Combination Therapies Containing Diaryl Macrocycles - Patent application

Abstract

The present disclosure relates to methods and compositions for treating cancer with diaryl macrocycles in combination with KRAS inhibitors, such as inhibitors of KRAS G12C.

Description

[Technical field]

[0001] The present disclosure relates to methods and compositions for treating cancer with diaryl macrocycles in combination with KRAS inhibitors, such as inhibitors of KRAS G12C. [Background technology]

[0002] Kirsten Rat Sarcoma Viral Oncogene Homolog KRAS is one of three RAS protein family members (N, H, and K-RAS) that are small membrane-bound intracellular GTPase proteins. KRAS cycles between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. Active GTP-bound KRAS interacts with numerous effectors that stimulate multiple signaling pathways (e.g., PI3K-AKT-MTOR, RAF-MEK-ERK) and affect various cellular processes (e.g., survival, proliferation, cytoskeleton organization).

[0003] KRAS is one of the most frequently mutated cancer genes (18%, Catalogue of Somatic Mutations in Cancer (COSMIC) database v90) in a wide range of human cancers, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, uterine cancer, bladder cancer, gastric cancer, kidney cancer, breast cancer, skin cancer, prostate cancer, acute myeloid leukemia, cervical cancer, hepatic acute lymphoblastic leukemia, ovarian cancer, and brain cancer. KRAS mutations occur mainly in KRAS codons 12 and 13, with lower frequencies in codons 18, 61, 117, and 146, and have different effects on tumor cell signaling based on codon and missense mutations (Stolze et al. Sci Rep. 2015;5:8535).

[0004] Direct targeting of the single KRAS mutation G12C with covalent modalities has produced a range of preclinical results, from insensitive to responsive, in mouse tumor models harboring the KRAS G12C mutation (Ostrem et al, Nature. 2013, 503(7477):548-51). Tumor regression has been reported in the treatment of patients with KRAS G12C-mutated non-small cell lung cancer or colorectal cancer with the KRAS G12C inhibitors AMG510 (Canon et al, Nature, 2019, 575, 217-223) and MRTX849 (Hallin et al, Cancer Discovery, 2020, 10(1) 54-71) in clinical trials. However, intrinsic and acquired resistance is expected to limit KRAS inhibitors used as single agents in clinical applications, due to the development of signaling adaptations or selection of minor variants. The KRAS G12C inhibitor MRTX849 showed tumor regression in only 17 / 26 (65%) of KRAS G12C-positive cell lines and patient-derived mouse xenograft models of multiple tumor types, but multiple resistance mechanisms such as KRAS nucleotide cycling and feedback reactivation and / or bypass KRAS dependency limit the efficacy and duration of MRTX849 responses in preclinical models (Hallin et al, Cancer Discovery, 2020, 10(1), 54-71). Covalent inhibitors of KRAS G12C have been reported to be more effective when combined with immune checkpoint inhibitory monoclonal antibodies such as those that block programmed death-1 (PD-1) (Canon et al, Nature, 2019, 575, 217-223). Combinations that target MAPK pathway feedback reactivation, RTK-induced PI3K pathway activation, increased apoptosis, and suppress the inflammatory tumor microenvironment will be necessary to provide significant improvements in clinical benefit.

[0005] Tumor cells reprogram the tumor microenvironment through numerous processes that are hallmarks of cancer, such as immunosuppression, induction of angiogenesis, and altered metabolism (Hanahan and Weinberg, Cell 2011, 144(5), 646-674). Numerous studies show that oncogenic KRAS signaling induces the expression of numerous immune regulators, such as TGFβ, GM-CSF, CXCL8, interleukin-6 (IL-6), and IL-10, that interact with the tumor microenvironment and render it immunosuppressive (Cavalho et al Cancer Res 2018, 78(1), 7-14; Cullis et al., Cold Spring Harb. Perspect. Med 8, a031849; Maldegem and Downward, Immunity 2020, 52, 14 - 16). Mutant KRAS-driven cancers are known to reprogram the stroma into a pro-tumorigenic state (Carvalho et al Cancers 2019, 11(12), 2010), and tumorigenicity is inhibited by blocking autocrine cytokine signaling (Zhu et al., Cancer Discov 2014, 4, 452-65). One example is IL-6 secretion by mutant KRAS tumor cells. IL-6 is known to be upregulated in lung cancer and mediates signaling pathways that promote KRAS-driven lung tumorigenesis (Brooks et al., Cancer Res 2016. 76(4), 1 - 11). Mutant KRAS tumor cells secrete vascular endothelial growth factor (VEGF) and other angiogenic factors such as CXC chemokines that initiate angiogenesis, a paracrine process (Matsuo et al Mol Cancer Res 2009, 7(6), 799-808). Other paracrine processes remodel the stroma as well as alter tumor cell processes in addition to immune evasion and angiogenesis. For example, mutant KRAS cells can secrete insulin-like growth factor-1, which increases the mitochondrial capacity of tumor cells via IGF1R signaling (Tape et al., Cell 2016, 165(4), 910 - 920).Therefore, effective therapies for cancer patients with mutant KRAS will require targeting the tumor cells as well as the tumor microenvironment.

[0006] SRC kinases have been identified as contributing broadly to resistance to cancer treatments such as radiotherapy, chemotherapy, and targeted therapy (Zhang S and Yu D. Trends Pharmacol Sci. 2012;33(3):122-8). SRC family kinases can promote cell proliferation signaling from growth factor receptors in various ways, such as initiating signaling pathways required for DNA synthesis, receptor turnover, controlling actin cytoskeleton reorganization and motility, and survival (Bromann et al, Oncogene 2004;23(48):7957-68). KRAS was reported to induce a Src / PEAK1 / ErbB2 kinase amplification loop that causes metastatic growth and treatment resistance in pancreatic cancer (Kelber et al, Cancer Res. 2012;72(10):2554-64). The SRC inhibitor dasatinib was found to enhance the antitumor activity of MEK inhibitors through inhibition of TAZ activity, and the combination of dasatinib and trametinib represents a promising strategy for the treatment of KRAS-driven cancers (Rao et al, Eur J Cancer. 2018 Aug;99:37-48). FAK has a pivotal role in signaling pathways mediated by integrins, RTKs, RAS, and TGFβ (Kanteti et al, Oncotarget. 2016;7(21):31586-601), and may also suppress p53 expression and promote cell survival (Golubovskaya et al, International Review of Cytology. 2007;263:103-153). Recent findings indicate that integrins are involved in the regulation of cancer stem cell biology and are required for cancer progression, metastasis, and drug resistance via SRC / FAK signaling (Seguin et al, Trends Cell Biol. 2015;25(4):234-40). Src has been identified as a key mediator of thyroid cancer pro-tumorigenic processes and a promising therapeutic target for thyroid cancer.

[0007] Single-agent Src inhibition promotes a more invasive phenotype through the IL-1β>FAK>p130Cas>c-Jun>MMP signaling axis, and combined inhibition of FAK and Src has the potential to block Src inhibitor-induced phenotypic conversion and resistance (Kessler et al, Oncogene. 2019; 38:2565-2579). Compensatory upregulation of the PI3K / AKT signaling pathway is a resistance mechanism in targeting KRAS mutations, promoting cancer cell survival. Through phosphorylation of Y397, FAK directly interacts with the SH2 domain of p85, a regulatory subunit of PI3K that activates the PI3K pathway to suppress doxorubicin-induced apoptosis (van Nimwegen et al, Mol Pharmacol. 2006; 70(4):1330-1339). Phosphorylation of FAK at Y925 by Src creates a docking site for GRB2, which activates the small GTPase RAS and downstream ERK2 (MAPK) (Kanteti et al, Oncotarget. 2016;7(21):31586-601). Paxillin is a major component of focal adhesions that form a structural link between the extracellular matrix and the actin cytoskeleton. In cancer cells, its function is restricted by Src- and FAK-mediated phosphorylation. Dual inhibition of FAK and Src inhibitors is much more effective compared to FAK inhibition alone, as evidenced by increased cell detachment, inhibition of AKT / ERK1 / 2 and Src, and increased apoptosis (Golubovskaya et al, Molecular Cancer Research. 2003; 1(10):755-764). RhoA-FAK is a signaling axis required for the maintenance of KRAS-driven lung adenocarcinoma. Pharmacological inhibition of FAK downregulates p-AKT and does not lead to the development of PI3K / AKT-dependent compensatory mechanisms in vivo (Konstantinidou et al, Cancer Discov. 2013, 3(4):444-57).The KRAS G12C inhibitor AMG-510 is less effective in KRAS G12C mutant colon cancer than in NSCLC (Govindan et al, Annals of Oncology, 2019, 30 (suppl_5): v159-v193. 10.1093 / annonc / mdz244). Mutant KRAS-activated p-STAT3 (Tyr705) in the absence of IL-6 secretion and elevated BCL-XL expression by STAT3 were reported to contribute to mutant KRAS-mediated apoptosis resistance in colon cancer (Zaanan et al, J Biol Chem. 2015; 290(39):23838-49). Thus, inhibition of JAK2, which results in modulation of STAT3 phosphorylation, may be used to enable a synergistic apoptotic response in KRAS mutant colon cancer, as well as other mutant KRAS cancers. In addition, Src and FAK control STAT3, which regulates the expression of angiogenic factors such as VEGF (Niu et al Oncogene 2002, 21(13), 2000 - 8), as well as various cytokines (Cavalho et al Cancers 2019, 11(12), 2010). Collectively, Src, FAK, and JAK2 have important roles in mutant KRAS cancers by enabling angiogenesis in tumors, creating tumor-promoting immune responses in the tumor microenvironment, and promoting both tumor cell intrinsic and extrinsic tumor cell signaling. Furthermore, combined inhibition of Src, FAK, and JAK2 would have further utility in diseases with an inflammatory component, such as asthma, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and fibrosis.

[0008] Overall, direct pharmacological targeting of activated RAS proteins is challenging and has yet to achieve successful treatment in the clinic, but early antitumor activity has been observed with the KRAS G12C inhibitors AMG510 and MRTX849 in patients with KRAS G12C-mutated cancers in Phase 1 clinical trials. The combination of an SRC / FAK / JAK2 inhibitor with an agent that inhibits KRAS G12C represents a novel therapeutic invention that maximizes the antitumor activity and duration of response from agents that inhibit KRAS G12C for the treatment of patients with KRAS G12C mutations. Summary of the Invention

[0009] The combination of an agent that inhibits KRAS G12C and one or more compounds that inhibit FAK, SRC and / or JAK2 has been disclosed to provide robust responses in cancers that harbor KRAS G12C mutations.

[0010] In one embodiment, the present disclosure provides a method for treating cancer comprising administering to a host animal a therapeutically effective amount of one or more compounds that inhibit FAK, SRC, and / or JAK2 in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C. In some embodiments, the host animal is a human patient. In some embodiments, the host animal is an experimental animal, such as a rodent.

[0011] In another aspect, the present disclosure provides a method for treating cancer, comprising administering to a host animal a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C. In some embodiments, the host animal is a human patient. In some embodiments, the host animal is an experimental animal, such as a rodent.

[0012] In another embodiment, the disclosure provides one or more compounds that inhibit FAK, SRC and / or JAK2, or pharma- ceutically acceptable salts thereof, for use in treating cancer in a patient, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C.

[0013] In another embodiment, the disclosure provides a compound that inhibits FAK, SRC and JAK2, or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a patient in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C.

[0014] In another aspect, the disclosure provides the use of one or more of the compounds, or pharma- ceutically acceptable salts thereof, in the preparation of a medicament comprising a therapeutically effective amount of a compound that inhibits FAK, SRC and / or JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, for treating cancer in a patient.

[0015] In another aspect, the disclosure provides the use of the compound, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, for treating cancer in a patient.

[0016] In another aspect, the disclosure provides a composition comprising a therapeutically effective amount of one or more compounds that inhibit FAK, SRC and / or JAK2, or pharma- ceutically acceptable salts thereof, for use in treating cancer in a patient, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C.

[0017] In another aspect, the disclosure provides a composition comprising a therapeutically effective amount of a compound that inhibits FAK, SRC and JAK2, or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a patient, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C.

[0018] In another aspect, the disclosure provides a medicament comprising one or more compounds that inhibit FAK, SRC and / or JAK2, or pharma- ceutically acceptable salts thereof, in fixed or free combination, in combination with an agent that inhibits KRAS G12C, or a pharma- ceutically acceptable salt thereof.

[0019] In another aspect, the disclosure provides a drug comprising a compound that inhibits FAK, SRC and JAK2, or a pharma- ceutically acceptable salt thereof, in fixed or free combination with an agent that inhibits KRAS G12C, or a pharma- ceutically acceptable salt thereof.

[0020] In another embodiment, the disclosure provides a synergistic composition of one or more compounds that inhibit FAK, SRC and / or JAK2 and an agent that inhibits KRAS G12C, wherein the two components contact each other at a site.

[0021] In another embodiment, the disclosure provides a synergistic composition of a compound that inhibits FAK, SRC and JAK2 and an agent that inhibits KRAS G12C, wherein the two components contact each other at a site.

[0022] In another embodiment, the present disclosure provides a synergistic composition of one or more compounds that inhibit FAK, SRC and / or JAK2 and an agent that inhibits KRAS G12C, wherein the two components contact each other only in the human body.

[0023] In another embodiment, the present disclosure provides a synergistic composition of a compound that inhibits FAK, SRC and JAK2 and an agent that inhibits KRAS G12C, wherein the two components contact each other only within the human body.

[0024] In some embodiments, the compound that inhibits FAK, SRC, and JAK2 is a compound of formula 1: [ka]

[0025] [In the formula,

[0026] M is for CR 5 or N;

[0027] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0028] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0029] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0030] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0031] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0032] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0033] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0034] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0035] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0036] or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments of the above aspects, the compound that inhibits FAK, SRC, and JAK2 has the following chemical formula: [ka] (herein referred to as Compound 1)

[0038] or a pharma- ceutically acceptable salt thereof.

