Covalent inhibitors of kras

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):or a pharmaceutically acceptable salt, stereoisomer, isotopic form or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5, L1, L2, L3, E, m1, m2 and * are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

1 . A compound having the following structure (I): 
       
         
           
           
               
               
           
         
       
        or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
 G 1  and G 2  are each independently N or CH; 
 L 1  is a bond or —NR 6 —; 
 L 2  is a bond or alkylene; 
 L 3  is a bond, —O—, —NR 6 —, —S—, —S(═O)— or —S(═O) 2 —; 
 R 1  is unsubstituted naphthyl or optionally substituted quinolinyl when at least one or R 3a , R 3b , R 4a  and R 4b  is not H; or R 1  has the following structure (R 1 ’): 
                     
  wherein:
 each  represents an aromatic ring; 
 A 1 , A 2 , A 3  and A 4  are each independently C or N; 
 X is O, S, N, NH, C(═O), CR 1e  or NR 1e ′; 
 Y is O, S, N, NH, C(═O), CR 1f  or NR 1f ; 
 Z is O, S, N, NH, C(═O), CR 1g  or NR 1g ′; 
 one of R 1a , R 1b , R 1c  and R 1d  is a covalent bond to the carbon marked with *, and the other of R 1a , R 1b , R 1c  and R 1d  are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, alkylaminyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy; cycloalkyl, heterocyclyl, aminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; 
 R 1e , R 1f  and R 1g  are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, alkylaminyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkylaminyl, cycloalkylaminyl, alkylcarbonylaminyl, heterocyclyl, aminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and 
 R 1e ’, R 1f  and R 1g ’ are each independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, 
 provided that when each of A 1 , A 2 , A 3  and A 4  are C, R 1a  is a covalent bond to the carbon marked with *, one of R 1b , R 1c  and R 1d  is methyl and: i) X is NH, Y is N and Z is CR 1g ; ii) Y is N and Z is NH; iii) X is NH, Y is CR 1f  and Z is CR 1g ; or iv) X is NH, Y is CR 1f  and Z is N, then at least one of R 1b , R 1c , R 1a , R 1e , R 1f  and R 1g  is not H, or at least one of R 3a , R 3b , R 4a  and R 4b  is C 1 -C 6  cyanoalkyl, and provided that at least one of X, Y and Z is O, N or NH; 
 
 R 2a , R 2b  and R 2c  are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkylaminyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy; cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl; 
 R 3a  and R 3b  are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl,C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a  and R 3b  join to form oxo, a carbocyclic or heterocyclic ring; or R 3a  is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b  joins with R 4b  to form a carbocyclic or heterocyclic ring; 
 R 4a  and R 4b  are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a  and R 4b  join to form oxo, a carbocyclic or heterocyclic ring; or R 4a  is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6  cyanoalkyl, C 1 -C 6  carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b  joins with R 3b  to form a carbocyclic or heterocyclic ring; 
 R 5  is amino, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkynyl; C 1 -C 6  haloalkyl, C 1 -C 6  hydroxylalkly, C 1 -C 6  cyanoalkyl, alkoxy, aminylalkyl, aminylalkynyl, alkoxyalkyl, alkoxyalkynyl, alkylcarbonylaminyl, aminylalkylcarbonylaminyl, aminylcarbonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl; —NR a R b , C 1 -C 6  alkylphosphoryl, C 1 -C 6  alkylphosphorylaminyl, , heteroarylalkyloxy or heteroarylalkylaminyl, wherein R a  is H or C 1 -C 6  alkyl, and R b  is C 1 -C 6  alkyl; 
 R 6  is, at each occurrence, independently H or C 1 -C 6  alkyl; 
 m 1  and m 2  are each independently 1, 2 or 3; and 
 E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein, 
 wherein each occurrence of alkyl, alkynyl, alkenyl, alkylene, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylaminyl, haloalkyl, hydroxylalkyl, alkoxy, alkoxyalkyl, haloalkoxy, heterocyclylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl, and carbocyclic and heterocyclic rings is optionally substituted with one or more substituents unless otherwise specified; and 
 provided the compound is not a compound in Table 2. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound has the following structure (I′a): 
       
         
           
           
               
               
           
         
       
        wherein:
   represents a double or triple bond; 
 Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 - or —NR 8 S(═O) 2 —; 
 R 8  is H, C 1 -C 6  alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8  cycloalkyl or heterocyclylalkyl; 
 R 8′  is H, —OH, —CN or C 1 -C 6  alkyl; 
 when  is a double bond then R 9  and R 10  are each independently H, halo, cyano, carboxyl, C 1 -C 6  alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 9  and R 10  join to form a carbocyclic, heterocyclic or heteroaryl ring; and 
 when  is a triple bond then R 9  is absent and R 10  is H, C 1 -C 6  alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl, 
 wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic and heteroaryl rings is optionally substituted with one or more substituents unless otherwise specified. 
 
     
     
         3 . The compound of  claim 2 , wherein the compound has one of the following structures (I′b), (I′c), (I’d) or (I′e): 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       . 
     
     
         4 . The compound of  claim 1 , wherein R 1  has the following structure: 
       
         
           
           
               
               
           
         
       
        provided that when R 1b  is methyl, then at least one of R 1c , R 1d , R 1e , R 1f  and R 1g  is not H. 
     
     
         5 . The compound of  claim 1 , wherein X is NH, Y is N and Z is CR 1g . 
     
     
         6 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein the other of R 1a , R 1b , R 1c  and R 1d , and each of R 1e , R 1f  and R 1g  are each independently H, amino, halo, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, alkylaminyl or cycloalkyl. 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 1  has one of the following structures: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       . 
     
     
         13 . The compound of  claim 1 , wherein R 2c  is H. 
     
     
         14 . The compound of  claim 1 , wherein R 2a  and R 2b  are each independently halo, haloalkyl, alkyl, or alkoxy. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein R 2a  is fluoro and R 2b  is chloro. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein L 3  is a bond. 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein —L 3 —R 5  has one of the following structures: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       . 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The compound of  claim 1 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
        wherein R 3a  and R 4a  are independently —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl. 
     
     
         28 - 30 . (canceled) 
     
     
         31 . The compound of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       . 
     
     
         32 . The compound of  claim 1 , wherein E has one of the following structures: 
       
         
           
           
               
               
           
         
       
       . 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 1 , wherein L 1  is a bond. 
     
     
         35 . The compound of  claim 1 , wherein L 2  is a bond. 
     
     
         36 . The compound of  claim 1 , wherein the compound is selected from a compound in Table 1. 
     
     
         37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         39 . A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of  claim 38  to a subject in need thereof. 
     
     
         40 - 45 . (canceled)