Combination therapy involving diaryl macrocyclic compounds

Abstract

The present disclosure relates to a method and composition for treating cancer using a diaryl macrocycle combined with a KRAS inhibitor, such as a KRAS G12C inhibitor.

Description

Technology Field

[0001] The present disclosure relates to a method and composition for treating cancer using a diaryl macrocycle combined with a KRAS inhibitor, such as a KRAS G12C inhibitor. Background Technology

[0002] The Kirsten Rat Sarcoma Viral Oncogene homolog KRAS is one of three members of the RAS protein family (N, H, and K-RAS) that are 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 various effectors to stimulate various signaling pathways (e.g., PI3K-AKT-MTOR, RAF-MEK-ERK), thereby influencing various cellular processes (e.g., survival, proliferation, cytoskeletal organization).

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

[0004] Direct targeting of a single KRAS mutation G12C via a shared approach produced diverse preclinical outcomes ranging from insensitivity to responsiveness in mouse tumor models with KRAS G12C mutations (Ostrem et al, Nature. 2013, 503(7477):548-51). In clinical studies, the KRAS G12C inhibitor AMG510 (Canon et al, Nature , 2019, 575, 217-223) and MRTX849 (Hallin et al, Cancer Discovery Tumor regression has been reported in the treatment of patients with KRAS G12C mutant non-small cell lung cancer or colorectal cancer (*, 2020, 10(1) 54-71). However, endogenous and acquired resistance are expected to limit the use of KRAS inhibitors as monotherapy in clinical application due to the development of signaling adaptations or the selection of minority variants. The KRAS G12C inhibitor MRTX849 demonstrated tumor regression in only 17 out of 26 (65%) patient-derived mouse xenograft models from KRAS G12C-positive cell lines and multiple tumor types, and multiple resistance mechanisms, including KRAS nucleotide cycles, feedback reactivation, and / or bypass KRAS dependence, limit the efficacy and duration of response of MRTX849 in nonclinical models (Hallin et al., Cancer Discovery , 2020, 10(1), 54-71). Covalent inhibitors of KRAS G12C have been reported to be more effective when bound to immune checkpoint inhibitor monoclonal antibodies, such as those blocking programmed death-1 (PD-1) (Canon et al, Nature , 2019, 575, 217-223). A combination of targeting MAPK pathway feedback reactivation, RTK-induced PI3K pathway activation, and increased apoptosis, and suppressing the inflammatory tumor microenvironment, would be necessary to provide significant improvement in clinical benefit.

[0005] Tumor cells reprogram the tumor microenvironment through many processes characteristic of cancer (e.g., immunosuppression, induction of angiogenesis, altered metabolism) (Hanahan and Weinberg, Cell 2011, 144(5), 646-674). Many studies suggest that oncogenic KRAS signaling interacts with the tumor microenvironment to induce the expression of various immunomodulatory factors, such as TGFβ, GM-CSF, CXCL8, interleukin-6 (IL-6), and IL-10, which trigger immunosuppressive responses. (Cavalho et al. Cancer Res 2018, 78(1), 7-14; Cullis et al., Cold Spring Harb. Perspective. Med 8, a031849; Maldegem and Downward; Immunity 2020, 52, 14-16). Mutant KRAS-induced cancers are known to reprogram the stroma to be tumorigenic (Carvalho et al. Cancers Tumor formation is inhibited by disrupting autocrine cytokine signaling (2019, 11(12), 2010). 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-induced lung tumor formation (Brooks et al., Cancer Res 2016, 76(4), 1-11). It is a paracrine process for mutant KRAS tumor cells to initiate angiogenesis by secreting other angiogenic factors such as vascular endothelial growth factor (VEGF) and CXC chemokines (Matsuo et al. Mol CancerRes 2009, 7(6), 799-808). Other paracrine processes, in addition to immune evasion and angiogenesis, remodel the stroma and alter tumor cell processes. For example, mutant KRAS cells can secrete insulin-like growth factor-1, which increases tumor cell mitochondrial capacity through IGF1R signaling (Tape et al., Cell 2016, 165(4), 910-920). Therefore, effective treatments for cancer patients with KRAS mutations must target not only the tumor microenvironment but also the tumor cells.

