KRAS G12C inhibitors

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof:

wherein:

X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8;

Y is a bond, O, S or NR 5;

R 1 is —C(O)C(R A ) C(R B ) p or —SO 2 C(R A ) C(R B ) p;

R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9;

Z is C1-C4 alkylene;

each R 3 is independently C1-C3 alkyl, oxo, or haloalkyl;

L is a bond, —C(O)—, or C1-C3 alkylene;

R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7;

each R 5 is independently hydrogen or C1-C3 alkyl;

R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;

each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR 5 , —C(O)N(R 5 ) 2 , —N(R 5 ) 2 , wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR 5 , —N(R 5 ) 2 , or heteroaryl;

each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

R A is absent, hydrogen, or C1-C3 alkyl;

each R B is independently hydrogen, C1-C3 alkyl, alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;

m is zero or an integer between 1 and 2;

p is one or two; and wherein,

when is a triple bond then R A is absent, R B is present and p equals one,

or when is a double bond then R A is present, R B is present and p equals two, or R A , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7.

2. The compound of claim 1 , wherein R 1 —X is:

wherein the piperazinyl ring is optionally substituted with R 8.

3. The compound of claim 2 , wherein R 1 is —C(O)C(R A ) C(R B ) p , wherein is a triple bond R A is absent, p is one and R B is C1-C3 alkyl, or is a double bond, R A is hydrogen or C1-C3 alkyl, p is two and each R B is independently hydrogen, C1-C3 alkyl, dialkylaminylalkyl or heterocyclylalkyl.

4. The compound of claim 1 , wherein R 1 is —C(O)CH═CH 2.

5. The compound of according to claim 1 , wherein Y is O.

6. The compound of claim 1 , wherein R 2 is heterocyclylalkyl.

7. The compound of claim 6 , wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl, methylazetidinyl, difluoroazetidinyl, tetrahydropyran, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, isopropylpyrrolidinyl, cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl, dihalopiperdinyl, fluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl, piperidinonyl, thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl.

8. The compound of claim 1 , wherein R 2 is —ZR 5 R 10.

9. The compound according to claim 1 , wherein R 4 is aryl optionally substituted with one or more R 7.

10. The compound of claim 9 , wherein the aryl is selected from the group consisting of phenyl and naphthyl optionally substituted with one or more R 7.

11. The compound according to claim 1 , wherein R 4 is heteroaryl.

12. The compound of claim 11 , wherein the heteroaryl is pyridinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl or benzothiazolyl.

13. The compound according to claim 1 , wherein R 4 is aralkyl optionally substituted with one or more R 7.

14. The compound according to claim 1 , wherein L is a bond.

15. The compound according to claim 1 , wherein R 8 is heteroalkyl, C2-C4 alkynyl, or C1-C3alkyl optionally substituted with —OR 5 , cyano or heteroaryl.

16. The compound of claim 15 , wherein R 8 is C1-C3 alkyl substituted with —OR 5.

17. The compound of claim 15 , wherein R 8 is oxazolylmethyl.

18. The compound of claim 1 , wherein the compound is of Formula I-B:

where the piperazinyl ring is optionally substituted with R 8.

19. The compound of claim 18 , wherein R 2 is heterocyclylalkyl.

20. The compound of claim 19 , wherein the heterocyclyl portion of the heterocyclylalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl, each optionally substituted with one or more R 9.

21. The compound of claim 16 , wherein R 8 is heteroalkyl, C2-C4 alkynyl, or C1-C3alkyl optionally substituted or —OR 5 , cyano or heteroaryl.

22. The compound according to claim 18 , wherein L is a bond and R 4 is aryl or heteroaryl, each optionally substituted with one or more R 6 or R 7.

23. The compound of claim 1 , wherein R 1 —X is:

wherein A and B are a spirocyclic ring system, wherein A and B are the same or different and independently represent a 4-6 membered saturated ring system optionally substituted with one or more R 8.

24. The compound according to claim 23 , wherein R 4 is aryl optionally substituted with one or more R 7.

25. The compound of claim 24 , wherein the aryl is selected from the group consisting of phenyl and naphthyl optionally substituted with one or more R 7.

26. The compound according to claim 23 , wherein L is a bond.

27. The compound according to claim 23 , wherein the spirocyclic ring system formed by A and B are selected from the group consisting of:

28. The compound of claim 1 , wherein R 4 is phenyl or naphthyl, wherein each of the phenyl and naphthyl are optionally substituted with one or more R 9.

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

30. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , and a pharmaceutically acceptable excipient.

31. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound according to claim 1 , pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

32. A method for treating non-small cell lung cancer comprising administering to a patient having non-small cell lung cancer a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.

33. The method of claim 32 , wherein the non-small cell lung cancer is a KRas G12C-associated cancer.

34. A method for treating non-small cell lung cancer in a patient in need thereof, the method comprising (a) determining that the non-small cell lung cancer is associated with a KRas G12C mutation; and (b) administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.