Compounds 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: 
         X 1  is N or CR 1 ; 
         X 2  is N or CR 2 ; wherein no more than one of X 1  or X 2  is N; 
         X 3  is N or CR 23 ; 
         X 4  is N or CR 24 ; wherein at least one of X 3  and X 4  is N; 
         R 1  is H, halo, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; 
         R 2  is H, halo, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; or R 1  and R 2 , taken together, form a 5-7 membered aryl or heteroaryl ring optionally substituted with 1-4 occurrences of R 9 ; 
         each R 9  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic; 
         R 23  is H, halo, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; 
         R 24  is H, halo, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; 
         R′ is a C 1-3  aliphatic optionally substituted with 1-4 occurrences of R 10 ; 
         each R 10  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN or unsubstituted C 1-2  aliphatic, or two R 10  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O;
 R 3  is selected from 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 19  is selected from H; a C 3-7  cycloaliphatic optionally substituted with 1-4 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN; or a C 1-6  aliphatic, wherein up to two methylene units of said C 1-6  aliphatic are optionally and independently replaced by G R  and wherein said C 1-6  aliphatic is optionally substituted with 1-4 R 20 ; 
         G R  is —NH—, —NR 21 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 21 —, —NC(═N—CN)N—, —NHCO—, —NR 21 CO—, —NHC(O)O—, —NR 21 C(O)O—, —SO 2 NH—, —SO 2 NR 21 —, —NHSO 2 —, —NR 21 SO 2 —, —NHC(O)NH—, —NR 21 C(O)NH—, —NHC(O)NR 21 —, —NR 21 C(O)NR 21 , —OC(O)NH—, —OC(O)NR 21 —, —NHSO 2 NH—, —NR 21 SO 2 NH—, —NHSO 2 NR 21 —, —NR 21 SO 2 NR 21 —, —SO—, or —SO 2 —; 
         R 21  is C 1-6  aliphatic or C 3-7  cycloaliphatic optionally substituted with 1-6 occurrences of halogen, N(R X ) 2 , R X , —OR X , —SR X , —NO 2 , —CF 3 , —CN, —CO 2 R X , —COR X , OCOR X , CONHR X , or NHCOR X ; 
         each R X  is independently selected from H or an unsubstituted C 1-6  aliphatic; 
         each R 20  is independently selected from halogen, OH, OR 22 , NO 2 , NH 2 , NHR 22 , N(R 22 ) 2 , SH, SR 22 , CN, or R 22 ; or two R 20 , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O; 
         each R 22  is independently selected from a C 1-6  aliphatic or C 3-7  cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN; 
         R 25  is —(U) m —Y; 
         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 26 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 26 —, —NC(═N—CN)N—, —NHCO—, —NR 26 CO—, —NHC(O)O—, —NR 26 C(O)O—, —SO 2 NH—, —SO 2 NR 26 —, —NHSO 2 —, —NR 26 SO 2 —, —NHC(O)NH—, —NR 26 C(O)NH—, —NHC(O)NR 26 —, —NR 26 C(O)NR 26 , —OC(O)NH—, —OC(O)NR 26 —, —NHSO 2 NH—, —NR 26 SO 2 NH—, —NHSO 2 NR 26 —, —NR 26 SO 2 NR 26 —, —SO—, or —SO 2 —; 
         R 26  is a C 1-6  aliphatic, C 3-10  cycloaliphatic, C 6-10  aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl; wherein said aliphatic, cycloaliphatic, aryl, heteroaryl or heterocyclyl is optionally substituted with halogen, R X , —OR X , —SR X , —NO 2 , —CF 3 , —CN, —CO 2 R X , —COR X , OCOR X , CONHR X , or NHCOR X ; 
         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; 
         m is 0 or 1; 
         Y is H, halogen, CN, NO 2 , NH 2 , NHR, N(R) 2 , 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 1-8 occurrences of J Y ; 
