Quinoxalines useful 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  and R 2  are each independently halogen or -L-R′; 
       L is a bond or is an optionally substituted C 1-6  alkylidene chain wherein up to two non-adjacent methylene units of L are optionally and independently replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)NR—, —OC(O)NR—, —NRNR—, —NRNRC(O)—, —NRC(O)—, —NRC(O)O—, —NRC(O)NR—, —SO—, —SO 2 —, —NRSO 2 —, —SO 2 NR—, —NRSO 2 NR—, —O—, —S—, or —NR—; 
       each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-6  aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted group selected from C 1-8  aliphatic; a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or wherein R and R′ taken together, or two occurrences of R′ taken together, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
       X 1  is C═O, S═O, SO 2 , or C═NR; 
       X 2  is NR, S, O, or C(R) 2 ; and 
       R 3  is an optionally substituted group selected from: C 1-6  aliphatic; a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R 3  is optionally substituted with m independent occurrences of Z—R Y , wherein m is 0-5; each independent occurrence of Z is a bond or is a C 1 -C 6  alkylidene chain, wherein up to two methylene units of Z are optionally replaced by —C(O)—, —C(O)C(O)—, —C(O)NR—, —C(O)NRNR—, —CO 2 —, —OC(O)—, —NRC(O)O—, —O—, —NRC(O)NR—, —OC(O)NR—, —NRNR, —NRC(O)—, —S—, —SO—, —SO 2 —, —NR—, —SO 2 NR—, or —NRSO 2 —; and each occurrence of R Y  is independently R′, halogen, NO 2 , or CN, provided that: 
       a) when X 1  is CO, then R 2  is not C(S)NH 2  or CN; 
       b) when X 1  is CO, X 2  is NH, and R 2  is 3,4-OMe-phenyl, then R 3  is not n-butyl; 
       c) when X 1  is CO and X 2  is CH 2 , then R 1  and R 2  are not both hydrogen; 
       d) when X 1  is SO 2  and X 2  is O, then R 1  and R 2  are not both hydrogen; 
       e) when R 1  and R 2  are both hydrogen, X 1  is CO, and X 2  is SO 2  or NH, then R 3  is not unsubstituted benzyl, phenyl, or cyclohexyl; 
       f) when R 1  and R 2  are each methyl, then:
 i) when X 1  is CO and X 2  is NH, then R 3  is not unsubstituted cyclohexyl or unsubstituted benzyl; and 
 ii) when X 1  is CO and X 2  is CH 2 , then R 3  is not unsubstituted benzyl; 
 
     
   
   
       2 . The compound of  claim 1  wherein
 a) when X 1  is CO, then R 2  is not C(S)NH 2  or CN;   b) when X 1  is CO, X 2  is NH, and R 2  is 3,4-OMe-phenyl, then R 3  is not n-butyl;   c) when X 1  is CO, and X 2  is CH 2 , then R 1  and R 2  are not both hydrogen;   d) when X 1  is SO 2 , and X 2  is O, then R 1  and R 2  are not both hydrogen;   e) when R 1  and R 2  are both hydrogen, X 1  is CO, and X 2  is SO 2  or NH, then R 3  is not unsubstituted benzyl, phenyl, or cyclohexyl;   f) when R 1  and R 2  are each methyl, then:
 i) when X 1  is CO, and X 2  is NH, then R 3  is not unsubstituted cyclohexyl or unsubstituted benzyl; and 
   i) when X 1  is CO, and X 2  is CH 2 , then R 3  is not unsubstituted benzyl;   
   
   
       3 . The compound of  claim 2 , wherein R 1  and R 2  are each independently halogen or -L-R′. 
   
   
       4 . The compound of  claim 2 , wherein R 1  and R 2  are each independently hydrogen, halogen, or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , OR′, —CH 2 OR′, SR′, —CH 2 SR′, C(O)OR′, —NRCOR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , SO 2 R′, or —SO 2 N(R′) 2 . 
   