[0039] In some embodiments of the above aspects, the at least one agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule that inhibits KRAS G12C. In some embodiments of the above aspects, the at least one agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C. In some embodiments of the above aspects, the biological agent that inhibits KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA. In some embodiments of the above aspects, the at least one agent that inhibits KRAS G12C is a small molecule inhibitor.

[0040] Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and through the practice of the present disclosure. The compounds of the present disclosure can be described as embodiments in any of the following recited clauses. It will be understood that any of the embodiments described herein can be used in conjunction with any other embodiment described herein, unless the embodiments are mutually inconsistent.

[0041] 1. A method for treating cancer comprising administering to a host animal, such as a human patient in need of treatment, a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C.

[0042] 2. The compound that inhibits FAK, SRC and JAK2 is a compound of formula 1: [ka]

[0043] [In the formula,

[0044] M is for CR 5 or N;

[0045] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0046] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0047] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0048] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0049] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0050] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0051] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0052] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0053] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0054] or a pharma- ceutically acceptable salt thereof.

[0055] 3. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0056] or a pharma- ceutically acceptable salt thereof.

[0057] 4. The cancer is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 4. The method of any one of clauses 1 to 3, wherein the cancer is selected from the group consisting of human ovarian serous cystadenocarcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0058] 5. The method of any one of clauses 1 to 4, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0059] 6. The method of any one of clauses 1 to 5, wherein said cancer is non-small cell lung cancer.

[0060] 7. The method of any one of clauses 1 to 5, wherein said cancer is colorectal cancer.

[0061] 8. The method of any one of clauses 1 to 7, wherein said compound that inhibits FAK, SRC, and JAK2 is administered simultaneously with, prior to, or subsequent to at least one of said agents that inhibit KRAS G12C.

[0062] 9. The method of any one of clauses 1 to 8, wherein IL-6 secretion from said cancer is reduced.

[0063] 10. The method of any one of clauses 1 to 9, wherein at least one said agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0064] 11. The method of any one of clauses 1 to 10, wherein at least one said agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C.

[0065] 12. The method of clause 11, wherein the biological agent that inhibits KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0066] 13. The method of any one of clauses 1 to 10, wherein at least one said agent that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0067] 14. The method of any one of clauses 1 to 10 or 13, wherein at least one of said agents that inhibit KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0068] 15. The method of any one of clauses 1 to 10, 13 or 14, wherein at least one said agent that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0069] 16. The method of any one of clauses 1 to 10, 13 or 14, wherein at least one said agent that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0070] 17. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 17. The method of any one of clauses 1 to 16, wherein the agent that inhibits G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0071] 18. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and inhibits at least one of KRAS. 17. The method of any one of clauses 1 to 16, wherein the agent that inhibits G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0072] 19. The method of any one of clauses 1 to 18, wherein said host animal has not been previously treated and is a human patient in need of such treatment.

[0073] 20. The method of any one of clauses 1 to 18, wherein the host animal is a human patient in need of such treatment who has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0074] 21. The method of any one of clauses 1 to 18 or 20, wherein the host animal is a human patient in need of such treatment, having undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy and having developed acquired resistance to said treatment, and / or having developed bypass resistance to said treatment, and / or having developed bypass resistance to said treatment controlled by FAK, SRC or JAK2.

[0075] 22. A compound that inhibits FAK, SRC and JAK2, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in a patient in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C.

[0076] 23. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0077] [In the formula,

[0078] M is for CR 5 or N;

[0079] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0080] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C10 Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0081] Each R 2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0082] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0083] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0084] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0085] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0086] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0087] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0088] or a pharma- ceutically acceptable salt thereof.

[0089] 24. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0090] or a pharma- ceutically acceptable salt thereof.

[0091] 25. The cancer is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 25. The compound according to any one of clauses 22 to 24, wherein the compound is selected from the group consisting of human ovarian carcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0092] 26. The compound according to any one of clauses 22 to 25, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0093] 27. The compound according to any one of clauses 22 to 26, wherein said cancer is non-small cell lung cancer.

[0094] 28. The compound according to any one of clauses 22 to 26, wherein said cancer is colorectal cancer.

[0095] 29. The compound according to any one of clauses 22 to 28, wherein the method comprises administering said compound which inhibits FAK, SRC and JAK2 simultaneously with, prior to or subsequent to, at least one of said agents which inhibit KRAS G12C.

[0096] 30. A compound according to any one of clauses 22 to 29, which reduces IL-6 secretion from said cancer.

[0097] 31. The compound according to any one of clauses 22 to 30, wherein at least one of said agents that inhibit KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0098] 32. The compound according to any one of clauses 22 to 31, wherein at least one of said agents that inhibit KRAS G12C is a biological agent that inhibits KRAS G12C.

[0099] 33. The compound according to clause 32, wherein said biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0100] 34. The compound according to any one of clauses 22 to 31, wherein at least one of said agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0101] 35. The compound according to any one of clauses 22 to 31 or 34, wherein at least one of said agents that inhibit KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0102] 36. The compound according to any one of clauses 22 to 31, 34 or 35, wherein at least one of said agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0103] 37. The compound according to any one of clauses 22 to 31, 34 or 35, wherein at least one of said agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0104] 38. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 38. The compound of any one of clauses 22 to 37, wherein said agent that inhibits G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0105] 39. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and inhibits at least one of KRAS. 38. The compound of any one of clauses 22 to 37, wherein said agent that inhibits G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0106] 40. The compound according to any one of clauses 22 to 39, wherein said patient has not received any prior treatment.

[0107] 41. The compound according to any one of clauses 22 to 39, wherein said patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0108] 42. The compound according to any one of clauses 22 to 39, wherein the patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy and has developed acquired resistance to said treatment, and / or has developed bypass resistance to said treatment, and / or has developed bypass resistance to said treatment controlled by FAK, SRC or JAK2.

[0109] 43. Use of a compound or a pharma- ceutically acceptable salt thereof in the preparation of a medicament comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, for treating cancer in a patient.

[0110] 44. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0111] [In the formula,

[0112] M is for CR 5 or N;

[0113] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0114] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C10 Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0115] Each R 2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0116] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0117] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0118] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0119] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0120] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0121] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0122] or a pharma- ceutically acceptable salt thereof.

[0123] 45. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0124] or a pharma- ceutically acceptable salt thereof.

[0125] 46. ​​The cancer is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 46. ​​The use according to any one of clauses 43 to 45, wherein the cancer is selected from the group consisting of: epithelial carcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0126] 47. The use according to any one of clauses 43 to 46, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0127] 48. The use according to any one of clauses 43 to 46, wherein the cancer is non-small cell lung cancer.

[0128] 49. The use according to any one of clauses 43 to 46, wherein said cancer is colorectal cancer.

[0129] 50. The use according to any one of clauses 43 to 49, wherein the drug comprising the compound that inhibits FAK, SRC and JAK2 is administered to the patient simultaneously with, prior to or after at least one agent that inhibits KRAS G12C.

[0130] 51. The use according to any one of clauses 43 to 50, for reducing IL-6 secretion from said cancer.

[0131] 52. The use according to any one of clauses 43 to 51, wherein at least one said agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0132] 53. The use according to any one of clauses 43 to 52, wherein at least one said agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C.

[0133] 54. The use according to any one of clauses 43 to 53, wherein said biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0134] 55. The use according to any one of clauses 43 to 52, wherein at least one said agent that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0135] 56. The use according to any one of clauses 43 to 52 or 55, wherein at least one of said agents that inhibit KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0136] 57. The use according to any one of clauses 43 to 52, 55 or 56, wherein at least one said agent that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0137] 58. The use according to any one of clauses 43 to 52, 55 or 56, wherein at least one said agent that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0138] 59. The compound inhibiting FAK, SRC, and JAK2 is provided in a medicament in an amount of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 59. The use of any one of clauses 43 to 58, wherein said agent inhibiting G12C is provided in an amount of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0139] 60. The compound that inhibits FAK, SRC, and JAK2 is provided in a drug in an amount of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and at least one KRAS 59. The use of any one of clauses 43 to 58, wherein said agent inhibiting G12C is provided in an amount of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0140] 61. The use according to any one of clauses 43 to 60, wherein the patient has not received any prior treatment.

[0141] 62. The use according to any one of clauses 43 to 60, wherein the patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0142] 63. The use according to any one of clauses 43 to 60 or 62, wherein the patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy and has developed acquired resistance to said treatment, and / or has developed bypass resistance to said treatment, and / or has developed bypass resistance to said treatment controlled by FAK, SRC or JAK2.

[0143] 64. A composition comprising a therapeutically effective amount of a compound or pharma- ceutically acceptable salt thereof that inhibits FAK, SRC and JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, for treating cancer in a patient.

[0144] 65. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0145] [In the formula,

[0146] M is for CR 5 or N;

[0147] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0148] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0149] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0150] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0151] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0152] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0153] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0154] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0155] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0156] or a pharma- ceutically acceptable salt thereof.

[0157] 66. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0158] 66. The composition according to clause 64 or 65, which is:

[0159] 67. The cancer is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 67. The composition of any one of clauses 64 to 66, wherein the cancer is selected from the group consisting of: uterine carcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0160] 68. The composition of any one of clauses 64 to 67, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0161] 69. The composition of any one of clauses 64 to 68, wherein the cancer is non-small cell lung cancer.

[0162] 70. The composition according to any one of clauses 64 to 68, wherein the cancer is colorectal cancer.

[0163] 71. The composition according to any one of clauses 64 to 70, wherein the composition comprising the compound that inhibits FAK, SRC, and JAK2 is administered to the patient simultaneously with, prior to, or subsequent to, at least one agent that inhibits KRAS G12C.

[0164] 72. The composition of any one of clauses 64 to 71, which reduces IL-6 secretion from said cancer.

[0165] 73. The composition according to any one of clauses 64 to 72, wherein at least one of said agents that inhibit KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0166] 74. The composition according to any one of clauses 64 to 73, wherein at least one of said agents that inhibit KRAS G12C is a biological agent that inhibits KRAS G12C.

[0167] 75. The composition according to clause 74, wherein said biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0168] 76. The composition of any one of clauses 64 to 73, wherein at least one of said agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0169] 77. The composition of any one of clauses 64 to 73 or 76, wherein at least one of the agents that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0170] 78. The composition of any one of clauses 64 to 73, 76 or 77, wherein at least one of said agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0171] 79. The composition of any one of clauses 64 to 73, 76 or 77, wherein at least one of said agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0172] 80. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 80. The composition of any one of clauses 64 to 79, wherein said agent that inhibits G12C is administered in a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0173] 81. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and inhibits at least one of KRAS. 80. The composition of any one of clauses 64 to 79, wherein said agent that inhibits G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0174] 82. The composition of any one of clauses 64 to 81, wherein the host animal is a human patient who has not been previously treated and is in need of such treatment.

[0175] 83. The composition of any one of clauses 64 to 81, wherein the host animal is a human patient in need of such treatment, having undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0176] 84. The composition of any one of clauses 64 to 81 or 83, wherein the host animal is a human patient in need of such treatment, having undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy and having developed acquired resistance to said treatment, and / or having developed bypass resistance to said treatment, and / or having developed bypass resistance to said treatment controlled by FAK, SRC or JAK2.

[0177] 85. A drug comprising a compound that inhibits FAK, SRC and JAK2, or a pharma- ceutically acceptable salt thereof, in combination with at least one agent that inhibits KRAS G12C, in a fixed or free combination.

[0178] 86. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0179] [In the formula,

[0180] M is for CR 5 or N;

[0181] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0182] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C10 Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0183] Each R 2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0184] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0185] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0186] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0187] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0188] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0189] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0190] or a pharma- ceutically acceptable salt thereof.

[0191] 87. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0192] or a pharma- ceutically acceptable salt thereof.

[0193] 88.ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 88. The drug of any one of clauses 85 to 87, which provides a synergistic effect against a cancer selected from the group consisting of human ovarian carcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0194] 89. The drug according to any one of clauses 85 to 88, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0195] 90. The drug according to any one of clauses 85 to 89, wherein the cancer is non-small cell lung cancer.

[0196] 91. The drug according to any one of clauses 85 to 89, wherein the cancer is colorectal cancer.

[0197] 92. The drug according to any one of clauses 85 to 89, wherein the cancer is pancreatic cancer.

[0198] 93. A drug according to any one of clauses 85 to 92, which reduces IL-6 secretion from the cancer.

[0199] 94. The agent according to any one of clauses 85 to 93, wherein at least one of said agents inhibiting KRAS G12C is a biological agent inhibiting KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0200] 95. The drug according to any one of clauses 85 to 94, wherein at least one of said agents that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C.

[0201] 96. The drug according to clause 95, wherein the biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0202] 97. The drug according to any one of clauses 85 to 95, wherein at least one of said agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0203] 98. The drug of any one of clauses 85 to 95 or 97, wherein at least one of said agents that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0204] 99. The agent according to any one of clauses 85 to 95, 97 or 99, wherein at least one of said agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0205] 100. The agent according to any one of clauses 85 to 95, 97 or 99, wherein at least one of said agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0206] 101. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 101. The drug of any one of clauses 85 to 100, wherein said agent that inhibits G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0207] 102. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and at least one of KRAS 101. The medicament of any one of clauses 85 to 100, wherein said agent inhibiting G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0208] 103. A synergistic composition of a compound that inhibits FAK, SRC and JAK2 and an agent that inhibits KRAS G12C, wherein the two components contact each other at a site.

[0209] 104. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0210] [In the formula,

[0211] M is for CR 5 or N;

[0212] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0213] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0214] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0215] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0216] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0217] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0218] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0219] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0220] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0221] or a pharma- ceutically acceptable salt thereof.

[0222] 105. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0223] 105. The synergistic composition according to clause 103 or 104, which is:

[0224] 106. The synergistic composition according to any one of clauses 103 to 105, wherein the site is a cancer or a cancer cell.

[0225] 107. The site is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer 107. The synergistic composition of any one of clauses 103 to 106, wherein the cancer is selected from the group consisting of: uterine carcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer.

[0226] 108. The synergistic composition according to clause 107, wherein said cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer.

