Substituted Pyrrolo[2,3-d]pyrimidines as Inhibitors of Protein Kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein 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: 
         R 1  is H, —NO 2 , —CN, —OCF 3 , halogen, or amino; or C 1-6 aliphatic, C 3-7 cycloaliphatic, C 1-6 alkoxy, or C 1-4 haloalkyl optionally substituted with 0-10 J R  groups; 
         R 2  is H, —NO 2 , —CN, —OCF 3 , halogen, or amino; or C 1-6 aliphatic, C 3-7 cycloaliphatic, C 1-6 alkoxy, or C 1-4 haloalkyl optionally substituted with 0-10 J R  groups; 
         Z 1  is C 1-6 aliphatic or C 3-10 cycloaliphatic optionally substituted with 0-10 J Z  groups; if the bond between Z 1  and C is a double bond, then Z 1  may also be ═O, ═NR, or ═C(R) 2 ; 
         Z 2  is H or halogen; or C 1-10 haloalkyl, C 1-4 haloalkoxy, Y, —(V n )—CN, —(V n )—NO 2 , —(V n )—OH, —(V n )—(C 1-6 aliphatic), —(V n )—(C 3-12 heterocyclyl), —(V n )—(C 6-10 aryl), —(V n )-(5-10 membered heteroaryl), or —(V n )—(C 3-10 cycloaliphatic) optionally substituted with 0-10 J Z  groups; or 
         Z 1  and Z 2 , together with the carbon atom to which they are attached, form ring Q; 
         Z 3  is H or C 1-6 alkyl optionally substituted with 0-3 J Z  groups; or 
         Z 1 , Z 2 , and Z 3 , together with the carbon atom to which they are attached, form an 6-14 membered saturated, partially saturated, or unsaturated bicyclic ring having 0-3 heteroatoms; 
         if the bond between Z 1  and C is a triple bond, then Z 2  is absent; 
         if the bond between Z 1  and C is a double bond or a triple bond, then Z 3  is absent; 
         Q is a 3-8 membered saturated or partially saturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said Q is optionally and independently fused to Q 1  or Q 2 ; or to both Q 1  and Q 2 ; wherein said Q is optionally substituted with 0-4 J Q  groups; 
         Q 1  is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said Q 1  group is optionally substituted with 0-4 J Q  groups; 
         Q 2  is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur wherein said Q 2  group is optionally substituted with 0-4 J Q  groups; 
         R is H, optionally substituted C 1-6  aliphatic, C 3-10  cycloaliphatic, C 6-10  aryl, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-14 membered saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur wherein each R is optionally substituted with 0-10 J R  groups; 
         each J Q  and J Z  substituent on an unsaturated carbon atom is independently selected from hydrogen, —OCF 3 , C 1-6 haloalkyl, N(R) 2 , OR, halogen, Y, —(V n )—CN, —(V n )—NO 2 , —(V n )—OH, —(V n )—(C 1-6 aliphatic), —(C 3-10 cycloaliphatic)-C(O)R, —(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl); —(V n )—(C 3-12 heterocyclyl), —(V n )—(C 6-10 aryl), —(V n )-(5-10 membered heteroaryl), —(V n )—(C 3-10 cycloaliphatic); wherein each J Q  and J Z  is optionally substituted with up to 10 J R  groups; 
         each J Q  and J Z  substituent on a saturated carbon atom is selected from those listed above for an unsaturated carbon and also the following: ═O, ═NN(R a ) 2 , ═NNHC(O)R a , ═NNHCO 2 (C 1-4 alkyl), ═NNHSO 2 (C 1-4 alkyl), and ═NR a  wherein each J Q  and J Z  is optionally substituted with up to 10 J R  groups; 
         each J Q  and J Z  substituent on a nitrogen atom is independently selected from hydrogen, Y, —(V n )—CN, —(V n )—NO 2 , —(V n )—OH, —(V n )—(C 1-6 aliphatic), —(C 3-10 cycloaliphatic)-C(O)R, —(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl), —(V n )—(C 3-12 heterocyclyl), —(V n )—(C 6-10 aryl), —(V n )-(5-10 membered heteroaryl), —(V n )—(C 3-10 cycloaliphatic); wherein two J Z  groups, on the same substituent or different substituents, together with the atom(s) to which each J Z  group is bound, can optionally form an optionally substituted 3-14 membered saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein each J Q  and J Z  is optionally substituted with up to 10 J R  groups; 
         J R  is selected from halogen, —N(R b ) 2 , SR b , OR b , oxo, C 1-4 haloalkoxy, C 1-4 haloalkyl, L, -(L n )-(C 1-6 alkyl), -(L n )-(C 3-12 heterocyclyl), -(L n )-(C 6-10 aryl), -(L n )-(5-10 membered heteroaryl), -(L n )-(C 3-10 cycloalipahtic), -(L n )-NO 2 , -(L n )-CN, -(L n )-OH, —CO 2 R b , —COR b , —OC(O)R b , —NC(O)R b ; 
         L is C 1-10 alkyl wherein up to three methylene units are replaced by —NR b —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR b —, —C(═N—CN), —NR b CO—, —NR b C(O)O—, —SO 2 NR b —NR b SO 2 —, —NR b C(O)NR—, —OC(O)NR b —, —NR b SO 2 NR b —, —SO—, or —SO 2 —; 
         V is C 1-10 aliphatic wherein up to three methylene units are replaced by G V , wherein G V  is selected from —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO 2 NR—, —NRSO 2 —, —NRC(O)NR—, —OC(O)NR—, —NRSO 2 NR—, —SO—, or —SO 2 —; 
         Y is C 1-10 aliphatic, wherein up to three methylene units are replaced by G Y  wherein G Y  is selected from —NR—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO 2 NR—, —NRSO 2 —, —NRC(O)NR—, —OC(O)NR—, —NRSO 2 NR—, —SO—, or —SO 2 —; 
         R a  is hydrogen or C 1-6  aliphatic group optionally substituted with 0-3 J R  groups; 
         R b  is hydrogen or an unsubstituted C 1-6  aliphatic group; 
         n is 0 or 1; 
         provided that: 
         when R 1  and R 2  are H, and Z 2  and Z 3  are H, then Z 1  is not methyl; 
         when R 1  is CH 3  and R 2  is H, then Z 1 , Z 2 , and Z 3  are not all H; 
         when R 1  and R 2  are H, and Z 2  and Z 3  are H, then Z 1  is not unsubstituted phenyl, 4-pyridyl, or one of the structures shown below: 
       
