Heteroaryls and uses thereof

Abstract

This invention provides compounds of formula IA-i-a or IB-i-a and subsets thereof: wherein Z, HY, R 1 , R 2 , R 3 , G 1 , W, n, and A and subsets thereof are as described in the specification. The compounds are inhibitors of PI3K and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

1 - 73 . (canceled) 
     
     
         74 . A compound of formula IA or IB: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is —C(O)N(R 3 ) 2 , —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR 3 N(R 3 ) 2 , —C(═N—NH 2 )NH 2 , or —C(═N)N(R 3 ) 2 ; 
         each occurrence of R 3  is independently hydrogen or an optionally substituted C 1-6 aliphatic; 
         Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
         each occurrence of R 2  is independently R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12a , and: 
         each occurrence of R 12a  is independently halogen, —CN, —NO 2 , —R 12c , —N(R 12b ) 2 , —OR 12b , —SR 12c , —S(O) 2 R 12c , —C(O)R 12b , —C(O)OR 12b , —C(O)N(R 12b ) 2 , —S(O) 2 N(R 12b ) 2 , —OC(O)N(R 12b ) 2 , —N(R 12e )C(O)R 12b , —N(R 12e )SO 2 R 12c , —N(R 12e )C(O)OR 12b , —N(R 12e )C(O)N(R 12b ) 2 , or N(R 12e )SO 2 N(R 12b ) 2 , or two occurrences of R 12b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;
 each occurrence of R 12b  is independently hydrogen or an optionally substituted group selected from C 1 -C 6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 12c  is independently an optionally substituted group selected from C 1 -C 6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 12d  is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 12e  is independently hydrogen or an optionally substituted C 1-6  aliphatic group; 
 each occurrence of V 2  is independently —N(R 12e )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 12e )—, —S(O) 2 N(R 12e )—, —OC(O)N(R 12e )—, N(R 12e )C(O)—, —N(R 12e )SO 2 —, —N(R 12e )C(O)O—, —N(R 12e )C(O)N(R 12e )—, —N(R 12e )SO 2 N(R 12e )—, —OC(O)—, or —C(O)N(R 12e )—O—; and 
 
         T 2  is an optionally substituted C 1 -C 6  alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 13 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 13 )—, —S(O) 2 N(R 13 )—, —OC(O)N(R 13 )—, —N(R 13 )C(O)—, —N(R 13 )SO 2 —, —N(R 13 )C(O)O—, —N(R 13 )C(O)N(R 13 )—, —N(R 13 )S(O) 2 N(R 13 )—, —OC(O)—, or —C(O)N(R 13 )—O— or wherein T 2  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R 13  is hydrogen or an optionally substituted C 1-4 aliphatic group; 
         n is 0 to 4; 
         W is selected from —C(R 7 ) 2 —, —C(═C(R 7 ) 2 )—, —C(R 7 ) 2 O—, —C(R 7 ) 2 NR 7a —, —O—, —N(R 7b )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)NR 7a —, and —N(R 7a )C(O)—, wherein:
 each occurrence of R 7  is independently hydrogen, or an optionally substituted group selected from C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, and —CN; 
 each occurrence of R 7a  is independently hydrogen or optionally substituted C 1-6  aliphatic or optionally substituted C 3-6  cycloaliphatic; 
 each occurrence of R 7b  is independently hydrogen, optionally substituted C 1-6  aliphatic, optionally substituted C 3-6  cycloaliphatic, —C(O)R 7a , —C(O)OR 7a , S(O)R 7a , or —S(O) 2 R 7a ; or 
 wherein any two occurrences of R 7 , R 7a , or R 7b  taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 or wherein any two occurrences of R 7a  and R 2 , or R 7b  and R 2  taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 G 1  is N; and 
 
