Isoindolinone inhibitors of phosphatidylinositol 3-kinase

Abstract

The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. 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 having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is N or CH; 
         X 2  is N, CH, or C—CH 3 ; 
         R 1  is selected from a phenyl ring, a 5-6 membered heteroaryl ring, a pyridone ring, or a 9-10 membered fused bicyclic heteroaryl or heterocyclic ring system wherein each of said rings or ring systems is optionally substituted with 1 or 2 independent occurrences of R 1a  and each of said heteroaryl or heterocyclic rings has 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur; 
         R 1a  is chloro, fluoro, C 1-8 aliphatic, —(CH 2 ) 0-2 C 3-6 cycloaliphatic, —(CH 2 ) 0-2 -5-6 membered heterocyclic having up to two heteroatoms selected from nitrogen, oxygen, or sulfur, —CN, —C(O)C 1-4 aliphatic, —C(O)NH(C 1-4 aliphatic), —C(O)N(C 1-4 aliphatic) 2 , —C(O)OC 1-4 aliphatic, —S(O) 2 NH(C 1-4 aliphatic), —S(O) 2 N(C 1-4 aliphatic) 2 , or —S(O) 2 C 1-4 aliphatic, wherein up to 3 non-adjacent carbon atoms of said aliphatic or cycloaliphatic of R 1a  can be substituted for by —O—, —S—, or —N(R 1b )— and wherein each of said aliphatic, cycloaliphatic, or heterocyclic of R 1a  is optionally and independently substituted with up to 4 occurrences of J R ; 
         each J R  is independently fluoro, oxo, —(CH 2 ) 0-2 CN, —(CH 2 ) 0-2 CF 3 , —C(O)R 1b , —C(O)N(R 1b ) 2 , —C(O)O(R 1b ), —N(R 1b ) 2 , —N(R 1b )C(O)R 1b , —(CH 2 ) 0-2 OR 1b , phenyl, or a 5-6 membered heteroaryl, 4-6 heterocyclyl, or 9-11 fused bicyclic heteroaryl or heterocyclyl, each of said heteroaryl or heterocyclyl rings having up to 3 atoms selected from nitrogen, oxygen, or sulfur, wherein each of said cycloaliphatic, phenyl, heteroaryl, or heterocyclyl is optionally substituted with up to 2 R 1c ; 
         each R 1b  is, independently, selected from hydrogen, C 1-8 aliphatic, —(CH 2 ) 0-1 C 3-6 cycloaliphatic, —(CH 2 ) 0-1 C 4-6 heterocyclic having up to two heteroatoms selected from N or O, or two R 1b  together with the atom to which they are bonded form a 5-6 membered heterocyclic ring, wherein each aliphatic, cycloaliphatic, or heterocyclic is optionally substituted with up to three F atoms or up to two —OH, —C 1-2 alkyl, or —OC 1-2 alkyl groups; 
         each R 1c  is, independently, fluoro, chloro, C 1-4 aliphatic, —(CH 2 ) 0-2 OH, —CN, —C(O)C 1-4 aliphatic, or —C(O)OC 1-4 aliphatic; 
         R 2  is hydrogen, F, Cl, CF 3 , C 1-2 aliphatic, C 3-4 cycloaliphatic, —N(CH 3 ) 2 , —N(CH 2 ) 3 , —OCF 3 , —OCHF 2 , or —OC 1-2 aliphatic; 
         R 3  is hydrogen, C 1-6 aliphatic, C 3-6  cycloaliphatic, C 4-7  heterocyclyl having 1 or 2 atoms selected from N or O, —(CH 2 ) 0-1 CF 3 , —OH, —OC 1-6 aliphatic, —OC 3-6 cycloaliphatic, —OC 3-6 heterocyclyl having one oxygen atom, —O(CH 2 ) 2 OC 1-2 aliphatic, or —OC 1-2 alkylC(O)OC 1-3 aliphatic, or benzyl; and 
         R 4  is hydrogen or C 1-6 alkyl; or R 3  and R 4  together with the carbon to which they are bonded form a 3-6 membered cycloaliphatic ring, a 3-6 membered heterocyclic ring having up to two atoms selected from N or O, or a C 2 alkenyl, wherein each of said aliphatic, cycloaliphatic, or heterocyclyl of R 3 , R 4 , or R 3  and R 4  together is optionally substituted with up to three F atoms, or up to two C 1-2 alkyl, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, —OH, or —OC 1-2 alkyl groups; 
         A is N or CR A ; 
         B is N or CR B , or A=B is a sulfur atom; 
         C is N or CR C ; 
         D is N or CR D ; 
         E is N or CR E  wherein no more than two of A, B, C, D, or E is N; 
         R A  is hydrogen, CH 3 , or OCH 3 ; 
         R B  is hydrogen, F, Cl, C 1-3 aliphatic, —(CH 2 ) 0-1 CF 3 , —(CH 2 ) 0-1 CHF 2 , or —O(CH 2 ) 0-1 CF 3 ; 
         R C  is hydrogen, F, Cl, C 1-3 aliphatic, —(CH 2 ) 0-1 CF 3 , —(CH 2 ) 0-1 CHF 2 , N(R 1b ) 2 , —OH, —O(CH 2 ) 0-1 CF 3 , or —OC 1-8 aliphatic, wherein up to 2 non-adjacent carbon atoms of said aliphatic can be substituted for by —O—; 
         R D  is hydrogen, fluoro, chloro, C 1-4 aliphatic, —C(O)OH, —C(O)OC 1-4 aliphatic, —C(O)N(R 1b ) 2 , —CN, —C(R D1 )═N—OR 1b , —N(R 1b ) 2 , —N(R D1 )C(O)C 1-4 aliphatic, —N(R D1 )C(O)phenyl, —N(R D1 )S(O) 2 C 1-4 aliphatic, —N(R D1 )S(O) 2 N(R 1b ) 2 , —N(R D1 )S(O) 2 -phenyl —OH, —OC 1-8 aliphatic, —O(CH 2 ) 0-1 C 3-6 cycloaliphatic, —SC 1-4 aliphatic, —S(O)C 1-4 aliphatic, —S(O) 2 C 1-4 aliphatic, or —S(O) 2 N(R 1b ) 2 ; wherein up to 2 non-adjacent carbon atoms of said aliphatic, cycloaliphatic, or heterocyclic of R D  can be substituted for by —O— and each of said aliphatic, cycloaliphatic, or phenyl of R D  can be substituted with up to 5 fluorine atoms; or R D  and R C  together with the atoms to which they are attached form a phenyl or pyridyl ring; 
         each R D1  is, independently, hydrogen or C 1-2 alkyl; and 
         R E  is hydrogen, F, Cl, —NHC(O)C 1-8 aliphatic, —OH, —OC 1-2 aliphatic, —(CH 2 ) 0-1 CF 3 , —(CH 2 ) 0-1 CHF 2 , C 1-3 aliphatic, C 3-4 cycloaliphatic, N(R 1b ) 2 , azetidin-1-yl. 
       
