Combination therapies

Abstract

To provide combination therapies for treating KRas G12C cancers.SOLUTION: The present invention provides a method comprising administering to a subject a therapeutically effective amount of a combination of a SHP-2 inhibitor and a KRAS G12C inhibitor of Formula (I), pharmaceutical compositions comprising therapeutically effective amounts of the inhibitors, kits comprising the compositions, and methods of use thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a combination therapy useful for treating cancer. In particular, the present invention relates to a therapeutically effective combination of a Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) inhibitor and a KRas G12C inhibitor, a pharmaceutical composition containing the inhibitor, a kit containing the composition, and methods of using the same.

Background Art

[0002] Kirsten rat sarcoma 2 virus oncogene homolog (「KRas」) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between an inactive (GDP-bound) state and an active (GTP-bound) state to transmit upstream cell signals received from multiple tyrosine kinases to downstream effectors and regulate a variety of processes including cell proliferation (see, for example, Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of active KRas in malignancy was observed over 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and result in constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas. (See, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas constitute approximately 40% of these KRas driver mutations in lung adenocarcinoma, and the G12C transversion is the most frequently observed activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, doi:10.1158 / 1078-0432.CCR-11-3265, published online September 26, 2012).

[0004] Due to the well-known role of KRas in malignancy and the discovery of these frequent mutations of KRas in various tumor types, KRas has become a very attractive target in cancer therapy in the pharmaceutical industry. Despite 30 years of extensive discovery efforts to develop KRas inhibitors for treating cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to obtain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity, including those that interfere with effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Angew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358), as well as those that target KRas G12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551), remain highly desirable and are being investigated. Clearly, there remains an interest and ongoing attempts to develop inhibitors of KRas, particularly inhibitors of activated KRas variants including KRas G12C.

[0006] The KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzyme activity and exhibit single-agent activity that inhibits the in vitro proliferation of cell lines having the KRas G12C mutation. However, the relative potency and / or the observed maximum effect of any given KRas G12C inhibitor can vary among KRAS mutant cell lines. The reasons for the range of potencies and the observed maximum effect(s) are not fully understood, but certain cell lines appear to have different inherent resistances. Accordingly, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

[0007] In one aspect, the combination therapies of the invention synergistically increase the potency of KRas G12C inhibitors, resulting in improved efficacy of the KRas G12C inhibitors disclosed herein. In another aspect, the combination therapies of the invention provide improved clinical benefit to patients as compared to treatment with the KRas G12C inhibitors disclosed herein as a single agent.

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

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Summary of the Invention

[0009] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject a therapeutically effective amount of an SHP-2 inhibitor and a KRAS G12C inhibitor of formula (I)

Chemical Formula

[0010] For use in the methods provided herein, a KRas G12C inhibitor compound of formula I having formula I-A [Chemical formula] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L, and m are as defined in formula I, and the piperazinyl ring is R 8is optionally substituted, and R 8 as defined by formula I) is also included.

[0011] For use in the methods provided herein, a KRas G12C inhibitor compound of formula I having formula I-B [Chemical formula] or a pharmaceutically acceptable salt thereof (wherein R 1 , R 3 , R 4 , L, and m are as defined by formula I, and R 2 is a heterocyclylalkyl optionally substituted with one or more R 9 , wherein R 9 is as defined by formula I, and the piperazinyl ring is optionally substituted with R 8 , wherein R 8 is as defined by formula I) is also included.

[0012] In another aspect of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRas G12C inhibitor compound of formula I, formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is provided for use in the methods.

[0013] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0014] In some aspects of the present invention, the KRas G12C inhibitor compound and the SHP-2 inhibitor are the only active agents in the provided compositions and methods.

[0015] Examples of SHP-2 inhibitors suitable for the provided compositions and methods include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), RMC-4630 (Revolution Medicine), and TNO155 (Novartis).

[0016] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, the method comprising contacting the cancer cells with a therapeutically effective amount of a combination of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0017] A method for treating cancer in a subject in need of cancer treatment, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a cancer associated with KRas G12C), for example, as determined using an assay or kit approved by a regulatory authority, such as the FDA; and (b) administering to the patient a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor, is also provided herein.

[0018] Also provided herein is a kit comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The kit comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is also provided for use in the treatment of KRas G12C cancer.

[0019] In related aspects, the present invention provides a kit comprising a dose of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the growth of cancer cells in a subject. The kit may optionally include an insert containing instructions for administration of the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert may provide the user with a set of instructions for using the SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0020] In some embodiments of any of the methods described herein, prior to treatment with the compositions or methods of the present invention, the patient has been treated with one or more of chemotherapy, a targeted anti-cancer agent, radiation therapy, and surgery, and optionally, the prior treatment has failed, and / or the patient has undergone surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has previously been determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agent(s).

Mode for Carrying Out the Invention

[0021] The present invention relates to a combination therapy for treating KRas G12C cancer. In particular, the present invention is a method for treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and methods of using the same.

[0022] The combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof synergistically increases the potency of the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B against cancer cells expressing KRas G12C, thereby increasing the efficacy and therapeutic index of the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof.

[0023] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated herein by reference.

[0024] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein that includes an amino acid substitution from glycine to cysteine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Cys.

[0025] As used herein, "KRas G12C inhibitor" refers to the compounds of the invention represented by formula (I), formula I-A, and formula I-B described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the invention interact with KRas G12C and irreversibly bind thereto by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., example number 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof).

[0026] As used herein, "disease or disorder associated with KRas G12C" refers to a disease or disorder related to, mediated by, or having a KRas G12C mutation. Non-limiting examples of diseases or disorders associated with KRas G12C are cancers associated with KRas G12C.

[0027] As used herein, "SHP-2" or "SHP2" refers to a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signal transduction via the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositide 3-kinase-AKT pathways.

[0028] As used herein, "SHP-2 inhibitor" or "SHP2 inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the enzymatic activity of the SHP-2 phosphatase.

[0029] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, and other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject experiences and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject is identified or diagnosed as having a KRas G12C mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using an assay or kit approved by a regulatory authority). The subject can be a subject having a tumor (s) that is positive for the KRas G12C mutation (e.g., identified as positive using an assay or kit approved by a regulatory authority, such as the FDA). The subject can be a subject having a tumor with a KRas G12C mutation (e.g., the tumor has been so identified using a kit or assay approved by a regulatory authority, such as the FDA). In some embodiments, the subject is suspected of having a cancer associated with the KRas G12C gene. In some embodiments, the subject has a clinical record indicating the presence of a tumor with a KRas G12C mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0030] As used herein, the term "pediatric patient" refers to a patient less than 16 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (from birth to 1 month of age), infants (from 1 month to 2 years of age), children (from 2 years to 12 years of age), and adolescents (from 12 years to 21 years (up to the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996, Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002, and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0031] In some embodiments of any of the methods or uses described herein, an assay used to determine whether a patient (e.g., a patient suspected of having a cancer associated with KRas G12C, a patient having one or more symptoms of a cancer associated with KRas G12C, and / or a patient at high risk of developing a cancer associated with KRas G12C) has a KRas G12C mutation may include, for example, next-generation sequencing, immunohistochemical examination, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, this assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or an antigen-binding fragment thereof.

[0032] The term "regulatory authority" refers to a national agency for the national approval of the medical use of pharmaceuticals. For example, a non-limiting example of a regulatory authority is the US Food and Drug Administration (FDA).

[0033] The term "amino" refers to -NH2.

[0034] The term "acyl" refers to -C(O)CH3.

[0035] As used herein, the term "alkyl" refers to straight-chain and branched-chain aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0036] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are substituted by halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0037] The term "haloalkyloxy" refers to -O-haloalkyl.

[0038] An "alkylene" group is an alkyl group as defined above that is positioned between two other chemical groups and functions to link them. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0039] The term "alkoxy" refers to -OC1-C6 alkyl.

[0040] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and in a further example, 3 to 6 carbons, and the cycloalkyl group is further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0041] The term "heteroalkyl" refers to an alkyl group as defined herein in which one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.

[0042] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0043] The term "dihydroxyalkyl" refers to an alkyl group as defined herein in which two carbon atoms are each replaced by a hydroxyl group.

