2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof

1. A compound having the following structure (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

A is N, CH or C—CN;

G 1 and G 2 are each independently N or CH;

L 1 is a bond or NR 7 ;

L 2 is a bond or alkylene;

R 1 is aryl;

R 2a , R 2b and R 2c are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, 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 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;

R 5a and R 5b are, at each occurrence, independently H, hydroxyl, halo or C 1 -C 6 alkyl, or R 5a and R 5b join to form oxo;

R 6 is heterocyclyl or heteroaryl;

R 7 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl;

m 1 and m 2 are each independently 1, 2 or 3;

n is an integer from 1 to 6;

X is —O— or —NR 7 —; 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, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, haloalkyl, 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 that at least one occurrence of R 3a , R 3b , R 4a or R 4b is not H.

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 is phenyl or naphthyl.

5. The compound of claim 1 , wherein R 1 is substituted with halo, amino, hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —OC(═O)R or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.

6. The compound of claim 1 , wherein R 1 has one of the following structures:

7. The compound of claim 1 , wherein R 2c is H.

8. The compound of claim 1 , wherein R 2a and R 2b are each independently halo, haloalkyl, alkyl, or alkoxy.

9. The compound of claim 1 , wherein R 6 is azetidinyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl, pyridinonyl, pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl, thiomorpholinyl, pyrrolopyridinyl, imidazolyl, benzoimidazolyl, or an oxidized analogue thereof, dioxolanyl, or tetrahydropyranyl.

10. The compound of claim 1 , wherein R 6 is substituted with oxo, cyano, halo, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, heteroaryl, or combinations thereof.

11. The compound of claim 1 , wherein R 6 has one of the following structures:

12. 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 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.

13. The compound of claim 1 , wherein at least one of R 3a , R 3b , R 4a or R 4b is C 1 -C 6 alkyl.

14. The compound of claim 13 , wherein C 1 -C 6 alkyl is methyl.

15. The compound of claim 2 , wherein Q is —C(═O)—.

16. The compound of claim 2 , wherein each of R 9 and R 10 are H.

17. The compound of claim 1 , wherein E has one of the following structures:

18. The compound of claim 1 , wherein the compound has one of the following structures:

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

20. A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 19 to a subject in need thereof.

21. The method of claim 20 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.