Thiophene-carboxamides useful as inhibitors of protein kinases

Abstract

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

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is H, C 1-6 aliphatic, or C 3-6 cycloaliphatic; 
 G is —C(R) 2 — or —O—; 
 L is C 0-3 aliphatic optionally substituted with 0-3 J L ; 
 
         Ring A is triazolyl optionally substituted with 0-3 J A ; 
         Ring B is 5-6 membered aromatic monocyclic ring containing 0-3 heteroatoms selected from O, N, and S; Ring B is optionally substituted with 0-5 J B  and optionally fused to Ring B′; 
         Ring B′ is a 5-8 membered aromatic or nonaromatic monocyclic ring containing 0-3 heteroatoms selected from O, N, and S;
 Ring B′ is optionally substituted with 0-4 J B′ ; 
 
         each J A , J B , and J B′  is independently C 1-6 haloalkyl, halo, NO 2 , CN, Q, or —Z-Q; 
         Z is independently C 1-6 aliphatic optionally interrupted with 0-3 occurrences of —NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, —SO—, or —SO 2 —; each Z is optionally substituted with 0-2 J Z ; 
         Q is H; C 1-6 aliphatic; a 3-8-membered aromatic or nonaromatic monocyclic ring having 0-3 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 L  and J 2  is independently H, halo, C 1-6  aliphatic, C 3-6 cycloaliphatic, NO 2 , CN, —NH 2 , —NH(C 1-4  aliphatic), —N(C 1-4  aliphatic) 2 , —OH, —O(C 1-4  aliphatic), —CO 2 H, —CO 2 (C 1-4  aliphatic), —O(haloC 1-4  aliphatic), or halo(C 1-4  aliphatic); 
         each J Q  is independently M or —Y-M; 
         each Y is independently an unsubstituted C 1-6 aliphatic optionally interrupted with 0-3 occurrences of —NR—, —O—, —S—, —C(O)—, —SO—, or —SO 2 —; 
         each M is independently H, C 1-6  aliphatic, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), C 3-6  heterocyclyl, halo, NO 2 , CN, OH, OR′, SH, SR′, NH 2 , NHR′, N(R′) 2 , COH, COR′, CONH 2 , CONHR′, CONR′ 2 , NHCOR′, NR′COR′, NHCONH 2 , NHCONHR′, NHCON(R′) 2 , SO 2 NH 2 , SO 2 NHR′, SO 2 N(R′) 2 , NHSO 2 R′, or NR′SO 2 R′; 
         R is H or unsubstituted C 1-6 aliphatic; 
         R′ is unsubstituted C 1-6 aliphatic; or two R′ groups, together with the atom to which they are bound, form an unsubstituted 3-8 membered nonaromatic monocyclic ring having 0-1 heteroatoms independently selected from O, N, and S. 
       
     
     
         2 . The compound of  claim 1 , wherein G is —C(R) 2 —. 
     
     
         3 . The compound of  claim 1 , wherein G is O. 
     
     
         4 . The compound of any one of  claims 1 - 3 , wherein R 1  is H. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein Ring A 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5 , wherein Ring A is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 5  or  claim 6 , wherein Ring B is a 6 membered aromatic ring containing 0-2 nitrogen atoms and Ring B is optionally substituted with 0-5 J B . 
     
     
         8 . The compound of any one of  claims 1 - 7 , wherein Ring B is fused to Ring B′ and Ring B is optionally substituted with 0-5 J B  and Ring B′ is optionally substituted with 0-4 J B′ . 
     
     
         9 . The compound of  claim 8 , wherein Ring B′ is a 5-6 membered aromatic ring containing 0-3 heteroatoms selected from O, N, and S, wherein Ring B′ is optionally substituted with 0-4 J B′ . 
     
     
         10 . The compound of any one of  claims 5 - 9 , wherein J A  is H, C 1-6  aliphatic, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), C 3-6  heterocyclyl, halo, NO 2 , CN, OH, OR, SH, SR, NH 2 , NHR, N(R) 2 , COH, COR, CONH 2 , CONHR, CONR 2 , NHCOR, NRCOR, NHCONH 2 , NHCONHR, NHCON(R) 2 , SO 2 NH 2 , SO 2 NHR, SO 2 N(R) 2 , NHSO 2 R, or NRSO 2 R. 
     