[0044] The term "alkylaminyl" refers to -NR x -alkyl, where R x is hydrogen. In one embodiment, R x is hydrogen.

[0045] The term "dialkylaminyl" refers to -N(R y )2, where each R y is C1-C3 alkyl.

[0046] The term "alkylaminylalkyl" refers to -alkyl-NR x -alkyl, where R x is hydrogen. In one embodiment, R x is hydrogen.

[0047] The term "dialkylaminylalkyl" refers to -alkyl-N(R y)2, each R y is C1-C4 alkyl, -alkyl-N(R y The alkyl in 2 may be optionally substituted with hydroxy or hydroxyalkyl.

[0048] An "aryl" group is a C6-C aryl group containing one to three aromatic rings, which are optionally substituted. 14 In one embodiment, the aryl group is a C6-C 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0049] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may be independently optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, (C1-C6)alkyl(C6-C8)alkyl, (C6-C9)alkyl, (C6-C10)alkyl, (C1-C12)alkyl, (C1-C13)alkyl, (C1-C14)alkyl, (C1-C15)alkyl, (C1-C16)alkyl, (C1-C17)alkyl, (C1-C18)alkyl, (C1-C19)alkyl, (C1-C20)alkyl, (C1-C21)alkyl, (C1-C22)alkyl, (C1-C23)alkyl, (C1-C24)alkyl, (C1-C25)alkyl, (C1-C26)alkyl, (C1-C27)alkyl, (C1-C28)alkyl, (C1-C29)alkyl, (C1-C21 ...1)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1-C21)alkyl, (C1 10 ) aryl. An example of a substituted aralkyl is one in which an alkyl group is substituted with a hydroxyalkyl.

[0050] A "heterocyclyl" or "heterocycle" group is a ring structure having from about 3 to about 12 atoms, e.g., 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. A heterocyclyl may be a monocyclic, bicyclic, spirocyclic or bridged ring system. A heterocycle group has R on a carbon or nitrogen at one or more positions. 7 Optionally substituted with R 7is as defined by formula I. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxaazabicycloheptane. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0051] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined herein linked to the remainder of the molecule via an alkyl linker, and the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0052] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic array, and having 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S in addition to carbon atoms.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0053] The "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, and the radical is on the alkyl group, and both of these are, independently, optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoindolylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0054] As used herein, an "effective amount" of a compound is an amount sufficient to negatively modulate or inhibit the activity of a desired target, i.e., SHP-2 or KRas G12C. Such an amount can be administered as a single dose or according to a dosing schedule, whereby the amount is effective.

[0055] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to relieve symptoms, or reduce symptoms in any manner, or stop or halt the progression of a disease state, or negatively modulate or inhibit the activity of SHP-2 or KRas G12C. Such an amount can be administered as a single dose or according to a dosing schedule, whereby the amount is effective.

[0056] As used herein, a "therapeutically effective amount" of a combination of two compounds is an amount that synergistically increases the activity of the combination as compared to the therapeutically effective amount of each compound in the combination, i.e., an amount that is not merely additive. Alternatively, in vivo, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an increased overall survival ("OS") period in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an increased progression-free survival ("PFS") period in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in increased tumor regression in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in increased tumor growth inhibition in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an improvement in the duration of stable disease in a subject as compared to treatment with the KRas G12C inhibitor alone.The amounts of the respective compounds in the combination may be the same as or different from the therapeutically effective amounts of the respective compounds when administered alone as monotherapy, as long as the combination is synergistic. Such amounts may be administered as a single dose or according to a dosing schedule, whereby the amounts are effective.

[0057] As used herein, "treatment" refers to any manner that alleviates or favorably changes the symptoms or conditions of a disease state, disorder, or disease. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0058] As used herein, alleviation of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any reduction, whether permanent or temporary, continuous or transient, that may result from or be related to the administration of the composition.

[0059] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a KRAS inhibitor or SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or the length of treatment by the combination therapy described herein) means that the parameter can vary up to 10% above or below the numerical value recited for that parameter. For example, a dosage of about 5 mg / kg can vary between 4.5 mg / kg and 5.5 mg / kg. The "about" used at the beginning of a list of parameters means to modify each parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0060] Inhibitor compound In one aspect of the present invention, there is provided a method of treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0061] 1. SHP-2 inhibitor Src homology 2 (SH2) domain-containing phosphatase 2 ("SHP-2") is a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signal transduction via the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositide 3-kinase (PI3K)-AKT-mTOR pathways. The SHP-2 polypeptide consists of two Src homology 2 (SH2) domains (N-SH2 and C-SH2) in the N-terminal region, as well as two potential Grb2 SH2 domain binding sites in the C-terminal region.

[0062] SHP-2 has been shown to exhibit a non-mutational drug resistance mechanism in response to anti-tyrosine kinase inhibitors (TKIs). For example, increased SHP-2 phosphatase activity has been shown to confer resistance to the TKI inhibitor imatinib (see, e.g., Li et al., (2018) Toxicol. Appl. Pharmacol. 360-249-256). Addition of an SHP-2 inhibitor has been shown to overcome resistance by blocking both the RAF / MEK / ERK pathway and the PI3K / AKT / mTOR pathway. Furthermore, adaptive resistance leading to direct KRas G12C inhibition by reactivation of the MAPK pathway, and failure of inactivation of the PI3K / AKT / mTOR pathway, were overcome by dual inhibition including a PI3K inhibitor (see, e.g., Misale et al., Clin. Cancer Res., Online Publication doi:10.1158 / 1078-0432.CCR 18-0368). Considering that SHP-2 can regulate the PI3K / AKT / mTOR pathway, dual inhibition using SHP-2 may be able to overcome different intrinsic cellular adaptation and / or acquired resistance mechanisms leading to KRas G12C inhibition.

[0063] Several inhibitors that are active against SHP-2 have been developed. Exemplary SHP-2 inhibitors include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), RMC-4630 (Revolution Medicine), and TNO155 (Novartis). RMC-4630 and TNO155 are in Phase 1 human clinical trials in adult patients with certain advanced solid tumors.

[0064] Methods for producing SHP-2 inhibitors are well known to those skilled in the art, and SHP-2 inhibitors can be obtained from a variety of commercial suppliers in forms suitable for both research and human use. In addition, SHP-2 inhibitors suitable for use in the compositions and methods disclosed herein, and methods for preparing such inhibitors, are disclosed in U.S. Patent Application Publication Nos. US2019 / 0127378, US2018 / 0251471, US2018 / 0201623, US2018 / 0186770, US2018 / 0170862, US2018 / 0065949, US2017 / 0204080, US2017 / 0166510, US2017 / 0011975, US2012 / 00334186, US2012 / 0257184, US2011 / 0190315, US2009 / 0042788, US2008 / 0194563, US2008 / 0058431, US2008 / 0058431, US2004 / 0121384, US2004 / 0043434, and US2004 / 0110800.

[0065] 2. KRas G12C inhibitor In one embodiment, the KRas G12C inhibitor used in the method is a compound of formula (I)

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

[0066] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula I-A

Chem.

[0067] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula I-B

Chem.

[0068] Non-limiting examples of the KRas G12C inhibitor compounds of formula (I), formula I-A, and formula I-B useful in the methods disclosed herein include Examples 1 to 678 (as numbered in WO2019 / 099524) having the following structures,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0069] In one embodiment, the KRas G12C inhibitor is [Chemistry] or a pharmaceutically acceptable salt thereof, and is selected from.

[0070] In one embodiment, the KRas G12C inhibitor is [Chemistry] (referred to as Example 234) or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the KRas G12C inhibitor is [Chemistry] (referred to as Example 359) or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the KRas G12C inhibitor is [Chemistry] (referred to as Example 478) or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the KRas G12C inhibitor is

Chemical formula

[0074] The KRas G12C inhibitor used in the method of the present invention may have one or more chiral centers and can be synthesized as a mixture of stereoisomers, isomers with different spatial arrangements of those atoms in the same configuration. The compounds can be used as a mixture or using commercially available reagents and conventional isolation methods for stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma - Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns, according to the manufacturer's instructions, the individual components / enantiomers can be separated. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates for preparing individual enantiomers or diastereomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification including the claims refers to the compounds of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0075] In one embodiment, the KRas G12C inhibitor compound of Formula I, Formula I - A, or Formula I - B used in the present method comprises the trifluoroacetate salt of the above - mentioned compound.

[0076] Methods for manufacturing the KRas G12C inhibitors disclosed herein are known. For example, the co-owned and published international PCT applications WO2017 / 201161 and WO2019 / 099524 describe general reaction schemes for preparing compounds of formula I, formula I-A, or formula I-B, and also provide detailed synthetic routes for the preparation of each KRas G12C inhibitor disclosed herein.

[0077] An SHP-2 inhibitor and a KRas G12C compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition.

[0078] Pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, and a KRas G12C inhibitor according to the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof can each be formulated by any method well known in the art and prepared for administration by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal. In certain embodiments, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof are administered intravenously in a hospital setting. In one embodiment, the administration can be by the oral route.

[0079] The properties of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to materials that are compatible with living systems such as cells, cell cultures, tissues, or organisms and that do not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, the compositions can include, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0080] As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compounds identified above and exhibit minimal or no undesired toxicological effects. Examples of such salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as acids formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, but are not limited thereto. The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which particularly include quaternary ammonium salts of the formula -NR+Z−, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, which includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzylorate, and diphenylacetate).

[0081] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the treated patient. In one embodiment, for all of the above conditions, the dosage of the active compound ranges from about 0.01 to 300 mg / kg per day, for example, in the range of 0.1 to 100 mg / kg per day, and as a further example, in the range of 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage ranges from 0.01 to 3 weight / weight % in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active by itself, the effective dosage can be estimated as described above using the weight of the derivative, or by other means known to those skilled in the art.

[0082] A pharmaceutical composition comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof can also be used in the methods of use described herein.

[0083] Co-administration The SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms that can be co-administered sequentially. Another option is that when the route of administration is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, provided that both co-administration methods are part of the same therapeutic treatment or regimen.

[0084] For use in the present method, a pharmaceutical composition comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and / or a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof can be for simultaneous, separate, or sequential use. In one embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, is administered prior to administration of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, is administered after administration of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, is administered substantially simultaneously with administration of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof.

[0085] Separate administration of each inhibitor at different times and by different routes can, in some cases, be advantageous. Thus, the components of the combination, namely, a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, do not necessarily have to be administered at essentially the same time or in any particular order.

[0086] Oncology drugs are administered at the maximum tolerated dose (the "MTD"), which is typically the highest dose of the drug that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered at their respective MTDs. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD, and the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD, and the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered in an amount less than their respective MTDs. The administration can also be timed so that the peak pharmacodynamic effect of one compound coincides with the peak pharmacodynamic effect of the other.

[0087] In one embodiment, a single administration of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered once daily (i.e., at approximately 24-hour intervals) (i.e., once a day). In another embodiment, two administrations of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., twice a day). In another embodiment, three administrations of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., three times a day).

[0088] In one embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered once daily. In another embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered twice daily. In another embodiment, the SHP-2 inhibitor of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered three times daily.

[0089] In one embodiment, a single administration of a compound of a KRas G12C inhibitor of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and an SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is each administered once daily.

[0090] Examples of SHP-2 inhibitors suitable for the provided compositions and methods include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), RMC-4360, and TNO155 (Novartis).

[0091] Combination therapy In one aspect of the present invention, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0092] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, the method comprising contacting the cancer cells with a combination of an effective amount of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and an SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0093] In one embodiment, the combination therapy comprises a compound having the formula

Chemical formula

[0094] In one embodiment, the combination therapy comprises a compound having the formula

Chemical formula

[0095] In one embodiment, the combination therapy comprises a compound having the formula

Chemical formula

[0096] In one embodiment, the combination therapy is a compound having the formula [Chemical formula] It includes a combination of or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor. In one embodiment, the SHP-2 inhibitor is SHP-099. In one embodiment, the SHP-2 inhibitor is RMC-4550. In one embodiment, the SHP-2 inhibitor is RMC-4360. In one embodiment, the SHP-2 inhibitor is TNO155.

[0097] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" cancer cells includes administering the combinations provided herein to an individual or subject such as a human having KRas G12C, as well as introducing the combinations provided herein into a sample containing a cell preparation or purified preparation containing, for example, KRas G12C.

[0098] The methods described herein are designed to inhibit unwanted cell proliferation resulting from enhanced intracellular KRas G12C activity by negatively regulating the activity of KRas G12C. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including those described in the published international PCT applications WO2017 / 201161 and WO2019 / 099524. In addition, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12C activity by the amount of phosphorylated ERK and evaluating the efficacy of the treatment, and thus the dosage can be adjusted by the attending physician.

[0099] The compositions and methods provided herein can be used to treat cancers associated with KRas G12C in a subject in need thereof, by administering to the subject a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of cancers associated with KRas G12C to the KRas G12C inhibitor. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0100] In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an increased overall survival ("OS") period in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an increased progression-free survival ("PFS") period in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in increased tumor regression in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in increased tumor growth inhibition in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in improvement in the duration of stable disease in a subject as compared to treatment with the KRas G12C inhibitor alone. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., example numbers 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof).In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and TNO155.

[0101] In another embodiment, the SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof when disease progression is observed with KRas G12C monotherapy, and the combination therapy provides enhanced clinical benefit in patients by increasing OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 359 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and TNO155.In one embodiment, the treatment combination includes a therapeutically effective amount of Example No. 507 and SHP-099. In one embodiment, the treatment combination includes a therapeutically effective amount of Example No. 507 and RMC-4550. In one embodiment, the treatment combination includes a therapeutically effective amount of Example No. 234 and RMC-4360. In one embodiment, the treatment combination includes a therapeutically effective amount of Example No. 507 and TNO155.

[0102] The compositions and methods provided herein can be used for the treatment of a variety of cancers, including tumors such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain tumors, skin cancer, cervical cancer, testicular cancer, and the like. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas. More specifically, these compounds include: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urinary tract: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder carcinoma, papillary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, glioma, sarcoma;Gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), fallopian tube (carcinoma); Hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: can be used to treat neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.;

[0103] A method for treating cancer in a subject in need of cancer treatment, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a cancer associated with KRas G12C), such as by using an assay or kit approved by a regulatory authority, such as the FDA; and (b) administering to the patient a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. Also provided herein is a method. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example number 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 234 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 234 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 234 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 234 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 359 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 359 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 359 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 359 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example number 478 and SHP-099.In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 478 and TNO155. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and SHP-099. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and RMC-4550. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 234 and RMC-4360. In one embodiment, the treatment combination comprises a therapeutically effective amount of Example No. 507 and TNO155.

