Phosphatidylinositol 3-kinase inhibitors

Abstract

The present disclosure provides selective phosphoinositide 3-kinase gamma inhibitors of Formula (I) including (I-a), (I-b), (I-c), and (I-d), or pharmaceutically acceptable salts thereof. These compounds are useful for the treatment of conditions mediated by one or more PI3K isoforms, such as PI3K gamma (PI3Kγ). The present disclosure further provides methods of inhibiting phosphoinositide 3-kinase gamma using these compounds for treatment of disorders related to phosphatidylinositol 3-kinase gamma activity.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein: 
       A is CH 2 , CH(C 1-6 alkyl), O, or S; 
       Y is CH or N; 
       Z is CH or N; 
       W is N, CH, or CX; wherein X is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       NHG, CHG 2 , COOH, OG, SO 2 G, SO 2 NHG, NGSO 2 G, C 1-6 alkyl-NGSO 2 G, NHC(O)G, NHC(O)NG 2 , C(O)NHG, C(O)NG 2 , C 3-10 cycloalkyl, and 3-10 membered heterocyclyl, wherein each 3-10 membered heterocyclyl independently contains 1 or 2 heteroatoms, wherein the 1 or 2 heteroatoms are selected from the group consisting of 0, N, and S, and wherein each C 3-10 cycloalkyl or 3-10 membered heterocyclyl is independently optionally substituted with one or more G, wherein:
 Q 1  is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH or halo, and 
 each G is independently selected from the group consisting of H, D, OH, C 1-6 alkoxy, oxo, NH 2 , SO 2 (C 1-6 alkyl), C(O)—C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, and C 1-6 alkyl, wherein the C 3-10 cycloalkyl or C 1-6 alkyl is independently optionally substituted with one or more D, OH, C 1-6 alkoxy, CN, N(C 1-6 alkyl) 2 , SO 2 (C 1-6 alkyl), or halo, or 
 two G groups, together with the atoms to which they are attached, form a C 3-10 cycloalkyl or 3-10 membered heterocyclyl, 
 
       provided that, when Y and Z are each CH, and W is CX, then X is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       R 1  is C 1-6 alkyl, C 3-10 cycloalkyl, or C 1-6 alkyl-C 3-10 cycloalkyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, or C 1-6 alkyl-C 3-10 cycloalkyl is independently optionally substituted with one or more halo; and 
       R 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein:
 L is H, halo, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or OH, and 
 each Q 2  and Q 3  is independently C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl is independently optionally substituted with one or more halo. 
 
     
     
         2 . The compound of  claim 1 , wherein at least one of Y, Z and W is N. 
     
     
         3 . The compound of  claim 1 , wherein the compound has the structure of Formula (I-b): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein R 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein Q 2  is methyl, ethyl, isopropyl, cyclopropyl, or difluoromethyl. 
     
     
         7 . The compound of  claim 1 , wherein the compound has the structure of Formula (I-c): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound has the structure of Formula (I-d): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein X is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein X is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein X is selected from the group consisting of NHG, OG, NHSO 2 G, and C(O)NG 2 . 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein X is selected from the group consisting of OMe, OCD 3 , NHSO 2 Me, NHSO 2 Et, C(O)NH 2 , C(O)NHMe, and C(O)NMe 2 . 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein Z is N, A is CH 2 , Y is CH, and W is CH, or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof. 
     
     
         17 . The compound of  claim 1 , wherein the compound has the structure of Formula (I-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         18 . The compound of  claim 1 , wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of selectively inhibiting a growth or a proliferation phosphoinositide 3-kinase gamma (PI3Kγ) comprising contacting the PI3Kγ with a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         21 . A method of treating a disorder of uncontrolled cellular proliferation related to one or more PI3K isoforms, such as PI3K gamma (PI3Kγ), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         22 . A method of treating an autoimmune disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         23 . A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled)