Combination therapy of KRAS G12D inhibitor and SHP-2 inhibitor

Abstract

The present invention relates to combination therapies for treating KRas G12D cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRAS G12D inhibitor of formula (I), a pharmaceutical composition comprising a therapeutically effective amount of the inhibitors, a kit comprising the composition, and methods of use thereof.

Description

[Technical field]

[0001] The present invention relates to combination therapies useful for treating cancer. In particular, the present invention relates to therapeutically effective combinations of Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) inhibitors and KRas G12D inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. [Background technology]

[0002] Kirsten rat sarcoma 2 viral 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 inactive (GDP-bound) and active (GTP-bound) states, transforming upstream cellular signals received from multiple tyrosine kinases into downstream effectors that regulate a wide variety of processes, including cell proliferation (e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed more than 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 lead to constitutive activation and downstream signaling of KRas 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 resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence constitute approximately 33% of these KRas driver mutations in lung adenocarcinoma, with the G12D mutation being a common activating mutation (see, e.g., Li, Balmain and Counter, (2018) Nat Rev Cancer Dec; 18(12): 767-777; Sanchez-Vega, et al, (2018) Cell; 173, 321-337).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas to treat cancer, only a single KRas G12C inhibitor (KRas G12C inhibitor sotorasib) has demonstrated sufficient safety and / or efficacy to gain regulatory approval (see, e.g., FDA Approves First KRAS Inhibitor: Sotorasib. [No authors listed] Cancer Discov. 2021 Aug;11(8):OF4. doi:10.1158 / 2159-8290. CD-NB2021-0362. Epub 2021 Jun 22). To date, no KRas G12D inhibitor has demonstrated sufficient safety and / or efficacy to gain regulatory approval.

[0005] Compounds that inhibit KRas activity remain highly desirable, including those that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and those that target KRas G12D (see, e.g., K-Ras(G12D) Has a Potential Allosteric Small Molecule Binding Site, Feng H, Zhang Y, Bos PH, Chambers JM, Dupont MM, Stockwell BR, Biochemistry, 2019 May 28;58(21):2542-2554. doi:10.1021 / acs.biochem.8b01300. Epub 2019 May 14, and Second harmonic generation detection of Ras conformational changes and discovery of a small molecular binder, Donohue E, Khorsand S, Mercado G, Varney KM, Wilder PT, Yu W, MacKerell AD Jr, Alexander P, Van QN, Moree B, Stephen AG, Weber DJ, Salafsky J, McCormick F., Proc Natl Acad Sci USA 2019 Aug 27;116(35):17290-17297, doi:10.1073 / pnas.1905516116. Epub 2019 Aug 9) and are under investigation. Clearly, there remains a continuing interest and effort to develop inhibitors of KRas, particularly inhibitors of activated KRas mutants, including KRas G12D.

[0006] The KRas G12D inhibitors disclosed herein are potent inhibitors of KRas G12D signaling and exhibit single-agent activity in inhibiting the in vitro proliferation of cell lines with KRas G12D mutations, although the relative potency and / or maximum observed effect of any given KRas G12D inhibitor may vary between KRAS mutant cell lines. The range of potency and the reason(s) for the maximum observed effect are not fully understood, although certain cell lines appear to have different inherent resistance. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12D inhibitors in vitro and in vivo.

[0007] The combination therapy of the present invention, in one aspect, synergistically increases the potency of the KRas G12D inhibitor, resulting in improved efficacy of the KRas G12D inhibitors disclosed herein.The combination therapy of the present invention, in another aspect, provides patients with improved clinical benefit compared to treatment with the KRas G12D inhibitors disclosed herein as single agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Der et al.,(1982)Proc.Natl Acad.Sci.USA 79(11):3637-3640 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Li, Balmain and Counter, (2018) Nat Rev Cancer Dec;18(12):767-777 [Non-Patent Document 5] Sanchez-Vega, et al, (2018) Cell;173,321-337

Outdoor Configuration 6

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Outdoor Tools9

[0009] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an SHP-2 inhibitor and a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -COR 5 , -CO2N(R 5 ) 2- or 5- to 6-membered heteroaryl; Y is a bond, O, or NR 5 and R 2 is hydrogen, -N(R 5 )2, heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 5 )2, -L-NHC(=NH)NH2, -LC(O)N(R 5 )2, -L-C1~C6 haloalkyl, -L-OR 5 , -L-(CH2OR 5 )(CH2) n OR 5 , -L-NR 5 C(O)-aryl, -L-COOH, or -LC(=O)OC1-C6 alkyl, -L-NR 5 The heterocyclyl and aryl portions of C(O)-aryl, and the heterocyclyl portion of -L-heterocyclyl, and the cycloalkyl portion of -L-cycloalkyl can each be selected from one or more R 6 The aryl or heteroaryl of -L-aryl and -L-heteroaryl may be optionally substituted with one or more R 7 may be optionally substituted with each L is independently a C1-C4 alkylene optionally substituted with hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; R 3 is aryl or heteroaryl, and the aryl or heteroaryl is selected from one or more R 8 optionally replaced by R 4 is hydrogen, halogen, or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl, Each R 6 are independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, arC1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 5 )2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R 5 )2, -CH2NHC(O)OC1~C6 alkyl, -CH2NHC(O)N(R 5 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, or -OC(O)heterocyclyl, -CH2heterocyclyl, wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH, and the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo, Q is a bond or O; Each R 7 are independently halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2, Each R 8 are independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, deutero C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl.

[0010] In one aspect of the invention, KRas G12D inhibitors include the compound MRTX1133 or MRTX1133 analogs and related compounds such as any of the compounds disclosed and described in WIPO Publication WO2021 / 041671, including Ex. 252 (MRTX1133), 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. , Ex.243, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, Ex.246, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)meth 251, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, Ex.253, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, Ex.259, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol, and Ex.282, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient.

[0011] In another aspect of the invention, a pharmaceutical composition is provided for use in a method comprising a combination of a therapeutically effective amount of an SHP-2 inhibitor and a KRas G12D inhibitor compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0012] In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12D inhibitor of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

[0013] In some aspects of the invention, the KRas G12D inhibitor compound and the SHP-2 inhibitor are the only active agents in the compositions and methods provided.

[0014] 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)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-4630 (Revolution Medicine), and TNO155 (Novartis).

[0015] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12D inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of a combination of a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12D inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0016] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of Formula I, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the KRas G12D-associated cancer to the KRas G12D inhibitor.

[0017] Also provided herein is a kit comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.Also provided is a kit comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating KRas G12D cancer.

[0018] In a related aspect, the invention provides a kit containing an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells in a subject. The kit in some cases includes a package insert having instructions for administering the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0019] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally, the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally, the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapeutic agent, optionally, the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, optionally, the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s). [Brief description of the drawings]

[0020] [Figure 1] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with TNO155 (LS180 colon cancer cell line). [Diagram 2] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with RMC-4550 (GP2D colon cancer cell line). [Diagram 3] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with TNO155 (Panc 02.03 pancreatic cancer cell line). [Figure 4] 1 shows the mean tumor volume in mouse xenografts for MRTX1133 alone and in combination with TNO-155 (AsPC-1 pancreatic cancer cell line). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention relates to combination therapy for treating KRas G12D cancer. Specifically, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12D inhibitor of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, the method, the pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, the kit comprising the composition, and the method of use thereof.

[0022] The combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the potency of the KRas G12D inhibitor compound of formula (I) against cancer cells expressing KRas G12D, thereby increasing the efficacy and therapeutic index of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0023] definition 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 mentioned herein are incorporated by reference.

[0024] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence specified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Asp.

[0025] As used herein, "KRas G12D inhibitor" refers to a compound of the present invention represented by formula (I) as described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12D. In one embodiment, the KRas G12D inhibitor is a compound selected from compound numbers 1-458 (numbered in WO2021 / 041671), or a pharma- ceutically acceptable salt thereof.

[0026] As used herein, "KRas G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

[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 signaling through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0028] As used herein, "SHP-2 inhibitor" or "SHP2 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of SHP-2 phosphatase.

[0029] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, such as mice, rats, 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 is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12D mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12D mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be a subject with tumor(s) that are positive for the KRas G12D mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a KRas G12D mutation (e.g., the tumor has been identified as such using a regulatory approved, e.g., FDA approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12D gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with KRas G12D (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0030] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age, including but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB 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 is used to determine whether a patient has a KRas G12D mutation using a sample (e.g., a biological sample or a biopsy sample, such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12D-associated cancer, a patient with one or more symptoms of a KRas G12D-associated cancer, and / or a patient with an increased risk of developing a KRas G12D-associated cancer), and can include, for example, next-generation sequencing, immunohistochemistry, 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, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

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

[0033] The term "amino" refers to --NH.sub.2.

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

[0035] The term "alkyl" as used herein refers to straight- 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 have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl.

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

[0038] An "alkylene" group is an alkyl group, as defined herein above, that is positioned between and serves to link two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.

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

[0040] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, e.g., 3 to 8 carbons, and further examples, 3 to 6 carbons, which cycloalkyl groups are additionally 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 above, in which one or more carbon atoms in the chain is 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 substituted with a hydroxyl group.

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

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

[0046] The term "alkylaminylalkyl" means -alkyl-NR x -alkyl, 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 C-C alkyl group containing one to three aromatic rings, which are optionally substituted. 14 In one embodiment, the aryl group is a C6-C 10 Examples of aryl groups include, without limitation, 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, independently, may be optionally substituted or unsubstituted. Examples of aralkyl groups are (C1-C6)alkyl(C6-C8)alkyl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. 10 ) aryl. An example of a substituted aralkyl is one in which an alkyl group is substituted with a hydroxyalkyl.

[0050] A "heterocyclyl" or "heterocyclic" group is a ring structure having 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 can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocyclic group has an R on a carbon or nitrogen at one or more positions. 7 Optionally substituted with R 7is as defined for formula I. Heterocyclic groups are also optionally substituted independently on the nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, without limitation, 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 oxazabicycloheptane. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0051] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, attached to the remainder of the molecule via an alkyl linker, wherein 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 pi electrons shared in a cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolyl, and aryl. nyl, 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, tetrahydrofuranyl, Examples of thiadiazolyl include isoquinolinyl, 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, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0053] A "heteroarylalkyl" group comprises a heteroaryl group covalently bonded to an alkyl group, where the radical is on the alkyl group, either of which is 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, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethylisoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[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 G12D. Such an amount may be administered as a single dosage or according to a regimen, and is thereby effective.

[0055] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to alleviate or in any way reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of SHP-2 or KRas G12D. Such an amount may be administered as a single dosage or may be administered according to a regimen, thereby being effective.

[0056] As used herein, a "therapeutically effective amount" of two compounds is an amount that synergistically increases the activity of the combination together, i.e., beyond merely additive, compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in increased overall survival ("OS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in increased progression-free survival ("PFS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12D inhibitor alone. The amount of each compound in the combination may be the same or different from the therapeutically effective amount of each compound when administered alone as a monotherapy, so long as the combination is synergistic. Such amounts may be administered as a single dosage or may be administered according to a regimen whereby it is effective.

[0057] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0058] As used herein, alleviation of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0059] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of a KRAS inhibitor or SHP-2 inhibitor or its pharma- ceutically acceptable salt, or the length of treatment time with a combination therapy described herein), means that the parameter may vary up to 10% below or above the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. When used at the beginning of a list of parameters, "about" is meant to modify the respective 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, and about 25% or more.

[0060] Inhibitor Compounds In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12D inhibitor according to Formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0061] 1.SHP-2 inhibitors 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 signaling through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase (PI3K)-AKT-mTOR pathways. The SHP-2 polypeptide consists of two Src homology 2 (SH2) domains (N-SH2 and C-SH2) located in the N-terminal region and two potential Grb2 SH2 domain binding sites located 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 to direct KRas G12C inhibition due to failure to reactivate the MAPK pathway and inactivate the PI3K / AKT / mTOR pathway was overcome by dual inhibition including a PI3K inhibitor (e.g., Misale et al., Clin. Cancer Res., Online Publication doi:10.1158 / 1078-0432. CCR 18-0368).

[0063] Several inhibitors have been developed that exhibit activity against SHP-2. Exemplary SHP-2 inhibitors include, but are not limited to, 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-4630 (Revolution Medicine), and TNO155 (Novartis). RMC-4630 and TNO155 are in Phase 1 human clinical trials for adult patients with certain advanced solid tumors.

[0064] Methods for producing SHP-2 inhibitors are well known to those of skill in the art, and SHP-2 inhibitors may be obtained from a wide variety of commercial suppliers in forms suitable for both research or human use. In addition, SHP-2 inhibitors suitable for use in the compositions and methods disclosed herein, and methods for preparing such inhibitors, are described in U.S. Patent Application Publication Nos. 2019 / 0127378, 2018 / 0251471, 2018 / 0201623, 2018 / 0186770, 2018 / 0170862, 2018 / 0065949, 2017 / 0204080, 201 These are disclosed in US Pat. Nos. 7 / 0166510, 2017 / 0011975, 2012 / 00334186, 2012 / 0257184, 2011 / 0190315, 2009 / 0042788, 2008 / 0194563, 2008 / 0058431, 2008 / 0058431, 2004 / 0121384, 2004 / 0043434, and 2004 / 0110800.

[0065] 2. KRas G12D inhibitors In one embodiment, the KRas G12D inhibitor used in the method has formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -COR 5 , -CO2N(R 5 ) 2- or 5- to 6-membered heteroaryl; Y is a bond, O, or NR 5 and R 2 is hydrogen, -N(R 5 )2, heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 5 )2, -L-NHC(=NH)NH2, -LC(O)N(R 5 )2, -L-C1~C6 haloalkyl, -L-OR 5 , -L-(CH2OR 5 )(CH2) n OR 5 , -L-NR 5 C(O)-aryl, -L-COOH, or -LC(=O)OC1-C6 alkyl, -L-NR 5 The heterocyclyl and aryl portions of C(O)-aryl, and the heterocyclyl portion of -L-heterocyclyl, and the cycloalkyl portion of -L-cycloalkyl can each be selected from one or more R 6 The aryl or heteroaryl of -L-aryl and -L-heteroaryl may be optionally substituted with one or more R 7 may be optionally substituted with each L is independently a C1-C4 alkylene optionally substituted with hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; R 3 is aryl or heteroaryl, and the aryl or heteroaryl is selected from one or more R 8 optionally replaced by R 4 is hydrogen, halogen, or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl, Each R6 are independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, arC1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 5 )2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R 5 )2, -CH2NHC(O)OC1~C6 alkyl, -CH2NHC(O)N(R 5 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 5 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, or -OC(O)heterocyclyl, -CH2heterocyclyl, wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH, and the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo, Q is a bond or O; Each R 7 are independently halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2, Each R 8are independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, deutero C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl.

[0066] Non-limiting examples of KRas G12D inhibitor compounds of formula (I) useful in the methods disclosed herein are selected from the group consisting of compound numbers 1-458 (as numbered in WO2021 / 041671), which include the following structures, or a pharma- ceutically acceptable salt thereof. In one embodiment, the KRas G12D inhibitor is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0067] In one aspect of the invention, KRas G12D inhibitors include the compound MRTX1133 or MRTX1133 analogs and related compounds such as any of the compounds disclosed and described in WIPO Publication WO2021 / 041671, including Ex. 252 (MRTX1133), 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. , Ex.243, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol, Ex.246, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)meth 251, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalen-2-ol, Ex.253, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, Ex.259, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol, and Ex.282, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol, or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient.

[0068] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 243 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0069] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 246 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0070] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 251 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0071] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 252 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof. This compound is also known as MRTX1133 and may be referred to in this application as "MRTX1133."

[0072] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 253 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0073] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 259 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0074] In one embodiment, the KRas G12D inhibitor is [ka] (also referred to as Example 282 in WO2021 / 041671) or a pharma- ceutically acceptable salt thereof.

[0075] The KRas G12D inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, i.e., isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for the isolation of stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare the individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever this specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0076] In one embodiment, the KRas G12D inhibitor compound of formula I used in the method comprises a trifluoroacetate salt of the compound.

[0077] Methods for producing the KRas G12D inhibitors disclosed herein are known. For example, co-owned published International PCT Application No. 2021 / 041671 describes a general reaction scheme for preparing compounds of formula I, and also provides detailed synthetic routes for the preparation of each of the KRas G12D inhibitors disclosed herein.

[0078] The SHP-2 inhibitor and the KRas G12D compound of formula (I) or a pharma- ceutically acceptable salt thereof may be formulated into a pharmaceutical composition.

[0079] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, and a KRas G12D inhibitor, or a pharma- ceutically acceptable salt thereof, according to the present invention, and a pharma- ceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor, or a pharma- ceutically acceptable salt thereof, can be independently formulated by any method known in the art and prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, and the KRas G12D inhibitor, or a pharma- ceutically acceptable salt thereof, are administered intravenously in a hospital setting. In one embodiment, administration can be by oral route.

[0080] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0081] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, the acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and the 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. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, including in particular quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion that includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citric acid, tartaric acid, ascorbic acid, benzoate, cinnamate, mandelic acid, benzylic acid, and diphenylacetate).

[0082] The active compound is contained in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and further examples, 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages range from 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0083] A pharmaceutical composition comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, may be used in the methods of use described herein.

[0084] Simultaneous administration The SHP-2 inhibitor, or its pharmaceutically acceptable salt, and the KRas G12D inhibitor, or its pharmaceutically acceptable salt, can be formulated into separate or individual dosage forms, which can be co-administered one after the other.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, but both methods of co-administration are part of the same therapeutic treatment or regimen.

[0085] The pharmaceutical compositions comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, and / or a KRas G12D inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the method may be for simultaneous, separate, or sequential use. In one embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered prior to the administration of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered after the administration of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered approximately simultaneously with the administration of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0086] Separate administration of each inhibitor at different times and by different routes may be advantageous in some cases. Thus, the components in the combination, i.e., the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt thereof, do not necessarily have to be administered essentially simultaneously or in any order.

[0087] Oncology drugs are typically administered at the maximum tolerated dose ("MTD"), which is the highest dose of the drug that does not cause unacceptable side effects. In one embodiment, the KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered at their respective MTD. In one embodiment, the KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD. In one embodiment, the KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD. In one embodiment, the KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered below their respective MTDs. Administration can be timed such that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0088] In one embodiment, a single dose of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered per day (i.e., about 24 hours apart) (i.e., QD). In another embodiment, two doses of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., BID). In another embodiment, three doses of the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., TID).

[0089] In one embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered QD. In another embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered BID. In another embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, of the invention, is administered TID.

[0090] In one embodiment, the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0091] 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)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, and TNO155 (Novartis).

[0092] Combination therapy In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12D inhibitor of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12D-associated cancer. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

[0093] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12D inhibitor, comprising contacting the cancer cell with an effective amount of a combination of a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12D inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0094] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0095] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0096] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0098] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0099] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0100] In one embodiment, the combination therapy comprises a compound of the formula: [ka] 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.

[0101] As used herein, the term "contacting" refers to bringing together the moieties indicated in an in vitro system or an in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual or subject, such as a human, having KRas G12D, and introducing, for example, a combination provided herein into a sample containing a cell or purified preparation containing KRas G12D.

[0102] By negatively regulating the activity of KRas G12D, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced KRas G12D activity in cells. The ability of a compound to inhibit KRas G12D can be monitored in vitro using known methods, including those described in published International PCT Application No. 2021 / 041671. Similarly, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12D activity of the amount of phosphorylated ERK to assess the effectiveness of treatment, and dosage can be adjusted accordingly by the attending physician.

[0103] The compositions and methods provided herein may be used to treat a KRas G12D-associated cancer in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the KRas G12D-associated cancer to the KRas G12D inhibitor. In one embodiment, the KRas G12D-associated cancer is pancreatic cancer, colon cancer, endometrial cancer, and non-small cell lung cancer.

[0104] In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased overall survival ("OS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased progression-free survival ("PFS") in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12D inhibitor alone. In one embodiment, the KRas G12D inhibitor is a compound selected from compound numbers 1-458 (numbered in WO2021 / 041671), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 252, 243, 246, 251, 253, 259, or 282, or a pharma- ceutically 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 therapeutic combination comprises therapeutically effective amounts of Example Nos. 252 and SHP-099.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and RMC-4360.In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and TNO155.

[0105] In another embodiment, the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with a KRas G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, once disease progression is observed for KRas G12D monotherapy, and the combination therapy provides an enhanced clinical benefit for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease duration in the patient. In one embodiment, the KRas G12D inhibitor is a compound selected from compound numbers 1-458 (numbered in WO2021 / 041671), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 252, 243, 246, 251, 253, 259, or 282, or a pharma- ceutically 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 therapeutic combination comprises a therapeutically effective amount of Example No. 252 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 251 and SHP-099.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and TNO155.

[0106] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors such as lung, colon, pancreatic, prostate, breast, brain, skin, cervical, testicular, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colon, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds can be used to treat: Heart: 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, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucocorticoid, erythroblastoma ... , gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (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, tetanus) tumour, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampulla of Vater cancer, bile duct cancer; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteosarcoma) steochronfroma) (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, 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);Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), Fallopian tubes (carcinoma); Hematologic: Hematologic Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0107] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of Formula I, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the KRas G12D-associated cancer to the KRas G12D inhibitor. In one embodiment, the KRas G12D inhibitor is a compound selected from compound numbers 1-458 (numbered in WO2021 / 041671), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 252, 243, 246, 251, 253, 259, or 282, or a pharma- ceutically 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 therapeutic combination comprises a therapeutically effective amount of Example No. 252 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 243 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 243 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 243 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 243 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and RMC-4550.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 246 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 282 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 282 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 282 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 282 and TNO155.

[0108] In one embodiment, the compound of formula I is administered as a capsule for a period of time. In one embodiment, a tablet or capsule formulation of the compound of formula I is administered in an amount of about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 2 ... g ~ about 15 mg, about 15 mg - about 100 mg, about 15 mg - about 95 mg, about 15 mg - about 90 mg, about 15 mg - about 85 mg, about 15 mg - about 80 mg, about 15 mg - about 75 mg, about 15 mg - about 70 mg, about 15 mg - about 65 mg, about 15 mg - about 60 mg, about 15 mg ~ about 55 mg, about 15 mg - about 50 mg, about 15 mg - about 45 mg, about 15 mg - about 40 mg, about 15 mg - about 35 mg, about 15 mg - about 30 mg, about 15 mg - about 25 mg, about 15 mg - about 20 mg, about 20 mg - about 100 mg, about 20 mg - about 95 mg, about 2 0mg to about 90mg, about 20mg to about 85mg, about 20mg to about 80mg, about 20mg to about 75mg, about 20mg to about 70mg, about 20mg to about 65mg, about 20mg to about 60mg, about 20mg to about 55mg, about 20mg to about 50mg, about 20mg to about 45mg, about 2 0mg to about 40mg, about 20mg to about 35mg, about 20mg to about 30mg, about 20mg to about 25mg, about 25mg to about 100mg, about 25mg to about 95mg, about 25mg to about 90mg, about 25mg to about 85mg, about 25mg to about 80mg, about 25mg to about 75mg, about 25mg to about 70mg, about 25mg to about 65mg, about 25mg to about 60mg, about 25mg to about 55mg, about 25mg to about 50mg, about 25mg to about 45mg, about 25mg to about 40mg, about 25mg to about 35mg, about 25mg to about 30mg, about 30mg to about 100mg, About 30mg to about 95mg, about 30mg to about 90mg, about 30mg to about 85mg, about 30mg to about 80mg, about 30mg to about 75mg, about 30mg to about 70mg, about 30mg to about 65mg, about 30mg to about 60mg, about 30mg to about 55mg, about 30mg to about 50mg,about 30mg to about 45mg, about 30mg to about 40mg, about 30mg to about 35mg, about 35mg to about 100mg, about 35mg to about 95mg, about 35mg to about 90mg, about 35mg to about 85mg, about 35mg to about 80mg, about 35mg to about 75mg, about 35mg to about 70mg, about 35mg to about 65mg, about 35mg to about 60mg, about 35mg to about 55mg, about 35mg to about 50mg, about 35mg to about 45mg, about 35mg to about 40mg, about 40mg to about 100mg, about 40mg to about 95mg, about 40mg to about 90mg, about 40mg to about 85mg, about 40mg to about 80mg, about 40mg to about 75mg, about 40mg to about 70mg, about 40mg to about 65mg, about 40mg to about 60mg, about 40mg to about 55mg, about 40mg to about 50mg, about 40mg to about 45mg, about 45mg to about 100mg, about 45mg to about 95mg, about 45mg to about 90mg, about 45mg to about 85mg, about 45mg to about 80mg, about 45mg to about 75mg, about 45mg to about 70mg, about 45mg to about 65mg, about 45mg to about 60mg, about 45mg to about 55mg, about 45mg to about 50mg, about 50mg to about 100mg, about 50mg to about 95mg, about 50mg to about 90mg, about 50mg to about 85mg, about 50mg to about 80mg, about 50mg to about 75mg, about 50mg to about 70mg, about 50mg to about 65mg, about 50mg to about 60mg, about 50mg to about 55mg, about 55mg to about 100mg, about 55mg to about 95mg, about 55mg to about 90mg, about 55mg to about 85mg, about 55mg to about 80mg, about 55mg to about 75mg, about 55mg to about 70mg, about 55mg to about 65mg, about 55mg to about 60mg, about 60mg to about 100mg, about 60mg to about 95mg, about 60mg to about 90mg, about 60mg to about about 85mg, about 60mg to about 80mg, about 60mg to about 75mg, about 60mg to about 70mg, about 60mg to about 65mg, about 65mg to about 100mg, about 65mg to about 95mg, about 65mg to about 90mg, about 65mg to about 85mg, about 65mg to about 80mg, about 65mg to about 75mg, about 65mg to about 70mg, about 70mg to about 100mg, about 70mg to about 95mg, about 70mg to about 90mg, about 70mg to about 85mg, about 70mg to about 80mg, about 70mg to about 75mg, about 75mg to about 100mg, about 75mg to about 95mg, about 75mg to about 90mg,Approximately 75mg to approximately 85mg, approximately 75mg to approximately 80mg, approximately 80mg to approximately 100mg, approximately 80mg to approximately 95mg, approximately 80mg to approximately 90mg, approximately 80mg to approximately 85mg, approximately 85mg to approximately 10 0mg, about 85mg to about 95mg, about 85mg to about 90mg, about 90mg to about 100mg, about 90mg to about 95mg, about 95mg to about 100mg, about 10mg, about 15mg, about 20m g, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of formula I (e.g., a compound selected from compound numbers 1-553, e.g., compound numbers 234, 359, 478, or 507). In one embodiment, the compound of formula I is orally administered once a day (QD) every day for a period of time. In one embodiment, the compound of formula I is orally administered twice a day (BID) every day for a period of time. In one embodiment, the compound of formula I is administered at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 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) during the period. , about 20mg to about 80mg, about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 500mg, about 40mg to about 480mg, about 40mg to about 460mg, about 40mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40 mg ~ about 220mg, about 40mg - about 200mg, about 40mg - about 180mg, about 40mg - about 160mg, about 40mg - about 140mg, about 40mg - about 120mg,about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 500mg, about 60mg to about 480mg, about 60mg to about 460mg, about 60mg to about 440mg, about 60mg to about 420mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 6 0mg to about 160mg, about 60mg to about 140mg, about 60mg to about 120mg, about 60mg to about 100mg, about 60mg to about 80mg, about 80mg to about 500mg, about 80mg to about 480mg, about 80mg to about 460mg, about 80mg to about 440mg, about 80mg to about 420mg, about 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80m ​​g to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 100mg to about 500mg, about 100mg to about 480mg, about 100mg to about 460mg, about 100mg to about 440mg, about 100mg to about 420mg, about 100mg to about 400mg, about 100mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100m g 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 mg, about 120 mg to about 340 mg,about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 500mg, about 140mg to about 480mg, about 140mg to about 460mg, about 140mg to about 440mg, about 140mg to about 420mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg 0mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 500mg, about 180mg to about 480mg, about 180mg to about 460mg, about 180mg to about 440mg, about 180mg to about 420mg, about 180mg to about 400mg, about 180mg to about 380mg, about 180mg to about 360mg, about 18 0mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to about 480mg, about 200mg to about 460mg, about 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg,about 200mg to about 300mg, about 200mg to about 280mg, about 200mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 500mg, about 220mg to about 480mg, about 220mg to about 460mg, about 220mg to about 440mg, about 220mg to about 420mg, , about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 3 40mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 480mg, about 260mg to about 460mg, about 260mg to about 440mg, about 260mg to about 420mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, about 260mg to about 280mg, about 280mg to about 500mg, about 280mg About 480mg, about 280mg to about 460mg, about 280mg to about 440mg, about 280mg to about 420mg, about 280mg to about 400mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 30 0mg to about 340mg, about 300mg to about 320mg, about 320mg to about 500mg, about 320mg to about 480mg, about 320mg to about 460mg, about 320mg to about 440mg, about 320mg to about 420mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 320mg to about 340mg, about 340mg to about 500mg, about 340mg to about 480mg, about 340mg to about 460mg, about 340mg to about 440mg, about 340mg to about 420mg, about 340mg to about 400mg, about 340mg to about 380mg,Approximately 340mg to approximately 360mg, approximately 360mg to approximately 500mg, approximately 360mg to approximately 480mg, approximately 360mg to approximately 460mg, approximately 360mg to approximately 440mg, approximately 360mg to approximately 420mg, approximately 360mg to approximately 400mg, approximately 360mg to approximately 380mg, approximately 380mg Approx. 500 mg, approx. 380 mg ~ approx. 480 mg, approx. 380 mg ~ approx. 460 mg, approx. 380 mg ~ approx. 440 mg, approx. 380 mg ~ approx. 420 mg, approx. 400mg to about 440mg, about 400mg to about 420mg, about 420mg to about 500mg, about 420mg to about 480mg, about 420mg to about 460mg, about 420mg to about 440mg, about 440mg to about 500mg, about 440mg to about 480mg, about 440mg to about 460mg, about 460mg to about 500mg, about 460mg to about 480mg, about 480mg to about 500mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500mg).

[0109] In one embodiment, the combination therapy comprises a daily (for a period) administration of a compound of formula I, for example, 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 100mg, about 10mg to about 80mg, about 10mg to about 60mg, about 10mg to about 40mg, about 10mg to about 20mg, about 20mg to about 400mg, about 20mg to about 380mg, about 20mg to about 360mg, about 20mg to about 340mg, about 20mg to about 320mg, about 20mg to about Approximately 300mg, approximately 20mg to approximately 280mg, approximately 20mg to approximately 260mg, approximately 20mg to approximately 240mg, approximately 20mg to approximately 220mg, approximately 20mg to approximately 200mg, approximately 20mg to approximately 180mg, approximately 20mg to approximately 160mg, approximately 20mg to approximately 140mg, approximately 20mg to approximately 120mg, approximately 20mg to about 100mg, about 20mg to about 80mg, about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg , approx. 40 mg ~ approx. 280 mg, approx. 40 mg ~ approx. 260 mg, approx. 40 mg ~ approx. 240 mg, approx. 40 mg ~ approx. 220 mg, approx. 40 mg ~ approx. 200 mg, approx. 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60m g ~ about 260mg, about 60mg - about 240mg, about 60mg - about 220mg, about 60mg - about 200mg, about 60mg - about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg,About 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80mg to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 100mg to about 400mg, about 10 0mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 24 0mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 400mg,Approximately 180mg to approximately 380mg, approximately 180mg to approximately 360mg, approximately 180mg to approximately 340mg, approximately 180mg to approximately 320mg, approximately 180mg to approximately 300mg, approximately 180mg to approximately 280mg, approximately 180mg to approximately 260mg, approximately 180mg to approximately 240mg, approximately 180mg to approximately 22 0mg, about 180mg to about 200mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 200mg to about Approximately 260mg, approximately 200mg to approximately 240mg, approximately 200mg to approximately 220mg, approximately 220mg to approximately 400mg, approximately 220mg to approximately 380mg, approximately 220mg to approximately 360mg, approximately 220mg to approximately 340mg, approximately 220mg to approximately 320mg, approximately 220mg to approximately 300mg, approximately 220 mg ~ approx. 280 mg, approx. 220 mg ~ approx. 260 mg, approx. 220 mg ~ approx. 240 mg, approx. 240 mg ~ approx. 400 mg, approx. 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, about 260mg to about 280 mg, approx. 280 mg ~ approx. 400 mg, approx. 280 mg ~ approx. 380 mg, approx. 280 mg ~ approx. 360 mg, approx. 280 mg ~ approx. 340 mg, approx. 280 mg ~ approx. 320 mg, approx. 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg), and an SHP-2 inhibitor administered, for example, once daily (during a period of time),or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the KRAS G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is orally administered once daily. In one embodiment, the KRAS G12D inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is orally administered twice daily.

[0110] Those skilled in the art will recognize that both in vivo and in vitro testing using suitable, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound or combination to treat or prevent a given disorder.

[0111] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human, dose ranging and efficacy studies in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0112] Synergy In one embodiment, the addition of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, against a cancer or cancer cell line expressing KRas G12D.Any method for determining whether two compounds exhibit synergy can be used to determine the synergistic effect of the combination.

[0113] Several mathematical models have been developed to determine if two compounds act synergistically, ie, have more than merely additive effects. 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), and 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 well known models in the pharmaceutical industry and can be used to calculate a "synergy score" indicating whether synergy has been detected and the magnitude of such synergy. These synergy scores are combined to generate a composite synergy score that can be used to evaluate and characterize KRas G12D inhibitor compounds of formula (I) in combination with SHP-2 inhibitors.

[0114] In general, the mathematical model uses data obtained from single drug values ​​to determine the predicted additive effect of the combination, which is compared to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered to be synergistic. For example, the Bliss independence model compares the observed combination response (YO) with the predicted combination response (YP), which is obtained based on the assumption that there is no effect from drug-drug interactions. The combination effect is typically declared to be synergistic if YO is greater than YP.

[0115] In some embodiments, "synergistic effect" as used herein refers to a combination of a KRAS inhibitor or a pharma- ceutically acceptable salt thereof, and an SHP-2 inhibitor or a pharma- ceutically acceptable salt thereof, that results in an effect, e.g., any beneficial or desirable result, including a clinical outcome or endpoint described herein, that is greater than the sum of the effects observed when the compound of formula I or a pharma- ceutically acceptable salt thereof (e.g., a compound selected from compound numbers 1-458 numbered in WO2021 / 041671) and the SHP-2 inhibitor or a pharma- ceutically acceptable salt thereof, are administered alone. In one embodiment, the KRas G12D inhibitor is a compound selected from compound numbers 1-458 (numbered in WO2021 / 041671), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 252, 243, 246, 251, 253, 259, or 282, or a pharma- ceutically 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 therapeutic combination comprises a therapeutically effective amount of Example No. 252 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 252 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 243 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 246 and TNO155.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 251 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4550. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and RMC-4360. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 253 and TNO155. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and SHP-099. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 259 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 259 and TNO155. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and SHP-099. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4550. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and RMC-4360. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 282 and TNO155.

[0116] In some embodiments, the methods provided herein provide a method for determining whether or not a patient has a tumor that is refractory to treatment (e.g., relative to the size of one or more solid tumors in the patient prior to treatment) that is at least 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 years, 1 week to 1 years, 1 week to 1 years, 1 week to 2 years, 1 week to 2 years, 1 week to 2 years, 1 week to 2 years, ~12 months, 1 week ~ 10 months, 1 week ~ 9 months, 1 week ~ 8 months, 1 week ~ 7 months, 1 week ~ 6 months, 1 week ~ 5 months, 1 week ~ 4 months, 1 week ~ 3 months, 1 week ~ 2 months, 1 week ~ 1 month, 2 weeks ~ 2 years, 2 weeks ~ 22 months, 2 weeks ~ 20 months, 2 weeks ~ 18 months, 2 weeks ~ 16 months, 2 weeks ~ 14 months, 2 weeks ~ 12 months, 2 weeks ~ 10 months, 2 weeks ~ 9 months, 2 weeks ~ 8 months, 2 weeks ~ 7 months, 2 weeks ~ 6 months, 2 weeks ~ 5 months, 2 weeks ~ 4 months, 2 weeks ~ 3 months, 2 weeks ~ 2 months, 2 weeks ~ 1 month, 1 month ~ 2 years, 1 month ~ 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 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 to 8 months) of reduction in volume of one or more solid tumors in a patient after treatment with the combination therapy for a period of 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 85%, 2% to 60%, 2% to 6 ... 0%, 2%~55%, 2%~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~7 0%, 4%~65%, 4%~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~ 75%, 6%~70%, 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8% ~80%, 8%~75%, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~8 5%, 10%~80%, 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15 %~95%, 15%~90%, 15%~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%,15%~25%、15%~20%、20%~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%、The reduction may be 70% to 80%, 70% to 75%, 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%).

[0117] The phrase "survival time" refers to the length of time between identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death (caused by the cancer) of the mammal. Methods of increasing survival time in a mammal with cancer are described herein.

[0118] In some embodiments, any of the methods described herein may be used to measure an increase in patient survival (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%). ,1%~75%,1%~70%,1%~65%,1%~60%,1%~55%,1%~50%,1%~45%,1%~40%,1%~35%,1%~30%,1%~25%,1%~20%,1%~15%,1%~10%,1%~5%,5%~400%,5%~380%,5%~3 60%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~ 70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~24 0%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20% ~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%,30%~300%、30%~280%、30%~260%、30%~240%、30%~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%、~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%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 26 0% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%).

[0119] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally, the previous treatment was unsuccessful, and / or the patient has undergone surgery, optionally, the surgery was unsuccessful, and / or the patient has been treated with a platinum-based chemotherapeutic agent, optionally, the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, optionally, the previous treatment with the kinase inhibitor was unsuccessful, and / or the patient has been treated with one or more other therapeutic agent(s).

[0120] kit The present invention also relates to a kit comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. Also provided is a kit comprising an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating hematological cancers.

[0121] In a related aspect, the present invention provides a kit containing a dose of an SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a dose of a KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly KRas G12D-expressing cancer cells, in a subject. The kit in some cases includes a package insert having instructions for administering the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SHP-2 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12D inhibitor compound of formula (I), or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. EXAMPLES

[0122] Example A SHP-2 inhibitors synergistically increase the activity of KRas G12D inhibitors against KRas G12D-expressing cell lines This example demonstrates that the combination of an exemplary KRas G12D inhibitor compound of Formula I (i.e., MRTX1133) and an SHP-2 inhibitor synergistically inhibits the growth of tumor cell lines expressing KRas G12D.

[0123] A panel of colon, pancreatic, lung, gastric, and endometrial cell lines harboring the KRas G12D mutation was assembled to determine whether combining an SHP-2 inhibitor with the exemplary KRas G12D inhibitors disclosed herein would result in synergistic activity. The populations included SNU61 (colon, KCLB#00061), LS180 (colon, ATCC#CL-187), Panc 05.04 (pancreatic, ATCC#CRL-25 ... 02.03 (pancreas ATCC #CRL-2553), SNU-407 (colon, AddexBio #C0009016), LS513 (colon, ATCC #CRL-213) 4), A427 (lung, ATCC #HTB-53), HPAC (pancreas, ATCC #CRL-2119), AGS (stomach, ATCC #CRL-1739), SNU-119 7 (colon, KCLB#01197.1), SNU-1033 (colon, KCLB#01033), SNU-410 (pancreas, KCLB#00410), HEC-1-B( Endometrium, ATCC#HTB-113), SU.86.86 (pancreas, ATCC#CRL-1837), SNU-C2B (colon, ATCC#CCL-250), Panc These included 08.13 (pancreas, ATCC#CRL-2551), SUIT-2 (pancreas, JCRB #JCRB1094), HPAF-II (pancreas, ATCC#CRL-1997), Panc 04.03 (pancreas, ATCC#CRL-2555), HCC-1588 (lung, KCLB#71588), GP2D (colon, SigmaAldrich#95090714), AsPC-1 (pancreas, ATCC CRL-1682), SW 1990 (pancreas, ATCC CRL-2172), and PANC-1 (pancreas, ATCC#CRL-1469).

[0124] Assays to determine synergy scores for pairwise combinations for each cell line were performed in triplicate. Three 96-well plates for determining baseline luminescence and an additional 4 wells of separate 96-well control plates were seeded with 2000 cells / well of a particular cell line in a total volume of 90 μl of growth medium appropriate for that cell line, e.g., RPMI 1640 medium supplemented with 10% FBS and any cell line-specific reagents required for growth. Plates were incubated overnight at 37° C. in a 5% CO2 atmosphere.

[0125] For each of the designated baseline wells, 30 μl of Cell-Titer Glo reagent (CTG, Promega Corporation) was added to each well and the plate was 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.

[0126] A series of working stock 1000x drug dilutions in 100% DMSO were prepared, including 8-point single agent dilutions of MRTX1133 and 5-point single agent dilutions of SHP-2 inhibitors. The dilutions used for MRTX1133 and SHP-2 inhibitors varied for each individual compound but ranged from 3-6x / serial dilution.

[0127] Ten-fold intermediate dose plates were prepared in serum-free RPMI medium containing arrayed single agent dilutions of MRTX1133 or SHP-2 inhibitors. In addition, a matrix of 40 dilution combinations of MRTX1133 and SHP-2 inhibitors were prepared as test samples.

[0128] To each corresponding well of three 96-well plates seeded with the appropriate cell lines above, 10 μl of each of the 40 combinations of 10x single agents and dose matrix was added and the plates were incubated for 72 hours at 37 C in a 5% CO2 atmosphere. A 30 μl aliquot of Cell-Titer Glo reagent (CTG) was added to each test well, 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.

[0129] Using the raw data and metadata files as input files, percent effect for each treatment condition was calculated and analyzed using four independent mathematical reference models designed to determine if two test compounds exhibit synergy: Loewe additivity, Bliss independence, Highest Single Agent, and ZIP.

[0130] The data output from each mathematical model is the assignment of a relative synergy score. The data reported in Table 1 are the Loewe additivity, Bliss independence, Highest Single Agent, and the sum of the ZIP scores (the "Composite Synergy Score"). [Table 1]

[0131] A custom R script was written integrating open source Bioconductor packages to batch process metadata files containing experimental parameters and raw data files. A variety of numerical and graphical outputs were generated to summarize the data. Single drug parameters were generated using GRmetrics Clark N, Hafner M, Kouril M, Muhlich J, Niepel M, Williams E, Sorger P, Medvedovic M(2016).“GRcalculator:an online tool for calculating and mining drug response data.”doi:10.6084 / m9.figshare.4244408.v1,http: / / www.grcalculator.org / .

[0132] A combined score of 22-80 was interpreted as a synergistic hit, while a combined score of 11-21 indicated an additive effect and a score of <0-10 indicated no benefit. These results demonstrate that certain members of the panel of KRas G12D cell lines exhibited synergistic effects for combinations of SHP-2 inhibitors and MRTX1133, justifying further investigation into combination efficacy testing in in vivo models.

[0133] Example B In vivo model to investigate KRas G12D inhibitor-SHP-2 inhibitor combinations Immunodeficient nude / nude mice are inoculated with cells carrying the KRas G12D mutation in the right hind flank. Tumor volumes of 200–400 mm 3 When the mice reach a size of 1000x, the mice are divided into 4-5 groups of 5 mice each. The first group receives vehicle only. The second group receives a single dose of the KRas G12D inhibitor twice daily at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that does not result in complete tumor regression. The second group receives a single dose of the KRas G12D inhibitor twice daily for 2 consecutive days, optionally followed by a 5-day rest period, at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that does not result in complete tumor regression. The third group receives a single dose of the SHP1 inhibitor at a concentration that results in maximal or submaximal biological effect, depending on the cell line and single agent activity, that does not result in complete tumor regression. The fourth group receives a single dose of a KRas G12D inhibitor in combination with a single dose of an SHP-2 inhibitor, using a schedule of twice daily for two consecutive days followed by five days off. Treatment duration varies from cell line to cell line, but is typically 15-28 days. Tumor volumes are measured using calipers every 2-3 days, and tumor volume is calculated by the following formula: 0.5 x (length x width). 2 The greater degree of tumor growth inhibition for the combination in this model demonstrates that combination therapy is more likely to provide a clinically significant benefit to treated subjects compared with treatment with a KRas G12D inhibitor alone.

[0134] 20-25 nude / nude mice per study were given 5 × 10 6 Each mouse was inoculated with LS180, GP2D, Panc 02.03, or AsPC-1 cells. The tumor volume was approximately 200 mm 3 ~400mm 3Upon reaching (study day 0), five mice in each of the groups were administered ip vehicle alone (10% Captisol in 50 mM citrate buffer pH 5.0), the Kras G12D inhibitor MRTX1133 (10% Captisol in 50 mM citrate buffer, pH 5.0) at 30 mg / kg on either a twice daily schedule or a twice daily schedule of 2 consecutive days followed by 5 days off, the SHP2 inhibitor TNO-155 (in water, 0.5% methylcellulose and 0.1% Tween 80) at 10 mg / kg twice daily, or the SHP2 inhibitor RMC-4550 (10% Captisol in 50 mM citrate buffer pH 5.0) at 30 mg / kg once daily, or either the Kras G12D inhibitor TNO-155 or RMC-4550 on either schedule at 30 mg / kg. Tumor volumes, measured on a given day for five mice per group, were averaged and are reported for LS180, GP2D, Panc 02.03, and AsPC-1 in Tables 2, 3, 4, and 5, respectively.

[0135] Example C KRas G12D inhibitor MRTX-1133 in combination with a SHP-2 inhibitor (LS180 colon cancer cell line) Twenty-five nude / nude mice were inoculated with LS180 cells in the right hind flank. Tumors grew to approximately 250 mm 3 When the immunization rate reached 100%, five treatment groups were established with five mice per group. The results of this study are provided in Table 2. [Table 2]

[0136] As shown in Table 2, administration of MRTX1133 at 30 mg / kg BID (twice per day) as a single agent showed 45% tumor growth inhibition at day 15 (daily administration) and 4% tumor growth inhibition at day 15 (twice per week administration). Administration of the SHP-2 inhibitor TNO155 at 10 mg / kg BID daily as a single agent showed 48% tumor growth inhibition at day 15. The combination of the SHP-2 inhibitor TNO155 and MRTX1133 administered twice per week resulted in 76% growth inhibition at day 15.

[0137] The results are also shown in FIG.

[0138] Example D KRas G12D inhibitor MRTX-1133 in combination with a SHP-2 inhibitor (GP2D TGI-38 colon cancer cell line) Twenty nude / nude mice were inoculated with GP2D cells in the right hind flank. Tumors were approximately 300 mm 3 When the immunization rate reached 100%, four treatment groups were established with 5 mice per group. The results of this study are provided in Table 3. [Table 3]

[0139] As shown in Table 3, administration of MRTX1133 as a single agent at 30 mg / kg BID (twice per day) daily showed 96% tumor growth inhibition at day 35. Administration of the SHP-2 inhibitor RMC-4550 as a single agent at 30 mg / kg QD (once per day) daily showed 56% tumor growth inhibition at day 35. The combination of RMC-4550 and MRTX1133 administered BID daily resulted in -19% tumor regression at day 35.

[0140] The results are also shown in FIG.

[0141] Example E KRas G12D inhibitor MRTX-1133 in combination with an SHP-2 inhibitor (Panc 02.03 TGI-43 pancreatic cancer cell line) Experimental Procedure. 25 nude / nude mice were inoculated with Panc 02.03 cells in the right hind flank. Tumors grew to approximately 300 mm 3 When the immunization rate reached 100%, four treatment groups were established with 5 mice per group. The results of this study are provided in Table 4. [Table 4]

[0142] As shown in Table 4, administration of MRTX1133 at 30 mg / kg BID (twice per day) as a single agent showed -33% tumor regression (daily administration) and 72% tumor growth inhibition (twice per week administration) on day 22. Administration of the SHP-2 inhibitor TNO155 at 10 mg / kg BID daily as a single agent showed 58% tumor growth inhibition on day 22. The combination of TNO155 and MRTX1133 administered twice per week resulted in -33% tumor regression on day 22.

[0143] The results are also shown in FIG.

[0144] Example F KRas G12D inhibitor MRTX-1133 in combination with an SHP-2 inhibitor (AsPC-1 TGI-70 pancreatic cancer cell line) Experimental Procedure Twenty nude / nude mice were inoculated with AsPC-1 cells in the right hind flank. Tumors grew to approximately 200 mm 3 When the immunization rate reached 100%, four treatment groups were established with 5 mice per group. The results of this study are provided in Table 5. [Table 5]

[0145] As shown in Table 5, administration of MRTX1133 at 30 mg / kg BID (twice per day) daily as a single agent showed -28% tumor regression on day 23. Administration of the SHP-2 inhibitor TNO155 at 10 mg / kg BID daily as a single agent showed 0% tumor growth inhibition on day 23. The combination of TNO155 and MRTX1133 administered twice daily resulted in -52% tumor regression on day 23.

[0146] The results are also shown in FIG.

[0147] These results demonstrate that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating enhanced in vivo antitumor efficacy of the combination against KRas G12D-expressing cancers.

[0148] While the invention has been described in relation to particular embodiments thereof, which are capable of further modification, it will be understood that this application is generally intended to cover any variation, use, or alteration of the invention in accordance with the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and that may apply to the essential features set forth above and that fall within the scope of the following appended claims.

