Heterocyclic compounds and uses thereof

Abstract

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

1 - 98 . (canceled) 
     
     
         99 . A method for treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a compound that selectively modulates phosphatidyl inositol-3 kinase (“PI3 kinase”) gamma isoform over alpha, beta, and delta isoforms. 
     
     
         100 . The method of  claim 99 , wherein the compound selectively inhibits PI3 kinase gamma isoform over alpha, beta, and delta isoforms. 
     
     
         101 . The method of  claim 100 , wherein the compound has an activity of at least 2× against PI3 kinase gamma isoform relative to alpha, beta, and delta isoforms. 
     
     
         102 . The method of  claim 101 , wherein the compound has an activity of at least 5× against PI3 kinase gamma isoform relative to alpha, beta, and delta isoforms. 
     
     
         103 . The method of  claim 100 , wherein the compound has an IC 50  value of less than 100 nM against PI3 kinase gamma isoform in a PI3-Kinase Promega Assay. 
     
     
         104 . The method of  claim 103 , wherein the compound has an IC 50  value of more than 100 nM against PI3 kinase alpha, beta, and delta isoforms in a PI3-Kinase Promega Assay. 
     
     
         105 . The method of  claim 99 , wherein the cancer is a solid tumor. 
     
     
         106 . The method of  claim 99 , wherein the cancer is lung cancer, melanoma, prostate cancer, glioblastoma, endometrial cancer, pancreatic cancer, renal cell carcinoma, colorectal cancer, breast cancer, thyroid cancer, or ovarian cancer. 
     
     
         107 . The method of  claim 106 , wherein the cancer is non-small cell lung cancer. 
     
     
         108 . The method of  claim 106 , wherein the cancer is melanoma. 
     
     
         109 . The method of  claim 99 , wherein the subject is a human and wherein the PI3 kinase is human PI3 kinase. 
     
     
         110 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable form thereof, wherein
 Cy is aryl or heteroaryl substituted by 0 or 1 occurrence of R 3  and 0, 1, 2, or 3 occurrence(s) of R 5 ; 
 W b   5  is CR 8 , CHR 8 , or N; 
 R 8  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl or nitro; 
 B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 occurrence(s) of R 2 ; 
 each R 2  is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, or carbonate; 
 X is —(CH(R 9 )) z —; 
 Y is —N(R 9 )—C(═O)—, —C(═O)—N(R 9 )—, —C(═O)—N(R 9 )—(CHR 9 )—, —N(R 9 )—S(═O)—, —S(═O)—N(R 9 )—, —S(═O) 2 —N(R 9 )—, —N(R 9 )—C(═O)—N(R 9 )—, or —N(R 9 )—S(═O) 2 —; 
 z is an integer of 1, 2, 3, or 4; 
 R 3  is alkyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl, hydroxyl, or nitro; 
 each R 5  is independently alkyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro; 
 each R 9  is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two adjacent occurrences of R 9  together with the atoms to which they are attached form a 4- to 7-membered ring; 
 W d  is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more R 10 , R 11 , R 12 , or R 13 , and 
 wherein R 10 , R 11 , R 12 , and R 13  are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety; 
 with the proviso that the compound is not: 
 
       
         
           
           
               
               
           
         
       
     
     
         111 . A method of treating a PI3K mediated disorder in a subject, the method comprising administering a therapeutically effective amount of a compound of  claim 110  to said subject. 
     
     
         112 . A compound, which is: