Substituted quinazolines as inhibitors of KRAS G12C

1. A method for covalently binding the cysteine 12 residue of a KRAS G12C protein in a human subject with a KRAS G12C-mutated cancer, wherein the method comprises administering to the human subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

A is CR 1 or CR 2b ;

B is CR 1 or CR 2 C;

R 1 is heterocyclyl, heteroaryl or aryl, wherein the heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, cyanoC 1 -C 6 alkyl, cyanoC 3 -C 8 cycloalkyl, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, aminylsulfone, aminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 cycloalkylalkyl and C 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl and heteroaryl;

R 2a is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;

R 2b , when present, is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;

R 2c , when present, is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;

W is CR 6 ;

X is N;

Y is CR 6 ;

each R 6 is independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —CO 2 NR a R b , wherein R a and R b are each independently H or C 1 -C 6 alkyl or R a and R b join to form a carbocyclic or heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl, arylalkyloxy or a bond to L;

Z is N;

L 1 is a bond or NR 7 ;

R 7 is H or C 1 -C 6 alkyl;

G 1 is CH or N;

each R 3a is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;

each R 3b is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;

each R 4a is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;

each R 4b is independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;

G 2 is CH or N;

L 2 is a bond or alkylene;

m 1 is 1, 2 or 3;

m 2 is 1, 2 or 3;

E is:

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 or hydroxylalkyl;

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, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic ring;

when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;

with the proviso that:

(1) (a) W is CR 6 , where R 6 is a bond to L 1 ; or

(b) Y is CR 6 , where R 6 is a bond to L 1 ; and

(2) if R 1 is pyridinyl, then at least one of R 2a , R 2b or R 2c is not H.

2. The method of claim 1 , wherein the KRAS G12C-mutated cancer is selected from the group consisting of a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer and lung cancer.

3. The method of claim 1 , wherein the compound has the following structure (I′a):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

(i) R′ is R 1 ; and

R″ is R 2c ; or

(ii) R′ is H; and

R″ is R 1 .

4. The method of claim 3 , wherein the compound has the following structure (I′b), structure (I′c), structure (I′d), or structure (I′e):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

5. The method of claim 4 , wherein the compound has the following structure (I′f), structure (I′g), structure (I′h), structure (I′i), structure (I′j), structure (I′l), or structure (I′m):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

6. The method of claim 5 , wherein Q is —C(═O)—.

7. The method of claim 5 , wherein Q is —S(═O) 2 —, —NR 8 C(═O)— or —NR 8 S(═O) 2 —.

8. The method of claim 7 , wherein R 8 is H or hydroxylalkyl.

9. The method of claim 5 , wherein:

(i) R 9 is H; or

(ii) R 10 is H; or

iii) R 9 is H and R 10 is H.

10. The method of claim 5 , wherein R 10 is alkylaminylalkyl or hydroxylalkyl.

11. The method of claim 5 , wherein the compound has the following structure (I′j):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. The method of claim 11 , wherein

13. The method of claim 12 , wherein R 1 is heteroaryl.

14. The method of claim 13 , wherein L 1 is a bond.

15. The method of claim 14 , wherein L 2 is a bond.

16. The method of claim 15 , wherein:

R 2a is Cl; and

R 2b is F.

17. The method of claim 16 , wherein:

Y is CR 6 , wherein R 6 is heterocyclylalkyloxy.

18. The method of claim 17 , wherein one of R 3a , R 3b , R 4a , and R 4b is CH 3 and the other seven of R 3a , R 3b , R 4a , and R 4b are independently H.

19. The method of claim 18 , wherein R 1 is thiophenyl, pyridinyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, benzothiophenyl or dihydrobenzodioxinyl.

20. The method of claim 19 , wherein the KRAS G12C-mutated cancer is selected from the group consisting of a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

21. The method of claim 13 , wherein R 1 is thiophenyl, pyridinyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, benzothiophenyl or dihydrobenzodioxinyl.

22. The method of claim 21 , wherein L 1 is a bond.

23. The method of claim 22 , wherein L 2 is a bond.

24. The method of claim 23 , wherein:

—R 2a is Cl; and

R 2b is F.

25. The method of claim 24 , wherein:

Y is CR 6 , wherein

R 6 is heterocyclylalkyloxy.

26. The method of claim 11 , wherein one of R 3a , R 3b , R 4a , and R 4b is CH 3 and the other seven of R 3a , R 3b , R 4a , and R 4b are independently H.

27. The method of claim 26 , wherein the KRAS G12C-mutated cancer is selected from the group consisting of a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer and lung cancer.

28. The method of claim 1 , wherein R 1 is substituted with one or more independently selected substituents.

29. The method of claim 1 , wherein R 1 is aryl.

30. The method of claim 29 , wherein R 1 is phenyl or naphthyl.

31. The method of claim 1 , wherein R 1 is heteroaryl.

32. The method of claim 31 , wherein R 1 is thiophenyl, pyridinyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, benzothiophenyl or dihydrobenzodioxinyl.

33. The method of claim 32 , wherein R 1 is substituted with one or more substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 2 -C 6 alkenylcarbonylaminyl.

34. The method of claim 1 , wherein R 1 is:

35. The method of claim 1 , wherein R 2a is H.

36. The method of claim 1 , wherein R 2a is halo, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.

37. The method of claim 1 , wherein:

R 2b , when present, is H or halo; and

R 2c , when present, is H or halo.

38. The method of claim 1 , wherein:

(i) each R 3a is independently H, aminylcarbonyl or cyano; and

(ii) each R 4a is independently H, aminylcarbonyl or cyano.

39. The method of claim 1 , wherein:

each R 3a is independently H;

each R 3b is independently H;

each R 4a is independently H; and

each R 4b is independently H.

40. The method of claim 1 , wherein:

(i) L 1 is a bond; or

(ii) L 2 is a bond; or

(iii) L 1 is a bond and L 2 is a bond.

41. The method of claim 1 , wherein E is:

42. The method of claim 1 , wherein the compound is selected from the group consisting of:

and a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

43. The method of claim 1 , wherein the pharmaceutical composition is administered orally to the human subject in need thereof or via injection to the human subject in need thereof.