[0006] SRC kinases have been identified as contributing extensively to resistance to cancer treatments, including radiation therapy, chemotherapy, and targeted therapy (Zhang S and Yu D. Trends Pharmacol Sci. 2012;33(3):122-8). SRC family kinases can promote mitotic signaling from growth factor receptors in various ways, including the initiation of signaling pathways necessary for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangement, motility, and survival (Bromann et al, Oncogene 2004;23(48):7957-68). KRAS has been reported to induce a Src / PEAK1 / ErbB2 kinase amplification loop that leads to metastatic growth and treatment resistance in pancreatic cancer (Kelber et al, Cancer Res . 2012;72(10):2554-64). The SRC inhibitor dasatinib has been shown to enhance the antitumor activity of MEK inhibitors by inhibiting TAZ activity, and the combination of dasatinib and trametinib represents a potential strategy for the treatment of KRAS-induced cancers (Rao et al, Eur J Cancer. 2018 Aug;99:37-48). FAK plays an important role in signaling pathways mediated through integrins, RTKs, RAS, and TGF β (Kanteti et al, Oncotarget. 2016;7(21):31586-601) It is also possible that inhibiting p53 expression promotes cell survival (Golubovskaya et al, International Review of Cytology . 2007; 263:103-153). Recent research results indicate that integrins participate in the regulation of cancer stem cell biology and are required for cancer progression, metastasis, and drug resistance through SRC / FAK signaling (Seguin et al, Trends Cell Biol . 2015;25(4):234-40). Src has been identified as a key mediator in the pre-tumor formation process of thyroid cancer and a promising therapeutic target for thyroid cancer.

[0007] Inhibition of Src as a single substance promotes a more invasive phenotype through the IL-1β>FAK>p130Cas>c-Jun>MMP signaling axis, and combined inhibition of FAK and Src may block Src inhibitor-induced phenotypic switching and tolerance (Kessler et al. Oncogene . 2019; 38:2565-2579). Compensatory upregulation of the PI3K / AKT signaling pathway is a resistance mechanism targeting KRAS mutations that promote cancer cell survival. FAK mediated by phosphorylated Y397 directly interacts with the SH2 domain of p85, a regulatory subunit of PI3K, to activate the PI3K pathway and inhibit doxorubicin-induced apoptosis (van Nimwegen et al, Mol Pharmacol. 2006; 70(4):1330-1339). In Y925, Src-mediated phosphorylation of FAK creates a docking site for GRB2, which activates the small GTP protein RAS and downstream ERK2 (MAPK) (Kanteti et al, Oncotarget. 2016;7(21):31586-601). Paxilin is a major component of focal adhesion, which forms structural connections between the extracellular matrix and the actin cytoskeleton. In cancer cells, its function is regulated through Src and FAK-mediated phosphorylation. Dual inhibition by FAK and Src inhibitors was significantly more effective compared to FAK inhibition alone, as demonstrated by increased cell dissociation, 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 necessary for the maintenance of KRAS-induced lung adenocarcinoma. Pharmacological inhibition of FAK in vivo downregulates p-AKT and does not trigger the emergence of PI3K / AKT-dependent compensatory mechanisms (Konstantinidou et al, Cancer Discov . 2013, 3(4):444-57). The KRAS G12C inhibitor AMG-510 is less effective in KRAS G12C mutant colorectal cancer than in NSCLC (Govindan et al, Annals of Oncology , 2019, 30 (suppl_5): v159-v193. 10.1093 / annonc / mdz244). It has been reported that mutant KRAS activates p-STAT3 (Tyr705) without IL-6 secretion, and that BCL-XL upregulation by STAT3 contributes to mutant KRAS-mediated apoptosis resistance in colorectal cancer (Zaanan et al, J Biol Chem2015, 290(39):23838-49). Therefore, inhibition of JAK2, which induces the regulation of STAT3 phosphorylation, can be used to enable synergistic apoptotic responses in KRAS-mutated colon cancer as well as other mutant KRAS cancers. In addition, Src and FAK are related to VEGF (Niu et al. Oncogene Expression of angiogenic factors such as 2002, 21(13), 2000-8) and various cytokines (Cavalho et al. Cancers It regulates STAT3, which regulates 2019, 11(12), 2010). Taken together, Src, FAK, and JAK2 play a key role in mutant KRAS cancer by enabling angiogenesis in tumors, generating pro-tumor immune responses in the tumor microenvironment, and promoting both endogenous and exogenous tumor cell signaling. Furthermore, combined inhibition of Src, FAK, and JAK2 will have additional utility in diseases with pro-inflammatory components, such as asthma, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and fibrosis.