     
     
         2 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1 is 
       
       
         
           
           
               
               
           
         
       
       wherein R 1a  is —C 1-4 alkyl, optionally and independently substituted with —CN, up to three F atoms, or up to two CH 3 , —OC 1-2 alkyl, or —OH groups;
 R 2  is C 1-2 alkyl; 
 R 3  is hydrogen, —OH, —OC 1-4  alkyl, or C 1-4 alkyl optionally substituted with up to two —OH groups; 
 R 4  is hydrogen or CH 3 , or R 3  and R 4  together form a C 3-6 cycloalkyl ring optionally substituted with up to two OH groups, or a 4-6 membered heterocyclic ring having one oxygen or anitrogen atom optionally substituted with C 1-4 alkyl, —C(O)C 1-4 alkyl, or C(O)O C 1-4 alkyl; 
 R C  is hydrogen, F, C 1-2 alkyl, or —OC 1-2 alkyl; and 
 R D  is —OR D1 , —C(O)N(R D1 )R D2 , —S(O) 2 N(R D1 )R D2 , —S(O) 1-2 R D2 , —N(R D1 )S(O) 2 R D2 , or —N(R D1 )S(O) 2 N(R D1 )R D2 , wherein 
 R D1  is hydrogen or C 1-2 alkyl, and R D2  is C 1-4 alkyl, —(CH 2 ) 0-1 C 3-6 cycloalkyl, or —(CH 2 ) 0-1 C 4-6 heterocyclyl having up to two oxygen or nitrogen atoms, each alkyl, cycloalkyl, or heterocyclyl optionally substituted with up to three F atoms or up to two —OH groups. 
 