       
         
           
           
               
               
           
         
       
       and
 when R 1  and R 2  are H, Z 1  and Z 2  taken together are not —C≡C—CH 2 CH 2 COOH. 
 
     
     
         2 . The compound according to  claim 1  wherein Z 1 , Z 2 , and Z 3 , together with the carbon atom to which they are attached, form the bicyclic ring shown in Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 Q 3  is 3-8 membered saturated, unsaturated, or partially saturated monocyclic ring; Q and Q 3  are each optionally and independently substituted with 0-4 J Q  groups. 
 
     
     
         3 . The compound according  claim 2  wherein Q 3  is a cyclopropyl group and both Q and Q 3  are each optionally substituted with 0-2 J Q  groups as shown in formula III: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein Z 1  and Z 2 , together with the carbon atom to which they are attached, form a compound as shown in Formula IV: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 11  is selected from C, N, O, or S; 
 Z 12  is selected from C, N, O, or S; 
 Q is a 3-8 membered saturated or partially saturated monocyclic ring, optionally fused to Q 1  or Q 2 ; 
 Q 1  and Q 2  are each independently a 3-8 membered saturated, unsaturated, or partially saturated monocyclic ring; 
 Q, Q 1  and Q 2  each independently contain up to three heteroatoms selected from O, N, or S; 
 m is 0-4; and is independently selected for Q, Q 1  and Q 2 ; and 
 Z 3  is H; or if the bond between C and Z 11  is a double bond, then Z 3  is absent. 
 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The compound according to  claim 1 , wherein Z 12  is carbon and the fused ring of Q, Q 1 , and optionally Q 2  is as shown in Formula V: 
       
         
           
           
               
               
           
         
       
       wherein Q, Q 1 , and Q 2  each independently and optionally contain
 a) 0-2 heteroatoms selected from O, N, or S; and 
 b) 0-4 J Q  substituents. 
 
     
     
         10 . The compound according to  claim 9 , wherein the hydrogen atoms at the point of fusion between ring Q and ring Q 1  is in the cis conformation as shown in Formula VI: 
       
         
           
           
               
               
           
         
       
     
     
         11 - 19 . (canceled) 
     
     
         20 . The compound according to  claim 10 , wherein ring Q is a 5-7 membered cycloaliphatic. 
     
     
         21 . The compound according to  claim 10 , wherein Q 1  is a 6-membered aryl or 5-6 membered heteroaryl ring. 
     
     
         22 . The compound according to  claim 10 , wherein Q 1  is a 5-8 membered cycloaliphatic ring. 
     
     
         23 . The compound according to  claim 10 , wherein Q 1  is a 5-8 membered heterocyclic ring. 
     
     
         24 . The compound according to  claim 1 , wherein Q or Q-Q 1  is represented is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 both R 7  and J Q  are each independently selected from hydrogen, Y, —(V n )—CN, —(V n )—NO 2 , —(V n )—OH, —(V n )—(C 1-6 aliphatic), —(V n )—(C 3-12 heterocyclyl), —(V n )—(C 6-10 aryl), —(V n )-(5-10 membered heteroaryl), —(V n )—(C 3-10 cycloaliphatic), and —(C 3-10 cycloaliphatic)-(C 3-12 heterocyclyl); 
 
       each Q and Q 1 , m is independently 0-3; and
 each R 7  and J Q  is optionally and independently substituted with 0-10 J R  groups. 
 
     
     
         25 - 36 . (canceled) 
     
     
         37 . The compound according to  claim 1 , wherein Z 1  and Z 2  do not join to form a ring and Z 3  is H or is absent. 
     
     
         38 . The compound according to  claim 37 , wherein Z 1  is H or C 1-6 aliphatic optionally substituted with 0-3 J Z  groups. 
     
     
         39 - 59 . (canceled) 
     
     
         60 . A compound of formula VIII: 
       
         
           
           
               
               
           
         
       
       wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         61 . A compound selected from Table 3. 
     
     
         62 . (canceled) 
     
     
         63 . A method of inhibiting JAK 2 or JAK3 kinase activity in a patient comprising administering to said patient a compound according to  claim 1  or a composition comprising said compound. 
     
     
         64 . A method of inhibiting JAK2 or JAK3 kinase activity in a biological sample comprising administering to contacting said biological sample with a compound according to  claim 1  or a composition comprising said compound. 
     
     
         65 . 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, comprising the step of administering to said patient a compound of  claim 1  or a composition comprising said compound. 
     
     
         66 - 73 . (canceled) 
     
     
         74 . A method of treating or lessening the severity of a myeloproliferative disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to  claim 1  or a composition comprising said compound. 
     
     
         75 - 76 . (canceled) 
     
     
         77 . A method of inhibiting ROCK kinase activity in a patient or biological sample comprising administering to said patient a compound according to  claim 1  or a composition comprising said compound. 
     
     
         78 - 86 . (canceled) 
     
     
         87 . A composition comprising an effective amount of compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle.