Certain chemical entities, compositions and methods

Abstract

Chemical entities that modulate PI3 kinase activity, and chemical entities, pharmaceutical compositions, and methods of treatments of diseases and conditions associated with P13 kinase activity are described herein.

1 - 59 . (canceled) 
     
     
         60 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 W a   1  is CR 3 ; 
 W a   2  is CR 5 ; 
 W a   3  is CR 6 ; 
 W a   4  is N; 
 W b   5  is CR 8  or CHR 8 ; 
 W d  is 
 
       
       
         
           
           
               
               
           
         
         
           R a  is hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl; 
           R 11  is hydrogen, alkyl, halo, amino, amido, hydroxy, or alkoxy; 
           R 12  is hydrogen, alkyl, cyano, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, carboxylic acid, alkoxycarbonyl, or amido; 
           B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II: 
         
       
       
         
           
           
               
               
           
         
         
           W c  is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; 
           q is an integer of 0, 1, 2, 3, or 4; 
           X is absent or is —(CH(R 9 )) z — and each instance of z is independently an integer of 1, 2, 3, or 4; 
           Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)(CHR 9 ) z —, —C(═O)—, —N(R 9 )C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —, wherein when W b   5  is N, no more than one of X or Y is absent; 
           R 1  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; 
           R 2  is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; 
           R 3  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, halo, cyano, hydroxyl, nitro, aryl, or heteroaryl; 
           R 5 , R 6 , and R 8  are independently hydrogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 amido, amino, acyl, C 1 -C 4 acyloxy, C 1 -C 4 sulfonamido, halo, cyano, hydroxy or nitro; and 
           each instance of R 9  is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, or C 2 -C 10 heteroalkyl. 
         
       
     
     
         61 . The compound of  claim 60 , wherein the compound is a compound of Formula VII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         62 . The compound of  claim 60 , wherein W c  is aryl or heterocycloalkyl. 
     
     
         63 . The compound of  claim 60 , wherein R 3  is alkyl. 
     
     
         64 . The compound of  claim 60 , wherein R 5 , R 6 , and R 8  are hydrogen. 
     
     
         65 . The compound of  claim 60 , wherein X is —(CH(R 9 )) z — and z is an integer of 1. 
     
     
         66 . The compound of  claim 60 , wherein Y is absent. 
     
     
         67 . The compound of  claim 60 , wherein R 12  is iodo, bromo, 
       
         
           
           
               
               
           
         
       
     
     
         68 . The compound of  claim 60 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         69 . The compound of  claim 60 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         70 . A compound of Formula IX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 W a   1  and W a   2  are independently CR 5 , S, N, or NR 4 ; 
 W a   4  is independently CR 7 , S, N, or NR 4 ; 
 
         wherein no more than two adjacent ring atoms are nitrogen or sulfur, and when W a   1  is S, one of W a   2  and W a   4  is N or NR 4 ;
 W b   5  is CR 8 , N, or NR 8 ; 
 B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; 
 
       
       
         
           
           
               
               
           
         
         
           W c  is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; 
           q is an integer of 0, 1, 2, 3, or 4; 
           W d  is a heterocycloalkyl, aryl or heteroaryl moiety; 
           X is —(CH(R 9 )) z —; 
           each instance of z independently is an integer of 1; 
           Y is absent; 
           R 1  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; 
           R 2  is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; 
           R 4  is hydrogen, acyl, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, or C 1 -C 4 heteroalkyl; 
           R 5 , R 7 , and R 8  are independently hydrogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, C 1 -C 4 heteroalkyl, acyl, C 1 -C 4 alkoxy, C 1 -C 4 amido, amino, C 1 -C 4 acyloxy, C 1 -C 4 sulfonamido, halo, cyano, hydroxy or nitro; and 
           each instance of R 9  is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, or C 2 -C 10 heteroalkyl. 
         
       
     
     
         71 . The compound of  claim 70 , wherein the compound is a compound of Formula XIII or Formula X: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 B is a moiety of Formula II; 
 
       
       
         
           
           
               
               
           
         
         
           wherein W c  is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and 
           q is an integer of 0, 1, or 2; 
           W d  is: 
         
       
       
         
           
           
               
               
           
         
         
           X is (CH 2 ) z ; 
           Y is absent; 
           z is 1; 
           R 1  is hydrogen, fluoro, chloro, cyano, methyl, isopropyl, —CF 3 , methoxy, or nitro; 
           R 2  is halo, hydroxy, cyano, or nitro; 
           R 4  is hydrogen or methyl; 
           R 5  is hydrogen or methyl; 
           R 7  is hydrogen or methyl; 
           R 11  is amino; and 
           R 12  is hydrogen, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl. 
         
       
     
     
         72 . The compound of  claim 70 , wherein R 12  is iodo, bromo, 
       
         
           
           
               
               
           
         
       
     
     
         73 . The compound of  claim 70 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         74 . A pharmaceutical composition comprising a compound of  claim 60 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         75 . A pharmaceutical composition comprising a compound of  claim 70 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         76 . A method of treating a disorder comprising administering an effective amount of a compound of  claim 60  to a subject suffering from the disorder, wherein the disorder is selected from cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, and cardiac disease. 
     
     
         77 . A method of treating a disorder comprising administering an effective amount of a compound of  claim 70  to a subject suffering from the disorder, wherein the disorder is selected from cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, and cardiac disease.