         HY is 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 14  is independently —R 14a  or -T 1 -R 14d , wherein:
 each occurrence of R 14a , as valency and stability permit, is independently fluorine, ═O, ═S, —CN, —NO 2 , —R 14c , N(R 14b ) 2 , —OR 14b , SR 14c , —S(O) 2 R 14c , —C(O)R 14b , —C(O)OR 14b , —C(O)N(R 14b ) 2 , —S(O) 2 N(R 14 ) 2 , —OC(O)N(R 14 ) 2 , —N(R 14e )C(O)R 14b , —N(R 14e )SO 2 R 14c , —N(R 14e )C(O)OR 14b , —N(R 14e )C(O)N(R 14b ) 2 , or —N(R 14e )SO 2 N(R 14b ) 2 , or two occurrences of R 14b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 14b  is independently hydrogen or an optionally substituted group selected from C 1 -C 6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 14c  is independently an optionally substituted group selected from C 1 -C 6  aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 14d  is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 
 each occurrence of R 14e  is independently hydrogen or an optionally substituted C 1-6  aliphatic group; and 
 T 1  is an optionally substituted C 1 -C 6  alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 14a )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 14a )—, —S(O) 2 N(R 14a )—, —OC(O)N(R 14a )—, —N(R 14a )C(O)—, —N(R 14a )SO 2 —, —N(R 14a )C(O)O—, —NR 14a C(O)N(R 14a )—, —N(R 14a )S(O) 2 N(R 14a )—, —OC(O)—, or —C(O)N(R 14a )—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         n is 0-6; 
         m is 1 or 2; 
         p is 0, 1, or 2. 
       
     
     
         75 . The compound of  claim 74 , wherein HY is 
       
         
           
           
               
               
           
         
       
       wherein both occurrences of m are 1. 
     
     
         76 . The compound of  claim 74 , wherein W is —C(R 7 ) 2 —, wherein one occurrence of R 7  is hydrogen and the other occurrence of R 7  is hydrogen, optionally substituted C 1-6  aliphatic, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, or —CN; and wherein each occurrence of R 7a  is independently hydrogen or optionally substituted C 1-6  aliphatic; and each occurrence of R 7b  is independently hydrogen, optionally substituted C 1-6  aliphatic, —C(O)R 7a , or —S(O) 2 R 7a ; or wherein two occurrences of R 7b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered heterocyclic ring. 
     
     
         77 . The compound of  claim 74 , wherein W is —C(H)(N(R 7b ) 2 )—, —CH 2 —, —C(H)(OR 7a )—, —NR 7b —, or —N(R 7a )C(O)—, wherein each occurrence of R 7a  is independently hydrogen or optionally substituted C 1-6  aliphatic; and each occurrence of R 7b  is independently hydrogen or optionally substituted C 1-6  aliphatic. 
     
     
         78 . The compound of  claim 74 , wherein Ring A is 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0 to 3. 
     
     
         79 . The compound of  claim 74 , wherein ring A is a group selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein ring A is optionally further substituted by n occurrences of R 2 , and wherein R 2a  is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
       
     
     
         80 . The compound of  claim 74 , wherein Ring A is a group selected from: 
       
         
           
           
               
               
           
         
         wherein ring A is optionally further substituted by n occurrences of R 2 , and wherein R 2a  is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
       
     
     
         81 . The compound of  claim 74 , wherein ring A is a naphthyl group; each occurrence of R 2  is independently halogen, C 1-3  alkyl, —CN, C 1-3  haloalkyl, —OC 1-3  alkyl, —OC 1-3 haloalkyl, —NHC(O)C 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, —NHS(O) 2 C 1-3  alkyl, or —C(O)H; and n is 0 to 3. 
     
     
         82 . The compound of  claim 74 , wherein ring A is a naphthyl group, R 2  is halogen and n is 1 to 2. 
     
     
         83 . The compound of  claim 74 , wherein Ring A is a phenyl group; each occurrence of R 2  is independently halogen, C 1-3  alkyl, —CN, C 1-3 haloalkyl, —OC 1-3  alkyl, —OC 1-3 haloalkyl, —NHC(O)C 1-3  alkyl, —NHC(O)NHC 1-3  alkyl, —NHS(O) 2 C 1-3  alkyl, or —C(O)H; and n is 0 to 3. 
     
     
         84 . The compound of  claim 74 , wherein Ring A is a phenyl group, R 2  is halogen and n is 1 to 2. 
     
     
         85 . A pharmaceutical composition comprising the compound of  claim 74 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         86 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         87 . A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of the compound of  claim 74 , or a pharmaceutically acceptable salt thereof. 
     
     
         88 . The method of  claim 87 , wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, or ovarian cancer. 
     
     
         89 . A method of treating an inflammatory or cardiovascular disorder in a patient comprising administering to said patient a therapeutically effective amount of the compound of  claim 74 , or a pharmaceutically acceptable salt thereof. 
     
     
         90 . The method of  claim 89 , wherein the inflammatory or cardiovascular disorder is selected from allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis, autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure. 
     
     
         91 . A method for inhibiting PI3K or VPS34 activity in a patient comprising administering a composition comprising a therapeutically effective amount of the compound of  claim 74 , or a pharmaceutically acceptable salt thereof.