[0227] 109. The synergistic composition according to clause 107, wherein said cancer is non-small cell lung cancer.

[0228] 110. The synergistic composition according to clause 107, wherein said cancer is colorectal cancer.

[0229] 111. The synergistic composition according to clause 107, wherein said cancer is pancreatic cancer.

[0230] 112. The synergistic composition of any one of clauses 106 to 111, which reduces IL-6 secretion from said cancer.

[0231] 113. The synergistic composition according to any one of clauses 103 to 112, wherein said agent inhibiting KRAS G12C is a biological agent inhibiting KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0232] 114. The synergistic composition according to any one of clauses 103 to 113, wherein said agent inhibiting KRAS G12C is a biological agent inhibiting KRAS G12C.

[0233] 115. The synergistic composition according to clause 114, wherein said biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0234] 116. The synergistic composition according to any one of clauses 103 to 112, wherein at least one of said agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0235] 117. The synergistic composition of any one of clauses 103 to 112 or 116, wherein at least one of the agents that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0236] 118. The synergistic composition according to any one of clauses 103 to 112, 116 or 117, wherein at least one of said agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0237] 119. The synergistic composition of any one of clauses 103 to 112, 116 or 117, wherein at least one of said agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0238] 120. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS 119. The synergistic composition of any one of clauses 103 to 119, wherein said agent inhibiting G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0239] 121. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and at least one of KRAS 119. The synergistic composition of any one of clauses 103 to 119, wherein said agent inhibiting G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0240] 122. The synergistic composition of any one of clauses 106 to 119, wherein said cancer or cancer cells have been pre-contacted with at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0241] 123. The synergistic composition according to any one of clauses 106 to 119, wherein said cancer or cancer cells have previously been in contact with at least one prior treatment with one or more chemotherapeutic agents or immunotherapies, and / or have developed acquired resistance to said treatment, or have developed bypass resistance to said treatment, and / or have developed bypass resistance to said treatment controlled by FAK, SRC or JAK2.

[0242] 124. A synergistic composition of a compound that inhibits FAK, SRC and JAK2 and an agent that inhibits KRAS G12C, wherein said two components come into contact with each other only in the human body.

[0243] 125. The compound that inhibits FAK, SRC and JAK2 is a compound of the following formula 1: [ka]

[0244] [In the formula,

[0245] M is for CR 5 or N;

[0246] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-and;

[0247] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0248] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0249] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0250] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0251] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0252] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0253] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0254] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0255] or a pharma- ceutically acceptable salt thereof.

[0256] 126. The compound that inhibits FAK, SRC and JAK2 has the following chemical formula: [ka] Compound

[0257] 126. The synergistic composition according to clause 124 or 125, which is:

[0258] 127. A synergistic composition according to any one of clauses 124 to 126, wherein said agent inhibiting KRAS G12C is a biological agent inhibiting KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0259] 128. The synergistic composition according to any one of clauses 124 to 127, wherein said agent inhibiting KRAS G12C is a biological agent inhibiting KRAS G12C.

[0260] 129. The synergistic composition according to clause 128, wherein said biological agent inhibiting KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA.

[0261] 130. The synergistic composition according to any one of clauses 124 to 128, wherein at least one of said agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0262] 131. The synergistic composition of any one of clauses 124 to 128 or 130, wherein at least one of the agents that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0263] 132. The synergistic composition according to any one of clauses 124 to 128, 130 or 131, wherein at least one of said agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

[0264] 133. The synergistic composition according to any one of clauses 124 to 128, 130 or 131, wherein at least one of said agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

[0265] 134. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and at least one of KRAS The synergistic composition of any one of clauses 124 to 133, wherein said agent inhibiting G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

[0266] 135. The compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg, and at least one of KRAS 134. The synergistic composition of any one of clauses 124 to 133, wherein said agent inhibiting G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

[0267] 136. The synergistic composition according to any one of clauses 124 to 135, wherein the human body has not undergone any prior treatment.

[0268] 137. The synergistic composition according to any one of clauses 124 to 135, wherein the human body has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy.

[0269] 138. The synergistic composition according to any one of clauses 124 to 135 or 137, wherein said host animal is a human patient in need of such treatment, who has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy, and / or has developed acquired resistance to said treatment, or has developed bypass resistance to said treatment, and / or has developed bypass resistance to said treatment controlled by FAK, SRC or JAK2. [Brief description of the drawings]

[0270] [Figure 1A] FIG. 1A shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H358 cells harboring a KRAS G12C mutation after 24 hours. [Figure 1B] FIG. 1B shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H358 cells harboring a KRAS G12C mutation after 48 hours. [Figure 1C] FIG. 1C shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H2122 cells harboring a KRAS G12C mutation after 24 hours. [Figure 1D] FIG. 1D shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H2122 cells harboring a KRAS G12C mutation after 48 hours. [Figure 1E] FIG. 1E shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H1373 cells harboring a KRAS G12C mutation after 24 hours. [Figure 1F]FIG. 1F shows the levels of caspase-3 / 7 activated by compound 1 (1 μM), AMG-510 (50 nM), and compound 1 (1 μM) + AMG510 (50 nM) in H1373 cells harboring a KRAS G12C mutation after 48 hours. [Figure 2A] FIG. 2A is a chart showing a 2D dose-response matrix following treatment of H2122 cells with various concentrations of compound 1 from 0 nM to 3000 nM, and the KRAS inhibitor AMG-510 from 0 nM to 10000 nM. [Figure 2B] FIG. 2B is a chart showing a 2D dose-response matrix following treatment of H2122 cells with various concentrations of compound 1 from 0 nM to 3000 nM, and the KRAS inhibitor MRTX849 from 0 nM to 10000 nM. [Figure 3A] Figure 3A is a graph showing the reduction in IL-6 secretion in H358 and H2122 NSCLC cell lines treated with Compound 1 in combination with AMG-510 for 48 hours. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. [Figure 3B] FIG. 3B is a chart showing the reduction in secretion of IL-6, MCP-1, TGF-β1, PDGF-BB, and MIP-3-alpha in H358 cells treated with a combination of Compound 1 and AMG-510 for 48 hours. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. [Figure 3C] FIG. 3C is a chart showing the reduction in secretion of IL-6, IGFBP-4, and NAP-2 in H2122 cells treated with a combination of Compound 1 and AMG-510 for 48 hours. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. [Figure 3D]FIG. 3D is a chart showing the reduction in secretion of IL-6, GRO, GRO-alpha, IL-10, osteopontin, and osteoprotegerin in H358 cells treated with a combination of Compound 1 and AMG-510 for 24 hours. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. [Figure 3E] FIG. 3E is a graph showing the reduction in IL-6 secretion in H2122 NSCLC cell lines treated with Compound 1 in combination with MRTX849 for 48 hours. (a) Control; (b) MRTX849; (c) Compound 1; (d) Compound 1+MRTX849. [Figure 3F] FIG. 3F is an ELISA assay showing the reduction of IL-6 secretion in H2122 NSCLC cell lines treated with Compound 1 in combination with MRTX849 for 48 hours. [Figure 3G] FIG. 3G is a graph showing the effect of compound 1 alone, MRTX849 alone, and the combination of compound 1 and MRTX849 on IL-6 mRNA expression from H2122 cells at 24 and 48 hours after treatment. [Figure 4A] Figure 4A is a chart showing the antitumor efficacy of Compound 1 in combination with AMG-510 in xenograft tumors derived from H358 cells harboring a KRAS G12C mutation. (●) Control; (▼) Compound 1 (15 mg / kg BID); (◆) AMG-510 (10 mg / kg QD); (●) Compound 1 (15 mg / kg BID) + AMG-510 (10 mg / kg QD). [Figure 4B] Figure 4B is a chart showing the body weight of mice bearing xenograft tumors derived from H358 cells harboring a KRAS G12C mutation when treated with compound 1 in combination with AMG-510. (●) control; (▼) compound 1 (15 mg / kg BID); (◆) AMG-510 (10 mg / kg QD); (●) compound 1 (15 mg / kg BID) + AMG-510 (10 mg / kg QD). [Figure 5A]Figure 5A is a chart showing the antitumor efficacy of compound 1 in combination with AMG-510 in the LU11693 PDX model harboring the KRAS G12C mutation. The dose of AMG-510 was reduced to 30 mg / kg QD after 14 days of treatment. Two mice in the combination treatment group were terminated on day 13. (●) control; (■) compound 1 (15 mg / kg BID); (▲) AMG-510 (100 mg / kg QD); (▼) compound 1 (15 mg / kg BID) + AMG-510 (100 mg / kg QD). [Figure 5B] Figure 5B is a chart showing the weight of mice bearing LU11693 PDX with KRAS G12C mutation when treated with compound 1 in combination with AMG-510. The dose of AMG-510 was reduced to 30 mg / kg QD after 14 days of treatment. Two mice in the combination treatment group were terminated on day 13. (●) control; (■) compound 1 (15 mg / kg BID); (▲) AMG-510 (100 mg / kg QD); (▼) compound 1 (15 mg / kg BID) + AMG-510 (100 mg / kg QD) [Figure 6A] FIG. 6A is a chart showing the effect of Compound 1 in combination with AMG-510 on survival in a xenograft tumor model derived from H2122 cells harboring a KRAS G12C mutation. The dose level of AMG-510 was 10 mg / kg QD. Control; Compound 1 (15 mg / kg BID); AMG-510 (10 mg / kg QD); Compound 1 (15 mg / kg BID) + AMG-510 (10 mg / kg QD) [Figure 6B] FIG. 6B is a chart showing the effect of Compound 1 in combination with AMG-510 on survival in a xenograft tumor model derived from H2122 cells harboring a KRAS G12C mutation. The dose level of AMG-510 was 30 mg / kg QD. Control; Compound 1 (15 mg / kg BID); AMG-510 (30 mg / kg QD); Compound 1 (15 mg / kg BID) + AMG-510 (30 mg / kg QD) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0271] Before the present invention is further described, it should be understood that the present invention is not limited to the particular embodiments described, as such embodiments may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0272] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. All patents, applications, published applications and other applications referenced herein are incorporated by reference in their entirety. If the definitions set forth in this section are contrary to or inconsistent with the definitions set forth in the patents, applications, other applications incorporated herein by reference, the definitions set forth in this section shall take precedence over the definitions incorporated herein by reference.

[0273] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as a predicate for use of exclusive terminology such as "solely," "only," and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0274] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0275] In order to provide a more concise description, some of the quantitative expressions given herein are not modified with the term "about". Whether or not the term "about" is explicitly used, all quantitative values ​​given herein are intended to refer to the actual given value, and are also intended to refer to the approximation to such given value that would be reasonably estimated based on ordinary skill in the art, and it is understood that such approximation includes the equivalent value and approximation to such given value that results from experimental and / or measurement conditions. Whenever a yield is given as a percentage, such a yield refers to the mass of the entity, which is given with respect to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Concentrations given as percentages refer to mass ratios, unless otherwise indicated.

[0276] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Although any method and material similar or equivalent to the method and material described herein can be used to carry out or test this invention, the preferred method and material will now be described.All publications mentioned in this specification are incorporated herein by reference to disclose and describe the method and / or material related to the cited publication.

[0277] Unless otherwise stated, the methods and techniques of the present embodiment are generally carried out according to conventional methods well known in the art, and as described in various general and more specific documents cited and discussed throughout this specification.See, for example, Loudon, Organic Chemistry, 4th Edition, New York: Oxford University Press, 2002, pp.360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, Wiley-Interscience, 2001.

[0278] Chemical nomenclature for the compounds described herein has generally been derived using commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0279] It is recognized that certain features of the invention that are described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of the embodiments with respect to chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein as if each and every combination were individually and explicitly disclosed, so long as such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of chemical groups described in the embodiments that describe such variables are also specifically embraced by the present invention and are disclosed herein as if each and every such subcombination of chemical groups were individually and explicitly disclosed.

[0280] The methods described herein are used to treat a "host animal" with cancer that requires treatment. In one embodiment, the methods described herein can be used for both human clinical and veterinary applications. Thus, a "host animal" can be administered with the combinations described herein, and the "host animal" can be a human (e.g., a human patient, also known as a patient), or in the case of veterinary applications, a laboratory animal, an agricultural animal, or a livestock animal. In one embodiment, the host animal can be a human, or a laboratory animal, such as a rodent (e.g., a mouse, a rat, etc.), and the like.

[0281] As used herein, the term "disease" includes, but is not limited to, cancer, pain, inflammatory diseases such as allergies, asthma, autoimmune diseases, celiac disease, glomerulonephritis, hepatitis, inflammatory bowel disease (e.g., ulcerative colitis), pre-perfusion injury, transplant rejection, psoriasis, and rheumatoid arthritis; polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

[0282] As used herein, the term "cancer" includes, but is not limited to, non-small cell lung cancer (NSCLC), such as ALCL, adenocarcinoma, squamous cell lung carcinoma, large cell carcinoma, and large cell neuroendocrine tumors, lung cancer, such as small cell lung cancer (SCLC), breast cancer, such as neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, luminal A, luminal B, triple negative breast cancer, triple positive breast cancer, HER2+, and the like, thyroid cancer, such as colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, gastric cancer, such as cholangiocarcinoma, ovarian cancer, gastric cancer, such as gastric adenocarcinoma, colorectal cancer (CRC), inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid tumor, and the like. neoplasms), sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cancer such as cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC), childhood glioma CML, prostate cancer, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, uterine cancer such as serous and clear cell endometrial cancer, endometrial cancer, and the like, oral cancer, endocrine cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and stomach cancer. It will be recognized that the term "cancer" includes both primary cancer or tumor and metastatic cancer or tumor, and includes all stages of cancer as known in the art. For example, metastatic NSCLC, metastatic CRC, metastatic pancreatic cancer, metastatic colorectal cancer, metastatic HNSCC, metastatic uterine cancer, and the like. It will be recognized that the term "cancer" includes cancer that causes increased expression or genetic mutation in certain genes, such as small GTPases (e.g., KRAS and the like) and receptor tyrosine kinases such as EGFR and the like, which may lead to disease progression.

