KRAS G12C INHIBITORS

The present invention relates to novel tricyclic heterocyclic compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions including the tricyclic heterocyclic compounds and salts, and methods of using the compounds and salts to treat cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer.

The MAPK/ERK signaling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses including cell proliferation, differentiation, and apoptosis. KRas protein is an initiator of the MAPK/ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRas binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRas is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP). In its GTP -bound active state, KRas recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRas-GTP are c-Raf and PI3 -kinase. KRas, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRas gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK/ERK signal which promotes cancerous cell growth.

Missense mutations of KRas at codon 12 are the most common mutations and markedly diminish GTPase activity.

Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it has been a difficult therapeutic target. (Cox, A.D. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014,

13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web.

Nat. Rev. Cancer 2011, 11, 761-774).

WO2015/054572 and WO2016/164675 disclose certain quinazoline derivatives capable of binding to KRas G12C. WO2016/044772 also discloses methods of using such quanzoline derivatives. W02020/0081282 discloses KRas G12C inhibitors.

WO2018/206539 and WO2020/178282 disclose certain heteroaryl compounds capable of binding to KRas G12C RAS proteins.

There remains a need to provide alternative, small molecule KRas inhibitors. In particular, there is a need to provide more potent, orally deliverable KRas inhibitors that are useful for treating cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. There is also a need to provide small molecule KRas inhibitors that exhibit greater efficacy at the same or reduced KRas inhibitory activity. Further, there is a desire to provide KRas inhibitors that exhibit better pharmacokinetic/pharmacodynamic properties. Also, there is a need to provide more potent KRas inhibitors that exhibit increased efficacy with reduced or minimized untoward or undesired effects. The present invention addresses one or more of these needs by providing novel KRas inhibitors.

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is -OCH2-, -N(R6)CH2, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-;

B is -CH2- or -C(O)-;

Y is -C(CN)- or -N-;

Ri is -CN, -C(O)C≡CR8, or a group of the formula

R2 is H, methyl, or -CH2CN;

R3 and R5 are each independently H, halogen, -C0-3 alkyl-cyclopropyl, -C1-6 alkyl optionally substituted 1-3 times with R10, or -O-C1-6 alkyl optionally substituted 1-3 times with R10;

R4 is H, halogen, or -C1-6 alkyl optionally substituted 1-3 times with R10;

R6 is H or -C1-6 alkyl optionally substituted 1-3 times with R10;

R7 is H, halogen, -NR11R12, -CH2NR11R12, -C1-6 alkyl optionally substituted 1-3 times with R10 or R13, -C0-3 alkyl cyclopropyl, or -O-C1-6 alkyl optionally substituted 1-3 times with R10 or R13;

R8 is H, -C1-4 alkyl optionally substituted 1-3 times with R10, or -C3-6 cycloalkyl optionally substituted 1-3 times with R10;

R9 is H, halogen, -CN, -C0-3 alkyl-C3-6 cycloalkyl, or -C1-6 alkyl optionally substituted 1-3 times with R10;

R10 is independently at each occurrence halogen, oxygen, hydroxy, -C1-4 alkyl, or -O-C1.4 alkyl;

R11 and R12 are each independently H, -C1-4 alkyl, or -C1-4 heteroalkyl, wherein R11 and R12 may combine to form a heterocycloalkyl; and

Ri3 is independently at each occurrence -N-C1-4 alkyl.

As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms, e.g., “-C1-6 alkyl.”

Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, pentyl, and hexyl. As used herein, the term heteroalkyl means saturated linear or branched-chain monovalent hydrocarbon radicals containing two to five carbon atoms and at least one heteroatom, e.g., “-C1-4 heteroalkyl.” As used herein, the term cycloalkyl means saturated monovalent cyclic molecules with three to six carbon atoms, e.g., “-C3-6 cycloalkyl.” Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term cycloheteroalkyl means saturated monovalent cyclic molecules with two to five carbon atoms and at least one heteroatom, e.g., “-C3-6 cycloheteroalkyl.” Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.

In cases where a zero is indicated, e.g., -C0-3 alkyl-C3-6 cycloalkyl, the alkyl component of the substituent group can be absent, thus, if R9 of Formula I is a cyclopropyl group with no lead alkyl, the substituent would be described by the -C0-3 alkyl-cyclopropyl substituent as described for R9 (i.e., the substituent group would be -C0-cyclopropyl).

Regarding R11 and R12, the two groups may combine with the nitrogen they are attached to when chemistry allows to form a heterocycloalkyl . Examples of said heterocycloalkyl groups include, but are not limited to, piperidine, piperazine, and morpholine.

In an embodiment the present invention provides a compound of Formula la

where Ri, R2, R3, R4, R5, A, B, and Y are as defined above, or a pharmaceutically acceptable salt thereof.

In an embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, or a pharmaceutically

acceptable salt thereof. In a further embodiment the present invention provides a compound of formula I or la wherein A is -OCH2- or -OCH2CH2-, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of formula I or la wherein A is -OCH2CH2-, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein B is -C(O)-, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein Y is -C(CN)-or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein Y is -N-, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein Ri is -CN, -C(O)C≡CR8, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein Ri is a group of the formula

or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein R2 is H or methyl, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein R2 is H, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein R3 is H, halogen, methyl, methoxy, ethyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein R3 is halogen, (preferably F or Cl), or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein R4 is H or halogen, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein R4 is H or F, or a pharmaceutically acceptable salt thereof

In a further embodiment the present invention provides a compound of Formula I or la wherein R5 is halogen (preferably Cl) or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of formula I or la wherein R6 is H or CH3, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein R9 is H, or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound of Formula I or la wherein R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or

-CH2 -morpholine, or a pharmaceutically acceptable salt thereof. In yet a further embodiment the present invention provides a compound of Formula I or la wherein R7 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R9 is H and Rv is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2 -morpholine, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH and R7 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R7 and R9 are both H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R1 is -CN, -C(O)C≡CR8 and R8 is H, methyl, -CH2F, or -CH2OH or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Ri is a group of the formula

and R7 and R9 are both H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Ri is a group of the formula

and R7 is tert-butyl and R9 is -CN, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, and B is -C(O)-, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2- or -OCH2CH2- and B is -C(O)-, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2CH2- and B is -C(O)-, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, B is C(O) and R2 is H or -CH3, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2- or -OCH2CH2-, B is -C(O)- and R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2CH2-, B is -C(O)- and R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, B is -C(O)- and R2 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2- or -OCH2CH2-, B is -C(O)- and R2 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2CH2-, B is -C(O)- and R2 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2CH2- and R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2CH2- and R2 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein B is -C(O)- and R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein B is -C(O)- and R2 is H, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R3 and R5 are each independently selected from H, halogen or methyl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R3 or R5 are halogen, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R3 and R5 are halogen, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein R3 and R5 are each independently selected from F or Cl, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -C(CN)- and R4 is H or halogen (preferably F or Cl), or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -N- and R4 is H or halogen (preferably F or Cl), or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -C(CN)-, and R3 and R5 are each independently selected from methyl or halogen, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -C(CN)-, and R3 and R5 are each halogen (preferably F or Cl), or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -N-, R3 and R5 are each independently selected from methyl or halogen, or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein Y is -N-, R3 and R5 are each halogen (preferably F or Cl), or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2; B is -CH2- or -C(O)-; Y is -C(CN)-or -N-; Ri is -CN, -C(O)C≡CR8, or a group of the formula

R2 is H or methyl; R3 and R5 are each H, F, Cl or methyl; R4 is H or F; R6 is H or methyl; R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, -CH2-morpholine ortert-butyl; R8 is methyl, -CH2F or -CH2OH; and R9 is H, F, Cl, -CH2F, -CF3, -CH2OH or CN; or a pharmaceutically acceptable salt thereof

In yet a further embodiment the present invention provides a compound of Formula I or la wherein A is -OCH2- or -OCH2CH2-; B is -CH2- or -C(O)-; Y is -C(CN)-or -N-; R2, R7, and R8 are each H; R4 is H or halogen; R3 and R5 are each halogen; or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of the Formula Π:

wherein R is

X is Cl or F;

and m is 1 or 2.

or a pharmaceutically acceptable salt thereof

The present invention also provides a compound of the Formula Ila:

wherein R is

X is Cl or F;

and m is 1 or 2.

or a pharmaceutically acceptable salt thereof.

Another way to describe the compound of Formula II is with Formula lb:

or a pharmaceutically acceptable salt thereof, wherein:

A is -OCH2- or -OCH2CH2-;

Y is -C(CN)- or -N-;

R3 is Cl or F;

R4 is H or F when Y is C(CN); and

R4 is F when Y is N.

Another way to describe the compound of Formula Ila is with Formula lb, wherein A is

The present invention also provides a compound selected from any one of

Formulae III- VI below:

or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound of Formula III which is:

or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound of Formula IV which is:

or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound of Formula V which is:

or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound of Formula VI which is:

or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition comprising a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

The present invention also provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof. In various embodiments, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. In preferred embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In still more preferred embodiments, the cancer is non-small cell lung cancer.

In still yet another form, the present invention comprises a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C protein. In another embodiment, the cancer is non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C mutant protein. In another embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C mutant protein. In yet another embodiment, the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C mutant protein. In another embodiment, the present invention comprising a method of treating KRas G12C mutant bearing cancers of other origins.

The present invention also provides a method of treating a patient with a cancer that has a KRAS G12C mutation comprising administere to a patient in need thereof an effective amount of a compound according to any one of Formulae I- VI or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of modulating a mutant KRas G12C enzyme in a patient in need thereof, by administering a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof. Preferably the method comprises inhibiting a human mutant KRas G12C enzyme.

The present invention also provides a method of treating cancer in a patient in need thereof, wherein the patient has a cancer that was determined to express the KRas G12C mutant protein. The method comprises administering to a patient an effective amount of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof. The G12C mutational status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and/or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine the mutational status (e.g. G12C mutational status, in one or more cancer cells or in circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi -analyte profiling.

The present invention also provides a compound or a pharmaceutically acceptable salt thereof according to any one of Formulae I- VI for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer. Preferably, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer.

In preferred embodiments the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In still more preferred embodiments, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells that express the mutant KRas G12C protein. Preferably, the cancer is selected from: KRas G12C mutant non-small cell lung cancer, KRas G12C mutant colorectal cancer, and KRas G12C mutant pancreatic cancer. In another embodiment, the cancer is non-small cell lung cancer, and one or more cells express KRas G12C mutant protein. In another embodiment, the cancer is colorectal cancer, and one or more cells express KRas G12C mutant protein. In another embodiment, the cancer is pancreatic cancer, and one or more cells express KRas G12C mutant protein. In another embodiment, the patient has a cancer that was determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

The present invention also provides for the use of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. Preferably, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. In preferred embodiments, the cancer is non small cell lung cancer, pancreatic cancer, or colorectal cancer. In still more preferred embodiments, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells that express the mutant KRas G12C protein. Preferably, the cancer is selected from KRas G12C mutant non-small cell lung cancer, KRas G12C mutant colorectal cancer, and KRas G12C mutant pancreatic cancer.

The present invention also provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C protein. The present invention also provides a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CD4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically

acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof, in the treatment of cancer. The present invention also provides a combination comprising a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 or PD-L1 inhibitor, a CD4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.

The present invention also provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C protein. The present invention also provides a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with a PD-1 or PD-L1 inhibitor, for use in the treatment of cancer. The present invention also provides a combination comprising a compound according to any one of Formulae I- VI, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. In one embodiment, the compound is a compound of Formula I-VI or a pharmaceutically acceptable salt thereof. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is nivolumab. In another embodiment, the PD-1 or PD-L1 inhibitor is cimiplimab. In another embodiment, the PD-1 or PD-L1 inhibitor is sentilimab. In another embodiment, the PD-1 or PD-L1 inhibitor is atezolizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is aveiumab. In another embodiment, the PD-1 or PD-L1 inhibitor is durvalumab. In another embodiment, the PD-1 or PD-L1 inhibitor is lodapilimab. In another embodiment, the cancer is non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C mutant protein. In another embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C mutant protein. In another embodiment, the cancer is mutant pancreatic

cancer in which the cancer has one or more cells that express a KRas G12C mutant protein. In another embodiment, the present invention comprising a method of treating KRas G12C mutant bearing cancers of other origins.

What is Claimed is

1. A compound of the formula:

wherein:

A is -OCH2-, -N(R6)CH2, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-;

B is -CH2- or -C(O)-;

Y is -C(CN)- or -N-;

Ri is -CN, -C(O)CºCR8, or a group of the formula

R2 is H, methyl, or -CH2CN;

R3 and R5 are each independently H, halogen, -C0-3 alkyl-cyclopropyl, -C1- 6 alkyl optionally substituted 1-3 times with R10, or -O-C1-6 alkyl optionally substituted 1-3 times with R10;

R4 is H, halogen, or -C1-6 alkyl optionally substituted 1-3 times with R10; R6 is H or -C1-6 alkyl optionally substituted 1-3 times with R10;

R7 is H, halogen, -NR11R12, -CH2NR11R12, -C1-6 alkyl optionally substituted 1-3 times with R10 or R13, -C0-3 alkyl cyclopropyl, or -O-C1-6 alkyl optionally substituted 1-3 times with R10 or R13;

R8 is H, -C1-4 alkyl optionally substituted 1-3 times with R10, or -C3-6 cycloalkyl optionally substituted 1-3 times with R10;

R9 is H, halogen, -CN, -C0-3 alkyl-C3-6 cycloalkyl, or -C1-6 alkyl optionally substituted 1-3 times with R10;

R10 is independently at each occurrence halogen, oxygen, hydroxy, -C1-4 alkyl, or -O-C1-4 alkyl;

R11 and R12 are each independently H, -C1-4 alkyl, or -C1-4 heteroalkyl, wherien R11 and R12 may combine to form a cycloheteroalkyl; and

Ri3 is independently at each occurrence -N-C1-4 alkyl,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein A is -OCH2CH2-, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein B is -C(O)-, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein Y is -C(CN)- or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-3, wherein Y is -N- or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-5, wherein Ri is a group of the formula

and wherein R7 is H, F, Cl, methyl, ethoxy, ethyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof.

The compound according to any one of claims 1-5, wherein Ri is a group of the formula

and wherein R9 is H, F, Cl, -CHF2, -CF3, or -CH2OH, or a pharmaceutically acceptable salt thereof.

8 The compound according to any one of claims 1-5, wherein Ri is -CN, -C(O)CºCR8, or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1-8, wherein R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

10 The compound according to any one of claims 1-9, wherein R3 is H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl or a pharmaceutically acceptable salt thereof.

11 The compound according to any one of claims 1-10, wherein R4 is H, F, or Cl, or a pharmaceutically acceptable salt thereof.

12 The compound according to any one of claims 1-11, wherein R5 is H, -CHF2, - CH2F, -CH2OH, or -CH2OCH3, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, of the formula:

wherein:

A is -OCH2- or -OCH2CH2-;

Y is C(CN)or N;

R3 is Cl or F;

R4 is H or F when Y is C(CN); and

R4 is F when Y is N,

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein A is

15. The compound according to claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15, which is:

17. A pharmaceutical composition comprising a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

18. A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 17, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

19. A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

20. The method according to claim 19 wherein the cancer is non-small cell lung cancer, and wherein one or more cells express KRas G12C mutant protein.

21. The method according to claim 19 wherein the cancer is colorectal cancer, and wherein one or more cells express KRas G12C mutant protein.

22. The method according to claim 19 wherein the cancer is pancreatic cancer, and wherein one or more cells express KRas G12C mutant protein.

23. The method according to claim 19 wherein the patient has a cancer that was determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

24. A method of treating a patient with a cancer that has a KRAS G12C mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

25. The method according to any one of claims 19 to 24, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof.

26. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, for use in therapy.

27. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16 for use in the treatment of cancer.

28. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 27 wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

29. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16 for use in simultaneous, separate or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CD4/CDK6 inhibitor, or a

pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.