[0104] In one embodiment, the compound of Formula I is administered as a capsule over a period of time. In one embodiment, the tablet or capsule formulation of the compound of Formula I contains from about 10 mg to about 100 mg (e.g., from about 10 mg to about 95 mg, from about 10 mg to about 90 mg, from about 10 mg to about 85 mg, from about 10 mg to about 80 mg, from about 10 mg to about 75 mg, from about 10 mg to about 70 mg, from about 10 mg to about 65 mg, from about 10 mg to about 60 mg, from about 10 mg to about 55 mg, from about 10 mg to about 50 mg, from about 10 mg to about 45 mg, from about 10 mg to about 40 mg, from about 10 mg to about 35 mg, from about 10 mg to about 30 mg, from about 10 mg to about 25 mg, from about 10 mg to about 20 mg, from about 15 mg to about 100 mg, from about 15 mg to about 95 mg, from about 15 mg to about 90 mg, from about 15 mg to about 85 mg, from about 15 mg to about 80 mg, from about 15 mg to about 75 mg, from about 15 mg to about 70 mg, from about 15 mg to about 65 mg, from about 15 mg to about 60 mg, from about 15 mg to about 55 mg, from about 15 mg to about 50 mg, from about 15 mg to about 45 mg, from about 15 mg to about 40 mg, from about 15 mg to about 35 mg, from about 15 mg to about 30 mg, from about 15 mg to about 25 mg, from about 15 mg to about 20 mg, from about 20 mg to about 100 mg, from about 20 mg to about 95 mg, from about 20 mg to about 90 mg, from about 20 mg to about 85 mg, from about 20 mg to about 80 mg, from about 20 mg to about 75 mg, from about 20 mg to about 70 mg, from about 20 mg to about 65 mg, from about 20 mg to about 60 mg, from about 20 mg to about 55 mg, from about 20 mg to about 50 mg, from about 20 mg to about 45 mg, from about 20 mg to about 40 mg, from about 20 mg to about 35 mg, from about 20 mg to about 30 mg, from about 20 mg to about 25 mg, from about 25 mg to about 100 mg, from about 25 mg to about 95 mg, from about 25 mg to about 90 mg, from about 25 mg to about 85 mg, from about 25 mg to about 80 mg, from about 25 mg to about 75 mg, from about 25 mg to about 70 mg, from about 25 mg to about 65 mg, from about 25 mg to about 60 mg, from about 25 mg to about 55 mg, from about 25 mg to about 50 mg, from about 25 mg to about 45 mg, from about 25 mg to about 40 mg, from about 25 mg to about 35 mg, from about 25 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 95 mg, from about 30 mg to about 90 mg, from about 30 mg to about 85 mg, from about 30 mg to about 80 mg, from about 30 mg to about 75 mg, from about 30 mg to about 70 mg, from about 30 mg to about 65 mg, from about 30 mg to about 60 mg, from about 30 mg to about 55 mg, from about 30 mg to about 50 mg,from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 35 mg to about 100 mg, from about 35 mg to about 95 mg, from about 35 mg to about 90 mg, from about 35 mg to about 85 mg, from about 35 mg to about 80 mg, from about 35 mg to about 75 mg, from about 35 mg to about 70 mg, from about 35 mg to about 65 mg, from about 35 mg to about 60 mg, from about 35 mg to about 55 mg, from about 35 mg to about 50 mg, from about 35 mg to about 45 mg, from about 35 mg to about 40 mg, from about 40 mg to about 100 mg, from about 40 mg to about 95 mg, from about 40 mg to about 90 mg, from about 40 mg to about 85 mg, from about 40 mg to about 80 mg, from about 40 mg to about 75 mg, from about 40 mg to about 70 mg, from about 40 mg to about 65 mg, from about 40 mg to about 60 mg, from about 40 mg to about 55 mg, from about 40 mg to about 50 mg, from about 40 mg to about 45 mg, from about 45 mg to about 100 mg, from about 45 mg to about 95 mg, from about 45 mg to about 90 mg, from about 45 mg to about 85 mg, from about 45 mg to about 80 mg, from about 45 mg to about 75 mg, from about 45 mg to about 70 mg, from about 45 mg to about 65 mg, from about 45 mg to about 60 mg, from about 45 mg to about 55 mg, from about 45 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 95 mg, from about 50 mg to about 90 mg, from about 50 mg to about 85 mg, from about 50 mg to about 80 mg, from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, from about 50 mg to about 55 mg, from about 55 mg to about 100 mg, from about 55 mg to about 95 mg, from about 55 mg to about 90 mg, from about 55 mg to about 85 mg, from about 55 mg to about 80 mg, from about 55 mg to about 75 mg, from about 55 mg to about 70 mg, from about 55 mg to about 65 mg, from about 55 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 95 mg, from about 60 mg to about 90 mg, from about 60 mg to about 85 mg, from about 60 mg to about 80 mg, from about 60 mg to about 75 mg, from about 60 mg to about 70 mg, from about 60 mg to about 65 mg, from about 65 mg to about 100 mg, from about 65 mg to about 95 mg, from about 65 mg to about 90 mg, from about 65 mg to about 85 mg, from about 65 mg to about 80 mg, from about 65 mg to about 75 mg, from about 65 mg to about 70 mg, from about 70 mg to about 100 mg, from about 70 mg to about 95 mg, from about 70 mg to about 90 mg, from about 70 mg to about 85 mg, from about 70 mg to about 80 mg, from about 70 mg to about 75 mg, from about 75 mg to about 100 mg, from about 75 mg to about 95 mg, from about 75 mg to about 90 mgfrom about 75 mg to about 85 mg, from about 75 mg to about 80 mg, from about 80 mg to about 100 mg, from about 80 mg to about 95 mg, from about 80 mg to about 90 mg, from about 80 mg to about 85 mg, from about 85 mg to about 100 mg, from about 85 mg to about 95 mg, from about 85 mg to about 90 mg, from about 90 mg to about 100 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or about 100 mg) of a compound of formula I (e.g., a compound selected from compound numbers 1 to 553, e.g., a compound selected from compound numbers 234, 359, 478, or 507). In one embodiment, the compound of formula I is orally administered once daily (QD) for a period of time. In one embodiment, the compound of formula I is orally administered twice daily (BID) for a period of time. In one embodiment, the compound of formula I is from about 20 mg to about 500 mg (e.g., from about 20 mg to about 480 mg, from about 20 mg to about 460 mg, from about 20 mg to about 440 mg, from about 20 mg to about 420 mg, from about 20 mg to about 400 mg, from about 20 mg to about 380 mg, from about 20 mg to about 360 mg, from about 20 mg to about 340 mg, from about 20 mg to about 320 mg, from about 20 mg to about 300 mg, from about 20 mg to about 280 mg, from about 20 mg to about 260 mg, from about 20 mg to about 240 mg, from about 20 mg to about 220 mg, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, from about 20 mg to about 140 mg, from about 20 mg to about 120 mg, from about 20 mg to about 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 20 mg to about 40 mg, from about 40 mg to about 500 mg, from about 40 mg to about 480 mg, from about 40 mg to about 460 mg, from about 40 mg to about 440 mg, from about 40 mg to about 420 mg, from about 40 mg to about 400 mg, from about 40 mg to about 380 mg, from about 40 mg to about 360 mg, from about 40 mg to about 340 mg, from about 40 mg to about 320 mg, from about 40 mg to about 300 mg, from about 40 mg to about 280 mg, from about 40 mg to about 260 mg, from about 40 mg to about 240 mg, from about 40 mg to about 220 mg, from about 40 mg to about 200 mg, from about 40 mg to about 180 mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg,About 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mgAbout 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mgAbout 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 22 0 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg,administered orally in an amount of about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg).

[0105] In one embodiment, the combination therapy is administered once or twice daily (for a certain period), for example, at about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg,about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mgfrom about 180 mg to about 380 mg, from about 180 mg to about 360 mg, from about 180 mg to about 340 mg, from about 180 mg to about 320 mg, from about 180 mg to about 300 mg, from about 180 mg to about 280 mg, from about 180 mg to about 260 mg, from about 180 mg to about 240 mg, from about 180 mg to about 220 mg, from about 180 mg to about 200 mg, from about 200 mg to about 400 mg, from about 200 mg to about 380 mg, from about 200 mg to about 360 mg, from about 200 mg to about 340 mg, from about 200 mg to about 320 mg, from about 200 mg to about 300 mg, from about 200 mg to about 280 mg, from about 200 mg to about 260 mg, from about 200 mg to about 240 mg, from about 220 mg to about 400 mg, from about 220 mg to about 380 mg, from about 220 mg to about 360 mg, from about 220 mg to about 340 mg, from about 220 mg to about 320 mg, from about 220 mg to about 300 mg, from about 220 mg to about 280 mg, from about 220 mg to about 260 mg, from about 220 mg to about 240 mg, from about 240 mg to about 400 mg, from about 240 mg to about 380 mg, from about 240 mg to about 360 mg, from about 240 mg to about 340 mg, from about 240 mg to about 320 mg, from about 240 mg to about 300 mg, from about 240 mg to about 280 mg, from about 240 mg to about 260 mg, from about 260 mg to about 400 mg, from about 260 mg to about 380 mg, from about 260 mg to about 360 mg, from about 260 mg to about 340 mg, from about 260 mg to about 320 mg, from about 260 mg to about 300 mg, from about 260 mg to about 280 mg, from about 280 mg to about 400 mg, from about 280 mg to about 380 mg, from about 280 mg to about 360 mg, from about 280 mg to about 340 mg, from about 280 mg to about 320 mg, from about 280 mg to about 300 mg, from about 300 mg to about 400 mg, from about 300 mg to about 380 mg, from about 300 mg to about 360 mg, from about 300 mg to about 340 mg, from about 300 mg to about 320 mg, from about 320 mg to about 400 mg, from about 320 mg to about 380 mg, from about 320 mg to about 360 mg, from about 340 mg to about 360 mg, from about 340 mg to about 400 mg, from about 340 mg to about 380 mg, from about 340 mg to about 360 mg, from about 360 mg to about 400 mg, from about 360 mg to about 380 mg, from about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg) of the compound of formula I by oral administration, and for example,It includes oral administration of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof administered once daily (during a certain period). In one embodiment, a KRAS G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is orally administered once daily. In one embodiment, a KRAS G12C inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is orally administered twice daily.,

