Heteroaryls and uses thereof

Abstract

This invention provides compounds of formula I-A or I-B: wherein HY, G 1 , G 2 , R 2 , R 12 , W 1 , W 2 , n, and Ring A are as described in the specification. The compounds are inhibitors of PI3K and/or mTor and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

1 . A compound of formula I-A or I-B: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 G 1  is N 
 G 2  is S; 
 Ring A is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 2  is independently R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12d , 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, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 12c  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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; 
 R 12  is hydrogen, halo, or an optionally substituted group selected from C 1-6  aliphatic, —C(O)N(R 5a ) 2 , 3-10-membered cycloaliphatic, —N(R 4b ) 2 , —OR 4a , or —SR 4a ; 
 or R 2  and R 12  form an optionally substituted 3-10-membered cycloaliphatic; 
 W 1  is selected from —C(O)C(R 4 ) 2 —, —C(R 4 ) 2 C(O)—, —C(O)O—, —OC(O)—, —C(O)NR 4a —, —NR 4a C(O)—, —C(═NR 4b )C(R 4 ) 2 —, —C(R 4 ) 2 C(═NR 4b )—, —C(═NR 4b )O—, —OC(═NR 4b )—, —C(═NR 4b )NR 4a —, —NR 4a C(═NR 4b )—, —S(O)C(R 4 ) 2 —, —C(R 4 ) 2 S(O)—, —S(O)O—, —OS(O)—, —S(O)NR 4a —, —NR 4a S(O)—, —S(O) 2 C(R 4 ) 2 —, —C(R 4 ) 2 S(O) 2 —, —S(O) 2 O—, —OS(O) 2 —, —S(O) 2 NR 4a —, —NR 4a S(O) 2 —, —C(S)C(R 4 ) 2 —, —C(R 4 ) 2 C(S)—, —C(S)O—, —OC(S)—, —C(S)NR 4a —, or —NR 4a C(S)—, wherein: 
 W 2  is —(C—W 3 ) r , or any two occurrences of W 2  is independently —C(R 5 )═C(R 5 )—;
 wherein each occurrence of W 3  is independently —(R 5 ) 2  or ═O; 
 r is 0 to 3; 
 each occurrence of R 4  is independently hydrogen, halo, or an optionally substituted C 1-6  aliphatic or —C(O)OR 4c ;
 each occurrence of R 4a  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 each occurrence of R 4b  is independently hydrogen, or a group selected from optionally substituted C 1-6 aliphatic, —OR 4c , or —N(R 4a ) 2 ; 
 each occurrence of R 4c  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 
 each occurrence of R 5  is independently hydrogen, halo, or an optionally substituted group selected from C 1-6  aliphatic, —C(O)N(R 5a ) 2 , 3-10-membered cycloaliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R 4b ) 2 , —OR 4a , or —SR 4a ;
 each occurrence of R 5a  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 
 
 HY is an optionally substituted group selected from: 
 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 4 , X 5 , X 6 , and X, is independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and O 2  is independently S, O or —NR 6 ; 
         each occurrence of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 4  and X 5 , X 6  and X 7 , Y 1  and Q 1 , Y 3  and Q 2 , or Y 4  and Y 5  taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
       
       wherein R 10  is —R 10b , —V 1 —R 10c , -T 1 -R 10b , or —V-T 1 -R 10b  wherein:
 V 1  is —NR 7 —, —NR 7 —C(O)—, —NR 7 —C(S)—, —NR 7 —C(NR 7 )—, —NR 7 C(O)OR 10a —, —NR 7 C(O)NR 7 —, —NR 7 C(O)SR 10a —, —NR 7 C(S)OR 10a —, —NR 7 C(S)NR 7 —, —NR 7 C(S)SR 10a —, —NR 7 C(NR 7 )OR 10a —, —NR 7 C(NR 7 )NR 7 —, —NR 7 S(O) 2 —, —NR 7 S(O) 2 NR 7 —, —C(O)—, —CO 2 —, —C(O)NR 7 —, —C(O)NR 7 O—, —SO 2 —, or —SO 2 NR 7 —; 
 each occurrence of R 10a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 T 1  is an optionally substituted C 1- C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 7 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —S(O) 2 N(R 7 )—, —OC(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )SO 2 —, —N(R 10a )C(O)O—, —NR 10a C(O)N(R 10a )—, —N(R 10a )S(O) 2 N(R 10a )—, —OC(O)—, or —C(O)N(R 7 )—O— or wherein T 1  forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 each occurrence of R 10b  is independently hydrogen, halogen, —CN, —NO 2 , —N(R 7 ) 2 , —OR 10a , —SR 10a , —S(O) 2 R 10a , —C(O)R 10a , —C(O)OR 10a , —C(O)N(R 7 ) 2 , —S(O) 2 N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 10a , —N(R 7 )SO 2 R 10a , —N(R 7 )C(O)OR 10a , —N(R 7 )C(O)N(R 7 ) 2 , or —N(R 7 )SO 2 N(R 7 ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 10c  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 
 R 7  and R 10c  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 independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 7  is independently hydrogen, —C(O)R 7a , —CO 2 R 7a , —C(O)N(R 7a ) 2 , —C(O)N(R 7a )—OR 7a , —SO 2 R 7a , —SO 2 N(R 7a ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
 wherein each occurrence of R 7a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each occurrence of R 6  is independently hydrogen, —C(O)R 6a , —CO 2 R 6a , —C(O)N(R 6b ) 2 , —SO 2 R 6a , —SO 2 N(R 6b ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur;
 wherein each occurrence of R 6a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur; and 
 wherein each occurrence of R 6b  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R 6b  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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 or 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 14b ) 2 , OC(O)N(R 14b ) 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, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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 14b )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 14ab )—, —S(O) 2 N(R 14b )—, —OC(O)N(R 14b )—, —N(R 14b )C(O)—, —N(R 14b )SO 2 —, —N(R 14b )C(O)O—, —NR 14b C(O)N(R 14b )—, —N(R 14b )S(O) 2 N(R 14b )—, —OC(O)—, or —C(O)N(R 14b )—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         q is 0-6; 
         m is 1 or 2; and 
         p is 0, 1, or 2. 
       
     
     
         2 . A compound of formula II-A or II-B: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 G 1  is CR 1 , wherein R 1  is H, —CN, halogen, or an optionally substituted group selected from C 1-6  aliphatic, 3-10-membered cycloaliphatic, or —Z—R 11 , wherein:
 Z is selected from an optionally substituted C 1-3 alkylene chain, —O—, —N(R 1a )—, —S—, —S(O)—, S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 1a —, —N(R 1a )C(O)—, —N(R 1a )CO 2 —, —S(O) 2 NR 1a —, —N(R 1a )S(O) 2 —, —OC(O)N(R 1a )—, —N(R 1a )C(O)NR 1a —, —N(R 1a )S(O) 2 N(R 1a )—, or —OC(O)—;
 R 1a  is hydrogen or an optionally substituted C 1-4 aliphatic, and 
 
 R 11  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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
 
 Ring A is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 2  is independently R 12a , -T 2 -R 12d , or —V 2 -T 2 -R 12d , 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, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 12c  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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; 
 R 12  is hydrogen, halo, or an optionally substituted group selected from C 1-6  aliphatic, —C(O)N(R 5a ) 2 , 3-10-membered cycloaliphatic, —N(R 4b ) 2 , —OR 4a , or —SR 4a ; 
 or R 2  and R 12  form an optionally substituted 3-10-membered cycloaliphatic; 
 W 1  is selected from —C(O)C(R 4 ) 2 —, —C(R 4 ) 2 C(O)—, —C(O)O—, —OC(O)—, —C(O)NR 4a —, —NR 4a C(O)—, —C(═NR 4b )C(R 4 ) 2 —, —C(R 4 ) 2 C(═NR 4b )—, —C(═NR 4b )O—, —OC(═NR 4b )—, —C(═NR 4b )NR 4a —, —NR 4a C(═NR 4b )—, —S(O)C(R 4 ) 2 —, C(R 4 ) 2 S(O)—, —S(O)O—, —OS(O)—, —S(O)NR 4a —, —NR 4a S(O)—, S(O) 2 C(R 4 ) 2 —, C(R 4 ) 2 S(O) 2 —, —S(O) 2 O—, —OS(O) 2 —, —S(O) 2 NR 4a —, —NR 4a S(O) 2 —, C(S)C(R 4 ) 2 —, C(R 4 ) 2 C(S)—, —C(S)O—, —OC(S)—, —C(S)NR 4a —, or —NR 4a C(S)—, wherein: 
 W 2  is —(C—W 3 ) r , or any two occurrences of W 2  is independently C(R 5 )═C(R 5 )—;
 wherein each occurrence of W 3  is independently (R 5 ) 2  or ═O; 
 r is 0 to 3; 
 each occurrence of R 4  is independently hydrogen, halo, or an optionally substituted C 1-6  aliphatic or C(O)OR 4c ;
 each occurrence of R 4a  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 each occurrence of R 4b  is independently hydrogen, or a group selected from optionally substituted C 1-6 aliphatic, —OR 4c , or —N(R 4a ) 2 ; 
 each occurrence of R 4c  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 
 each occurrence of R 5  is independently hydrogen, halo, or an optionally substituted group selected from C 1-6  aliphatic, —C(O)N(R 5a ) 2 , 3-10-membered cycloaliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R 4b ) 2 , —OR 4a , or —SR 4a ;
 each occurrence of R 5a  is independently hydrogen or optionally substituted C 1-6  aliphatic; 
 
 
 HY is an optionally substituted group selected from: 
 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 4 , X 5 , X 6 , and X 7  is independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and Q 2  is independently S, O or —NR 6 ; 
         each occurrence of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 4  and X 5 , X 6  and X 7 , Y 1  and Q, Y 3  and Q 2 , or Y 4  and Y 5  taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
       
       wherein R 10  is —R 10b , —V 1 —R 10c , -T 1 -R 10b , or —V-T 1 -R 10b  wherein:
 V 1  is —NR 7 —, —NR 7 —C(O)—, —NR 7 —C(S)—, —NR 7 —C(NR 7 )—, —NR 7 C(O)OR 10a —, —NR 7 C(O)NR 7 —, —NR 7 C(O)SR 10a —, —NR 7 C(S)OR 10a —, —NR 7 C(S)NR 7 —, —NR 7 C(S)SR 10a —, —NR 7 C(NR 7 )OR 10a —, —NR 7 C(NR 7 )NR 7 —, —NR 7 S(O) 2 —, —NR 7 S(O) 2 NR 7 —, —C(O)—, —CO 2 —, —C(O)NR 7 —, —C(O)NR 7 O—, —SO 2 —, or —SO 2 NR 7 —; 
 each occurrence of R 10a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 T 1  is an optionally substituted C 1- C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 7 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —S(O) 2 N(R 7 )—, —OC(O)N(R 7 )—, —N(R 7 )C(O)—, —N(R 7 )SO 2 —, —N(R 10a )C(O)O—, —NR 10a , C(O)N(R 10a )—, —N(R 10a )S(O) 2 N(R 10a )—, —OC(O)—, or —C(O)N(R 7 )—O— or wherein T 1  forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 each occurrence of R 10b  is independently hydrogen, halogen, —CN, —NO 2 , —N(R 7 ) 2 , OR 10a , SR 10a , S(O) 2 R 10a , C(O)R 10a , C(O)OR 10a , —C(O)N(R 7 ) 2 , —S(O) 2 N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 10a , —N(R 7 )SO 2 R 10a , —N(R 7 )C(O)OR 10a , —N(R)C(O)N(R 7 ) 2 , or N(R 7 )SO 2 N(R 7 ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 10c  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 
 R 7  and R 10c  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 independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 7  is independently hydrogen, —C(O)R 7a , —CO 2 R 7a , —C(O)N(R 7a ) 2 , —C(O)N(R 7a )—OR 7a , —SO 2 R 7a , —SO 2 N(R 7a ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
 wherein each occurrence of R 7a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 each occurrence of R 6  is independently hydrogen, —C(O)R 6a , —CO 2 R 6a , —C(O)N(R 6b ) 2 , —SO 2 R 6a , —SO 2 N(R 6b ) 2 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur;
 wherein each occurrence of R 6a  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur; and 
 wherein each occurrence of R 6b  is independently 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteratoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R 6b  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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
 or 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 14′ , —S(O) 2 R 14′ , —C(O)R 14b , —C(O)OR 14b , —C(O)N(R 14 ) 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 14′ , —N(R 14e )C(O)OR 14b , —N(R 14e )C(O)N(R 14 ) 2 , or N(R 14e )SO 2 N(R 14 ) 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, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 each occurrence of R 14′  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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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 14b )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 14b )—, —S(O) 2 N(R 14b )—, —OC(O)N(R 14b )—, —N(R 14b )C(O)—, —N(R 14b )SO 2 —, —N(R 14b )C(O)O—, —NR 14b  C(O)N(R 14b )—, —N(R 14b )S(O) 2 N(R 14b )—, —OC(O)—, or —C(O)N(R 14b )—O— or wherein T 1  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; 
 
         q is 0-6; 
         m is 1 or 2; and 
         p is 0, 1, or 2. 
       
     
     
         3 . The compound of  claim 1 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 4 , X 5 , X 6 , and X 7  is independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and Q 2  is independently S, O or —NR 6 ; 
         each occurrence of Y 1  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 6  and X 7 , or Y 1  and Q, taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         wherein each occurrence of R 14  is independently an optionally substituted C 1-6  aliphatic group. 
       
     
     
         4 . The compound of  claim 1 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each HY group is optionally additionally substituted with one or more occurrences of R 10  or R 14 . 
       
     
     
         5 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1  having the following formula V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 18 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 4 , X 5 , X 6 , and X, is independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and Q 2  is independently S, O or —NR 6 ; 
         each occurrence of Y 1  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 6  and X 7 , or Y 1  and Q, taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         wherein each occurrence of R 14  is independently an optionally substituted C 1-6  aliphatic group. 
       
     
     
         21 . The compound of  claim 18 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each HY group is optionally additionally substituted with one or more occurrences of R 10  or R 14 . 
       
     
     
         22 - 35 . (canceled) 
     
     
         36 . The compound of  claim 1  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The compound of  claim 1  having the structure VIII-A or VIII-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         G 3  is C═O or SO 2 ; 
         G 4  is O or NR 4a , wherein R 4a  is hydrogen or optionally substituted C 1-6 aliphatic; 
         t is 1 or 2. 
       
     
     
         38 - 42 . (canceled) 
     
     
         43 . The compound of  claim 37 , wherein G 1  is N and G 2  is S. 
     
     
         44 . (canceled) 
     
     
         45 . The compound of  claim 37 , having the structure VIII-A, or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The compound of  claim 37 , having the structure VIII-A-i or VIII-B-i 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
     
     
         47 . The compound of any  claim 37 , having a structure according to one of the following formulas: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . (canceled) 
     
     
         49 . The compound of  claim 37 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 4 , X 5 , X 6 , and X 7  is independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and Q 2  is independently S, O or —NR 6 ; 
         each occurrence of Y 1  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 6  and X 7 , or Y 1  and Q, taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         wherein each occurrence of R 14  is independently an optionally substituted C 1-6 aliphatic group. 
       
     
     
         50 . The compound of  claim 37 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each HY group is optionally additionally substituted with one or more occurrences of R 10  or R 14 . 
       
     
     
         51 . The compound of  claim 50 , wherein HY is selected from optionally substituted morpholino (iv) or dihydropyran (x). 
     
     
         52 . The compound of  claim 51 , wherein HY is selected from optionally substituted morpholino (iv). 
     
     
         53 . The compound of  claim 37 , wherein Ring A is an optionally substituted phenyl, naphthyl, quinoline, isoquinoline, or benzimidazole ring. 
     
     
         54 . The compound of  claim 53 , wherein Ring A is optionally substituted by R 2  and 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. 
     
     
         55 - 58 . (canceled) 
     
     
         59 . The compound of  claim 37  wherein each occurrence of R 5  is independently hydrogen, halo, or an optionally substituted group selected from C 1-6  aliphatic, —C(O)N(R 15b ) 2 , —C(O)OR 15b , —CH 2 N(R 15b ) 2 , —CH 2 OR 15b , —CH 2 SR 15c , 3-10-membered cycloalphatic, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         60 . (canceled) 
     
     
         61 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         62 . A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of  claim 1 . 
     
     
         63 . (canceled) 
     
     
         64 . A method of treating an inflammatory or cardiovascular disorder in a patient comprising administering to said patient a therapeutically effective amount of  claim 1 . 
     
     
         65 . (canceled) 
     
     
         66 . A method for inhibiting PI3K or mTor activity in a patient comprising administering a composition comprising a therapeutically effective amount of a compound of  claim 1 .