Claims

1. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: the method comprises administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRAS G12D inhibitor; the pharmaceutical composition comprises the SHP-2 inhibitor and / or the KRAS G12D inhibitor; The KRAS G12D inhibitor has the formula (I): 【Chemical 1】 [In the formula, R １ is hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -CO ２ R ５ , -CO ２ N (R ５ ) ２ or 5-6 membered heteroaryl; Y is a bond, O, or NR ５ and R ２ is hydrogen, -N(R ５ ) ２ , heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R ５ ) ２ , -L-NHC(=NH)NH ２ , -LC(O)N(R ５ ) ２ , -L-C1-C6 haloalkyl, -L-OR ５ , -L-(CH ２ OR ５ ) (CH ２ ) ｎ OR ５ , -L-NR ５ C(O)-aryl, -L-COOH, or -LC(=O)OC1-C6 alkyl, wherein said heterocyclyl and said -L-NR ５ The aryl portion of the C(O)-aryl, the heterocyclyl portion of the -L-heterocyclyl, and the cycloalkyl portion of the -L-cycloalkyl may be one or more R ６ wherein the aryl or the heteroaryl of the -L-aryl and the -L-heteroaryl may be optionally substituted with one or more R ７ may be optionally substituted with each L is independently C1-C4 alkylene optionally substituted with hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; R ３ is aryl or heteroaryl, and the aryl or heteroaryl is one or more R ８ is optionally replaced by R ４ is hydrogen, halogen, or C1-C3 alkyl; Each R ５ are independently hydrogen or C1-C3 alkyl; Each R ６ are independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO ２ F, -NHC(O)phenyl, -NHC(O)phenylSO ２ F, C1-C3 alkyl substituted pyrazolyl, ar C1-C3 alkyl-, tert-butyldimethylsilyloxy CH ２ -, -N(R ５ ) ２ , (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO ２ F, (C1-C3 alkoxy)C1-C3 alkoxy, —CH ２ OC(O)N(R ５ ) ２ , -CH ２ NHC(O)OC1-C6 alkyl, —CH ２ NHC(O)N(R ５ ) ２ , -CH ２ NHC(O)C1-C6 alkyl, —CH ２ (pyrazolyl), -CH ２ NHSO ２ C1-C6 alkyl, —CH ２ OC(O)heterocyclyl, —OC(O)N(R ５ ) ２ , —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH ３ ) ２ , —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, or —OC(O)heterocyclyl, —CH ２ heterocyclyl, wherein the phenyl of said -NHC(O)phenyl or said -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; and said -CH ２ the heterocyclyl of the heterocyclyl is optionally substituted with oxo; Q is a bond or O; Each R ７ are independently halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R ５ ) ２ and Each R ８ are independently halogen, cyano, hydroxy, C1-C4 alkyl, —S—C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, —O—C1-C3 haloalkyl, —S—C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, —CH ２ C(=O)N(R ５ ) ２ , —C3-C4 alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , deuterated C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl. or a pharmaceutically acceptable salt thereof.

2. The KRAS G12D inhibitor is 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 【Chemistry 2-12】 【Chemistry 2-13】 【Chemistry 2-14】 【Chemistry 2-15】 【Chemistry 2-16】 【Chemistry 2-17】 【Chemistry 2-18】 【Chemistry 2-19】 【Chemistry 2-20】 【Hua 2-21】 【Hua 2-22】 【Chemistry 2-23】 【Hua 2-24】 【Chemistry 2-25】 【Hua 2-26】 【Hua 2-27】 【Hua 2-28】 【Hua 2-29】 【Chemistry 2-30】 【Chemistry 2-31】 【Chemistry 2-32】 【Chemistry 2-33】 【Chemistry 2-34】 【Chemistry 2-35】 【Chemistry 2-36】 【Hua 2-37】 【Chemistry 2-38】 【Hua 2-39】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

3. The KRAS G12D inhibitor has the formula: 【Chemistry 3】 2. The pharmaceutical composition of claim 1, wherein the compound is:

4. The KRAS G12D inhibitor has the formula: 【Chemistry 4】 2. The pharmaceutical composition of claim 1, wherein the compound is:

5. The KRAS G12D inhibitor has the formula: 【Chemistry 5】 2. The pharmaceutical composition of claim 1, wherein the compound is:

6. The KRAS G12D inhibitor has the formula: 【Chemistry 6】 2. The pharmaceutical composition of claim 1, wherein the compound is:

7. The KRAS G12D inhibitor has the formula: 【Chemistry 7】 2. The pharmaceutical composition of claim 1, wherein the compound is:

8. The KRAS G12D inhibitor has the formula: 【Chemistry 8】 2. The pharmaceutical composition of claim 1, wherein the compound is:

9. The KRAS G12D inhibitor has the formula: 【Chemistry 9】 2. The pharmaceutical composition of claim 1, wherein the compound is:

10. 10. The pharmaceutical composition of any one of claims 1 to 9, 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).

11. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the SHP-2 inhibitor and the KRAS G12D inhibitor are administered on the same day.

12. The pharmaceutical composition of any one of claims 1 to 9, wherein the SHP-2 inhibitor and the KRAS G12D inhibitor are administered on different days.

13. The pharmaceutical composition of any one of claims 1 to 9, wherein the KRAS G12D inhibitor is administered at a maximally tolerated dose.

14. The pharmaceutical composition of any one of claims 1 to 9, wherein the SHP-2 inhibitor and the KRAS G12D inhibitor are each administered at a maximum tolerated dose.

15. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the therapeutically effective amount of the combination of the SHP-2 inhibitor and the KRAS G12D inhibitor results in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased stable disease duration in the subject compared to treatment with the KRAS G12D inhibitor alone.

16. The pharmaceutical composition of any one of claims 1 to 9, further comprising a pharmaceutically acceptable excipient.

17. 10. The pharmaceutical composition of any one of claims 1 to 9, for use in a method for inhibiting KRAS G12D activity in cancer cells, the method comprising contacting the cancer cells in which inhibition of KRAS G12D activity is desired with an effective amount of the pharmaceutical composition, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cells to the KRAS G12D inhibitor.

18. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cells to the KRAS G12D inhibitor.

19. 10. The pharmaceutical composition of any one of claims 1 to 9 for use in a method for increasing the sensitivity of cancer cells to a KRAS G12D inhibitor that is a compound of formula (I), said method comprising administering to a subject undergoing KRAS G12D therapy said pharmaceutical composition, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent, a therapeutically effective amount of an SHP-2 inhibitor, wherein said SHP-2 inhibitor synergistically increases the sensitivity of said cancer cells to said KRAS G12D inhibitor.

20. 20. The pharmaceutical composition of claim 19, wherein the therapeutically effective amount of the KRAS G12D inhibitor in the combination is about 0.01 to 100 mg / kg per day.

21. 21. The pharmaceutical composition of claim 20, wherein the therapeutically effective amount of the KRAS G12D inhibitor in the combination is about 0.1 to 50 mg / kg per day.

22. 20. The pharmaceutical composition of claim 19, wherein the therapeutically effective amount of the SHP-2 inhibitor in the combination is about 0.01 to 100 mg / kg per day.

23. 23. The pharmaceutical composition of claim 22, wherein the therapeutically effective amount of the SHP-2 inhibitor in the combination is about 0.1 to 50 mg / kg per day.

24. 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, chondromatous hamartoma, 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'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, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, carcinoma of the ampulla of Vater, bile duct carcinoma; 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 (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, sarcoma) blastoma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas); gynecological system: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), condylar carcinoma 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutic agent is selected from the group consisting of: tumors of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

25. 25. The pharmaceutical composition of claim 24, wherein the cancer is a KRAS G12D-associated cancer.

26. 25. The pharmaceutical composition of claim 24, wherein the cancer is non-small cell lung cancer.

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