[0106] One of ordinary skill in the art will understand that the ability of a test compound combination or a given combination to treat or prevent a disorder can be predicted by both in vivo and in vitro tests using suitable known and generally acceptable cell and / or animal models.,

[0107] One of ordinary skill in the art will further understand that human clinical trials, including first-in-human trials, dose-range finding trials, and efficacy trials in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well-known in the clinical and medical fields.,

[0108] Synergistic effect In one embodiment, the addition of an SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, against cancer or cancer cell lines expressing KRas G12C. Any method for determining whether two compounds exhibit a synergistic effect can be used to determine the synergistic effect of the combination.,

[0109] To determine whether two compounds act synergistically, i.e., act beyond mere additive effects, several mathematical models have been developed. For example, Loewe additivity (Loewe (1928) Physiol. 27:47 - 187), Bliss independence (Bliss (1939) Ann. Appl. Biol. 26:585 - 615), highest single agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13:504 - 513), as well as other models (Chou & Talalay (1984) Adv Enzyme Regul 22:27 - 55.#6382953, and Greco et al. (1995) Pharmacol Rev 47(2):331 - 85.#7568331) are models well - known in the pharmaceutical industry and can be used to calculate a "synergy score" indicating whether a synergistic effect was detected and the magnitude of such a synergistic effect. Combining these synergy scores generates a composite synergy score, which can be used to evaluate and characterize a KRas G12C inhibitor compound of formula (I), formula I - A, or formula I - B in combination with an SHP - 2 inhibitor.

[0110] Generally, a mathematical model uses data obtained from single - agent values to determine the predicted additive effect of a combination and compares it with the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model compares the observed combination response (Y O ) with the predicted combination response (Y P ) obtained based on the assumption that there is no interaction between drugs. When Y O is greater than Y P , typically, the combination effect shows synergy.

[0111] In some embodiments, as used herein, a "synergistic effect" refers to, for example, any of the beneficial or desired results including the clinical outcomes or endpoints described herein, an effect produced by a combination of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof) and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, which is greater than the sum of the effects observed when each is administered alone. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., Example number 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, and TNO155. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 234 and SHP-099. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 234 and RMC-4550. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 234 and TNO155. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 359 and SHP-099. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 359 and RMC-4550. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 359 and TNO155. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 478 and SHP-099. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 478 and RMC-4550. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 478 and TNO155. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 507 and SHP-099. In one embodiment, the treatment combination includes a therapeutically effective amount of Example number 507 and RMC-4550.In one embodiment, the combination therapy comprises a therapeutically effective amount of Example No. 507 and TNO155.

[0112] In some embodiments, the methods provided herein are during a period of 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months).1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65%, 6% to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 85%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20% of the volume of one or more solid tumors in a patient after treatment with combination therapy20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、resulting in a decrease of 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100% (e.g., as compared to the size of one or more solid tumors in a patient prior to treatment).

[0113] The term "survival time" means the length of time from the identification or diagnosis of a mammalian cancer (e.g., any of the cancers described herein) by a medical professional to the time of death of the mammal (caused by the cancer). Methods of increasing the survival period of a mammal having cancer are described herein.

[0114] In some embodiments, any of the methods described herein may be, during a patient's lifetime, (e.g., 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380%, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%,30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、70%~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%、240%~340%、240%~320%、240%~300%、can result in an increase of 240% - 280%, 240% - 260%, 260% - 400%, 260% - 380%, 260% - 360%, 260% - 340%, 260% - 320%, 260% - 300%, 260% - 280%, 280% - 400%, 280% - 380%, 280% - 360%, 280% - 340%, 280% - 320%, 280% - 300%, 300% - 400%, 300% - 380%, 300% - 360%, 300% - 340%, or 300% - 320% (e.g., as compared to patients having the same cancer who have received different treatments or no treatment).

[0115] In some embodiments of any of the methods described herein, prior to treatment with the compositions or methods of the invention, the patient has been treated with one or more of chemotherapy, a targeted anti-cancer agent, radiation therapy, and surgery, and optionally, the prior treatment has failed, and / or the patient has had surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has previously been determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agents(s).

[0116] Kit The present invention also relates to a kit comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. A kit comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is also provided for use in the treatment of KRas G12C cancer.

[0117] In related aspects, the present invention provides a kit comprising a dose of an SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the growth of cancer cells, particularly cancer cells associated with KRas G12C, in a subject. The kit may optionally include an insert containing instructions for administration of the SHP-2 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert may provide the user with a set of instructions for using the SHP-2 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0118] Example A The SHP-2 inhibitor synergistically increases the activity of the KRas G12C inhibitor against cell lines expressing KRas G12C. This example shows that the combination of exemplary KRas G12C inhibitor compounds of formula I, formula I-A, and formula I-B, and the SHP-2 inhibitor, synergistically inhibits the growth of tumor cell lines expressing KRas G12C.

[0119] To determine whether combining an SHP-2 inhibitor with the exemplary KRas G12C inhibitors disclosed herein results in synergistic activity, a panel of eight lung cancer and one colorectal cell lines with the KRas G12C mutation was assembled. The collection included NCI-H1373 (ATCC CRL-5866), NCI-H1792 (ATCC CRL-5895), NCI-H2030 (ATCC CRL-5985), NCI-H2122 (ATCC CRL-5985), HCC1171 (KCLB 71171), HCC44 (DSMZ ACC-534), LU99 (RCB1900), SW1573 (ATCC CRL-2170), and SW837 (ATCC CCL-235).

[0120] The assay for determining the synergistic effect score for each pair of cell lines was performed three times. To three 96-well plates for determining baseline luminescence and four additional wells of a separate 96-well control plate, a specific cell line at 2000 cells / well was seeded in a growth medium suitable for that cell line, e.g., RPMI 1640 medium supplemented with 10% FBS, and a total of 90 μl of any cell line-specific reagents required for growth. The plates were incubated overnight at 37 °C in a 5% CO2 atmosphere.

[0121] To each of the designated baseline wells, 30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) was added to each well, and the plates were incubated for 20 minutes with shaking at room temperature. Baseline luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0122] A series of working stock 1000X drug dilutions in 100% DMSO were prepared, including 8-point single-agent dilutions of the exemplary KRas G12C inhibitors of formula (I), formula I-A, and formula I-B and 5-point single-agent dilutions of the SHP-2 inhibitor. The dilutions used for the KRas G12C inhibitor and the SHP-2 inhibitor were different for each individual compound but were in the range of 3- to 6-fold / step dilutions.

[0123] Exemplary KRasG12C inhibitors tested in this example include the following. [Table 1]

[0124] The 10X intermediate dosing plates were prepared in serum-free RPMI medium containing arrayed single-dilutions of exemplary KRas G12C inhibitors or SHP-2 inhibitors of formula (I). Additionally, 40 matrix dilutions combinations of exemplary KRas G12C inhibitors of formula (I), formula I-A, or formula I-B and SHP-2 inhibitors were prepared as test samples.

[0125] To each corresponding well of three 96-well plates seeded with the appropriate cell line above, 10 μl of each 10X single agent and dose matrix 40 combination was added and the plates were incubated for 72 hours at 37 °C in a 5% CO2 atmosphere. 30 μl aliquots of Cell-Titer Glo reagent (CTG) were added to each test well and the plates were incubated for 20 minutes with shaking at room temperature, and luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0126] Using raw data and metadata files as input files, the response rate for each treatment condition was calculated and analyzed using four independent mathematical reference models (Loewe additivity, Bliss independence, highest single agent, and ZIP) designed to determine whether two test compounds exhibit a synergistic effect.

[0127] The output of the data from each mathematical model is the assignment of a relative synergy score. The data reported in Table 1 is the sum of the Loewe additivity, Bliss independence, highest single agent, and ZIP scores (the "combined synergy score"). [Table 2]

[0128] Composite scores of 27 or above were interpreted as synergistic hits, while composite scores of 17 - 26 indicated potential synergy. These results show that certain members of a panel of KRas G12C cell lines exhibit modest synergy with a combination of an SHP-2 inhibitor and exemplary Formula (I), Formula I-A, and Formula I-B KRas G12C inhibitor compounds, warranting further investigation of combination efficacy studies in in vivo models.

[0129] Example B In Vivo Model for Investigating Combinations of KRas G12C Inhibitors and SHP-2 Inhibitors Cells with a KRas G12C mutation or patient-derived tumor samples are inoculated into the right hind limb flanks of immunodeficient nude / nude mice. When the tumor volume reaches a size of 200 - 400 mm 3 , the mice are divided into four groups of 5 - 12 mice each. The first group is administered vehicle only. The second group is administered a single-agent dose of a KRas G12C inhibitor at a concentration that produces a maximal or sub-maximal biological effect depending on the cell line and single-agent activity, which does not result in complete tumor regression. The third group is administered a single-agent dose of an SHP-2 inhibitor at a concentration that produces a maximal or sub-maximal biological effect depending on the cell line and single-agent activity, which does not result in complete tumor regression. The fourth group is administered a single-agent dose of a KRas G12C inhibitor in combination with a single-agent dose of an SHP-2 inhibitor. The treatment period varies by cell line but is typically 21 - 35 days. Tumor volume is measured using calipers every 2 - 3 days, and tumor volume is calculated using the formula: 0.5 × (length × width) 2 A greater degree of tumor growth inhibition by the combination in this model indicates that combination therapy is likely to provide a clinically significant benefit to the treatment subjects compared to treatment with the KRas G12C inhibitor alone.

[0130] For each study, 20 nude / nude mice are administered 5 × 10 6Individual SW1573 cells, KYSE410 cells, or H358 cells were inoculated into the right hind limb. When the tumor volume reached approximately 300 - 350 mm 3 (study day 0), five mice in each of the four groups were orally administered vehicle only (10% captisol in 50 mM citrate buffer (pH 5.0)), 100 mg / kg of the KRAS G12C inhibitor compound 478 (10% captisol in 50 mM citrate buffer (pH 5.0)), 30 mg / kg of the SHP-2 inhibitor RMC-4550 (10% captisol in 50 mM citrate buffer (pH 5.0)), or 100 mg / kg of the KRas G12C inhibitor compound 478 and 30 mg / kg of RMC-4550 daily for 28 days. The tumor volumes measured at specific days for five mice per group were averaged and reported in Tables 2, 3, and 4 for SW1573 cells, KYSE410 cells, and H358 cells, respectively.

Table 3

[0131] As shown in Table 2, administration of compound 478 or RMC-4550 as single agents showed 81% and 68% tumor growth inhibition, respectively, on day 22. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 resulted in 23% tumor regression on day 22.

Table 4

[0132] As shown in Table 3, administration of compound 478 or RMC-4550 as single agents showed 93% and 90% tumor growth inhibition, respectively, on day 22. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 resulted in 78% tumor regression on day 22.

Table 5

[0133] As shown in Table 4, administration of compound 478 or RMC-4550 as a single agent showed 68% regression and 22% tumor growth inhibition on day 22, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 resulted in 81% tumor regression on day 22.

[0134] Similarly, 25 nude / nude mice were inoculated with 5×10 6 cells of H2122 in the right hind limb. When the tumor volume reached approximately 350 mm 3 (study day 0), five mice in each of the five groups were orally administered vehicle only (10% captisol in 50 mM citrate buffer (pH 5.0)), 100 mg / kg of the KRAS G12C inhibitor compound 478 (10% captisol in 50 mM citrate buffer (pH 5.0)), 30 mg / kg of the SHP-2 inhibitor RMC-4550 (10% captisol in 50 mM citrate buffer (pH 5.0)), 100 mg / kg of the KRas G12C inhibitor compound 478 and 30 mg / kg of RMC-4550 for 21 days, or 100 mg / kg of the KRas G12C inhibitor compound 478 daily for 16 days, and at this point, the administration of compound 478 was continued for an additional 13 days with co-administration of 30 mg / kg of RMC-4550 (separation group). The tumor volumes measured at specific days for five mice per group were averaged and reported in Table 5.

Table 6

[0135] As shown in Table 5, administration of compound 478 or RMC-4550 as a single agent showed 93% and 47% tumor growth inhibition on day 29, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 resulted in 29% tumor regression on day 29.

[0136] These results indicate that combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating an enhanced in vivo antitumor effect of the combination against cancers expressing KRas G12C.

[0137] Although the present invention has been described in connection with its specific embodiments, those embodiments are further modifiable, and this application is generally intended to cover any variations, uses, or adaptations of the present invention in accordance with the principles of the present invention, including departures from the present disclosure that come within the known or customary scope of practice of the art to which the present invention pertains and fall within the essential features set forth above and below in the scope of the appended claims.

Claims

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SHP-2 inhibitor and a KRAS G12C inhibitor of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof (In the formula, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring or spiro ring, said saturated or partially saturated monocyclic ring being selected from the group consisting of one or more R ８ is optionally replaced by Y is a bond, O, S, or NR ５ and R １ but, 【Chemistry 2】 or 【Chemistry 3】 and R ２ is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR ５ R １０ , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, each of said Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl being selected from one or more of R ９ and optionally substituted with Each Z is C １ -C ４ is alkylene, Each R ３ But independently, C １ -C ３ alkyl, oxo, haloalkyl, hydroxyl, or halogen; L is a bond, —C(O)—, or C １ -C ３ is alkylene, R ４ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl being selected from one or more R ６ , R ７ , or R ８ and optionally substituted with Each R ５ are independently hydrogen or C １ -C ３ is alkyl, R ６ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl being selected from one or more R ７ and optionally substituted with Each R ７ are independently halogen, hydroxyl, C １ -C ６ alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; R ８ But, Oxo, C １ -C ３ Alkyl, C ２ -C ４ Alkynyl, heteroalkyl, cyano, -C(O)OR ５ , -C(O)N(R ５ ) ２ , -N(R ５ ) ２ and said C １ -C ３ Alkyl is cyano, halogen, -OR ５ , -N(R ５ ) ２ or heteroaryl, Each R ９ are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C １ -C ６ alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, １ -C ６ The alkyl may be optionally substituted with cycloalkyl; Each R １０ are independently hydrogen, acyl, C １ -C ３ alkyl, heteroalkyl, or hydroxyalkyl; R １１ is haloalkyl, R Ａ Absent, hydrogen, deuterium, cyano, halogen, C １ -C ３ Alkyl, haloalkyl, heteroalkyl, -C(O)N(R ５ ) ２ or hydroxyalkyl, Each R Ｂ are independently hydrogen, deuterium, cyano, C １ -C ３ Alkyl, hydroxyalkyl, heteroalkyl, C １ -C ３ Alkoxy, halogen, haloalkyl, -ZNR ５ R １１ , -C(O)N(R ５ ) ２ , -NHC(O)C １ -C ３ Alkyl, -CH ２ NHC(O)C １ -C ３ alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl moiety is selected from halogen, hydroxyl, alkoxy, and C １ -C ３ and the heteroaryl or heteroaryl portion of the heteroarylalkyl is substituted with one or more substituents independently selected from R ７ is optionally replaced by 【Chemistry 4】 is a triple bond, R Ａ does not exist, and R Ｂ and p is 1 or or 【Chemistry 5】 is a double bond, R Ａ exists and R Ｂ is present and p is 2 or R Ａ , R Ｂ and the carbon atom to which they are attached may be one or more R ７ forming a 5-8 membered partially saturated cycloalkyl optionally substituted with m is zero or an integer from 1 to 2; and p is 1 or 2.

2. R １ -X is 【Chemistry 6】 and the piperazinyl ring is R ８ The method of claim 1 , optionally substituted with

3. R １ but, 【Chemistry 7】 The method according to claim 2, wherein 【Request 4】 【Chemical 8】 is a triple bond, R Ａ is absent, p is 1, and R Ｂ But, C １ -C ３ Alkyl, hydroxyalkyl, or C １ -C ３ The method of claim 3, wherein the aryl group is an alkoxy group.

5. 【Chemistry 9】 is a double bond, R Ａ is hydrogen, R Ｂ The method of claim 3 , wherein is hydrogen. 【Request 6】 【Chemical 10】 is a double bond, R Ａ is hydrogen, p is 2, and at least one R Ｂ are independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR ５ R １１ , -C(O)N(R ５ ) ２ , -NHC(O)C １ -C ３ alkyl, or heterocyclylalkyl, wherein the heterocyclyl moiety is halogen, hydroxyl, alkoxy, or C １ -C ３ The method of claim 3, wherein the alkyl group is substituted with one or more substituents independently selected from alkyl.

7. The at least one R Ｂ The method of claim 6 , wherein is a halogen.

8. The at least one R Ｂ The method of claim 6 , wherein is haloalkyl.

9. The at least one R Ｂ But -ZNR ５ R １１ The method according to claim 6, wherein

10. Z is methylene, R ５ is methyl and R １１ The method of claim 9, wherein is trifluoromethyl.

11. The at least one R Ｂ The method of claim 6 , wherein is cyano.

12. The at least one R Ｂ The method of claim 6 , wherein is hydroxyalkyl.

13. The at least one R Ｂ The method of claim 6 , wherein is heteroalkyl.

14. 14. The method of claim 13, wherein said heteroalkyl is methoxymethyl.

15. The at least one R Ｂ is -C(O)N(R ５ ) ２ and each R ５ The method of claim 6 , wherein is hydrogen.

16. The at least one R Ｂ is -C(O)N(R ５ ) ２ and each R ５ But, C １ -C ３ The method of claim 6, wherein the alkyl group is an alkyl group.

17. The at least one R Ｂ However, one or more R ７ The method of claim 6 , wherein R is an optionally substituted heteroaryl.

18. The heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from the group consisting of one or more R ７ 18. The method of claim 17 , wherein

19. The at least one R Ｂ However, one or more R ７ The method of claim 6, wherein the heteroaryl is optionally substituted heteroarylalkyl.

20. The heteroaryl portion of the heteroarylalkyl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is selected from the group consisting of one or more R ７ 20. The method of claim 19, optionally substituted with

21. The at least one R Ｂ However, one or more R ７ 7. The method of claim 6, wherein the heterocyclylalkyl is substituted with

22. The heterocyclyl portion of the heterocyclylalkyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each of which is selected from the group consisting of halogen, hydroxyl, alkoxy, and C. １ -C ３ 22. The method of claim 21, substituted with one or more groups independently selected from alkyl.

23. The method of any one of claims 6 to 22, wherein the double bond is in the E configuration.

24. The method of any one of claims 6 to 22, wherein the double bond is in the Z configuration.

25. [Chemical 11] is a double bond, p is 2, and each R Ｂ is hydrogen, R Ａ is deuterium, cyano, halogen, haloalkyl, heteroalkyl, -C(O)N(R ５ ) ２ or hydroxyalkyl.

26. R Ａ The method of claim 25 , wherein is a halogen.

27. R Ａ The method of claim 25 , wherein is haloalkyl.

28. R Ａ The method of claim 25 , wherein is cyano.

29. R Ａ The method of claim 25 , wherein is heteroalkyl.

30. 30. The method of claim 29, wherein said heteroalkyl is methoxymethyl.

31. 30. The method of claim 29, wherein said heteroalkyl is alkoxy.

32. R Ａ is -C(O)N(R ５ ) ２ and each R ５ The method of claim 25 , wherein is hydrogen.

33. R Ａ The method of claim 25 , wherein is hydroxyalkyl.

34. 【Chemical 12】 is a double bond, p is 2, and one R Ｂ is hydrogen, and the second R Ｂ is dialkylaminylalkyl, R Ａ The method of claim 2 , wherein is a halogen.

35. 【Chemical 13】 is a double bond, p is 2, and each R Ｂ is deuterium, R Ａ The method of claim 2 , wherein is deuterium.

36. 【Catalog 14】 is a double bond, p is 2, and one R Ｂ is hydrogen, R Ａ and one R Ｂ and the carbon atom to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

37. The method of any one of claims 2 to 36, wherein Y is O.

38. R ２ is hydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -ZNR ５ R １０ , heterocyclyl, and heterocyclylalkyl, each of said Z, heterocyclyl, or heterocyclylalkyl being independently selected from the group consisting of R ９ The method of any one of claims 2 to 37, optionally substituted with

39. R ２ However, one or more R ９ 40. The method of claim 38, wherein R is a heterocyclylalkyl optionally substituted with R.

40. The heterocyclyl of the heterocyclylalkyl is independently selected from the group consisting of azetidinyl, methylazetidinyl, difluoroazetidinyl, tetrahydropyran, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, isopropylpyrrolidinyl, cycloalkylalkylpyrrolidinyl, hydroxypyrrolidinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morphoalkylpyrrolidinyl, cyclo ... methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morphoalkylpyrrolidinyl, cycloalkylpyrrolidinyl, hydroxypyrrolidinyl, fluoropyrrolidinyl 40. The method of claim 39, wherein the aryl group is 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.

41. 41. The method of claim 40, wherein the (N-methyl)difluoropyrrolidinyl is 3,3-difluoro-1-methylpyrrolidinyl.

42. 41. The method of claim 40, wherein said heterocyclyl is N-methylpyrrolidinyl.

43. R ２ However, one or more R ９ 40. The method of claim 38, wherein the alkyl group is a dialkylaminylalkyl optionally substituted with

44. R ４ However, one or more R ７ The method of any one of claims 2 to 43, wherein R is aryl optionally substituted with R.

45. The aryl is one or more R ７ 45. The method of claim 44, wherein said alkyl group is selected from the group consisting of phenyl and naphthyl optionally substituted with.

46. The phenyl and the naphthyl each have one or more R selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. ７ 46. ​​The method of claim 45, optionally substituted with

47. R ７ 47. The method of claim 46, wherein is selected from the group consisting of halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, hydroxyl, and cyano.

48. R ４ The method of any one of claims 2 to 43, wherein is heteroaryl.

49. R ４ However, one or more R ７ The method of any one of claims 2 to 43, wherein the aryl group is an aralkyl optionally substituted with

50. The method of any one of claims 2 to 49, wherein m is zero.

51. The method of any one of claims 2 to 50, wherein L is a bond.

52. R ８ is heteroalkyl, C ２ -C ４ Alkynyl, or -OR ５ , cyano, or heteroaryl optionally substituted １ -C ３ The method of any one of claims 2 to 51, wherein the alkyl group is an alkyl group.

53. R ８ is optionally substituted with cyano; １ -C ３ 53. The method of claim 52, wherein said alkyl is alkyl.

54. R ８ The method of claim 52, wherein is cyanomethyl.

55. X is one R ８ The method of any one of claims 52 to 54, wherein said group is substituted with

56. The KRas G12C inhibitor is 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 【Chemistry 15-5】 【Chemistry 15-6】 【Chemistry 15-7】 【Chemistry 15-8】 【Chemistry 15-9】 【Chemistry 15-10】 【Chemistry 15-11】 【Chemistry 15-12】 【Chemistry 15-13】 【Chemistry 15-14】 【Chemistry 15-15】 【Chemistry 15-16】 【Chemistry 15-17】 【Chemistry 15-18】 【Chemistry 15-19】 【Chemistry 15-20】 【Chemistry 15-21】 【Chemistry 15-22】 【Chemistry 15-23】 【Chemistry 15-24】 【Chemistry 15-25】 【Chemistry 15-26】 【Chemistry 15-27】 【Chemistry 15-28】 【Chemistry 15-29】 【Chemistry 15-30】 【Chemistry 15-31】 【Chemistry 15-32】 【Chemistry 15-33】 【Chemistry 15-34】 【Chemistry 15-35】 【Chemistry 15-36】 【Chemistry 15-37】 【Chemistry 15-38】 【Chemistry 15-39】 【Chemistry 15-40】 【Chemistry 15-41】 【Chemistry 15-42】 【Chemistry 15-43】 【Chemistry 15-44】 【Chemistry 15-45】 【Chemistry 15-46】 【Chemistry 15-47】 【Chemistry 15-48】 【Chemistry 15-49】 【Chemistry 15-50】 【Chemistry 15-51】 【Chemistry 15-52】 【Chemistry 15-53】 【Chemistry 15-54】 【Chemistry 15-55】 【Chemistry 15-56】 or a pharma- ceutically acceptable salt thereof.

