Heteroaryls and uses thereof

Abstract

This invention provides compounds of formula IA-a or IB-a and subsets thereof: wherein Z, HY, R 1 , R 2 , 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 . (canceled) 
     
     
         2 . A compound of formula IA or IB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is CY, —C(O)N(R 3 ) 2 , —C(O)OR 3 , —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR 3 N(R 3 ) 2 , —C(═N—NH 2 )NH 2 , —C(═N)N(R 3 ) 2 , wherein:
 CY is 
 
 
       
         
           
           
               
               
           
         
         
            wherein: 
           G 2  is —N═, ═N—, or —N(R 3′ )—, wherein: 
           each occurrence of R 3  and R 3′  is independently hydrogen or an optionally substituted C 1-6  aliphatic, wherein: 
           X 1 , X 2 , and X 3 , are each independently N, NR 3′ , O, S, or CR 4 , provided that only one of X 1 , X 2 , or X 3  may be O, S, or NR 3′ ;
 each occurrence of R 4  is independently hydrogen, —CN, halogen, —Z 3 —R 6 , or an optionally substituted group selected from C 1-6  aliphatic, or 3-10-membered cycloaliphatic, wherein: 
 Z 3  is selected from an optionally substituted C 1-3  alkylene chain, —O—, —N(R 4a )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 4a —, —N(R 4a )C(O)—, —N(R 4a )CO 2 —, —S(O) 2 NR 4a —, —N(R 4a )S(O) 2 —, —OC(O)N(R 4a )—, —N(R 4a )C(O)NR 4a —, —N(R 4a )S(O) 2 N(R 4a )—, or —OC(O)—; 
 R 4a  is hydrogen or an optionally substituted C 1-4  aliphatic, and 
 R 6  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;
 or wherein two adjacent occurrences of R 3′  or R 4 , 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; 
 
         
         Ring A is a group selected 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 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 -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 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; 
         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 —, or —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, or sulfur, —N(R 7b ) 2 , —OR 7a , —SR 7a , halo, or —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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         G 1  is N 
         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 5 ; 
         each occurrence of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , and Y 9  is independently —CR 10  or N, provided no more than two occurrences of Y 6 , Y 7 , Y 8 , and Y 9  are 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 1 -T 1 -R 10b  wherein:
 V 1  is —NR 11 —, —NR 11 —C(O)—, —NR 11 —C(S)—, —NR 11 —C(NR 11 )—, —NR 11 C(O)OR 10a —, NR 11 C(O)NR 11 —, —NR 11 C(O)SR 10a , —NR 11 C(S)OR 10a —, —NR 11 C(S)NR 11 —, —NR 11 C(S)SR 10a —, —NR 11 C(NR 11 )OR 10a —,—NR 11 C(NR)NR 11 —, —NR 11 S(O) 2 —, —NR 11 S(O) 2 NR 11 —, —C(O)—, —CO 2 —, —C(O)NR 11 —, —C(O)NR 11 O—, —SO 2 —, or —SO 2 NR 11 —; 
 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 11 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 11 )—, —S(O) 2 N(R 11 )—, —OC(O)N(R 11 )—, —N(R 11 )C(O)—, —N(R 11 )SO 2 —, —N(R 11a )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 11 )—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 11 ) 2 , —OR 10a , —SR 10a , —S(O) 2 R 10a , —C(O)R 10a , —C(O)OR 10a , —C(O)N(R 11 ) 2 , —S(O) 2 N(R 11 ) 2 , —OC(O)N(R 11 ) 2 , —N(R 11 )C(O)R 10a , —N(R 11 )SO 2 R 10a , —N(R 11 )C(O)OR 10a , —N(R 11 )C(O)N(R 11 ) 2 , or —N(R 11 )SO 2 N(R 11 ) 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 10a  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 11  is independently hydrogen, —C(O)R 11a , —CO 2 R 11a , —C(O)N(R 11a ) 2 , —C(O)N(R 11a )—OR 11a , —SO 2 R 11a , —SO 2 N(R 11a ) 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 11a  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 5  is independently hydrogen, —C(O)R 5a , —CO 2 R 5a , —C(O)N(R 5b ) 2 , —SO 2 R 5a , —SO 2 N(R 5b ) 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 5a  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; 
 wherein each occurrence of R 5b  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 5b  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; 
 
       
       provided that:
 a) the compound is other than: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein R 1  is CY, and CY is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 2 , wherein X 1  is N, G 2  is —N(R 3′ )—, and X 2  and X 3  are CH. 
     
