Deazapurines useful as inhibitors of janus kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. 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.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is a 5-membered monocyclic heteroaryl selected from 
 
       
       
         
           
           
               
               
           
         
         wherein Ring A is optionally substituted with up to 1-3 occurrences of R 8 ; 
         R 1  is H, halogen or C 1-4  aliphatic; 
         R 2  is H, halogen or C 1-4  aliphatic; 
         R 5  is H, halogen, CN, NH 2 , NO 2 , CF 3 , C 1-4  aliphatic, cyclopropyl, NCH 3 , OCH 3 , —C(═O)NH 2 , —C(═O)CH 3 , —NC(═O)CH 3 , or OH; 
         R 3  is —(U) m —X; 
         U is a C 1-6  aliphatic, wherein up to two methylene units are optionally and independently replaced by G U  and wherein U is optionally substituted with 1-4 J U ; 
         G U  is —NH—, —NR 6 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 6 —, —NC(═N—CN)N—, —NHCO—, —NR 6 CO—, —NHC(O)O—, —NR 6 C(O)O—, —SO 2 NH—, —SO 2 NR 6 —, —NHSO 2 —, —NR 6 SO 2 —, —NHC(O)NH—, —NR 6 C(O)NH—, —NHC(O)NR 6 —, —NR 6 C(O)NR 6 , —OC(O)NH—, —OC(O)NR 6 —, —NHSO 2 NH—, —NR 6 SO 2 NH—, —NHSO 2 NR 6 —, —NR 6 SO 2 NR 6 —, —SO—, or —SO 2 —; 
         R 6  is C 1-6  aliphatic or a C 3-10 cycloaliphatic; or two R 6  groups, together with the atom to which they are attached, optionally form a 3-7 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R″, —OR″, —SR″, —NO 2 , —CF 3 , —CN, —CO 2 R″, —COR″, OCOR″, CONHR″, or NHCOR″, wherein R″ is H or an unsubstituted C 1-6  aliphatic; 
         m is 0 or 1; 
         X is H, halogen, CN, NO 2 , S(O)R, SO 2 R, or a group selected from a C 1-6 aliphatic, a C 3-10  cycloaliphatic, a C 6-10  aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein said group is optionally substituted with 1-4 J X ; 
         R is an optionally substituted group selected from a C 1-6  aliphatic, a C 3-10  cycloaliphatic, a C 6-10  aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein R is independently and optionally substituted with 1-6 occurrences of J R ; 
         each J R  is independently selected from halogen, L, -(L n )-R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, C(O)N(R′) 2 , —NHC(O)R′, or NR′C(O)R′; or two J R  groups, on the same substituent or different substituents, together with the atom(s) to which each J R  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         each J U  is independently selected from halogen, L, -(L n )-R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, C(O)N(R′) 2 , —NHC(O)R′, or NR′C(O)R′; or two J U  groups, on the same substituent or different substituents, together with the atom(s) to which each J U  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         each J X  is independently selected from halogen, L, -(L n )-R′, -(L n )-N(R′) 2 , -(L n )-SR′, -(L n )-OR′, -(L n )-(C 3-10  cycloaliphatic), -(L n )-(C 6-10  aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(5-10 membered heterocyclyl), oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, -(L n )-CF 3 , —CO 2 R′, —CO 2 H, —COR′, —COH, —OC(O)R′, —C(O)NHR′, C(O)N(R′) 2 , —NHC(O)R′; 
         each L is independently a C 1-6  aliphatic wherein up to three methylene units are replaced by —NH—, —NR 7 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 7 —, —NC(═N—CN)N, —NHCO—, —NR 7 CO—, —NHC(O)O—, —NR 7 C(O)O—, —SO 2 NH—, —SO 2 NR 7 —, —NHSO 2 —, —NR 7 SO 2 —, —NHC(O)NH—, —NR 7 C(O)NH—, —NHC(O)NR 7 —, —NR 7 C(O)NR 7 , —OC(O)NH—, —OC(O)NR 7 —, —NHSO 2 NH—, —NR 7 SO 2 NH—, —NHSO 2 NR 7 —, —NR 7 SO 2 NR 7 —, —SO—, or —SO 2 —; 
         each n is independently 0 or 1; 
         each R′ is independently H or C 1-6  aliphatic; or two R′ groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —OR*, —SR*, —NO 2 , —CF 3 , —CN, —CO 2 R*, —COR*, OCOR*, NHCOR*, wherein R* is H or C 1-6  aliphatic; 
         R 7  is selected from C 1-6  aliphatic, C 3-10  cycloaliphatic, C 6-10  aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; or two R 7  groups, on the same substituent or different substituents, together with the atom(s) to which each R 6  group is bound, form a 3-8 membered heterocyclyl; 
         each R 8  is independently —(C 1-3  aliphatic) y -R 9 , wherein R 8  is optionally substituted with 1-5 occurrences of J R8 ; 
         each y is independently 0 or 1; 
         R 9  is halogen, CN, NH 2 , NO 2 , CF 3 , C 1-4  aliphatic, cyclopropyl, NHR 10 , N(R 10 ) 2 , OR 10 , C(O)OR 10 , —C(O)NH 2 , —C(O)R 10 , —NC(O)R 10 , or OH; 
         R 10  is C 1-4  aliphatic; 
         each J R8  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, or unsubstituted C 1-2 aliphatic; or two J R8 , together with the carbon to which they are attached, form a cyclopropyl ring or C═O. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is H or halogen. 
     