     
         11 . The compound of  claim 10 , wherein J A  is H. 
     
     
         12 . The compound of any one of  claims 5 - 11 , wherein J B  is H, C 1-6  aliphatic, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), C 3-6  heterocyclyl, halo, NO 2 , CN, OH, OR, SH, SR, NH 2 , NHR, N(R) 2 , COH, COR, CONH 2 , CONHR, CONR 2 , NHCOR, NRCOR, NHCONH 2 , NHCONHR, NHCON(R) 2 , SO 2 NH 2 , SO 2 NHR, SO 2 N(R) 2 , NHSO 2 R, or NRSO 2 R. 
     
     
         13 . The compound of any one of  claims 5 - 12 , wherein J B′  is H, C 1-6  aliphatic, C 3-6 cycloaliphatic, halo(C 1-4  aliphatic), —O(haloC 1-4  aliphatic), C 3-6  heterocyclyl, halo, NO 2 , CN, OH, OR, SH, SR, NH 2 , NHR, N(R) 2 , COH, COR, CONH 2 , CONHR, CONR 2 , NHCOR, NRCOR, NHCONH 2 , NHCONHR, NHCON(R) 2 , SO 2 NH 2 , SO 2 NHR, SO 2 N(R) 2 , NHSO 2 R, or NRSO 2 R. 
     
     
         14 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A composition comprising a compound of any one of  claims 1 - 14 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         16 . A method of inhibiting protein kinase activity in a patient comprising administering to said patient
 a) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         17 . A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with:
 a) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         18 . The method of  claim 16  or  claim 17 , wherein said protein kinase is PLK. 
     
     
         19 . The method of  claim 18 , wherein said protein kinase is PLK1. 
     
     
         20 . 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) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         21 . The method according to  claim 16  or  claim 20 , 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:
 said additional therapeutic agent is appropriate for the disease being treated; and 
 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. 
 
     
     
         22 . 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) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         23 . A method of treating cancer in a patient wherein said method comprises administering to said patient
 a) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         24 . The method of  claim 23 , wherein said method comprises the step of disrupting mitosis of the cancer cells by inhibiting PLK with:
 a) a composition of  claim 15 ; or   b) a compound of any one of  claims 1 - 14 .   
     
     
         25 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein G is O, R 1  is H, and Ring A, Ring B, J A , J B  and L are as defined according to any one of  claims 1 - 14 , 
         comprising reacting a compound of formula 3 
       
       
         
           
           
               
               
           
         
         wherein G is O and Ring A, Ring B, J A , J B  and L are as defined according to any one of  claims 1 - 14 , 
         under suitable amide forming conditions to form the compound of formula I. 
       
     
     
         26 . A process for preparing a compound of formula 3: 
       
         
           
           
               
               
           
         
         wherein Ring A, Ring B, J A , J B  and L are as defined according to any one of  claims 1 - 14 , 
         comprising reacting a compound of formula 2: 
       
       
         
           
           
               
               
           
         
         with 
       
       
         
           
           
               
               
           
         
         wherein LG is a suitable leaving group and L, Ring B, and J B  are as defined according to any one of  claims 1 - 14 ; 
         under suitable O—C bond coupling conditions to form the compound of formula 3. 
       
     
     
         27 . The process of  claim 26 , further comprising the step of adding 
       
         
           
           
               
               
           
         
         wherein ring A is an aromatic ring containing a nitrogen atom capable of nucleophilic attack and J A  is as defined according to any one of  claims 1 - 14 ; to a compound of formula 1: 
       
       
         
           
           
               
               
           
         
         via suitable conjugate addition conditions to form the compound of formula 2. 
       
     
     
         28 . The process of  claim 27 , wherein 
       
         
           
           
               
               
           
         
         is a compound of formula 6: 
       
       
         
           
           
               
               
           
         
       
     
     
         29 . The process of  claim 28 , further comprising the step of treating a compound of formula 5: 
       
         
           
           
               
               
           
         
         with an aldehyde and a hydrazine to form the compound of formula 6.