     
         5 . The compound of  claim 2 , wherein X 1  and X 2  are N, G 2  is —N(R 3′ )—, and X 3  is CH. 
     
     
         6 . The compound of  claim 2 , wherein X 3  is N, G 2  is —N(R 3′ )—, and X 1  and X 2  are CH. 
     
     
         7 . The compound of  claim 2 , wherein X 1  is N, X 2  is CH, X 3  is —N(R 3′ )— and G 2  is ═N—. 
     
     
         8 . The compound of  claim 2 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         wherein each occurrence of X 5 , X 6 , and X 7  is independently —CR 10  or N, provided no more than two occurrences of X 5 , X 6 , and X 7  are N; 
         each occurrence of Q 1  and Q 2  is independently S, O or —NR 5 ; 
         each occurrence of Y 1  and Y 7  is independently —CR 10  or N;
 or wherein two adjacent occurrences of X 6  and X 7 , or Y 1  and Q 1 , 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. 
 
       
     
     
         9 . The compound of  claim 8 , wherein HY is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each HY group is optionally additionally substituted with one or more occurrences of R 10 , and   in xviii represents a single bond or a double bond. 
       
     
     
         10 .- 13 . (canceled) 
     
     
         14 . The compound of  claim 2 , 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. 
     
     
         15 . The compound of  claim 14 , 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. 
     
     
         16 . The compound of  claim 2 , wherein Ring A is 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and n is 0 to 3. 
     
     
         17 . The compound of  claim 16 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 16 , 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.   
     
     
         20 .- 23 . (canceled) 
     
     
         24 . The compound of  claim 1  having the following formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 X 4 , X 5  and X 6  are each independently —CR 10  or N, provided no more than two occurrences of X 4 , X 5  and X 6  are N; 
 or two adjacent groups selected from R 10 , X 4 , X 5 , and X 6 , taken together, form an optionally substituted group selected 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. 
 
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 24 , wherein all of X 4 , X 5 , or X 6  are CR 10 . 
     
     
         27 .- 32 . (canceled) 
     
     
         33 . The compound of  claim 24 , wherein Ring A is an optionally substituted 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and n is 0 to 3. 
     
     
         34 . The compound of  claim 33 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         35 . The compound of  claim 33 , 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, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
       
     
     
         36 . The compound of  claim 33 , 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.   
     
     
         37 .- 40 . (canceled) 
     
     
         41 . The compound of  claim 24 , wherein W is —C(R 7 ) 2 —, wherein one occurrence of R 7  is hydrogen and the other occurrence of R 7  is selected from hydrogen, optionally substituted C 1-4  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; 
 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 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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
 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, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
 
     
     
         42 . The compound of  claim 41 , 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. 
     
     
         43 .- 59 . (canceled) 
     
     
         60 . A composition comprising a compound of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         61 . A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 2 . 
     
     
         62 . The method of  claim 61 , further comprising administering an additional therapeutic agent. 
     
     
         63 . The method of  claim 61 , further comprising administering an additional chemotherapeutic agent. 
     
     
         64 . The method of  claim 61 , 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. 
     
     
         65 . A method of treating an inflammatory or cardiovascular disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 2 . 
     
     
         66 . The method of  claim 65 , 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. 
     
     
         67 . A method for inhibiting PI3K or VPS34 activity in a patient comprising administering a composition comprising a therapeutically effective amount of a compound of  claim 2 .