Compounds useful as protein 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.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         Ring A is 
       
       
         
           
           
               
               
           
         
          in which each substitutable carbon atom on Ring A is optionally substituted with halo, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, in which each of the C 1-6 alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with 1-3 of J A ; 
         Z is S, —NQ-, or O; 
         Z 1  is N; 
         X 1  is O, —NR 5 —, S, or —CR 5 R 5 ′—; 
         R 1  is a 6 membered ring selected from 
       
       
         
           
           
               
               
           
         
          or the six membered ring is optionally fused with Ring B, or 
         R 1  is 
       
       
         
           
           
               
               
           
         
          in which the 6 membered ring, the six membered ring fused with Ring B, or 
       
       
         
           
           
               
               
           
         
          are each optionally substituted with 1-5 R 5 ; 
         Each Y is independently C or N; 
         Each Ring B is independently a 3-8-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         Each R 2  and R 3  is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, a 3-8-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-12 membered saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 2  and R 3  is optionally substituted with 0-5 J 2  and J 3  respectively; 
         or R 2  and R 3  are taken together to form a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring formed by R 2  and R 3  is optionally substituted with 0-5 J 23 ; 
         Each R 5  or R 5′  is independently H, T 1 , Q, or -T 1 -Q; 
         Each T 1  is independently C 1-6 aliphatic wherein up to three methylene units of the C 1-6 aliphatic is optionally replaced with —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or
 —SO 2 —; each T 1  is optionally substituted with 0-2 J T ; 
 
         Each Q is independently H; C 1-6  aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-4 heteroatoms independently selected from O, N, and S; or an 8-12 membered aromatic or nonaromatic bicyclic ring system having 0-5 heteroatoms independently selected from O, N, and S; each Q is optionally substituted with 0-5 J Q ; 
         Each J Q , J T , J 2 , J 3 , and J 23  is independently selected from H, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), 3-6 membered heterocyclyl, halo, NO 2 , CN, or C 1-6  aliphatic wherein up to three methylene units of the C 1-6  aliphatic are optionally replaced with —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or —SO 2 —; 
         Each J A  or R J  is independently selected from H, halo, NO 2 , CN, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), 3-6 membered heterocyclyl, a 5-6-membered monocyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-12 membered aromatic bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or C 1-6  aliphatic wherein up to three methylene units of the C 1-6  aliphatic are optionally replaced with —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or
 —SO 2 —; 
 
         Each R is independently H or unsubstituted C 1-6 alkyl; 
         Each J is independently halo, CN, NO 2 , C 1-4 aliphatic, cycloalkyl, heterocycle, aryl, or heteroaryl, in which each of C 1-4 aliphatic, cycloalkyl, heterocycle, aryl, or heteroaryl, is optionally substituted with 1-3 of R J , or 
         Two J are taken together with the carbon atom to which they are attached to form a 3-8-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in which the ring is optionally substituted with 1-3 of R J ; or 
         One J and R 2  or R 3  are taken together with the carbon atoms to which they are attached to form a 3-8-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in which the ring is optionally substituted with 1-3 of R J ; 
         provided that 
         when R 2  and R 3  are both H or both methyl, X 1  is CH 2 , and Ring A is 
       
       
         
           
           
               
               
           
         
          then 
         R 1  is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1  wherein Z is S. 
     
     
         3 . The compound of  claim 1  or  claim 2 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1  or  claim 2 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claims 3  and  4 , wherein Z is S. 
     
     
         6 . The compound of any one of  claims 1 - 5 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       each optionally substituted with 1-5 R 5 . 
     
     
         7 . The compound of  claim 6 , wherein R 1  is pyridine-4-yl optionally substituted with 1-5 R 5 . 
     
     
         8 . The compound of any one of  claims 1 - 5 , wherein R 1  is a six membered ring fused with Ring B in which the six membered ring is 
       
         
           
           
               
               
           
         
       
       and Ring B is a 3-8-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in which the six membered ring and Ring B together are each optionally substituted with 1-5 R 5 . 
     