[0283] As used herein, the term "agent that inhibits KRAS G12C" includes, but is not limited to, any compound or agent known in the art that selectively inhibits the KRAS G12C gene or the protein encoded by the KRAS G12C gene, herein referred to as K-Ras G12C, that is involved in the RAS / MAPK signaling pathway, the K-Ras protein product of the KRAS gene has a missense mutation G12C. The terms KRAS gene, K-Ras, and RAS / MAPK signaling pathway are known and understood by those skilled in the art. It will be recognized that the KRAS G12C mutation encodes a mutation of the 12th glycine of the K-Ras protein to a cysteine ​​(also known as K-Ras G12C). It will be further recognized that the production of K-Ras G12C protein as the gene product of KRAS G12C gene can be the result of coding sequence mutation, for example, the substitution of thymine for guanine at position 34 of coding sequence.It will be further recognized that the agent that inhibits KRAS G12C can be any agent known in the art that selectively targets KRAS G12C gene, including agents that can selectively inhibit or otherwise selectively interfere with the transcription (and / or translation) of KRAS G12C gene (or its corresponding messenger RNA) into K-Ras G12C protein, such as siRNA, oligonucleotide, ribonucleic acid, and the like.It will be further recognized that the agent that inhibits KRAS G12C can be an agent that can selectively inhibit or otherwise selectively interfere with the transcription (and / or translation) of KRAS G12C and / or the translation of its corresponding messenger RNA, and can be a biological agent, such as siRNA, oligonucleotide, ribonucleic acid, and the like.Alternatively, it will be appreciated that the agent that inhibits KRAS G12C may be an agent that selectively inhibits a protein encoded by a KRAS G12C gene having a coding sequence that produces K-Ras G12C protein (e.g., a substitution of thymine for the 34th guanine in the KRAS coding sequence), and may be a biological agent such as an antibody (e.g., a monoclonal antibody or mAb), a small molecule drug / inhibitor (e.g., a small molecule inhibitor of KRAS G12C), or a targeted agent. Examples of an agent that inhibits KRAS G12C may include, but are not limited to, AMG-510, MRTX849, JNJ-74699157 (also known as ARS-3248), ARS-1620, MRTX1257, RM-007, or ADT-007. In some embodiments, the agent that inhibits KRAS G12C is a compound described in U.S. Patent Publication US20180334454, the disclosure of which is incorporated by reference herein for its representative agents that inhibit KRAS G12C (also known as representative small molecule inhibitors of KRAS G12C) and their preparation. In some embodiments, the agent that inhibits KRAS G12C has the following chemical formula: [ka] Represented by AMG510

[0284] or a pharma- ceutically acceptable salt thereof.

[0285] In some embodiments, the agent that inhibits KRAS G12C is a compound described in U.S. Patent Publications US20190270743 and US20190144444, which are incorporated by reference herein for their representative agents that inhibit KRAS G12C (also known as representative small molecule inhibitors of KRAS G12C) and their preparation. In some embodiments, the agent that inhibits KRAS G12C has the following chemical formula: [ka] Represented by MRTX849

[0286] or a pharma- ceutically acceptable salt thereof.

[0287] In some embodiments, the agent that inhibits KRAS G12C is AMG-510, MRTX849, or ARS-1620, or a pharma- ceutically acceptable salt thereof.

[0288] chemical definition As used herein, the term "alkyl" includes a chain of carbon atoms, which may be optionally branched, containing 1 to 20 carbon atoms. In one embodiment, alkyl is C1-C 12 , C1-C 10It should be further understood that alkyl groups may be advantageously limited in length, such as C1-C9, C1-C8, C1-C7, C1-C6, and C1-C4. Specifically, such specifically limited length alkyl groups, such as C1-C8, C1-C7, C1-C6, and C1-C4, and the like, may be referred to as "lower alkyl groups." Specific alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Exemplary substituents include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (=O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in various embodiments provided herein. It will be understood that "alkyl" may be combined with other groups, such as those provided above, to form functional alkyls. For example, as described herein, the combination of an "alkyl" group with a "carboxy" group may be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.

[0289] As used herein, the term "alkenyl" includes a chain of carbon atoms, which may be optionally branched, containing from 2 to 20 carbon atoms and also containing at least one carbon-carbon double bond (i.e., C=C). In certain embodiments, alkenyl includes C2-C 12It will be understood that the alkenyl groups may advantageously be limited in length, such as C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Specifically, such specifically limited length alkenyl groups, such as C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkenyl groups. Alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0290] As used herein, the term "alkynyl" includes a chain of carbon atoms, which may be optionally branched, containing from 2 to 20 carbon atoms and also containing at least one carbon-carbon triple bond (i.e., C≡C). In one embodiment, alkynyl is a C2-C 12 It will be understood that alkynyl groups may advantageously be limited in length, such as C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Specifically, such specifically limited length alkynyl groups, such as C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkynyl groups. Alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific alkenyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

[0291] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic group of 6 to 12 carbon atoms having a completely conjugated pi-electron system. In one embodiment, aryl is a C6-C 10It will be understood that the aryl group may advantageously be limited in size, such as aryl. Specific aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. The aryl group may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein.

[0292] As used herein, the term "cycloalkyl" refers to a 3- to 15-membered all-carbon monocyclic ring, or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system), such as an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring, where one or more of the rings may contain one or more double bonds, but the cycloalkyl does not contain a completely conjugated pi-electron system. In certain embodiments, a cycloalkyl is a C3-C 13 It will be understood that cycloalkyl may be advantageously limited in size, such as C3-C9, C3-C6 and C4-C6. Cycloalkyl may be unsubstituted or substituted as described for alkyl or as described in various embodiments provided herein. Specific cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like. Illustrated examples of specific cycloalkyl groups include, in the form of appropriately bonded moieties, the following entities: [ka] Examples include:

[0293] The term "heterocycloalkyl" as used herein refers to a monocyclic or fused ring group having 3 to 12 ring atoms in the ring, where at least one ring atom is a heteroatom such as nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon atoms. Heterocycloalkyls may contain 1, 2, 3 or 4 heteroatoms as appropriate. Heterocycloalkyls may have one or more double bonds, such as a double bond to nitrogen (e.g., C=N or N=N), but do not contain a fully conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyls may be advantageously limited in size, such as 3- to 7-membered heterocycloalkyls, 5- to 7-membered heterocycloalkyls, and the like. Heterocycloalkyls may be unsubstituted or substituted as described for alkyls or as described in the various embodiments provided herein. Specific heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and the like. Illustrative examples of cycloalkyl groups include, in the form of appropriately bonded moieties, the following entities: [ka] Examples include:

[0294] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms, also having a fully conjugated pi-electron system. It will be understood that in some embodiments, the heteroaryl may be advantageously limited in size, such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. The heteroaryl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Specific heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and carbazoloyl, and the like. Illustrated examples of specific heteroaryl groups include, in the form of appropriately attached moieties, the following entities: [ka] Examples include:

[0295] As used herein, "hydroxy" or "hydroxyl" refers to an --OH group.

[0296] As used herein, the term "alkoxy" refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0297] As used herein, "aryloxy" refers to an -O-aryl or -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like.

[0298] As used herein, "mercapto" refers to the group --SH.

[0299] As used herein, "alkylthio" refers to an -S-(alkyl) or -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0300] As used herein, "arylthio" refers to an -S-aryl or -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.

[0301] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0302] As used herein, "cyano" refers to the group --CN.

[0303] The term "oxo" refers to a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0304] As used herein, "bond" refers to a covalent bond.

[0305] The term "substituted" means that the particular group or moiety has one or more substituents. The term "unsubstituted" means that the particular group has no substituents. When the term "substituted" is used to describe a structural system, it is intended that the substitution occur at any valence-allowed position on the system. In some embodiments, "substituted" means that the particular group or moiety has one, two, or three substituents. In other embodiments, "substituted" means that the particular group or moiety has one or two substituents. In yet other embodiments, "substituted" means that the particular group or moiety has one substituent.

[0306] As used herein, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not occur. For example, "wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C6 alkyl ... 10 "Each hydrogen atom in the aryl, or monocyclic or bicyclic heteroaryl may be independently and optionally replaced by C1-C6 alkyl" means that the alkyl is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl, and the descriptions include C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 In the case where the aryl or monocyclic or bicyclic heteroaryl is substituted with an alkyl group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Includes situations where the aryl, or monocyclic or bicyclic heteroaryl is not substituted with an alkyl group.

[0307] As used herein, "independently" means that the event or situation described thereafter should be read on its own, relative to other similar events or situations. For example, in a situation where several equivalent hydrogen groups may be optionally replaced by another group described in the situation, the use of "independently and optionally" means that each instance of a hydrogen atom on that group may be replaced by another group, and the groups replacing each of the hydrogen atoms may be the same or different. Or, for example, when there are multiple groups, all of which may be selected from a set of possibilities, the use of "independently" means that each of those groups may be selected from a set of possibilities separately from any other group, and the groups selected in the situation may be the same or different.

[0308] As used herein, the term "pharmaceutically acceptable salt" refers to such salts as opposed to ions that may be used in pharmaceutical preparations. See generally, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those salts that are pharmacologically effective and suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic reaction. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, functional groups of both types, or more than one of each type, and thus may react with a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. Such salts include:

[0309] (1) Acid addition salts obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid and the like; or

[0310] (2) Salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.

[0311] Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharma- ceutically acceptable salt may be contemplated in connection with the embodiments described herein. Examples of pharma-ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne- Examples of suitable pharma- ceutically acceptable salts include 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma-ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0312] Any formula given herein is intended to represent a compound of that structural formula, as well as specific modifications or forms. For example, any formula given herein is intended to include a racemate, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any formula given herein is intended to refer to a hydrate, solvate, or polymorph of such a compound, or mixtures thereof. For example, the symbol [ka] A compound represented by a structural formula containing the symbol [ka] and specifically, [ka] and [ka] Both bonds of [ka] For example, in some representative embodiments, certain compounds provided herein have the following chemical formula: [ka]

[0033]

[0313] The above formula is [ka] It will be understood that this encompasses compounds with all stereochemical configurations at the relevant carbon atoms, including:

[0314] Embodiment In some embodiments, the methods described herein relate to the treatment of cancer comprising administering to a patient in need of treatment a therapeutically effective amount of one or more compounds that inhibit FAK, SRC and / or JAK2 in combination with an agent that inhibits KRAS G12C. In some embodiments, the methods described herein relate to the treatment of cancer comprising administering to a patient in need of treatment a therapeutically effective amount of a compound that inhibits FAK, SRC and / or JAK2 in combination with an agent that inhibits KRAS G12C. It will be appreciated that an inhibitor is any substance that reduces or suppresses the activity of another substance, such as a cell surface receptor (i.e., a receptor tyrosine kinase) or a kinase (i.e., a non-receptor tyrosine kinase), or the transcription and / or translation of a gene. It will be appreciated that a "compound that inhibits FAK, SRC and JAK2" is a compound that has affinity for all three biological targets, FAK, SRC and JAK2.

[0315] It has been surprisingly found that certain compounds described herein are inhibitors of FAK, SRC and JAK2 and can be used in combination with an agent that inhibits KRAS G12C to treat cancer in patients in need of treatment. In some embodiments, the combination of one or more compounds that inhibit FAK, SRC and / or JAK2 with an agent that inhibits KRAS G12C can provide a synergistic response in patients in need of cancer treatment. In some embodiments, the combination of a compound that inhibits FAK, SRC and / or JAK2 with an agent that inhibits KRAS G12C can provide a synergistic response in patients in need of cancer treatment. In some embodiments, a method of treating cancer is characterized by administering a combination of a therapeutically effective amount of a compound that inhibits FAK, SRC and JAK2 and a therapeutically effective amount of an agent that inhibits KRAS G12C. In some embodiments, the compound that inhibits FAK, SRC and JAK2 and the agent that inhibits KRAS G12C are formulated together. In some embodiments, the compound inhibiting FAK, SRC and JAK2 and the agent inhibiting KRAS G12C are administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC and JAK2 and the agent inhibiting KRAS G12C are formulated separately and administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC and JAK2 and the agent inhibiting KRAS G12C are formulated separately and administered sequentially. In some embodiments, the sequential administration of the compound inhibiting FAK, SRC and JAK2 and the agent inhibiting KRAS G12C can be achieved by administering the compound inhibiting FAK, SRC and JAK2 first and the agent inhibiting KRAS G12C second. In some embodiments, the sequential administration of the compound inhibiting FAK, SRC and JAK2 and the agent inhibiting KRAS G12C can be achieved by administering the agent inhibiting KRAS G12C first and the compound inhibiting FAK, SRC and JAK2 second.

[0316] In some embodiments, the compound that inhibits FAK, SRC, and JAK2 is a compound of formula 1: [ka]

[0317] [In the formula,

[0318] M is for CR 5 or N;

[0319] X 1 and X 2 are independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )- and;

[0320] Each R 1 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C( O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0321] Each R2 and R 3 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, -C(O)OR 7 or -C(O)NR 7 R 8 where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom in an aryl can be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O )N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1- C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0322] R 4and R 5 are each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, or -CF3;

[0323] R 6 is H, C1-C6 alkyl, or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently and optionally substituted with halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0324] Each R 7 and R 8 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl may be replaced by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N (C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS (O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -C(O)OC1-C6 alkyl, -C(O)NH2, -C( and optionally substituted, independently, by O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0325] Each R 9 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, or monocyclic or bicyclic heteroaryl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl or 5- to 7-membered heteroaryl is replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -OR 7 may be independently and optionally substituted by;

[0326] each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 are independently N, NH, or C(R 10 ), where each R 10 are independently H, deuterium, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3,

[0327] However, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of is N or NH.

[0328] or a pharma- ceutically acceptable salt thereof.

[0329] In some embodiments, R 1 is H or C1-C6 alkyl. In some embodiments, R 1is H or methyl. In some embodiments, R 1 One of them is H and the other is R. 1 Another of R is methyl. 2 is H. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 One of them is H and the other is R. 2 Another of X is methyl. 1 -NR 9 In some embodiments, R 9 is H. In some embodiments, X 1 is CHR 7 In some embodiments, R 7 is H. In some embodiments, X 2 In some embodiments, R 6 is H. In some embodiments, R 4 is F. In some embodiments, M is CR 5 and R 5 is H.

[0330] Macrocyclic compounds that are shown herein to be potent small molecule multi-targeted kinase inhibitors that exhibit activity against FAK, SRC and JAK2 include those having the following chemical formula: [ka]

[0033] Examples of compounds that can be used include, but are not limited to, (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one (also referred to herein as "Compound 1"),

[0331] Compound 1 has properties, such as antitumor properties, that are pharmacologically mediated by the inhibition of receptor and non-receptor tyrosine kinases. Compound 1 is disclosed in International Publication WO2015 / 112806, the preparation of which is incorporated herein by reference.

[0332] In some embodiments of the above aspects, the compound that inhibits FAK, SRC, and JAK2 has the following chemical formula: [ka] Compound

[0333] or a pharma- ceutically acceptable salt thereof.

[0334] The cancer may be any cancer that may be mediated by or associated with KRAS G12C or elevated expression of KRAS G12C, including, for example, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal carcinoma, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, It will be appreciated that the cancers that may be present include, but are not limited to, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer and lung cancer.

[0335] In some embodiments, the disclosure provides a method of treating a disease in a patient who has not been previously treated. In some embodiments, the disclosure provides a method of treating a disease in a patient who has been previously treated with one or more therapeutic agents. In some embodiments, the patient has been previously treated with one or more chemotherapeutic agents. In still other embodiments, the patient has been previously treated with one or more chemotherapeutic agents or immunotherapies and has developed acquired resistance to the treatment. In still other embodiments, the patient has been previously treated with one or more chemotherapeutic agents or immunotherapies and has developed bypass resistance to the treatment. In still other embodiments, the patient has been previously treated with one or more chemotherapeutic agents or immunotherapies and has developed bypass resistance to the treatment that is controlled by FAK, SRC or JAK2, and / or FAK.

[0336] Other chemotherapeutic agents that a patient may have been treated with prior to treatment with one or more of the compounds or biologics described herein include, but are not limited to, kinase inhibitors, adrenocorticoids and corticosteroids, alkylating agents, peptide and peptidomimetic signal transduction inhibitors, antiandrogens, antiestrogens, androgens, aclamycin and aclamycin derivatives, estrogens, antimetabolites, platinum compounds, amanitin, plant alkaloids, mitomycins, discodermolides, microtubule inhibitors, epothilones, inflammatory and proinflammatory substances, purine analogs, pyrimidine analogs, camptothecins, dolastatins, and / or immunotherapy.In some embodiments, the patient has been treated with a prior NSCLC therapy, such as pembrolizumab, platinum, platinum doublets, pemetrexed, carboplatin, paclitaxel, bevacizumab, atezolizumab, abraxane, and combinations thereof. In some embodiments, the patient has been previously treated for NSCLC with standard of care with one or more agents selected from the group consisting of pembrolizumab, platinum, platinum doublet, pemetrexed, carboplatin, paclitaxel, bevacizumab, atezolizumab, and abraxane.

[0337] In some embodiments, the patient has received prior treatment for colorectal cancer, such as fluorouracil (5-FU), leucovorin, irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, pembrolizumab, nivolumab, ipilimumab, encorafenib, binimetinib, and combinations thereof. In some embodiments, the patient is treated with FOLFOX (i.e., 5-FU + leucovorin + irinotecan) + / - bevacizumab, panitumumab or cetuximab, CAPEOX (i.e., oxaliplatin + capecitabine) + / - bevacizumab, FOLFIRI (i.e., 5-FU + leucovorin + irinotecan) + / - bevacizumab, cetuximab, panitumumab, ziv-Afliber. Have received prior standard of care treatment for colorectal cancer with one or more agents selected from the group consisting of Cepto or ramucirumab, FOLFOXIRI (i.e., irinotecan, oxaliplatin, leucovorin, 5-FU), irinotecan + cetuximab, panitumumab, or ramucirumab, pembrolizumab, nivolumab, nivolumab + ipilimumab, encorafenib, and binimetinib.

[0338] In some embodiments, the patient has been previously treated for pancreatic cancer with fluorouracil (5-FU), leucovorin, irinotecan, liposomal irinotecan, oxaliplatin, gemcitabine, Abraxane, erlotinib, capecitabine, and combinations thereof. In some embodiments, the patient has been previously treated for pancreatic cancer with standard of care with one or more agents selected from the group consisting of FOLFIRINOX (i.e., 5-FU + leucovorin + irinotecan + oxaliplatin), gemcitabine + Abraxane, gemcitabine + erlotinib, gemcitabine, 5-FU + liposomal irinotecan, FOLFIRI (i.e., 5-FU + leucovorin + irinotecan), FOLFOX (i.e., 5-FU, oxaliplatin, leucovorin), and capecitabine + / - oxaliplatin.

[0339] In some embodiments, the patient has been previously treated for uterine cancer (also known as endometrial cancer) with a drug such as carboplatin, cisplatin, paclitaxel, docetaxel, doxorubicin, liposomal doxorubicin, trastuzumab, topotecan, bevacizumab, temsirolimus stamoxifen, fulvestrant, aromatase inhibitors, and combinations thereof. In some embodiments, the patient has been previously treated for pancreatic cancer with standard of care with one or more agents selected from the group consisting of carboplatin + paclitaxel + / - trastuzumab, carboplatin or cisplatin + docetaxel, doxorubicin, or paclitaxel, liposomal doxorubicin, topotecan, bevacizumab, temsirolimus stamoxifen, fulvestrant, and aromatase inhibitors.

[0340] It will be appreciated that the KRAS G12C inhibitor used in conjunction with the combination therapy described herein can be any KRAS G12C inhibitor as described herein.Suitable examples of KRAS G12C inhibitors include KRAS G12C antibodies, siRNAs, ribonucleic acids, peptides, oligonucleotides, small molecule inhibitors of KRAS G12C (as described herein), and the like.In some embodiments, the KRAS G12C inhibitor can be AMG-510, MRTX849, JNJ-74699157 (also known as ARS-3248), ARS-1620, MRTX1257, RM-007, or ADT-007.

[0341] Pharmaceutical Compositions For therapeutic purposes, pharmaceutical compositions containing the compounds described herein may further include one or more pharma- ceutically acceptable additives. Pharmaceutically acceptable additives are substances that are non-toxic and otherwise biologically suitable for administration to patients. Such additives facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharma-ceutically acceptable additives include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers, or flavoring agents. In a preferred embodiment, the pharmaceutical composition according to the present invention is a sterile composition. Pharmaceutical compositions may be prepared using compounding techniques that are known or that become available to those skilled in the art.

[0342] Sterile compositions are also contemplated by the present invention, including compositions that comply with national and local regulations governing such compounds.

[0343] The pharmaceutical compositions and compounds described herein may be formulated as a solution, emulsion, suspension, or dispersion in a suitable pharmaceutical solvent or carrier, or as a pill, tablet, lozenge, suppository, sachet, dragee, granule, powder, powder for reconstitution, or capsule with a solid carrier, according to conventional methods known in the art for preparing various dosage forms.The pharmaceutical compositions of the present invention may be administered by a suitable delivery route, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.Preferably, the compositions are formulated for intravenous or oral administration.

[0344] For oral administration, the compounds of the present invention may be provided in solid form, such as tablets or capsules, or as solutions, emulsions, or suspensions.To prepare oral compositions, the compounds of the present invention may be formulated to provide a dosage of, for example, about 0.1 mg to 2 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Alternative representative dosages are within the range of about 0.1 mg / kg to 1 g / kg, or about 0.1 mg / kg to 5 mg / kg, or about 0.1 mg / kg to 1 mg / kg, or about 0.1 mg / kg to 0.6 mg / kg. Oral tablets may contain the active ingredient mixed with suitable pharma- ceutically acceptable additives, such as diluents, disintegrants, binders, lubricants, sweeteners, flavors, colorants, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Representative liquid oral additives include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are representative disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the digestive tract, or may be coated with an enteric coating.

[0345] Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient may be mixed with solid, semi-solid or liquid diluent.Soft gelatin capsules may be prepared by mixing active ingredient with water, oil such as peanut oil or olive oil, liquid paraffin, mixture of mono- and diglycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.

[0346] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized, i.e., presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharma- ceutically acceptable additives, such as: suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents, such as lecithin; and, if necessary, flavorings or colorings.

[0347] For parenteral use, such as intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agent of the present invention may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dose form, such as ampoules or disposable injection devices, in multi-dose form, such as vials from which the appropriate dose may be taken, or in solid form or preconcentrates that may be used to prepare injection formulations. Specific infusion doses range from about 1 to 1000 μg / kg / min of the agent mixed with a pharmaceutical carrier over a period ranging from a few minutes to a few days.

[0348] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the invention may be administered, for example, using a spray formulation which also contains a suitable carrier.For rectal administration, the pharmaceutical compositions of the invention may be formulated as suppositories.

[0349] For topical application, the compound of the present invention is preferably formulated as cream or ointment or similar vehicle suitable for topical administration.For topical administration, the compound of the present invention may be mixed with pharmaceutical carrier at a drug concentration of about 0.1% to about 10% to the vehicle.Another method of administration of the drug of the present invention may utilize a patch formulation to achieve transdermal delivery.

[0350] Medication and Administration In some embodiments of the methods and compositions described herein, a therapeutically effective amount of one or more compounds that inhibit FAK, SRC, and / or JAK2 is administered to a host animal in need of cancer treatment, such as a human patient, in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C. In some embodiments of the methods and compositions described herein, a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, particularly compound 1, is administered to a host animal in need of cancer treatment, such as a human patient, in combination with a therapeutically effective amount of an agent that inhibits at least one KRAS G12C.

[0351] As used herein, the term "in combination with" refers to the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, with at least one agent that inhibits KRAS G12C. It will be appreciated that the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, in combination with the administration of at least one agent that inhibits KRAS G12C may occur either when the one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, are administered prior to the at least one agent that inhibits KRAS G12C, or when the one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, are administered after the at least one agent that inhibits KRAS G12C. Furthermore, when the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, occurs simultaneously with the administration of at least one agent that inhibits KRAS G12C, the compounds administered may be formulated together in a composition or drug, or may be administered simultaneously as separate compositions or drugs.

[0352] As used herein, the term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that induces a biological or medical response in a patient, such as alleviating the symptoms of the disease or disorder being treated. In one embodiment, a therapeutically effective amount is an amount that can treat or alleviate a disease or symptom. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, such as the disorder being treated and the severity of the disorder; the activity of the particular compound being used; the particular compound being used; the age, weight, general health, sex and dietary habits of the patient; the time of administration, route of administration, and excretion rate of the particular compound being used; duration of treatment; drugs used in combination or simultaneously with the particular compound being used; and similar factors.

[0353] In some embodiments, the therapeutically effective amounts of the combination may be a synergistic combination that provides an enhanced therapeutic response compared to when the one or more compounds that inhibit FAK, SRC, and / or JAK2 and the at least one agent that inhibits KRAS G12C are administered individually. In some embodiments, the synergistic effect provided by administration of a therapeutically effective amount of a combination of one or more compounds that inhibit FAK, SRC, and / or JAK2 and the at least one agent that inhibits KRAS G12C is a more additive dose response compared to the response when each of the components of the combination is administered individually.

[0354] In some embodiments, the therapeutically effective combination may be a synergistic combination that provides an enhanced therapeutic response compared to when the compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, and the at least one agent that inhibits KRAS G12C are administered individually. In some embodiments, the synergistic effect provided by administration of a therapeutically effective combination of the compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, and the at least one agent that inhibits KRAS G12C, is a more additive dose response compared to the response when each of the components of the combination is administered individually.

[0355] In some embodiments, a representative dose for each compound or agent in the various methods and compositions described herein is within the range of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g. It will be appreciated that all possible subranges within the dose ranges described above are contemplated and are described herein. For example, a dose range of about 150 to about 500 mg for compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, provided in the methods and compositions described herein may be about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, g, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, including all possible doses and ranges as may be required based on such factors for determining a therapeutically effective amount as described herein. In some embodiments, the compounds that inhibit FAK, SRC, and JAK2 provided in the methods and compositions described herein, particularly compound 1, may be administered at about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

[0356] In some embodiments, representative doses for each compound or agent in the various methods and compositions described herein are within the range of about 0.1 mg to about 3 g per day, or about 1 mg to about 50 mg per day, or about 50 to about 250 mg per day, or about 150 to about 500 mg per day, or about 150 to about 250 mg per day, or about 250 mg to about 1 g per day, or about 100 mg to about 2 g per day, or about 500 mg to about 2 g per day, or about 500 mg to about 1 g per day. It will be appreciated that all possible subranges within the daily dose ranges described above are contemplated and are described herein. For example, a dose range of about 150 to about 500 mg per day for compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, provided in the methods and compositions described herein may be about 150 mg per day, about 160 mg per day, about 170 mg per day, about 180 mg per day, about 190 mg per day, about 200 mg per day, about 210 mg per day, about 220 mg per day, about 230 mg per day, about 240 mg per day, and about 250 mg per day, about 260 mg per day, about 270 mg per day, about 280 mg per day, about 290 mg per day, about 300 mg per day, about 310 mg per day, about 320 mg per day, about 360 mg per day, about 380 mg per day, about 390 mg per day, about 400 mg per day, about 410 mg per day, about 420 mg per day, about 430 mg per day, about 440 mg per day, about 450 mg per day, about 460 mg per day, about 470 mg per day, about 480 mg per day, about 490 mg per day, about 500 mg per day, about 510 mg per day, about 520 mg per day, about 530 mg per day, about 540 mg per day, about 550 mg per day, about 560 mg per day, about 570 mg per day, about 580 mg per day, about 590 mg per day, about 600 mg per day, about 610 mg per day, about 620 mg per day, about 630 mg per day, about 640 mg per day, about 650 mg per day, about 660 mg per day, about 670 mg per day, about 680 mg per day, about 690 mg per day, The dosages include about 0 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, about 500 mg / day, including all possible dosages and ranges as may be required based on such factors for determining a therapeutically effective amount as described herein. In some embodiments, the compounds that inhibit FAK, SRC, and JAK2 provided in the methods and compositions described herein, particularly compound 1, may be administered at about 40 mg / day, about 80 mg / day, about 120 mg / day, or about 160 mg / day.

