Compositions useful for treating disorders related to kit and pdgfr

Abstract

Compounds and compositions useful for treating disorders related to KIT and PDGFR are described herein.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         W is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
       
       wherein Ring A is selected from monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, bicyclic heteroaryl, cycloalkyl, and heterocyclyl;
 Z is selected from pyrazolyl substituted with one occurrence of R C ; 
 L is selected from —N(R 1 )—C(O)—, —N(R 1 )C(O)N(R 1 )—, —N(R 1 )C(O)N(R 1 )—(C 1 -C 6 alkylene)-, N(R 1 )—(C 1 -C 6 alkylene)-, —N(R 1 )—C(O)—(C 1 -C 6 alkylene)-, —N(R 1 )—S(O) 2 , and —N(R 1 )—S(O) 2 -(C 1 -C 6 alkylene)-, wherein each alkylene is independently substituted with 0-5 occurrences of R 2 ; 
 each RA is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, —N(R 1 )(R 1 ), cyano, and —OR 1 ; 
 each R B  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, hydroxyl, halo, C 1 -C 6 alkoxy, a haloalkyl, —N(R 1 )(R 1 ), and cyano; 
 R C  is selected from C 1 -C 6 alkyl, C 1 -C 6 alkynyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, cycloalkyl, monocyclic aryl, bicyclic aryl, monocyclic aryloxy, bicyclic aryloxy, monocyclic aralkyl, bicyclic aralkyl, monocyclic heterocyclyl, bicyclic heterocyclyl, monocyclic heterocyclylalkyl, bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 1 )(R 1 ), —(C 1 -C 6 alkylene)-S(O) 2 —N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —N(R 1 )(R 1 )—C(O)R 1 , —(C 1 -C 6 alkylene)-N(R 1 )—C(O)R 1 , —NR 1 S(O) 2 R 1 , —P(O)(R 1 )(R 1 ), and —OR 1 , wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a ; 
 each R D  is independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, hydroxyl, halo, a alkoxy, c 1 -C 6 haloalkyl, —N(R 2 )(R 2 ), and cyano; 
 each R 1  is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 thioalkyl, —NR″R″, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R b ; or 2 R 1  together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring; 
 each R 2  is independently selected from hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxyl, and - NR′R′; or 2 R 2  together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring; 
 each R a  and R b  is independently selected from hydrogen, halo, cyano, hydroxyl, C 1 -C 6  alkoxyl, —C(O)R′, C(O)OR′, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  heteroalkyl, C 1 -C 6 hydroxyalkyl, —NR′R′, and cycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences of R′; 
 each R′ is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl and cyano; or 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring; 
 each R″ is independently selected from hydrogen, C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, —C(O)—NR′R′, and —C(S)—NR′R′; and 
 q and r are independently 0, 1, 2, 3, or 4. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a bond. 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —N(R 1 )—C(O)—(C 1 -C 6 alkylene)-. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is monocyclic or bicyclic aryl. 
     
     
         7 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A  is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —N(R 1 )(R 1 ), and cyano. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R C  is selected from C 1 -C 6  alkyl, halo, C 1 -C 6  hydroxyalkyl, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 1 )(R 1 ) , —N(R   1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), S(O) 2 R 1 , and —OR 1 , wherein each C 1 -C 6  alkyl is independently substituted with 0-5 occurrences of R a . 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1  is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6  alkyl, C 1 -C 6 alkoxy, C 1 -C 6  haloalkyl, C 1 -C 6 hydroxyalkyl, and —NR″R″, wherein each C 1 -C 6 alkyl is independently substituted with 0-5 occurrences of R b ; or 2 R 1  together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring. 
     
     
         13 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier; and   a compound of  claim 1  and/or a pharmaceutically acceptable salt thereof.   
     
     
         14 . A method of treating mastocytosis comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  and/or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method of treating gastrointestinal stromal tumor comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  and/or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method of treating acute myeloid leukemia comprising administering to a patient a therapeutically effective amount of a compound of  claim 1  and/or a pharmaceutically acceptable salt thereof. 
     
     
         17 - 24 . (canceled) 
     
     
         25 . The method of  claim 14 , wherein the mastocytosis is systemic mastocytosis (SM) or cutaneous mastocytosis (CM). 
     
     
         26 . The method of  claim 14 , wherein the patient has a D816V mutation in KIT in Exon 17. 
     
     
         27 . The method of  claim 15 , wherein the patient has a D842V mutation in PDGFRα in Exon 18. 
     
     
         28 . The method of  claim 15 , wherein the patient has a D816V mutation in KIT in Exon 17. 
     
     
         29 . The method of  claim 15 , wherein the patient is refractory to treatment with imatinib, sunitinib, and/or regorafenib. 
     
     
         30 . The method of  claim 29 , wherein the patient has unresectable GIST. 
     
     
         31 . The method of  claim 16 , wherein the patient has a D816V mutation in KIT in Exon 17.