SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINES AS WEE1 INHIBITORS

Abstract

This invention provides for substituted pyrazolo[3,4-d]pyrimidine compounds of the Formula (I):as Wee1 inhibitors. The substituted pyrazolo[3,4-d]pyrimidine compounds may find use as therapeutic agents for the treatment of diseases. The substituted pyrazolo[3,4-d]pyrimidine compounds may also find particular use in oncology.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: 
         Y is hydrogen or R 4 ; 
         m is 0, 1, 2, or 3; 
         n is 0, 1, 2, 3, or 4; 
         R 1  is independently F, Cl, or methyl; 
         R 2  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl or —(C 1 -C 3  alkylene)CF 3 ; 
         R 3  is 
       
       
         
           
           
               
               
           
         
          wherein: 
       
       
         
           
           
               
               
           
         
         
            indicates an aromatic ring; 
           M 1  is CH or CR 3 ; 
           M 2  is CH, CR 3b , N, or absent; 
           M 3  is CH, CR 3b , N, O, or S; 
           M 4  is CH, CR 3 b, N, O, or S,
 provided that: 
 (1) when M 4  is O or S and M 2  is absent, then M 3  is CH, CR 3b  or N, and 
 (2) when M 3  is O or S and M 2  is absent, then M 4  is CH, CR 3b  or N; 
 
           R 3a  is C 3 -C 6  cycloalkyl optionally substituted by C 1 -C 6  haloalkyl or —CN, or C 1 -C 6  alkyl optionally substituted by halogen, —OH or —CN, provided that when R 3a  is C 1 -C 6  alkyl optionally substituted by halogen, —OH or —CN, then at least one of M 1 , M 2 , M 3 , and M 4  is CR 3b ; 
           R 3b  is halogen or —CN; 
         
         each R 4  is independently oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —C(O)R 17 , —C(O)OR 17 , —C(O)NR 17 R 18 , —CN, —Si(C 1 -C 6  alkyl) 3 , —OR 17 , —NR 17 R 18 , —OC(O)NR 17 R 18 , —NR 17 C(O)R 18 , —S(O) 2 R 17 , —NR 17 S(O) 2 R 18 , —S(O) 2 NR 17 R 18 , C 3 -C 6  cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3  alkylene)CN, —(C 1 -C 3  alkylene)OR 17 , —(C 1 -C 3  alkylene)NR 17 R 18 , —(C 1 -C 3  alkylene)CF 3 , —(C 1 -C 3  alkylene)C(O)R 17 , —(C 1 -C 3  alkylene)C(O)NR 17 R 18 , —(C 1 -C 3  alkylene)NR 17 C(O)R 18 , —(C 1 -C 3  alkylene)S(O) 2 R 17 , —(C 1 -C 3  alkylene)NR 17 S(O) 2 R 18 , —(C 1 -C 3 alkylene)S(O) 2 NR 17 R 18 , —(C 1 -C 3  alkylene)(C 3 -C 6  cycloalkyl) or —(C 1 -C 3  alkylene)(3- to 6-membered heterocyclyl), wherein each R 4  is independently optionally substituted by halogen, oxo, —OR 19 , —NR 19 R 20 , or —C(O)R 19 ,
 or two R 4 , when bound to the same carbon, are taken together with the carbon to which they are attached to form a C 3 -C 6  cycloalkyl or 3- to 6-membered heterocyclyl, each is optionally substituted by R 19 ; and 
 
         each R 17 , R 18 , R 19 , and R 20  is independently hydrogen, C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl or C 1 -C 6  alkyl, each of which is optionally substituted by halogen, oxo or —OH,
 or R 17  and R 18  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or —OH. 
 
       
     
     
         2 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is C 1 -C 6 alkyl. 
     
     
         5 . The compound of  claim 4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is isopropyl or ethyl. 
     
     
         6 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is C 3 -C 6 cycloalkyl. 
     
     
         7 . The compound of  claim 6 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is cyclopropyl. 
     
     
         8 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —(C 1 -C 3  alkylene)CF 3 . 
     
     
         9 . The compound of  claim 8 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —CH 2 CF 3 . 
     
     
         10 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein R 3a  is C 3 -C 6  cycloalkyl optionally substituted by C 1 -C 6  haloalkyl or —CN. 
     
     
         12 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3a  is C 1 -C 6  alkyl optionally substituted by halogen, —OH or —CN. 
     
     
         13 . The compound of  claim 1 , or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3a  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3b  is halogen. 
     
     
         15 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3b  is —CN. 
     
     
         16 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         17 - 23 . (canceled) 
     
     
         24 . The compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A, ring B, R 1 , and R 4  are taken together to form a moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A compound or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . (canceled) 
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. 
     
     
         28 . A method of treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         29 - 41 . (canceled)