[0357] In some embodiments, alternative representative doses for each compound or agent in the various methods and compositions described herein are within the range of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg. It will be appreciated that all possible subranges within the dose ranges described above are contemplated and are described herein. For example, a dose range of about 1.0 mg / kg to about 10 mg / kg for compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, provided in the methods and compositions described herein includes doses of about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, and about 10.0 mg / kg, including all possible doses and ranges that may be required based on such factors for determining a therapeutically effective amount, as described herein.

[0358] In some embodiments, alternative representative doses for each compound or agent in the various methods and compositions described herein are within the range of about 0.1 mg / kg to about 1 g / kg per day, or about 0.5 mg / kg to about 50 mg / kg per day, or about 0.5 mg / kg to about 25 mg / kg per day, or about 1.0 mg / kg to about 10 mg / kg per day, or about 1.0 mg / kg to about 5 mg / kg per day, or about 0.1 mg / kg to about 5 mg / kg per day, or about 0.1 mg / kg to about 1 mg / kg per day, or about 0.1 mg / kg to about 0.6 mg / kg per day. It will be appreciated that all possible subranges within the dose ranges described above are contemplated and are described herein. For example, a dose range of about 1.0 mg / kg to about 10 mg / kg per day for compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, provided in the methods and compositions described herein includes doses of about 1.0 mg / kg per day, about 2.0 mg / kg per day, about 3.0 mg / kg per day, about 4.0 mg / kg per day, about 5.0 mg / kg per day, about 6.0 mg / kg per day, about 7.0 mg / kg per day, about 8.0 mg / kg per day, about 9.0 mg / kg per day, and about 10.0 mg / kg per day, including all possible doses and ranges that may be required based on such factors for determining a therapeutically effective amount, as described herein.

[0359] It will be appreciated that various dosing schedules of each compound or agent administered individually (or together) can be applied to the methods and compositions described herein. It will be further appreciated that the dosing schedule of each compound or agent administered individually (or together) in the various methods and compositions described herein can be defined by a cycle of the dosing schedule, such a cycle being defined by the number of days of treatment, the number of administrations of each compound or agent administered individually (or together), the total dose of each compound or agent administered individually (or together), and the like. In some embodiments, a host animal in need of treatment, such as a human patient, can be administered each compound or agent administered individually (or together) for at least one cycle, at least two cycles, at least three cycles, at least four cycles, and the like. Alternatively, in some embodiments, a host animal in need of treatment, such as a human patient, can be administered each compound or agent administered individually (or together) for 1 to about 50 cycles, 1 to about 25 cycles, 1 to about 20 cycles, 1 to about 10 cycles, and the like. It will be appreciated that in some embodiments, the dosing schedule of each compound or agent administered individually (or together) in the various methods and compositions described herein may include holiday periods during which the compound or agent is not administered, and such holiday periods may be measured in days. In some embodiments, the dosing schedule of each compound or agent administered individually (or together) in the various methods and compositions described herein may be defined by a number of cycles as described herein, followed by a holiday period, followed by another number of cycles as described herein.

[0360] In some embodiments, a representative dosing schedule for each compound or agent in the various methods and compositions described herein may include administration of a single dose (QD) or divided dose units (e.g., BID (twice a day), TID (three times a day), QID (four times a day)). In some embodiments, the dosing schedule for each compound or agent in the various methods and compositions described herein may be the same, such as all compounds or agents in the various methods and compositions described herein are administered QD, BID, or a similar schedule. In some embodiments, the dosing schedule for each compound or agent in the various methods and compositions described herein may be different from each other, such as one compound or agent in the various methods and compositions described herein is administered QD and another compound or agent in the various methods and compositions described herein is administered BID. In some embodiments, the dosing schedule for each compound or agent in the various methods and compositions described herein may vary within a cycle, such as one compound or agent in the various methods and compositions described herein being administered QD (e.g., for a period of 1, 2, 3, 4, etc., QD) for a specified number of days, followed by BID (e.g., for a period of 1, 2, 3, 4, etc., BID) for a specified number of days. In some embodiments, the dosing schedule for each compound or agent in the various methods and compositions described herein may be the same or may vary within a cycle, such as one compound or agent in the various methods and compositions described herein being administered QD (e.g., for a period of 1, 2, 3, 4, etc., QD) for a specified number of days, followed by BID (e.g., for a period of 1, 2, 3, 4, etc., BID) for a specified number of days to match the cycle length, and another compound or agent being administered BID for a specified number of days to match the cycle length.

[0361] In some embodiments, the compound inhibiting FAK, SRC and JAK2, particularly compound 1, and the agent inhibiting KRAS G12C are administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC and JAK2, particularly compound 1, and the agent inhibiting KRAS G12C are formulated separately and administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC and JAK2, particularly compound 1, and the agent inhibiting KRAS G12C are formulated separately and administered sequentially. In some embodiments, the sequential administration of the compound inhibiting FAK, SRC and JAK2, particularly compound 1, and the agent inhibiting KRAS G12C can be achieved by administering the compound inhibiting FAK, SRC and JAK2, particularly compound 1, first (e.g., in the morning) and administering the agent inhibiting KRAS G12C second (e.g., in the afternoon or evening). In some embodiments, sequential administration of the compound that inhibits FAK, SRC, and JAK2, particularly compound 1, and the agent that inhibits KRAS G12C may be achieved by administering the agent that inhibits KRAS G12C first (e.g., in the morning) and the compound that inhibits FAK, SRC, and JAK2, particularly compound 1, second (e.g., in the afternoon or evening).

[0362] In some embodiments, a representative dosing schedule for each compound or agent in the various methods and compositions described herein may include administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, at a dose level of about 100 mg to about 300 mg QD for at least one day, followed by administration of an agent that inhibits KRAS G12C, particularly AMG510, at a dose level of about 800 mg to about 1.5 g QD. In some embodiments, administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, and an agent that inhibits KRAS G12C, particularly AMG510, at the dosing schedule described above may be given for 1 to about 20 cycles, each cycle being about 5 to about 20 days. In some embodiments, administration of compounds that inhibit FAK, SRC, and JAK2, particularly Compound 1, and agents that inhibit KRAS G12C, particularly AMG510, in the dosing schedules described above may be given for a specified number of days, such as from about 20 to about 200 days, indefinitely or until treatment is discontinued by the treating physician.

[0363] In some embodiments, a representative dosing schedule for each compound or agent in the various methods and compositions described herein may include administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, at a dose level of about 100 mg to about 300 mg QD for at least one day, followed by administration of an agent that inhibits KRAS G12C, particularly MRTX849, at a dose level of about 100 mg to about 300 mg BID. In some embodiments, administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, and an agent that inhibits KRAS G12C, particularly MRTX849, at the dosing schedule described above may be given for 1 to about 20 cycles, each cycle being about 5 to about 20 days. In some embodiments, administration of compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, and agents that inhibit KRAS G12C, particularly MRTX849, in the dosing schedules described above may be given for a specified number of days, such as from about 20 to about 200 days, indefinitely or until treatment is discontinued by the treating physician. EXAMPLES

[0364] Chemicals and Reagents

[0365] Compound 1 was prepared according to the methods described in WO2015 / 112806, as described therein, see in particular Example 90. WO2015 / 112806 is incorporated herein by reference for the preparation of Compound 1.

[0366] AMG510 was purchased from Active Biochem (catalog no. A-9132). Drugs were prepared in dimethyl sulfoxide (DMSO) at stock concentrations of 10-100 mmol / L and stored at -20°C. Further dilutions were made in culture medium to final concentrations before use. Phospho-STAT3 (Tyr705), phosphorylated-AKT (Ser473), phosphorylated-ERK1 / 2 (Thr202 / Tyr204), phosphorylated-FAK (Tyr576 / 577), STAT3, FAK, SRC, AKT, ERK, PARP, cleaved caspase-3, tubulin, and actin were purchased from Cell Signaling Technology (Beverly, MA).

[0367] cell line

[0368] Human NSCLC cell lines H358, H23, H2122, H1373 and H1792, which harbor the KRAS G12C mutation, were purchased from the American Type Culture Collection (ATCC). All cell lines were maintained in RPMI (Roswell Park Memorial Institute medium) 1640 supplemented with 1% penicillin / streptomycin / glutamine (Gibco) and 10% fetal bovine serum (FBS) (Gibco) in a 5% CO2, 37°C cell culture incubator and periodically assessed for mycoplasma contamination.

[0369] In vitro assays Example 1: Cell viability assay 2000 cells were seeded per well in 96- or 384-well white plates and then treated with the indicated compounds for 72 h (37 °C, 5% CO2). Cell proliferation was measured using the CellTiter-Glo luciferase-based ATP detection assay (Promega) according to the manufacturer's protocol. IC was calculated using GraphPad Prism software (GraphPad, Inc., San Diego, CA). 50 It was decided.

[0370] Results showing the % cell viability of KRAS G12C inhibitor (AMG510), compound 1, and the KRAS inhibitor AMG510 in combination with compound 1 (1 μM) in KRAS G12C mutant H358, H23, H2122, H1373, and H1792 cells are summarized in Table 1. Although H358, H23, H2122, H1373, and H1792 NSCLC cell lines endogenously express KRAS G12C mutations, the KRAS G12C inhibitor AMG510 showed moderate to weak inhibition of cell proliferation. We investigated the synergistic effect of compound 1 (1 μM) in combination with AMG510 on cell proliferation in H358, H23, H2122, H1373, and H1792 NSCLC cell lines harboring KRAS G12C mutations. Compound 1 alone showed only weak inhibitory activity against H358, H23, H2122, H1373 and H1792 NSCLC cell lines, with IC 50 The IC values ​​ranged from 1.9 to 5 μM. A potent synergistic effect was observed with the combination of AMG510 and compound 1. Compound 1 at a concentration of 1 μM was found to be more potent than AMG510 on H358 cell proliferation. 50 The combination caused much more complete cell growth inhibition compared with AMG510 treatment alone in H23, H2122, H1372, and H1792 NSCLC cell lines harboring the KRAS G12C mutation. [Table 1]

[0371] Results showing the % cell viability of KRAS G12C inhibitor MRTX849, compound 1, and the combination of KRAS inhibitor MRTX849 with compound 1 (1 μM) in KRAS G12C mutant H358 and H2122 cells were also determined. We investigated the effect of compound 1 (1 μM) in combination with MRTX849 on cell proliferation in H358 and H2122 NSCLC cell lines harboring KRAS G12C mutations. Compound 1 at 1 μM concentration reduced the IC of MRTX849 on H358 cell proliferation. 50was varied from 75 nM to 11 nM and from 182 nM to 42 nM for H2122 cell proliferation.

[0372] Results showing the % cell viability of KRAS G12C inhibitor ARS-1620, compound 1, and the combination of KRAS inhibitor ARS-1620 with compound 1 (1 μM) in KRAS G12C mutant H358 and H2122 cells were also determined. We investigated the effect of compound 1 (1 μM) in combination with ARS-1620 on cell proliferation in H358 and H2122 NSCLC cell lines harboring KRAS G12C mutations. Compound 1 at 1 μM concentration reduced the IC of ARS-1620 on H358 cell proliferation. 50 was varied from 488 nM to 88 nM and from 1287 nM to 52 nM for H2122 cell proliferation.

[0373] Example 2: Apoptosis Assay 2000 cells were seeded per well in 384-well white plates and then treated with compounds for 24 or 48 hours (37°C, 5% CO2). The Caspase-Glo® 3 / 7 Detection Assay (Promega) was used to measure cellular caspase-3 / 7 activity, a key feature of apoptosis, according to the manufacturer's protocol. Results are shown in Figure 1A-1F, showing the increase in caspase-3 / 7 activity in NSCLC cell lines (H358, H2122, H1373) with KRAS G12C mutations with AMG510 (50 nM), compound 1 (1 μM), and AMG510 (50 nM) in combination with compound 1 (1 μM) after 24 and 48 hours of treatment. Compound 1 alone increased caspase-3 / 7 activity in H358 and H2122 NSCLC cell lines (Figure 1A-1D). AMG510 alone increased caspase-3 / 7 activity in H358, H2122, and H1373 NSCLC cell lines (Figures 1A-1F). The combination of compound 1 with AMG510 caused stronger caspase-3 / 7 activation at both 24 and 48 h time points compared to AMG510 treatment alone in NSCLC cells harboring the G12C mutation (Figures 1A-1F).

[0374] Cleaved PARP and cleaved caspase-3 were evaluated as biomarkers of apoptosis. 500,000 cells per well were seeded in 24-well plates for 24 h and then treated with compounds for 4, 24 or 48 h. After treatment, cells were harvested and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1X Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates (approximately 20 μg) were resolved on 4-12% Bolt Bis-Tris precast gels in MES running buffer (Life Technologies), transferred to nitrocellulose membranes using a Trans-Blot Turbo Transfer System (Bio-Rad) and detected with PARP, cleaved caspase-3, tubulin and actin targeting antibodies (Cell Signaling Technology). Antibodies were typically incubated overnight at 4°C with gentle shaking, followed by washing and incubation with the appropriate HRP-labeled secondary antibody. Membranes were incubated with chemiluminescent substrate for 5 min at room temperature (SuperSignal West Femto, Thermo Scientific). Chemiluminescent images were obtained with a C-DiGit Imaging System (LI-COR Biosciences). Results in H358 KRAS G12C NSCLC cell line showed a large increase in cleaved PARP and cleaved caspase-3 after both 24 and 48 hours of treatment with the combination of AMG510 (100 nM) and compound 1 (1 μM). Treatment with AMG510 alone (100 nM) or compound 1 alone (1 μM) resulted in a small increase in cleaved PARP and cleaved caspase-3 protein. Activation of apoptosis was demonstrated by cleaved PARP and cleaved caspase-3 in H358 mutant KRAS G12C NSCLC cells after treatment with AMG510 (100 nM), compound 1 (1 μM), and a combination of AMG510 (100 nM) and compound 1 (1 μM) for 24 or 48 hours.Results in H2122 KRAS G12C NSCLC showed a significant increase in cleaved PARP and cleaved caspase-3 after 48 hours of treatment with a combination of AMG510 (100 nM) and compound 1 (1 μM). Treatment with AMG510 (100 nM) alone or compound 1 (1 μM) alone showed minimal to no increase in cleaved PARP and cleaved caspase-3 protein, significantly lower than the combination of compound 1 and AMG510. Activation of apoptosis was also demonstrated by cleaved PARP and cleaved caspase-3 in H2122 mutant KRAS G12C NSCLC cells after 48 hours of treatment with AMG510 (100 nM), compound 1 (1 μM), and the combination of AMG510 (100 nM) and compound 1 (1 μM).

