COVALENT INHIBITORS OF KRAS

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)