[0008] Overall, direct pharmacological targeting of activated RAS proteins has been challenging, and while initial antitumor activity was observed with the KRAS G12C inhibitors AMG510 and MRTX849 in Phase 1 clinical studies on cancer patients with KRAS G12C mutations, these have not yet led to successful treatment in clinical settings. The combination of SRC / FAK / JAK2 inhibitors and substances that inhibit KRAS G12C represents a novel therapeutic invention that maximizes the antitumor activity and duration of response of KRAS G12C inhibitors for the treatment of patients with KRAS G12C mutations.

[0009] summation

[0010] A combination of a substance that inhibits KRAS G12C and one or more compounds that inhibit FAK, SRC, and / or JAK2 has been found to provide a potent response in cancers harboring KRAS G12C mutations.

[0011] In one aspect, the present disclosure provides a method for treating cancer in a host animal, comprising the step of administering to a host animal a therapeutically effective amount of one or more compounds that inhibit FAK, SRC, and / or JAK2 in combination with at least one substance 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.

[0012] In another aspect, the present disclosure provides a method for treating cancer in a host animal, comprising the step of administering to a host animal a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, combined with at least one substance 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.

[0013] In another aspect, the present disclosure provides one or more compounds that inhibit FAK, SRC, and / or JAK2, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer in patients in combination with at least one substance that inhibits KRAS G12C in a therapeutically effective amount.

[0014] In another aspect, the present disclosure provides a compound that inhibits FAK, SRC, and JAK2 in combination with at least one substance that inhibits KRAS G12C in a therapeutically effective amount for use in the treatment of cancer in patients, or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present disclosure provides the use of one or more compounds that inhibit FAK, SRC, and / or JAK2, or pharmaceutically acceptable salts thereof, in the manufacture of a drug comprising a compound that inhibits FAK, SRC, and / or JAK2, combined with at least one substance that inhibits KRAS G12C in a therapeutically effective amount for treating cancer in a patient.

[0016] In another aspect, the present disclosure provides a use in the manufacture of a drug for treating cancer in a patient comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, combined with at least one substance that inhibits KRAS G12C.

[0017] In another aspect, the present disclosure provides a use of a compound that inhibits FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, combined with at least one substance that inhibits KRAS G12C, for treating cancer in a patient.

[0018] In another aspect, the present disclosure provides a use of a compound that inhibits FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, combined with at least one substance that inhibits KRAS G12C, for treating cancer in a patient.

[0019] In another aspect, the present disclosure provides a drug comprising one or more compounds that inhibit FAK, SRC, and / or JAK2, or pharmaceutically acceptable salts thereof, combined with a substance that inhibits KRAS G12C, or a pharmaceutically acceptable salt thereof, in a fixed or free combination.

[0020] In another aspect, the present disclosure provides a drug comprising a compound that inhibits FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, combined with a substance that inhibits KRAS G12C, or a pharmaceutically acceptable salt thereof, in a fixed or free combination.

[0021] In another aspect, the present disclosure provides a synergistic composition of one or more compounds that inhibit FAK, SRC and / or JAK2 and a substance that inhibits KRAS G12C, wherein the two components are in contact with each other at one location.

[0022] In another aspect, the present disclosure provides a synergistic composition of compounds that inhibit FAK, SRC, and JAK2 and a substance that inhibits KRAS G12C, wherein the two components are in contact with each other in situ.

[0023] In another aspect, the present disclosure provides a synergistic composition of one or more compounds that inhibit FAK, SRC and / or JAK2, and a substance that inhibits KRAS G12C, wherein the two components come into contact with each other only within the human body.

[0024] In another aspect, the present disclosure provides a synergistic composition of compounds that inhibit FAK, SRC, and JAK2, and a substance that inhibits KRAS G12C, wherein the two components come into contact with each other only within the human body.

[0025] In some embodiments, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I

[0026]

[0027] I

[0028] Here

[0029] M is CR 5 or N;

[0030] X 1 and X 2 is independently -C(R7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0031] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0032] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1- C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0033] R 4 and R5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0034] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0035] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1- Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0036] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0037] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0038] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0039] Or it is a pharmaceutically acceptable salt thereof.

[0040] In some specific embodiments of the above aspects, the compound inhibiting FAK, SRC, and JAK2 is of formula (referred herein as Compound 1)

[0041]

[0042] It is a compound of or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments of the above aspects, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C or a small molecule that inhibits KRAS G12C. In some embodiments of the above aspects, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C. In some embodiments of the above aspects, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C, which is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or siRNA. In some embodiments of the above aspects, at least one substance that inhibits KRAS G12C is a small molecule inhibitor.