     
     
         9 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1a  is C 1-2 alkyl, optionally substituted with up to 3 fluorine atoms. 
     
     
         10 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1a  is C 1-4 alkyl, optionally substituted with CN. 
     
     
         11 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2  is CH 3 . 
     
     
         12 . The compound according to  claim 8 , or a pharmaceutical acceptable salt thereof, wherein at least one of R 3  and R 4  is not hydrogen. 
     
     
         13 . The compound according to  claim 12 , or a pharmaceutical acceptable salt thereof, wherein each of R 3  and R 4  is CH 3 . 
     
     
         14 . The compound according to  claim 12 , or a pharmaceutical acceptable salt thereof, wherein R 3  and R 4  together form a 4-6 membered heterocyclic ring having one oxygen or a nitrogen atom optionally substituted with C 1-4 alkyl, —C(O)C 1-4 alkyl, or —C(O)OC 1-4 alkyl. 
     
     
         15 - 19 . (canceled) 
     
     
         20 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 2  is CH 3 ; 
         R 3  is hydrogen, C 1-2 alkyl, OH, or OCH 3 ; 
         R 4  is hydrogen or CH 3 ; 
         R C  is hydrogen; and 
         R D  is —OC 1-2 alkyl or —OC 3-5 cycloalkyl, each optionally substituted with up to 3 fluorine atoms. 
       
     
     
         21 . The compound according to  claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 1-(2,2-difluoroethyl)-1H-pyrazol-4-yl or 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . The compound according to claim  23 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         R 2  is CH 3 ; 
         R 3  is hydrogen, C 1-2 alkyl, OH, or OCH 3 ; 
         R 4  is hydrogen or CH 3 ; 
         R C  is hydrogen, F, Cl, C 1-3 aliphatic, (CH 2 ) 0-1 CF 3 , —OCF 3 , or —OC 1-8 aliphatic; and 
         R D  is —C(O)NHC 1-8 aliphatic. 
       
     
     
         25 . (canceled) 
     
     
         26 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein each of R C  and R D  is —OCH 3 . 
     
     
         27 . The compound according to  claim 8 , or a pharmaceutical acceptable salt thereof, wherein R D  is —C(O)OH, —C(O)N(R 1b ) 2 , —CN, —S(O) 2 C 1-8 aliphatic, or —S(O) 2 N(R 1b ) 2 . 
     
     
         28 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein each of R C  and R D  is, independently, hydrogen, fluoro, chloro, C 1-3 aliphatic, CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-2 aliphatic, wherein at least one of R C  and R D  is not hydrogen. 
     
     
         29 . The compound according to  claim 28 , or a pharmaceutical acceptable salt thereof, wherein R C  is hydrogen and R D  is —OC 1-3 alkyl, optionally substituted with up to 3 F atoms. 
     
     
         30 . (canceled) 
     
     
         31 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is a compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         33 - 34 . (canceled) 
     
     
         35 . A method of treating or lessening the severity of a disease or condition selected from an autoimmune disease or an inflammatory disease of the brain or spinal cord selected from multiple sclerosis, epilepsy, Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, or amyotrophic lateral sclerosis, comprising the step of administering to said patient a compound or salt thereof according to  claim 1 , or a pharmaceutical composition thereof. 
     
     
         36 . The method according to  claim 35 , wherein said disease or disorder is multiple sclerosis. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . A method of inhibiting PI3K-gamma kinase activity in a biological sample comprising contacting said biological sample with a compound according to  claim 1 , or a composition comprising said compound.