Heteroaryls and uses thereof

Abstract

This invention provides compounds of formula I: wherein R 1 , R 2 , CY, Y 1 , Y 2 , X 1 , X 2 , and X 3 are as described in the specification. The compounds are inhibitors of PI3K and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 when Y 2  is C, R 1  is H, —CN, halogen, —Z—R 3 , C 1-6  aliphatic, or 3-10-membered cycloaliphatic, wherein:
 Z is selected from an optionally substituted C 1-3  alkylene chain, —O—, —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 3  is 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; 
 
 R 2  is H, halogen, —W—R 5 , or —R 5 , wherein:
 W is selected from an optionally substituted C 1-3  alkylene chain, —O—, —N(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 2a —, —N(R 2a )C(O)—, —N(R 2a )CO 2 —, —S(O) 2 NR 2a —, N(R 2a )S(O) 2 —, —OC(O)N(R 2a )—, —N(R 2a )C(O)NR 2a —, —N(R 2a )S(O) 2 N(R 2a )—, or —OC(O)—. 
 R 2a  is hydrogen or an optionally substituted C 1-4  aliphatic, and 
 R 5  is 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; 
 
 
       X 1 , X 2 , and X 3  are each independently N or CR 6 , wherein each occurrence of R 6  is independently hydrogen, —CN, halogen, —V—R 7 , C 1-6  aliphatic, or 3-10-membered cycloaliphatic, wherein:
 V is selected from an optionally substituted C 1-3  alkylene chain, —O—, —N(R 6a )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)NR 6a —, —N(R 6a )C(O)—, —N(R 6a )CO 2 —, —S(O) 2 NR 6a —, —N(R 6a )S(O) 2 —, —OC(O)N(R 6a )—, —N(R 6a )C(O)NR 6a —, —N(R 6a )S(O) 2 N(R 6a )—, or —OC(O)—. 
 R 6a  is hydrogen or an optionally substituted C 1-4  aliphatic, and 
 R 7  is 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; 
 Y 1  is S, O, NR 8 , wherein R 8  is hydrogen or an optionally substituted C 1-4 aliphatic; 
 Y 2  is C, N 
 CY is 
 
       
         
           
           
               
               
           
         
         wherein each occurrence of R 4  is independently-R 4a  or -T 1 -R 4d , wherein:
 each occurrence of R 4a , as valency and stability permit, is independently fluorine, ═O, ═S, —CN, —NO 2 , —R 4c , —N(R 4b ) 2 , —OR 4b , —SR 4c , —S(O) 2 R 4c , —C(O)R 4b , —C(O)OR 4b , —C(O)N(R 4b ) 2 , —S(O) 2 N(R 4b ) 2 , —OC(O)N(R 4b ) 2 , —N(R 4e )C(O)R 4b , —N(R 4e )SO 2 R 4c , —N(R 4e )C(O)OR 4b , —N(R 4e )C(O)N(R 4b ) 2 , or —N(R 4e )SO 2 N(R 4b ) 2 , or two occurrences of R 4b , 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 4b  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 4c  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 4d  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 4e  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 4a )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 4a )—, —S(O) 2 N(R 4a )—, —OC(O)N(R 4a )—, —N(R 4a )C(O)—, —N(R 4a )SO 2 —, —N(R 4a )C(O)O—, —NR 4a C(O)N(R 4a )—, —N(R 4a )S(O) 2 N(R 4a )—, —OC(O)—, or —C(O)N(R 4a )—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; 
            represents a single or double bond; and 
       
       provided that the compound of formula I is other than Morpholine, 4-[5-(4,5-diphenyl-1H-imidazol-2-yl)-2-thienyl]-. 
     
     
         2 . The compound of  claim 1 , wherein one or more substituents are selected from:
 (a) Y 1  is S;   (b) Y 2  is C   (c) R 1  is CN or H;   (d) R 2  is an optionally substituted 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   (e) n is 0-2; or   (f) R 4  is —R 4a .   
     