[0375] Example 3: Immunoblot for cellular kinase phosphorylation assay 0.5 million cells per well were seeded in 6- or 24-well plates for 24 hours and then treated with compounds for 4, 24, or 48 hours. After treatment, cells were harvested and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1X Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates (approximately 20 μg) were resolved on 4-12% Bolt Bis-Tris precast gels in MES running buffer (Life Technologies), transferred to nitrocellulose membranes using the Trans-Blot Turbo Transfer System (Bio-Rad) and probed with antibodies targeting phosphorylated STAT3, FAK, SRC, HER2, AKT, ERK, S6 (Cell Signaling Technology), total STAT3, FAK, SRC, HER2, AKT, S6 ERK and cleaved caspase 3 (Cell Signaling Technology). Antibodies were typically incubated overnight at 4°C with gentle shaking, followed by washing and incubation with the appropriate HRP-conjugated secondary antibody. Membranes were incubated at room temperature for 5 min with chemiluminescent substrate (SuperSignal West Femto, Thermo Scientific). Chemiluminescent images were obtained with a C-DiGit Imaging System (LI-COR Biosciences). Inhibition of STAT3, ERK, AKT, and FAK phosphorylation by compound 1 (1 μM), AMG510 (100 nM), and compound 1 (1 μM) + AMG510 (100 nM) was measured after 4, 24, and 48 hours.

[0376] Results in H358 KRAS G12C NSCLC showed that compound 1 alone inhibited phosphorylated STAT3 (pSTAT3), phosphorylated FAK (pFAK) protein levels at 4, 24, and 48 hours. AMG510 did not inhibit pSTAT3 or pFAK protein levels at any time point. The combination of compound 1 and AMG510 inhibited pFAK and pSTAT3 protein levels at all time points. Compound 1 alone did not inhibit phosphorylated ERK (pERK) at any time point. AMG510 did not inhibit pERK at 4 hours of treatment, but did so after 24 and 48 hours of treatment. Compound 1 in combination with AMG510 inhibited pERK at all time points. Treatment with compound 1 alone or AMG510 alone showed minimal to zero inhibition of phosphorylated AKT (pAKT) up to 24 hours of treatment. Treatment with AMG510 alone for 48 hours elevated pAKT, while treatment with compound 1 alone for 48 hours reduced pAKT compared to control. The combination of compound 1 with AMG510 showed significant inhibition of pAKT after 24 and 48 hours of treatment, supporting a significant increase in apoptotic activation in the combined treatment.

[0377] The inhibition of phosphorylation of FAK, STAT3, SRC, HER2, ERK, AKT, and S6 and activation of apoptosis by cleaved caspase-3 by compound 1 (1 μM), MRTX849 (100 nM), and compound 1 (1 μM) + MRTX849 (100 nM) were evaluated in H2122 mutant KRAS G12C NSCLC cells after 4, 24, and 48 hours. The results in H2122 KRAS G12C NSCLC show that compound 1 alone suppressed the protein levels of phosphorylated STAT3 (pSTAT3), phosphorylated FAK (pFAK), and phosphorylated SRC at 4, 24, and 48 hours. MRTX849 did not suppress pSTAT3, pFAK, or pSRC protein levels at any time point. The combination of compound 1 and MRTX849 suppressed pFAK, pSTAT3, and pSRC protein levels at all time points. Compound 1 alone did not inhibit phosphorylated ERK (pERK) at any time point, while MRTX849 inhibited pERK at all time points. Compound 1 in combination with MRTX849 inhibited pERK at all time points. Treatment with compound 1 alone or MRTX849 alone inhibited phosphorylated AKT (pAKT) at all time points. Treatment with MRTX849 alone for 48 hours elevated pHER2. Compound 1 in combination with MRTX849 enhanced inhibition of pAKT and p-S6 after 4, 24 and 48 hours of treatment and inhibited pHER2 at 48 hours, supporting a significant increase in apoptotic activation as shown by cleaved caspase-3 in the combination treatment.

[0378] Inhibition of phosphorylation of FAK, STAT3, SRC, ERK, AKT, and S6 by compound 1 (1 μM), ARS1620 (1 μM), and compound 1 (1 μM) + ARS1620 (1 μM) was evaluated in H358 mutant KRAS G12C NSCLC cells after 4 hours, 24 hours, and 48 hours. Results in H358 KRAS G12C NSCLC show that compound 1 alone suppressed the protein levels of phosphorylated STAT3 (pSTAT3), phosphorylated FAK (pFAK), and phosphorylated SRC at 4, 24, and 48 hours. ARS1620 did not suppress pSTAT3, pFAK, or pSRC protein levels at any time point. The combination of compound 1 and ARS1620 suppressed pFAK, pSTAT3, and pSRC protein levels at all time points. The combination of compound 1 with ARS1620 inhibited pERK at all time points. Treatment with compound 1 alone or ARS1620 alone inhibited phosphorylated AKT (pAKT) up to 24 hours of treatment. Treatment with ARS1620 alone for 48 hours elevated pAKT, while treatment with compound 1 alone for 48 hours decreased pAKT compared to control. The combination of compound 1 with ARS1620 showed significant inhibition of pAKT and p-S6.

[0379] Results in H2122 KRAS G12C NSCLC show that compound 1 alone suppressed phosphorylated STAT3 (pSTAT3), phosphorylated FAK (pFAK) and phosphorylated SRC protein levels at 4, 24 and 48 hours. ARS1620 did not suppress pSTAT3, pFAK or pSRC protein levels at any time point. The combination of compound 1 and ARS1620 suppressed pFAK, pSTAT3 and pSRC protein levels at all time points. Compound 1 alone did not suppress phosphorylated ERK (pERK) at any time point, while ARS1620 suppressed pERK at 4 and 24 hours. The combination of compound 1 with ARS1620 suppressed pERK at 4 and 24 hours. Treatment with compound 1 alone or ARS1620 alone suppressed phosphorylated AKT (pAKT) at all time points. Combination of Compound 1 with ARS1620 demonstrated significantly enhanced inhibition of pAKT and p-S6 over ARS1620 treatment alone.

[0380] Example 4: H2122 NSCLC KRAS G12C 2D Assay H2122 NSCLC cells were used to identify synergistic combinations between AMG-510 or MRTX-849 and compound 1. 2000 cells / well were seeded in a single 96-well plate in a total volume of 80 μl RPMI supplemented with 10% fetal bovine serum (FBS). The next day, a combination matrix was created containing a dilution of drug AMG-510 or MRTX-849 (10 μM final concentration, diluted 3-fold to 1.5 nM) in the horizontal direction and a dilution of compound 1 (3 μM final concentration, diluted 3-fold to 37 nM) in the vertical direction. Cells were incubated for 96 hours at 37°C in 5% CO2. Afterwards, 36 μl of CellTiter-Glo reagent (Promega) was added to each well and the plate was incubated for 10 minutes at 37°C. Luminescence was quantified using a Synergy H1 microplate reader (Biotek) according to the manufacturer's instructions. Synergy was assessed by BLISS independent analysis on the Synergyfinder website (Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics. 2017 Aug 1;33(15):2413-2415).

[0381] In an in vitro combination screen, KRAS inhibitors (AMG-510 and MRTX-849) and compounds showed synergy in H2122 cells. A depiction of the dose-response matrix is ​​shown in Figures 2A-2B. Table 2 shows the Bliss synergy scores for the relevant drug doses. [Table 2]

[0382] Example 5: Compound 1 and its combination with AMG510 alters cytokine and growth factor secretion from mutant KRAS tumor cells Cytokine and growth factor assessment

[0383] ENA-78 (CXCL5), GCSF, GM-CSF, GRO alpha / beta / gamma, GRO alpha (CXCL1), I-309 (TCA-3 / CCL1), IL-1 alpha (IL-1 F1), IL-1 beta (IL-1 F2), IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8(CXCL8), IL-10, IL-12 p40 / p70, IL-13, IL-15, IFN-gamma, MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (MARC / CCL7), M-CSF, MDC (CCL22), MIG (CXCL9), MIP-1 beta (CCL4), MIP-1 delta (CCL15), RANTES (CCL5), SCF, SDF-1 alpha (CXCL12 alpha), TARC (CCL17), TGF beta 1, TNF alpha, TNF beta (TNFSF1B), EGF, IGF1, Angiogenin, Oncostatin M, Thrombopoietin (TPO), VEGF-A, PDGF-BB, Leptin, BDNF, BLC (CXCL13), Ck beta 8-1 (CCL23), Eotaxin-1 (CCL11), Eotaxin -2 (MPIF-2 / CCL24), Eotaxin-3 (CCL26), FGF-4, FGF-6, FGF-7 (KGF), FGF-9, Flt-3 ligand, Fractalkine (CX3CL1), GCP-2 (CXCL6), GDNF, HGF, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IL-16, IP-10 (CXCL10), LIF, LIGHT (TNFSF14), MCP-4 (CCL13), MIF, MIP-3 alpha (CCL20), NAP-2 (PPBP / CXCL7), NT-3, NT-4, Osteopontin (SPP1), Osteoprotegerin (TNFRSF11B), PARC (CCL18), PLGF, TGF beta 2, TGF beta 3, TIMP-1, TIMP-2

[0384] Experimental Method

[0385] Cytokine Array Cytokines present in NCI-H358 and NCI-H2122 culture supernatants were identified and quantitatively compared using Human Cytokine Antibody Array C5 (AAH-CYT-5-8, RayBiotech). One million cells per well were seeded in 6-well plates, allowed to adhere for 24 h, and then treated with AMG-510 (100 nM) / MRTX849 (100 nM), compound 1 (1 μM), or a combination of AMG-510 (100 nM) / MRTX849 (100 nM) and compound 1 (1 μM) for 24 or 48 h. After incubation with culture supernatants from H358 and H2122 cells overnight at 4 °C, the antibody array was blocked for 30 min at room temperature. The antibody array was then washed and reincubated with a biotinylated antibody mix overnight at 4 °C, followed by HRP-labeled streptavidin for 2 h at room temperature. After a final washing step, chemiluminescence detection buffer was added to the array and the chemiluminescence signal was captured using an iBright 1500 imaging system (Invitrogen). Spot density was quantified by using iBright Analysis Software. Comparisons were made using the RayBiotech Analysis tool for AAH-CYT-5.

[0386] ELISA 0.5 million cells were seeded per well in 6-well plates, allowed to adhere for 24 h, and then treated with AMG-510 (100 nM) / MRTX849 (100 nM), compound 1 (1 μM) or a combination of AMG-510 (100 nM) / MRTX849 (100 nM) and compound 1 (1 μM) for 48 h. To evaluate IL-6 secretion by tumor cells, supernatants were collected and human IL-6 ELISA assays were performed according to the manufacturer's instructions (R&D Biosystems). Briefly, microplate wells were incubated with either standard, control, and sample supernatants from H358 and H2122 cells for 2 h at room temperature. Next, the microplates were washed and incubated with human IL-6 complex for 2 h at room temperature, followed by washing and addition of substrate solution for 20 min. Finally, stop solution was added and optical density was evaluated using a microplate reader set at 450 nm. The measurement at 540 nm was subtracted to correct for optical imperfections in the plate.

[0387] qPCR 0.5 million cells were seeded per well in 6-well plates, allowed to attach for 24 h, and then treated with AMG-510 (100 nM) / MRTX849 (100 nM), compound 1 (1 μM) or a combination of AMG-510 (100 nM) / MRTX849 (100 nM) and compound 1 (1 μM) for 24 and 48 h. mRNA was prepared using the Rneasy Mini Kit (Qiagen) and cDNA was synthesized using SuperScript IV VILO (Invitrogen). qPCR was performed with diluted cDNA, appropriate Taqman probes and Taqman Fast Advanced Master mix (Applied Biosystems) using a QuantStudio 5 Thermal Cycler (Applied Biosystems). Relative mRNA levels were calculated using the 2-Ct method with RPL32 as an internal standard.

[0388] KRAS cell lines H358 and H2122, which were shown to secrete IL-6, were shown to be inhibited by compound 1 alone and in the presence of AMG510, with the inhibition of IL-6 secretion being greater with the combination of compound 1 and AMG-510 than with either compound individually. The results are shown in Figures 3A-3D.

[0389] Cytokine data was also generated in H2122 NSCLC cell line treated with compound 1 in combination with MRTX849 for 48 hours: (a) control; (b) MRTX849; (c) compound 1; (d) compound 1 + MRTX849 (Figure 3E).

[0390] The KRAS cell line H2122 was shown to secrete IL-6, and IL-6 was shown to be inhibited by compound 1 alone and in the presence of MRTX849, with greater inhibition of IL-6 secretion in the combination of compound 1 and MRTX849 than with either compound individually (Figures 3F-3G).