[0044] Further embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and the practice of the invention. Compounds of the present disclosure may be described as embodiments in any of the provisions listed below. It will be understood that any embodiment described herein may be used in connection with any other embodiment described herein, to the extent that the embodiments are not contradictory.

[0045] 1. A method for treating cancer in a host animal, such as a human patient requiring treatment, comprising the step of administering to a host animal a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, combined with at least one substance that inhibits KRAS G12C.

[0046] 2. In Item 1, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I.

[0047]

[0048] I

[0049] Here

[0050] M is CR 5 or N;

[0051] X1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0052] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0053] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1- C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0054] R 4 and R5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0055] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0056] Each R 7 and R 8 is 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; wherein 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 a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1- Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0057] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0058] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0059] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0060] A compound of or a pharmaceutically acceptable salt thereof.

[0061] 3. In item 1 or 2, the compound that inhibits FAK, SRC, and JAK2 is of the formula

[0062]

[0063] A compound of or a pharmaceutically acceptable salt thereof.

[0064] 4. In items 1 to 3, cancer refers to ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, pulmonary squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant A method selected from the group consisting of prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer, and lung cancer.

[0065] 5. In any one of items 1 to 4, 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.

[0066] 6. A method in which, in any one of items 1 to 5, the cancer is non-small cell lung cancer.

[0067] 7. A method in which, in any one of items 1 to 5, the cancer is colorectal cancer.

[0068] 8. A method in which, in any one of items 1 to 7, a compound inhibiting FAK, SRC, and JAK2 is administered simultaneously, before, or after at least one substance inhibiting KRAS G12C.

[0069] 9. A method in which IL-6 secretion from cancer is reduced in any one of items 1 to 8.

[0070] 10. A method in which, in any one of items 1 to 9, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0071] 11. A method in which, in any one of items 1 to 10, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C.

[0072] 12. In item 11, the biological substance inhibiting KRAS G12C is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0073] 13. A method in which, in any one of items 1 to 10, at least one substance that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0074] 14. A method in which, in any one of items 1 to 10 or 13, at least one substance that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0075] 15. A method in which, in any one of items 1 to 10, 13 or 14, at least one substance inhibiting KRAS G12C is AMG-510 or a pharmaceutically acceptable salt thereof.

[0076] 16. A method in which, in any one of items 1 to 10, 13 or 14, at least one substance inhibiting KRAS G12C is MRTX849 or a pharmaceutically acceptable salt thereof.

[0077] 17. In any one of the preceding items, the compound inhibiting 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; A method in which at least one substance that inhibits KRAS 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.

[0078] 18. In any one of items 1 to 16, the compound inhibiting 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 the KRAS G12C A method in which at least one substance 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.

[0079] 19. A method in which, in any one of the preceding items, the host animal is a human patient in need of treatment who has not received prior treatment.

[0080] 20. A method in any one of items 1 to 18, wherein the host animal is a human patient in need of treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents.

[0081] 21. A method in which, in any one of items 1 to 18 or 20, the host animal is a human patient requiring treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents and has developed acquired resistance to treatment and / or developed bypass resistance to treatment and / or developed bypass resistance to treatment controlled by FAK, SRC or JAK2.

[0082] 22. A compound that inhibits FAK, SRC, and JAK2 in combination with at least one substance that inhibits KRAS G12C in a therapeutically effective amount for use in the treatment of cancer in patients, or a pharmaceutically acceptable salt thereof.

[0083] 23. In Item 22, the compound that inhibits FAK, SRC, and JAK2 is the compound of Formula I.

[0084]

[0085] I

[0086] Here

[0087] M is CR 5 or N;

[0088] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0089] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0090] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0091] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0092] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0093] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0094] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0095] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0096] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0097] or a pharmaceutically acceptable salt thereof.

[0098] 24. In item 22 or 23, the compound that inhibits FAK, SRC, and JAK2 is of the formula

[0099]

[0100] A compound of or a pharmaceutically acceptable salt thereof.

[0101] 25. In any one of items 22 to 24, 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, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, A compound selected from the group consisting of castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer and lung cancer.

[0102] 26. A compound in which, in any one of items 22 to 25, 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.

[0103] 27. A compound in which, in any one of items 22 to 26, the cancer is non-small cell lung cancer.

[0104] 28. A compound in which, in any one of items 22 to 26, the cancer is colorectal cancer.

[0105] 29. A compound in any one of items 22 to 28, wherein the method comprises administering a compound that inhibits FAK, SRC, and JAK2 simultaneously, before, or after at least one substance that inhibits KRAS G12C.