     
         3 . The compound of  claim 2 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 2  is a 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, optionally substituted with 1-4 independent occurrences of R 9 , wherein R 9  is —R 9a , -T 2 -R 9d , or —V 2 -T 2 -R 9d , and:
 each occurrence of R 9a  is independently halogen, —CN, —NO 2 , —R 9c , —N(R 9b ) 2 , —OR 9b , —SR 9c , —S(O) 2 R 9c , —C(O)R 9b , —C(O)OR 9b , —C(O)N(R 9b ) 2 , —S(O) 2 N(R 9b ) 2 , —OC(O)N(R 9b ) 2 , —N(R 9e )C(O)R 9b , —N(R 9e )SO 2 R 9c , —N(R 9e )C(O)OR 9b , —N(R 9e )C(O)N(R 9b ) 2 , or —N(R 9e )SO 2 N(R 9b ) 2 , or two occurrences of R 9b , 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 9b  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 9c  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 9d  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 9e  is independently hydrogen or an optionally substituted C 1-6  aliphatic group; 
 each occurrence of V 2  is independently —N(R 9e )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 9e )—, —S(O) 2 N(R 9e )—, —OC(O)N(R 9e )—, —N(R 9e )C(O)—, —N(R 9e )SO 2 —, —N(R 9e )C(O)O—, —NR 9e C(O)N(R 9e )—, —N(R 9e )SO 2 N(R 9e )—, —OC(O)—, or —C(O)N(R 9e )—O—; and 
 T 2  is an optionally substituted C 1 -C 6  alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 7a )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 7a )—, —S(O) 2 N(R 7a )—, —OC(O)N(R 7a )—, —N(R 7a )C(O)—, —N(R 7a )SO 2 —, —N(R 7a )C(O)O—, —NR 7a C(O)N(R 7a )—, —N(R 7a )S(O) 2 N(R 7a )—, —OC(O)—, or —C(O)N(R 7a )—O— or wherein T 3  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring. 
 
     
     
         5 . The compound of  claim 1 , wherein Y 1  is S, Y 2  is C and the compound is represented by formula II: 
       
         
           
           
               
               
           
         
         wherein R 1  is CN or H. 
       
     
     
         6 . The compound of  claim 5 , wherein:
 R 2  is an optionally substituted 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;   n is 0-2; and   R 4  is —R 4a .   
     
     
         7 . The compound of  claim 6 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein:
 R 2  is an optionally substituted 6-10-membered aryl, or a 5-10-membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R 2  is optionally substituted with 1-4 independent occurrences of R 9 , wherein R 9  is —R 9a , -T 2 -R 9d , or —V 2 -T 2 -R 9d , and:
 each occurrence of R 7a  is independently halogen, —CN, —NO 2 , —R 7c , —N(R 7b ) 2 , —OR 7b , —SR 7c , —S(O) 2 R 9c , —C(O)R 9b , —C(O)OR 9b , —C(O)N(R 9b ) 2 , —S(O) 2 N(R 9b ) 2 , —OC(O)N(R 9b ) 2 , —N(R 9e )C(O)R 9b , —N(R 9e )SO 2 R 9c , —N(R 9e )C(O)OR 9b , —N(R 9e )C(O)N(R 9b ) 2 , or —N(R 9e )SO 2 N(R 9b ) 2 ; 
 each occurrence of R 9b  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, or two occurrences of R 9b , 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 9  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 9d  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 9e  is independently hydrogen or an optionally substituted C 1-6  aliphatic group; 
   each occurrence of V 2  is independently —N(R 7e )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 9e )—, —S(O) 2 N(R 9e )—, —OC(O)N(R 9e )—, —N(R 9e )C(O)—, —N(R 9e )SO 2 —, —N(R 9e )C(O)O—, —NR 9e C(O)N(R 9e )—, —N(R 9e )SO 2 N(R 9e )—, —OC(O)—, or —C(O)N(R 9e )—O—; and
 T 2  is an optionally substituted C 1 -C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 9a )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 9a )—, —S(O) 2 N(R 9a )—, —OC(O)N(R 9a )—, —N(R 9a )C(O)—, —N(R 9a )SO 2 —, —N(R 9a )C(O)O—, —NR 9a C(O)N(R 9a )—, —N(R 9a )S(O) 2 N(R 9a )—, —OC(O)—, or —C(O)N(R 9a )—O— or wherein T 2  or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; and n is 0-2. 
   
     
     
         9 . The compound of  claim 8 , wherein:
 R 2  is a phenyl group substituted with 1-3 independent occurrences of halogen, —CN, —NO 2 , —R 9c , —N(R 9b ) 2 , —OR 9b , —SR 9c , —S(O) 2 R 9c , —C(O)R 9b , —C(O)OR 9b , —C(O)N(R 9b ) 2 , —S(O) 2 N(R 9b ) 2 , —OC(O)N(R 9b ) 2 , —N(R 9e )C(O)R 9b , —N(R 9e )SO 2 R 9c , —N(R 9e )C(O)OR 9b , —N(R 9e )C(O)N(R 9b ) 2 , or —N(R 9e )SO 2 N(R 9b ) 2 ;   R 3  is hydrogen, C 1-4 alkyl, or C 1-4 fluoroalkyl; and   n is 0.   
     
     
         10 . The compound of  claim 9 , wherein:
 R 2  is a phenyl group substituted with 1-3 independent occurrences of halo, 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 —COH.   
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . 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 1 . 
     
     
         16 . The method of  claim 15 , 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. 
     
     
         17 . A method for inhibiting PI3K activity in a patient comprising administering a composition comprising an amount of a compound of  claim 1  effective to inhibit PI3K activity in the patient.