   
       5 . The compound of  claim 2 , wherein R 1  and R 2  are each independently H, Cl, Br, F, CF 3 , Me, Et, —COOH, NH 2 , —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CO(C 1 -C 4 alkyl), —CONH 2 , —C(O)OCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 (C 1 -C 4 alkyl), —SO 2 NH 2 , —SO 2 N(CH 3 ) 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy. 
   
   
       6 - 22 . (canceled) 
   
   
       23 . The compound of  claim 2 , wherein X 1  is C═O and compounds have the structure: 
     
       
         
         
             
             
         
       
     
   
   
       24 - 25 . (canceled) 
   
   
       26 . The compound of  claim 2 , wherein X 2  is NR and compounds have the structure: 
     
       
         
         
             
             
         
       
     
   
   
       27 . The compound of  claim 2 , wherein X 1  is C═O and X 2  is NR and compounds have the structure: 
     
       
         
         
             
             
         
       
     
   
   
       28 . (canceled) 
   
   
       29 . The compound of  claim 2 , wherein R 3  is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
   
   
       30 . The compound of  claim 2 , wherein R 3  is an optionally substituted C 1 - 6 aliphatic group, wherein the C 1 - 6 aliphatic group is optionally substituted with a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
   
   
       31 . The compound of  claim 29  or  claim 30 , wherein the 5-6 membered monocyclic or 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or the 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur is selected from one of the following groups: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       32 . The compound of  claim 31 , wherein R 3  is an optionally substituted group selected from i, ii, xxxix, x L , x L i, or x L ii. 
   
   
       33 . The compound of  claim 31 , wherein R 3  is an optionally substituted phenyl group (i). 
   
   
       34 . The compound of  claim 2 , wherein Z is a bond or is an optionally substituted C 1-6  alkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by —O—, —NR—, —S—, —SO 2 —, or —C(O)O—, —CO—, and R Y  is R′ or halogen. 
   
   
       35 . The compound of  claim 2 , wherein each occurrence of ZR Y , when present, is independently —C 1-3 alkyl, —O(C 1-3 alkyl), —OH, —S(C 1-3 alkyl), —SH, CF 3 , —OCF 3 , —SCF 3 , —F, —Cl, —Br, —CN, —COOR′, —COR′, —O(CH 2 ) 2 N(R)(R′), —O(CH 2 )N(R)(R′), —CON(R)(R′), —NRCOR′, —(CH 2 ) 2 OR′, —(CH 2 )OR′, —N(R)(R′), —(CH 2 ) 2 N(R)(R′), —(CH 2 )N(R)(R′), —SO 2 N(R)(R′), —NRSO 2 R′, or an optionally substituted group selected from pyrrolidinyl, morpholino, piperazinyl, piperidinyl, phenyl, phenoxy, benzyl, benzyloxy, triazolyl, pyrazolyl, or pyridyl. 
   
   
       36 . The compound of  claim 2 , wherein any substitutable nitrogen atom in an R 3  group is substituted with hydrogen, or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —CH 2 OR′, —CH 2 SR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(′) 2 , SO 2 R′, or —S(O) 2 N(R′) 2 . 
   
   
       37 . The compound of  claim 36 , wherein any substitutable nitrogen atom is substituted with H, Me, CF 3 , ethyl, propyl, butyl, pentyl, CO(C 1 -C 4 alkyl), —CONH 2 , —COO(C 1 -C 4 alkyl), —CH 2 OH, —SO 2 (C 1 -C 4 alkyl), —SO 2 NH 2 , SO 2 N(CH 3 ) 2 , or optionally substituted phenyl or benzyl. 
   
   
       38 . (canceled) 
   
   
       39 . A pharmaceutically acceptable composition comprising an effective amount of compound of  claim 1  or  claim 2 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
   
   
       40 - 45 . (canceled) 
   
   
       46 . A method of treating or lessening the severity of a disease of condition selected from allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, and solid and hematologic malignancies such as leukemias and lymphomas. 
   
   
       47 . The method of claim  44 , wherein the disease or disorder is asthma.