         each J Y  is independently selected from halogen, L, -(L n )-R 26 , -(L n )-N(R 26 ) 2 , -(L n )-SR 26 , -(L n )-OR 26 , -(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 26 , —CO 2 H, —COR 26 , —COH, —OC(O)R 26 , —C(O)NHR 26 , C(O)N(R 26 ) 2 , —NHC(O)R 26 , or NR 26 C(O)R 26 ; or two J Y  groups, on the same substituent or different substituents, together with the atom(s) to which each J Y  group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         each L is independently a C 1-6  aliphatic wherein up to three methylene units are replaced by —NH—, —NR L —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR L —, —NC(═N—CN)N, —NHCO—, —NR L CO—, —NHC(O)O—, —NR L C(O)O—, —SO 2 NH—, —SO 2 NR L —, —NHSO 2 —, —NR L SO 2 —, —NHC(O)NH—, —NR L C(O)NH—, —NHC(O)NR L —, —NR L C(O)NR L , —OC(O)NH—, —OC(O)NR L —, —NHSO 2 NH—, —NR L SO 2 NH—, —NHSO 2 NR L —, —NR L SO 2 NR L —, —SO—, or —SO 2 —; 
         each n is independently 0 or 1; 
         R L  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 L  groups, on the same substituent or different substituents, together with the atom(s) to which each R L  group is bound, form a 3-8 membered heterocyclyl; 
         each R is independently selected from a C 1-6  aliphatic or a C 3-6  cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN, or two R groups, together with the atom to which the R groups are bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring; 
         wherein each substitutable carbon of an R 3  ring is optionally and independently substituted with halogen; —R o ; —OR o ; —SR o ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R o ; —O(Ph) optionally substituted with R o ; —(CH 2 ) 1-2 (Ph), optionally substituted with R o ; —CH═CH(Ph), optionally substituted with R o ; —NO 2 ; —CN; —N(R o ) 2 ; —NR o C(O)R o ; —NR o C(S)R o ; —NR o C(O)N(R o ) 2 ; —NR o C(S)N(R o ) 2 ; —NR o CO 2 R o ; —NR o NR o C(O)R o ; —NR o NR o C(O)N(R o ) 2 ; —NR o NR o CO 2 R o ; —C(O)C(O)R o ; —C(O)CH 2 C(O)R o ; —CO 2 R o ; —C(O)R o ; —C(S)R o ; —C(O)N(R o ) 2 ; —C(S)N(R o ) 2 ; —OC(O)N(R o ) 2 ; —OC(O)R o ; —C(O)N(OR o )R o ; —C(NOR o )R o ; —S(O) 2 R o ; —S(O) 3 R o ; —SO 2 N(R o ) 2 ; —S(O)R o ; —NR o SO 2 N(R o ) 2 ; —NR o SO 2 R o ; —N(OR o )R o ; —C(═NH)—N(R o ) 2 ; or —(CH 2 ) 0-2 NHC(O)R o ; wherein each independent occurrence of R o  is selected from hydrogen, optionally substituted C 1-6  aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH 2 (Ph), or, two independent occurrences of R o , on the same substituent or different substituents, taken together with the atom(s) to which each R o  group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and wherein each of said optional substituents on the aliphatic group of R o  is independently selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), O(haloC 1-4  aliphatic), or haloC 1-4 aliphatic, wherein each of the foregoing C 1-4 aliphatic groups of R o  is unsubstituted; 