     
         4 . The compound according to  claim 3 , wherein R 1  is H. 
     
     
         5 . (canceled) 
     
     
         6 . The compound according to  claim 1 , wherein R 2  is H, Cl, F or CH 3 . 
     
     
         7 . The compound according to  claim 6 , wherein R 2  is H. 
     
     
         8 . (canceled) 
     
     
         9 . The compound according to  claim 1 , wherein Ring A is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
       
     
     
         10 . The compound according to  claim 9 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
         wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
       
     
     
         11 . (canceled) 
     
     
         12 . The compound according to  claim 1 , wherein Ring A is selected from 
       
         
           
           
               
               
           
         
         wherein Ring A is optionally substituted with 1-3 occurrences of R 8 . 
       
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The compound according to  claim 1 , wherein Ring A is unsubstituted by R 8  or substituted by one occurrence of R 8  and R 8  is halogen. 
     
     
         16 . (canceled) 
     
     
         17 . The compound according to  claim 1 , wherein R 3  is not H. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The compound according to  claim 17 , wherein m is 1 and U is selected from C(O)NH, C(O)NR 6 , NHC(O), NR 6 C(O), C(O), C(O)NHCH 2 , C(O)NR 6 CH 2 , NHC(O)CH 2  or NR 6 C(O)CH 2 . 
     
     
         21 . (canceled) 
     
     
         22 . The compound according to  claim 20 , wherein R 6  is C 1-3  aliphatic optionally substituted with —OH, —CF 3  or —CN. 
     
     
         23 . The compound according to  claim 17 , wherein m is 0. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The compound according to  claim 1 , wherein X is C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrrolyl, piperindinyl, pyrrolidinyl, dihydro-1H-pyrrolyl, tetrohydro-1H-pyranyl, tetrohydrofuranyl, wherein said group is optionally substituted with 1-4 J X . 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The compound according to  claim 26 , wherein each J X  is independently selected from C 1-4  straight or branched alkyl, C 2-4  straight or branched alkenyl, C 2-4  straight or branched alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chloro, fluoro, —OH, —OCH 3 , —CH 2 OCH 3 , —CH 2 OH, oxo, —CH 2 CN, —CH 2 CF 3 , —CN, or —CF 3 , CO 2 H, —CO 2 CH 3 , or —COCH 3 . 
     
     
         30 . The compound according to  claim 1 , having formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 - 50 . (canceled) 
     
     
         51 . A compound according to  claim 1 , selected from Compounds 2, 31-33, 57-72, 96-105, 117-129, 131 and 141-157 in Table 1 or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A compound according to  claim 1 , selected from Compound 159, 168-183, 191-197, 210-212, 215-222, 229-231 and 245-253 in Table 2 or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         54 . (canceled) 
     
     
         55 . A method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according to  claim 1  or with a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         56 . A method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound according to  claim 1  or with a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         57 . A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound according to  claim 1  or with a composition comprising said compound. 
     
     
         58 - 64 . (canceled)