Substituted cinnolines as inhibitors of KRAS G12C

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

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

wherein:

is a double bond;

is a double or triple bond;

Q is —C(═NR 8′ )—, —C(═O)—, —NR 8 C(═O)—, —NR 8 S(═O) 2 —, or —S(═O) 2 —;

X is CR 6 ;

Y is N;

Z is N;

L 1 is a bond;

L 2 is a bond or alkylene;

(i) R′ is R 1 ; and

R″ is R 2c ; or

(ii) R′ is H; and

R″ is R 1 ;

R 1 is heterocyclyl, aryl, or heteroaryl;

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

R 2b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, OC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, or heteroaryl;

R 2c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OH, OC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, or heteroaryl;

each R 3a is independently H, halo, CN, C 1 -C 6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, aminylcarbonyl, C(O)OH, NH 2 , OH, or C 2 -C 6 alkynyl;

each R 3b is independently H, halo, CN, C 1 -C 6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, aminylcarbonyl, C(O)OH, NH 2 , OH, or C 2 -C 6 alkynyl;

each R 4a is independently H, halo, CN, C 1 -C 6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, aminylcarbonyl, C(O)OH, NH 2 , OH, or C 2 -C 6 alkynyl;

each R 4b is independently H, halo, CN, C 1 -C 6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, aminylcarbonyl, C(O)OH, NH 2 , OH, or C 2 -C 6 alkynyl;

R 6 is H, CN, C 1 -C 6 alkyl, cyanoalkyl, amidinylalkyl, guanidinylalkyl, aminylalkyl, aminylcarbonyl, CO 2 NR a R b , NH 2 , alkylaminyl, haloalkylaminyl, amidinylalkylaminyl, guanidinylalkylaminyl, aminylalkylaminyl, hydroxyalkylaminyl, heterocyclylalkylaminyl, arylalkylaminyl, heteroarylalkylaminyl, heterocyclylaminyl, arylaminyl, heteroarylaminyl, OC 1 -C 6 alkyl, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, amidinylalkoxy, guanidinylalkoxy, aminylalkoxy, heterocyclylalkyloxy, arylalkyloxy, heteroarylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, aminylsulfonyl, heterocyclyl, aryl, or heteroaryl;

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

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

R a and R b , together with the nitrogen atom to which they are attached, form a heterocyclyl;

R 8 is H, C 1 -C 6 alkyl, or hydroxyalkyl; and

R 8′ is H, CN, C 1 -C 6 alkyl, or OH;

wherein each alkylene, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyanoalkyl, amidinylalkyl, aminylcarbonylalkyl, carboxyalkyl, guanidinylalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C 2 -C 6 alkynyl, aminylcarbonyl, alkoxycarbonyl, alkylaminyl, haloalkylaminyl, amidinylalkylaminyl, guanidinylalkylaminyl, aminylalkylaminyl, hydroxyalkylaminyl, heterocyclylalkylaminyl, arylalkylaminyl, heteroarylalkylaminyl, heterocyclylaminyl, arylaminyl, heteroarylaminyl, OC 1 -C 6 alkyl, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, amidinylalkoxy, guanidinylalkoxy, aminylalkoxy, heterocyclylalkyloxy, arylalkyloxy, heteroarylalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, aminylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO 2 , C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, cyanoC 1 -C 6 alkyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, C 3 -C 8 cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, C 2 -C 6 alkynyl, imino, aminylcarbonyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, aminyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 2 -C 6 alkenylcarbonylaminyl, OH, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, ═O, C 1 -C 6 thioalkyl, aminylsulfonyl, ═S, C 1 -C 6 alkylcycloalkyl, C 3 -C 8 cycloalkyl, cyanoC 3 -C 8 cycloalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl, C 1 -C 6 alkylheterocycloalkyl, heterocyclyl, aryl, and heteroaryl;

provided that:

(i) when is a double bond, then R 9 and R 10 are each independently H, CN, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C(O)OH, alkoxycarbonyl, or heteroaryl; or

(ii) when is a double bond, then R 9 and R 10 , together with the carbon atoms to which they are attached, form a carbocyclyl or heterocyclyl; and

(iii) when is a triple bond, then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl, or hydroxyalkyl.

2. The compound of claim 1 , wherein the compound has structure (I′f):

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

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

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Q is —C(═O)—.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein L 2 is a bond.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is optionally substituted aryl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is optionally substituted phenyl.

8. The compound of claim 6 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is substituted with one or more independently selected substituents.

9. The compound of claim 8 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the one or more substituents are independently selected from the group consisting of halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyanoC 1 -C 6 alkyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 8 cycloalkylalkyl, C 2 -C 6 alkynyl, aminylcarbonyl, C 1 -C 6 alkylaminylcarbonyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, OH, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, aminylsulfonyl, C 1 -C 6 alkylcycloalkyl, C 3 -C 8 cycloalkyl, cyanoC 3 -C 8 cycloalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 fused cycloalkyl, and heteroaryl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the one or more substituents are independently selected from the group consisting of fluoro, chloro, bromo, CN, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, aminylcarbonyl, OH, methoxy, and cyclopropyl.

11. The compound of claim 6 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is:

12. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is thiophenyl, pyridinyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl, or dihydrobenzodioxinyl, each optionally substituted.

14. The compound of claim 12 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is substituted with one or more independently selected substituents.

15. The compound of claim 14 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the one or more substituents are independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenylcarbonylaminyl, and OC 1 -C 6 alkyl.

16. The compound of claim 14 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the one or more substituents are independently selected from the group consisting of fluoro, chloro, methyl, and amino.

17. The compound of claim 12 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is:

18. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2a is halo.

19. The compound of claim 18 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2a is fluoro or chloro.

20. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2b is halo.

21. The compound of claim 20 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2b is fluoro or chloro.

22. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, 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.

23. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is H.

24. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein at least one of R 9 or R 10 is H.

25. The compound of claim 24 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 9 and R 10 are each independently H.

26. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

is:

27. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

is —C(═O)—CH═CH 2 .

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

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

29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.