[0391] In vivo experiments Method 1: Subcutaneous xenograft model in immunodeficient mice

[0392] Female athymic nude, SCID, NOD / SCID or SCID / Beige mice (5-8 weeks old) were used as host mice. For the subcutaneous cell-derived xenograft model, approximately 5 million cells in 100 μL serum-free medium supplemented with 50% Matrigel (Corning, Inc.) were subcutaneously implanted into the right flank of each host mouse. For the subcutaneous patient-derived xenograft model, tumor fragments derived from the host mice were subcutaneously implanted into the flank of each host mouse. Tumor size and body weight were measured on the indicated days. Tumor size was measured with an electronic caliper and expressed as length × width. 2Tumor volumes were calculated using a 1:1 ratio (×100) × 0.5 or similar formula. When the mean tumor volume reached a certain size, mice were randomly divided into treatment groups according to tumor size. Compound 1 was administered orally twice daily at a designated dose, and AMG-510 was administered orally once daily at a designated dose. For the brain orthotopic model, approximately 80,000 cells were implanted into the brain, and treatment of mice with control or test substances was started on day 7 after implantation.

[0393] Method 2: Tumor treatment and immunoblotting for in vivo pharmacodynamic experiments

[0394] Mice bearing xenograft tumors were humanely euthanized, and tumors were excised, rapidly frozen in liquid nitrogen, and stored at -80°C. Frozen tumor samples were processed in RIPA buffer at 4°C and protein was extracted. Lysate protein concentrations were determined by Rapid Gold BCA Protein Assay (Life Technologies, Inc.), and lysates were diluted so that protein concentrations were similar between samples. SDS loading samples were prepared by adding 1 volume of 4X LDS sample buffer (Life Technologies, Inc.) to 3 volumes of diluted protein lysate. Tumor SDS protein samples were processed by SDS-PAGE and immunoblotted with appropriate primary antibodies, followed by detection with HRP-conjugated secondary antibodies. Signals from immunoblots were detected with LI-COR's C-DiGit Blot Scanner using Image Studio Digit software (LI-COR).

[0395] Example 6: AMG in H358 cell-derived xenograft tumors - Effect of Compound 1 in Combination with 510 H358 cells carry a KRAS G12C mutation. SCID / Beige mice bearing H358 cell-derived tumors were treated with vehicle BID, compound 1 BID 15mg / kg, AMG-510 QD 10mg / kg, and compound 1 BID 15mg / kg in combination with AMG-510 QD 10mg / kg, respectively. Tumor volume (TMV) versus time data is shown in Figure 4A as mean ± SEM. After 26 days of treatment, compound 1 in combination with AMG-510 significantly reduced tumor volume compared to treatment with vehicle, compound 1 alone, or AMG-510 alone (p<0.0001 for all three comparisons, two-way repeated measures ANOVA analysis followed by post hoc Tukey multiple comparison test). Mouse body weights measured during the treatment period are shown in Figure 4B as mean ± SEM. There was no statistical significance between treatment groups (p=0.4233, two-way repeated measures ANOVA), suggesting that combined treatment with Compound 1 and AMG-510 did not result in any weight loss or overt abnormalities under these experimental conditions.

[0396] Example 7: AMG in H358 cell-derived xenograft tumors - Pharmacodynamic effects of compound 1 in combination with 510 To evaluate the pharmacodynamic effects of compound 1 in combination with AMG-510 in H358 cell-derived xenograft tumors, tumor lysates were prepared and analyzed by immunoblot using antibodies against candidate molecules selected from signaling pathways that can potentially be altered by compound 1 and / or AMG-510. The inhibitory activity of compound 1 against SRC and JAK2 was shown by the reduction of phosphorylated SRC (Y416) and STAT3 (Y705) signals in tumors treated with compound 1, either as a single agent or in combination with AMG-510, compared to vehicle treatment. Furthermore, the activity of compound 1 against FAK was shown by the reduction of phosphorylated FAK signals in the compound 1 and AMG-510 combination treatment group. Furthermore, the activity of AMG-510 against KRAS was shown by the reduction of the level of phosphorylated ERK (T202 / Y204) signals, a key downstream effector of KRAS signaling, in mice treated with AMG-510, either as a single agent or in combination with compound 1. Finally, the combination of compound 1 with AMG-510 also reduced phosphorylated AKT (S473) signaling, a key factor involved in cell survival and proliferation. Thus, compound 1 and AMG-510 combination treatment not only suppresses the activity of compound 1 and AMG-510 targets, such as SRC, FAK, JAK2, and KRAS, but also AKT, a key factor in the PI3K-AKT oncogenic pathway.

[0397] Example 8: AMG in the LU11693 patient-derived xenograft model of NSCLC harboring the KRAS G12C mutation - Effect of Compound 1 in Combination with 510 LU11693 PDX tumors harbor a KRAS G12C mutation. NOD / SCID mice bearing LU11693 PDX tumors were treated with vehicle BID, Compound 1 BID 15 mg / kg, AMG-510 QD 100 mg / kg, and Compound 1 BID 15 mg / kg in combination with AMG-510 QD 100 mg / kg, respectively. Tumor volume (TMV) versus time data is shown in FIG. 5A as mean ± SEM. Mouse body weights measured during the treatment period are shown in FIG. 5B as mean ± SEM. Treatment with AMG-510 QD 100 mg / kg, either as a single agent or in combination with Compound 1, significantly reduced mouse body weight. On day 13, two mice in the combination treatment group were euthanized due to weight loss, and starting on day 14, the dose of AMG-510 was reduced to 30 mg / kg QD in both AMG-510 monotherapy and compound 1 and AMG-510 combination treatment. After 21 days of treatment, compound 1 in combination with AMG-510 significantly reduced tumor volume compared to treatment with vehicle, compound 1 alone, or AMG-510 alone (p=0.0002 vs. vehicle, p=0.0181 vs. compound 1, p=0.0003 vs. AMG-510, mixed effects model followed by post-hoc Dunnett's multiple comparison test). As mentioned above, weight loss was observed in mice treated with AMG-510 QD 100 mg / kg, either as a single agent or in combination with compound 1. After dose reduction, body weight in the Compound 1 + AMG-510 combination group began to recover, and on day 21, body weight in the combination group was not significantly different from the vehicle-treated group (p=0.5487 vs. vehicle, one-way ANOVA followed by Dunnett's multiple comparison test).

[0398] Example 9: AMG - Compound 1 in combination with 510 improves survival in mice bearing xenograft tumors derived from H2122 cells The effect of combined treatment with compound 1 and AMG-510 on the survival of tumor-bearing mice was evaluated using KRAS G12CThe effect of the mutation was evaluated using a xenograft tumor model derived from H2122 cells. From day 5 after tumor cell implantation, SCID / Beige mice bearing xenograft tumors derived from H2122 cells were randomly divided into groups based on tumor size (n=10 per group) and treated with vehicle BID, compound 1 BID 15mg / kg, AMG-510 QD 10mg / kg, compound 1 BID 15mg / kg combined with AMG-510 QD 10mg / kg, AMG-510 QD 30mg / kg, and compound 1 BID 15mg / kg combined with AMG-510 QD 30mg / kg. To evaluate the survival effect, humane endpoints were set: moribund, 2000mm 3Each mouse was considered dead when it reached one of the following symptoms: tumor volume > 100 mg / kg, weight loss > 20% compared to baseline, exposure of tumor foci, and inability to drink or eat. The experiment was terminated on day 101 after tumor cell implantation. The median survival times for the groups treated with vehicle BID, compound 1 BID 15 mg / kg, AMG-510 QD 10 mg / kg, compound 1 BID 15 mg / kg in combination with AMG-510 QD 10 mg / kg, and AMG-510 QD 30 mg / kg were 34, 45, 52, 77, and 76.5 days, respectively; for the group treated with compound 1 BID 15 mg / kg in combination with AMG-510 QD 30 mg / kg, the median survival time was not reached when the experiment was terminated on day 101 after tumor cell implantation. Treatment with compound 1 in combination with AMG-510 at a dose level of 10 mg / kg AMG-510 statistically significantly increased median survival compared to treatment with AMG-510 alone (p<0.0019, log-rank test, compound 1 and AMG-510 combination vs. AMG-510, FIG. 6A). Treatment with compound 1 in combination with AMG-510 at a dose level of 30 mg / kg AMG-510 statistically significantly increased median survival compared to treatment with AMG-510 alone (p<0.0138, log-rank test, compound 1 and AMG-510 combination vs. AMG-510, FIG. 6B). These findings suggest that combination treatment with compound 1 and AMG-510 extends the survival of mice bearing H2122 cell-derived tumors compared to treatment with AMG-510 alone. The present invention includes the following aspects. [Section 1] 1. A method of treating cancer comprising administering to a host animal a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, wherein the compound: [C1] TIFF0007670711000034.tif3238 or a pharma- ceutically acceptable salt thereof. [Section 2] The cancers are ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain low-grade glioma, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, Item 2. The method according to item 1, wherein the cancer is selected from the group consisting of human ovarian serous cystadenocarcinoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer. [Section 3] Item 3. The method according to item 1 or 2, wherein the cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer. [Section 4] The method according to any one of items 1 to 3, wherein the cancer is non-small cell lung cancer. [Section 5] The method according to any one of paragraphs 1 to 3, wherein the cancer is colorectal cancer. [Section 6] 6. The method of any one of paragraphs 1 to 5, wherein the compound that inhibits FAK, SRC, and JAK2 is administered simultaneously with, prior to, or subsequent to at least one of the agents that inhibit KRAS G12C. [Section 7] The method according to any one of items 1 to 6, wherein IL-6 secretion from the cancer is reduced. [Section 8] 8. The method according to any one of paragraphs 1 to 7, wherein at least one of the agents that inhibit KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C. [Section 9] 9. The method of any one of paragraphs 1 to 8, wherein at least one of the agents that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C. [Section 10] 10. The method of claim 9, wherein the biological agent that inhibits KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA. [Section 11] Item 9. The method of any one of items 1 to 8, wherein at least one of the agents that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C. [Section 12] 12. The method of any one of paragraphs 1 to 8 or 11, wherein at least one of the agents that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007. [Section 13] 13. The method of any one of paragraphs 1 to 8, 11 or 12, wherein at least one of the agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof. [Section 14] 13. The method of any one of paragraphs 1 to 8, 11 or 12, wherein at least one of the agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof. [Section 15] the compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and 15. The method of any one of clauses 1 to 14, wherein the agent that inhibits G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg. [Section 16] the compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg; and 15. The method of any one of clauses 1 to 14, wherein the agent that inhibits G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg. [Section 17] 17. The method of any one of paragraphs 1 to 16, wherein the host animal is a human patient who has not been previously treated and is in need of such treatment. [Section 18] 17. The method of any one of paragraphs 1 to 16, wherein the host animal is a human patient in need of such treatment who has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy. [Section 19] 19. The method of any one of paragraphs 1 to 16 or 18, wherein the host animal is a human patient in need of such treatment who has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapies and has developed acquired resistance to said treatment and / or has developed bypass resistance to said treatment and / or has developed bypass resistance to said treatment controlled by FAK, SRC or JAK2. [Section 20] 1. A compound according to claim 1, wherein the compound is a compound of the formula: [Case 2] TIFF0007670711000035.tif4149 A compound which inhibits FAK, SRC, and JAK2, represented by the formula: or a pharma- ceutically acceptable salt thereof. [Section 21] 2. Use of a compound or a pharma- ceutically acceptable salt thereof in the preparation of a medicament comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, for treating cancer in a patient in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, wherein the compound is [C3] TIFF0007670711000036.tif4049 or a pharma- ceutically acceptable salt thereof.

Claims

1. A pharmaceutical composition for use in treating cancer in a human, said pharmaceutical composition comprising a compound that inhibits FAK, SRC, and JAK2; the pharmaceutical composition is combined with a therapeutically effective amount of at least one agent that inhibits KRAS G12C; The compound is 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; at least one agent that inhibits KRAS G12C is AMG-510, MRTX849, or ARS-1620, or a pharma- ceutically acceptable salt thereof; the cancer is colorectal cancer, pancreatic cancer, or lung cancer; Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1 , wherein the cancer is pancreatic cancer.

3. The pharmaceutical composition of claim 1 , wherein the cancer is lung cancer.

4. The pharmaceutical composition of claim 3 , wherein the cancer is non-small cell lung cancer.

5. The pharmaceutical composition of claim 1 , wherein the cancer is colorectal cancer.

6. 6. The pharmaceutical composition of claim 1, wherein the compound that inhibits FAK, SRC, and JAK2 is administered simultaneously with, prior to, or subsequent to at least one of the agents that inhibit KRAS G12C.

7. The pharmaceutical composition according to any one of claims 1 to 6, which reduces IL-6 secretion from the cancer.

8. 8. The pharmaceutical composition of claim 1, wherein at least one of the agents that inhibits KRAS G12C is ARS-1620 or a pharma- ceutically acceptable salt thereof.

9. 8. The pharmaceutical composition of claim 1, wherein at least one of the agents that inhibits KRAS G12C is AMG-510 or a pharma- ceutically acceptable salt thereof.

10. 8. The pharmaceutical composition of claim 1, wherein at least one of the agents that inhibits KRAS G12C is MRTX849 or a pharma- ceutically acceptable salt thereof.

11. the compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the agent that inhibits G12C is administered in a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg.

12. the compound that inhibits FAK, SRC, and JAK2 is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg; and 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the agent that inhibits G12C is administered at a dose of about 0.1 mg / kg to about 1 g / kg, or about 0.5 mg / kg to about 50 mg / kg, or about 0.5 mg / kg to about 25 mg / kg, or about 1.0 mg / kg to about 10 mg / kg, or about 1.0 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.6 mg / kg, or about 1.25 mg / kg to about 3.75 mg / kg, or about 1.0 mg / kg, about 2.0 mg / kg, or about 3.0 mg / kg, or about 4.0 mg / kg.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the human patient is pre-treated and in need of such treatment.

14. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the human patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapy and is in need of such treatment.

15. 15. The pharmaceutical composition of any one of claims 1 to 12 or 14, wherein the human patient has undergone at least one prior treatment with one or more chemotherapeutic agents or immunotherapies and has developed acquired resistance to said treatment and / or has developed bypass resistance to said treatment and / or has developed bypass resistance to said treatment controlled by FAK, SRC or JAK2, and is in need of such treatment.

16. The compound is 【Chemistry 2】 16. The pharmaceutical composition according to any one of claims 1 to 15, wherein

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