         wherein each substitutable nitrogen of a non-aromatic heterocyclic ring of R 3  is optionally and independently substituted with —R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R + ) 2 , —C(═NH)—N(R + ) 2 , or —NR + SO 2 R + ; wherein R +  is hydrogen, an optionally substituted C 1-6  aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH 2 (Ph), optionally substituted —(CH 2 ) 1-2 (Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R + , on the same substituent or different substituents, taken together with the atom(s) to which each R +  group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein each of said optional substituents on the aliphatic group or the phenyl ring of R′ is independently selected from NH 2 , NH(C 1-4  aliphatic), N(C 1-4  aliphatic) 2 , halogen, C 1-4  aliphatic, OH, O(C 1-4  aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4  aliphatic), O(halo C 1-4  aliphatic), or halo(C 1-4  aliphatic), wherein each of the foregoing C 1-4 aliphatic groups of R +  is unsubstituted; 
         R 4  is H or is a —C 1-2  aliphatic optionally substituted with 1-3 occurrences of R 11 ; 
         each R 11  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2  or unsubstituted C 1-2  aliphatic, or two R 11  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
         R 15  is H or unsubstituted C 1-2  alkyl; 
         R 5  is H or a C 1-6  aliphatic optionally substituted with 1-5 occurrences of R 12 ; 
         R 6  is H or a C 1-6  aliphatic optionally substituted with 1-5 occurrences of R 13 ; 
         each R 12  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic, or two R 12  groups, together with the carbon to which they are attached, form a cyclopropyl ring; 
         each R 13  is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic, or two R 13  groups, together with the carbon to which they are attached, form a cyclopropyl ring; or 
         R 5  and R 6  are taken together to form a 3-7 membered carbocyclic or heterocyclic saturated ring optionally substituted with 1-5 occurrences of R 12 ; or 
         R 4  and R 6 , taken together with the nitrogen to which R 4  is attached, form a 3-8 membered saturated, partially saturated or aromatic nitrogen-containing ring comprising up to two additional heteroatoms selected from N, O or S and optionally substituted with 1-4 occurrences of R 14 ; or 
         R 1  and R 4 , taken together with the nitrogen to which R 4  is attached, form a 3-8 membered saturated, partially saturated or aromatic nitrogen-containing ring comprising up to two additional heteroatoms selected from N, O or S and optionally substituted with 1-4 occurrences of R 14 ; or 
         each R 14  is independently selected from halogen, R″, NH 2 , NHR″, N(R″) 2 , SH, SR″, OH, OR″, NO 2 , CN, CF 3 , COOR″, COOH, COR″, OC(O)R″ or NC(O)R″; or any two R 14  groups, on the same substituent or different substituents, together with the atom(s) to which each R 14  group is bound, form a 3-7 membered saturated, unsaturated, or partially saturated carbocyclic or heterocyclic ring optionally substituted with 1-3 occurrences of R 16 ; 
         R″ is a C 1-3  aliphatic optionally substituted with 1-4 occurrences of R 10 ; 
         each R 16  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2  or unsubstituted C 1-2  aliphatic, or two R 16  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
         R 7  is H or C 1-4  aliphatic optionally substituted with 1-3 occurrences of R 17 ; 
         each R 17  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2  or unsubstituted C 1-2  aliphatic, or two R 17  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O; 
         R 8  is C 1-4  aliphatic optionally substituted with 1-6 occurrences of R 18 ; and 
         each R 18  is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2  or unsubstituted C 1-2  aliphatic, or two R 18  groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O. 
       
