydrobenzimidazolyl, morpholinyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, diazabicyclooctyl, diazabicyclononyl, diazabicyclodecyl, thiazepanyl, and thiazocanyl wherein each ring is independently optionally and independently substituted with J2 and independently and optionally substituted with one or more R 13  groups. 
 
     
     
         17 . The compound of  claim 16 , wherein:
 Q2 is selected from the group consisting of absent, cyclohexyl, diazabicyclooctyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, azetidinyl, morpholinyl, azepanyl, diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, dihydropyridyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, diazepanyl, and oxazepanyl wherein each ring is independently optionally and independently substituted with J2 and independently and optionally substituted with one or more R 13  groups.   
     
     
         18 . The compound of  claim 17  wherein:
 Q2 is selected from the group consisting of absent, cyclohexyl, 3,8-diazabicyclo[3.2.1.]octane, phenyl, pyridyl, piperidinyl, piperazinyl, diazepanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, azetidinyl, morpholinyl, azepanyl, 2,5 diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, octahydro-1H-pyrrolo[2,3-b]pyrazyl, octahydropyrrolo[1,2-a]pyrazyl, and oxazepanyl wherein each ring is independently optionally and independently substituted with J2 and independently and optionally substituted with one or more R 13  groups. 
 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 18  wherein T2 is absent. 
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 20  wherein Q2 is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         t is 0 or 1; and 
         q is 0 or 1. 
       
     
     
         23 - 25 . (canceled) 
     
     
         26 . The compound of  claim 11  wherein X is —S—. 
     
     
         27 . The compound of  claim 26  ring B is thiazolyl, thiadiazolyl or thienyl wherein ring B is substituted with R 3  and independently optionally and independently substituted with R 12 . 
     
     
         28 - 37 . (canceled) 
     
     
         38 . The compound of  claim 27  ring B is thiadiazolyl substituted with R 3 . 
     
     
         39 .- 46 . (canceled) 
     
     
         47 . The compound of  claim 27  ring B is thienyl substituted with R 3  and independently optionally and independently substituted with R 12 . 
     
     
         48 - 56 . (canceled) 
     
     
         57 . The compound of  claim 12  wherein ring B is pyrimidinyl substituted with R 3  and independently optionally and independently substituted with R 12 ′ and independently optionally substituted with R 12 . 
     
     
         58 - 65 . (canceled) 
     
     
         66 . The compound of  claim 12  wherein ring B is pyrazinyl substituted with R 3  and independently optionally and independently substituted with R 12 ′ and independently optionally substituted with R 12 . 
     
     
         67 - 74 . (canceled) 
     
     
         75 . The compound of  claim 11  wherein ring B is thiazolyl substituted with R 3  and independently optionally and independently substituted with R 12 . 
     
     
         76 - 88 . (canceled) 
     
     
         89 . The compound of  claim 11  wherein ring B is pyrazolyl substituted with R 3  and independently optionally and independently substituted with R 12 . 
     
     
         90 - 95 . (canceled) 
     
     
         96 . A composition comprising a compound of pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         97 . A method of treating or preventing a protein kinase-mediated condition in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof or composition of  claim 1 . 
     
     
         98 . The method of  claim 97 , wherein the protein kinase-mediated condition is a GSK 3 mediated condition. 
     
     
         99 . The method of  claim 98 , wherein the GSK 3 mediated condition is selected from the group consisting of diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, stroke, and rheumatoid arthritis. 
     
     
         100 . The method of  claim 97 , wherein the protein kinase-mediated condition is a PKCtheta mediated condition. 
     
     
         101 . The method of  claim 100 , wherein the PKCtheta mediated condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease, T cell leukaemias and lymphomas.