57. The KRas G12C inhibitor is 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof.

58. The KRas G12C inhibitor is 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof.

59. The KRas G12C inhibitor is 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof.

60. The KRas G12C inhibitor is 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof.

61. The KRas G12C inhibitor is 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof.

62. 62. The method of any one of claims 1 to 61, wherein the SHP-2 inhibitor is SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), RMC-4360, or TNO155 (Novartis).

63. 63. The method of claim 62, wherein the SHP-2 inhibitor is SHP-099.

64. 63. The method of claim 62, wherein the SHP-2 inhibitor is RMC-4550.

65. 63. The method of claim 62, wherein the SHP-2 inhibitor is RMC-4360 or TNO155.

66. 66. The method of any one of claims 1-65, wherein the SHP-2 inhibitor and the KRAS G12C inhibitor are administered on the same day.

67. 66. The method of any one of claims 1-65, wherein the SHP-2 inhibitor and the KRAS G12C inhibitor are administered on different days.

68. 68. The method of any one of claims 1 to 67, wherein the KRas G12C inhibitor is administered at a maximum tolerated dose.

69. 68. The method of any one of claims 1-67, wherein the SHP-2 inhibitor and the KRAS G12C inhibitor are each administered at a maximum tolerated dose.

70. 70. The method of any one of claims 1-69, wherein a therapeutically effective amount of the combination of said SHP-2 inhibitor and said KRAS G12C inhibitor results in increased overall survival, increased progression free survival, increased tumor growth regression, increased tumor growth inhibition, or increased duration of stable disease in the subject as compared to treatment with only said KRas G12C inhibitor.

71. 62. A pharmaceutical composition comprising a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRas G12C inhibitor of formula (I), formula IA, or formula IB as defined in any one of claims 1 to 61, and a pharmaceutically acceptable excipient.

72. 62. 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 an SHP-2 inhibitor and a KRas G12C inhibitor compound of formula (I), formula IA, or formula I-B as defined in any one of claims 1 to 61, or a pharmaceutical composition or pharma- ceutical acceptable salt thereof, wherein the SHP-2 inhibitor synergistically increases sensitivity of the cancer cell to the KRas G12C inhibitor.

73. 73. The method of any one of claims 1 to 70 and 72, wherein the SHP-2 inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

74. 62. A method for increasing sensitivity of cancer cells to a KRas G12C inhibitor compound of formula (I), formula IA, or formula I-B, comprising administering a therapeutically effective amount of an SHP-2 inhibitor to a subject undergoing KRas G12C therapy with a compound of formula (I), formula IA, or formula I-B as defined in any one of claims 1 to 61, or a pharma- ceutically acceptable salt thereof, alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent, wherein the SHP-2 inhibitor synergistically increases sensitivity of cancer cells to the KRas G12C inhibitor.

75. 75. The method of any of claims 73 and 74, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.01 to 100 mg / kg / day.

76. 76. The method of claim 75, wherein the therapeutically effective amount of the KRas G12C inhibitor in said combination is about 0.1 to 50 mg / kg / day.

77. 77. The method of any one of claims 74-76, wherein the therapeutically effective amount of the SHP-2 inhibitor in the combination is about 0.01-100 mg / kg / day.

78. 78. The method of claim 77, wherein said therapeutically effective amount of said SHP-2 inhibitor in said combination is about 0.1 to 50 mg / kg / day.

79. The cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotic hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), Meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, 79. The method according to any one of claims 1 to 70 and 73 to 78, wherein the tumor is selected from the group consisting of: Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

80. 80. The method of any one of claims 73 to 79, wherein the cancer is a KRas G12C associated cancer.

81. 81. The method of claim 80, wherein the cancer is non-small cell lung cancer.

82. 72. A kit comprising the pharmaceutical composition of claim 71 for treating KRas G12C cancer in a subject.

83. a) a pharmaceutical composition comprising an SHP-2 inhibitor; and b) a KRas G12C inhibitor, 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof (In the formula, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring or spiro ring, said saturated or partially saturated monocyclic ring being selected from the group consisting of one or more R ８ is optionally replaced by Y is a bond, O, S, or NR ５ and R １ but, 【Chemical 22】 or 【Chemistry 23】 and R ２ is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR ５ R １０ , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, each of said Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl being selected from one or more of R ９ and optionally substituted with Each Z is C １ -C ４ is alkylene, Each R ３ But independently, C １ -C ３ alkyl, oxo, haloalkyl, hydroxyl, or halogen; L is a bond, —C(O)—, or C １ -C ３ is alkylene, R ４ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, each of the cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl being selected from one or more R ６ , R ７ , or R ８ and optionally substituted with Each R ５ are independently hydrogen or C １ -C ３ is alkyl, R ６ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, or heteroaryl being selected from one or more R ７ and optionally substituted with Each R ７ are independently halogen, hydroxyl, C １ -C ６ alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, or Q-haloalkyl, where Q is O or S; R ８ But, Oxo, C １ -C ３ Alkyl, C ２ -C ４ Alkynyl, heteroalkyl, cyano, -C(O)OR ５ , -C(O)N(R ５ ) ２ , -N(R ５ ) ２ and said C １ -C ３ Alkyl is cyano, halogen, -OR ５ , -N(R ５ ) ２ or heteroaryl, Each R ９ are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C １ -C ６ alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, １ -C ６ The alkyl may be optionally substituted with cycloalkyl; Each R １０ are independently hydrogen, acyl, C １ -C ３ alkyl, heteroalkyl, or hydroxyalkyl; R １１ is haloalkyl, R Ａ Absent, hydrogen, deuterium, cyano, halogen, C １ -C ３ Alkyl, haloalkyl, heteroalkyl, -C(O)N(R ５ ) ２ or hydroxyalkyl, Each R Ｂ are independently hydrogen, deuterium, cyano, C １ -C ３ Alkyl, hydroxyalkyl, heteroalkyl, C １ -C ３ Alkoxy, halogen, haloalkyl, -ZNR ５ R １１ , -C(O)N(R ５ ) ２ , -NHC(O)C １ -C ３ Alkyl, -CH ２ NHC(O)C １ -C ３ alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl moiety is selected from halogen, hydroxyl, alkoxy, and C １ -C ３ and the heteroaryl or heteroaryl portion of the heteroarylalkyl is substituted with one or more substituents independently selected from R ７ is optionally replaced by 【Chemistry 24】 is a triple bond, R Ａ does not exist, and R Ｂ and p is 1 or or 【Chemistry 25】 is a double bond, R Ａ exists and R Ｂ is present and p is 2 or R Ａ , R Ｂ and the carbon atom to which they are attached may be one or more R ７ forming a 5-8 membered partially saturated cycloalkyl optionally substituted with m is zero or an integer from 1 to 2; p is 1 or 2. or 【Chemistry 26】 and pharma- ceutically acceptable salts thereof, １ , R ３ , R ４ , R ５ , R １０ , L, and m are as defined in formula I; R １１ is hydrogen, methyl, or hydroxyalkyl, and the piperidinyl ring is R ８ and optionally substituted with R ８ is as defined in formula I or 【Chemical 27】 and pharma- ceutically acceptable salts thereof, １ , R ３ , R ４ , L, and m are as defined in formula I; R ２ However, one or more R ９ heterocyclylalkyl optionally substituted with ９ is as defined in formula I, and said piperazinyl ring is R ８ and optionally substituted with R ８ is as defined in formula I; A kit for treating KRas G12C cancer in a subject.

84. 84. The kit of claim 82 or 83, further comprising an insert comprising instructions for administration of the pharmaceutical composition.

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