     
     
         2 . The compound according to  claim 1 , wherein said compound is selected from one of formulae I-a to I-i: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2 , wherein said compound is selected from one of formulae I-a, I-b, I-c or I-d. 
     
     
         4 . The compound according to  claim 3 , wherein said compound is selected from one of formulae I-c or I-d. 
     
     
         5 . The compound according to  claim 2 , wherein said compound is selected from one of formulae I-a, I-b, I-c, I-f, I-g or I-i and R 1  is H, Cl, F, R′, OH or OR′. 
     
     
         6 . The compound according to  claim 5 , wherein R 1  is H, CH 3 , Cl or F. 
     
     
         7 . The compound according to  claim 2 , wherein said compound is selected from one of formulae I-a, I-b, I-c, I-d, I-e or I-h, and R 2  is H, Cl, F, R′, OH or OR′. 
     
     
         8 . The compound according to  claim 7 , wherein R 2  is H, CH 3 , Cl or F. 
     
     
         9 . The compound according to  claim 2 , wherein said compound is of formula I-c, and R 1  is H, Cl or F and R 2  is H. 
     
     
         10 .- 16 . (canceled) 
     
     
         17 . The compound according to  claim 1 , wherein R 4  is H, CH 3 , CH 2 CH 3  or CH(CH 3 ) 2 . 
     
     
         18 . The compound according to  claim 17 , wherein R 4  is H or CH 3 . 
     
     
         19 . The compound according to  claim 18 , wherein R 4  is H. 
     
     
         20 . (canceled) 
     
     
         21 . The compound according to  claim 1 , wherein R 5  is H or a C 1-2  alkyl optionally substituted with up to 3 occurrences of R 12 . 
     
     
         22 . The compound according to  claim 21 , wherein R 5  is H or a C 1-2  alkyl. 
     
     
         23 . The compound according to  claim 1 , wherein R 6  is a C 1-4  aliphatic optionally substituted with 1-5 occurrences of R 13 . 
     
     
         24 .- 31 . (canceled) 
     
     
         32 . The compound according to  claim 1 , wherein R 4  and R 6 , taken together with the nitrogen to which R 4  is attached, form a 3-8 membered saturated, partially saturated or aromatic nitrogen-containing ring comprising up to two additional heteroatoms selected from N, O or S and optionally substituted with 1-4 occurrences of R 14 . 
     
     
         33 .- 40 . (canceled) 
     
     
         41 . The compound according to  claim 1 , wherein R 7  is H or C 1-2  alkyl optionally substituted with 1-3 occurrences of R 17 . 
     
     
         42 . (canceled) 
     
     
         43 . The compound according to  claim 1 , wherein R 8  is a C 1-4  aliphatic or cycloaliphatic optionally substituted with up to 6 occurrences of R 18 . 
     
     
         44 .- 48 . (canceled) 
     
     
         49 . The compound according to  claim 1 , wherein R 3  is selected from (1-a), (1-c), (1-k), (2-d), (2-e), (2-k), (2-w), (2-x), (3-d), (3-e), (3-g), (3-h), (3-i) and (3-j). 
     
     
         50 . The compound according to  claim 49 , wherein R 3  is selected from (1-a), (1-c), (1-k), (2-d), (2-e), (2-n), (2-o), (2-u), (2-x) and (2-z). 
     
     
         51 . The compound according to  claim 50 , wherein R 3  is selected from (1-a), (1-c), (2-d), (2-e), (2-n), (2-o), (2-u) and (2-x). 
     
     
         52 . The compound according to  claim 51 , wherein R 3  is selected from (1-c), (2-d), (2-n) and (2-o). 
     
     
         53 . The compound according to  claim 1 , wherein R 3  is unsubstituted. 
     
     
         54 . The compound according to  claim 1 , wherein up to two substitutable carbons and up to one substitutable nitrogens of a non-aromatic heterocyclic ring of the R 3  ring are substituted. 
     
     
         55 . The compound according to  claim 54 , wherein one substitutable carbon and up to one substitutable nitrogens of a non-aromatic heterocyclic ring of the R 3  ring are substituted. 
     
     
         56 . The compound according to  claim 55 , wherein one substitutable carbon of the R 3  ring is substituted. 
     
     
         57 . The compound according to  claim 52 , wherein R 3  is (2-n) and R 25  is C(O)NR 2 . 
     
     
         58 . The compound according to  claim 52 , wherein R 3  is (2-o) and R 25  is an optionally substituted aryl or heteroaryl. 
     
     
         59 . The compound according to  claim 58 , wherein R 25  is an optionally substituted phenyl. 
     
     
         60 . The compound according to  claim 52 , wherein R 3  is (1-c) or (2-d) and R 3  is unsubstituted. 
     
     
         61 . The compound according to  claim 1 , wherein said compound is selected from Table 1. 
     
     
         62 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         63 . (canceled) 
     
     
         64 . A method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according  claim 1 . 
     
     
         65 . A method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound according to  claim 1 . 
     
     
         66 . 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 transplantation, 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 . 
     
     
         67 - 72 . (canceled)