     
         9 . The compound of  claim 8 , wherein R 1  is pyridine-4-yl fused with a 5-6 membered heteroaryl, in which the fused pyridine-heteroaryl is optionally substituted with 1-5 R 5 . 
     
     
         10 . The compound of  claim 9 , wherein R 1  is pyridine-4-yl fused with a pyrrole ring, in which the fused pyridine-pyrrole is optionally substituted with 1-5 R 5 . 
     
     
         11 . The compound of  claim 8 , wherein R 1  is a dihydrobenzoxazine optionally substituted with 1-5 R 5 . 
     
     
         12 . The compound of any of  claims 1 - 5 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       in which the 5 membered ring fused with Ring B is optionally substituted with 1-5 R 5 . 
     
     
         13 . The compound of any one of  claims 1 - 8 , wherein X 1  is NR 5 . 
     
     
         14 . The compound of  claim 9 , wherein R 5  is -T 1 -Q. 
     
     
         15 . The compound of  claim 10 , wherein T 1  is C 1-4 alkyl. 
     
     
         16 . The compound of any one of  claim 10  or  11 , wherein Q is a 5-6-membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from O, N, and S; or a 9-10 membered aromatic bicyclic ring having 0-5 heteroatoms independently selected from O, N, and S. 
     
     
         17 . The compound of any of  claims 1 - 8 , wherein X 1  is 
       —CR 5 R 5 ′—. 
     
     
         18 . The compound of  claim 12 , wherein R 5  and R 5′  are both H. 
     
     
         19 . The compound of any one of  claims 1 - 14 , wherein R 2  and R 3  are each independently H or unsubstituted C 1-4 alkyl. 
     
     
         20 . The compound of  claim 15 , wherein R 2  and R 3  are both H. 
     
     
         21 . The compound of  claim 15 , wherein one of R 2  or R 3  is C 1-4  alkyl. 
     
     
         22 . The compound of  claim 15 , wherein both of R 2  or R 3  are C 1-4  alkyl. 
     
     
         23 . The compound of  claim 1  as represented by Formula II or by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1, or 2. 
     
     
         24 . The compound of  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A composition comprising a compound of any one of  claims 1 - 25 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         26 . A method of inhibiting protein kinase activity in a patient comprising administering to said patient a compound of any one of  claims 1 - 25 . 
     
     
         27 . A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with a compound of any one of  claims 1 - 25 . 
     
     
         28 . The method of  claim 26  or  claim 27 , wherein said protein kinase is PLK1. 
     
     
         29 . A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient a compound of any one of  claims 1 - 25 . 
     
     
         30 . The method according to  claim 29 , comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
 a) said additional therapeutic agent is appropriate for the disease being treated; and   b) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.   
     
     
         31 . A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient wherein said method comprises administering to said patient a compound of any one of  claims 1 - 25 . 
     
     
         32 . A method of treating cancer in a patient wherein said method comprises administering to said patient a compound of any one of  claims 1 - 25 . 
     
     
         33 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein Ring A, X 1 , J, R 2  and R 3  are as defined in any one of  claims 1 - 25 ; 
         comprising reacting a compound of formula B 
       
       
         
           
           
               
               
           
         
         wherein Ring A, X 1 , J, R 2  and R 3  are as defined according to  claim 1  and CP 1  is a suitable coupling partner; 
         with R 1 —CP 2 , wherein R 1  is as defined according to  claim 1  and CP 2  is the appropriate coupling partner to CP 1 ; 
         under suitable coupling conditions to form a compound of formula I. 
       
     
     
         34 . The process of  claim 33 , further comprising the step of reacting the compound of formula A: 
       
         
           
           
               
               
           
         
       
       under Sandmeyer conditions to form a compound of formula B.