[0106] 30. A compound in which IL-6 secretion from cancer is reduced in any one of items 22 to 29.

[0107] 31. In any one of items 22 to 30, the at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C or a compound that is a small molecule inhibitor of KRAS G12C.

[0108] 32. In any one of items 22 to 31, at least one substance that inhibits KRAS G12C is a compound that is a biological substance that inhibits KRAS G12C.

[0109] 33. In item 32, the biological substance that inhibits KRAS G12C is a compound that is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0110] 34. In any one of items 22 to 31, at least one substance that inhibits KRAS G12C is a compound that is a small molecule inhibitor of KRAS G12C.

[0111] 35. In any one of items 22 to 31 or 34, at least one substance that inhibits KRAS G12C is a compound that is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0112] 36. In any one of items 22 to 31, 34, or 35, at least one substance that inhibits KRAS G12C is a compound that is AMG-510 or a pharmaceutically acceptable salt thereof.

[0113] 37. In any one of items 22 to 31, 34, or 35, at least one substance that inhibits KRAS G12C is a compound that is MRTX849 or a pharmaceutically acceptable salt thereof.

[0114] 38. In any one of items 22 to 37, the compound inhibiting 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; At least one substance that inhibits KRAS G12C is a compound 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.

[0115] 39. In any one of items 22 to 37, the compound inhibiting 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 the KRAS G12C At least one inhibiting substance is a compound 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.

[0116] 40. In any one of items 22 to 39, the patient has not received prior treatment for the compound.

[0117] 41. In any one of items 22 to 39, the patient has received prior treatment with one or more chemotherapy agents or immunotherapy agents.

[0118] 42. In any one of items 22 to 39, the patient has received prior treatment with one or more chemotherapy agents or immunotherapy agents, and has developed acquired resistance to treatment, and / or has developed bypass resistance to treatment, and / or has developed bypass resistance to a compound regulated by FAK, SRC, or JAK2.

[0119] 43. Use of a compound inhibiting FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, in the preparation of a drug comprising a therapeutically effective amount of a compound inhibiting FAK, SRC, and JAK2 in combination with at least one substance inhibiting KRAS G12C for treating cancer in a patient.

[0120] 44. In Item 43, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I

[0121]

[0122] I

[0123] Here

[0124] M is CR 5 or N;

[0125] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0126] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0127] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0128] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0129] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0130] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0131] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0132] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0133] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0134] or a pharmaceutically acceptable salt thereof.

[0135] 45. In item 43 or 44, the compound that inhibits FAK, SRC, and JAK2 is of the formula

[0136]

[0137] A compound of or a pharmaceutically acceptable salt thereof.

[0138] 46. ​​In any one of items 43 to 45, 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, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, Uses selected from the group consisting of castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer and lung cancer.

[0139] 47. In any one of items 43 to 46, 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.

[0140] 48. Use in any one of items 43 to 46, wherein the cancer is non-small cell lung cancer.

[0141] 49. In any one of items 43 to 46, the cancer is colorectal cancer.

[0142] 50. In any one of items 43 to 49, the agent comprising a compound that inhibits FAK, SRC, and JAK2 is used for administration to a patient prior to or after, simultaneously with at least one substance that inhibits KRAS G12C.

[0143] 51. Use in which IL-6 secretion from cancer is reduced in any one of items 43 to 50.

[0144] 52. In any one of items 43 to 51, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0145] 53. In any one of items 43 to 52, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C.

[0146] 54. In any one of items 43 to 53, the biological material inhibiting KRAS G12C is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0147] 55. In any one of items 43 to 52, at least one substance that inhibits KRAS G12C is used as a small molecule inhibitor of KRAS G12C.

[0148] 56. Use in any one of items 43 to 52 or 55, wherein at least one material that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0149] 57. Use in any one of items 43 to 52, 55, or 56, wherein at least one substance inhibiting KRAS G12C is AMG-510 or a pharmaceutically acceptable salt thereof.

[0150] 58. Use in any one of items 43 to 52, 55, or 56, wherein at least one substance inhibiting KRAS G12C is MRTX849 or a pharmaceutically acceptable salt thereof.

[0151] 59. In any one of items 43 to 58, the compound inhibiting FAK, SRC, and JAK2 is 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 substance that inhibits KRAS 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 for use in a pharmaceutical product.

[0152] 60. In any one of items 43 to 58, the compound inhibiting FAK, SRC, and JAK2 is 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 that inhibits KRAS G12C. The substance 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 for use in a pharmaceutical preparation.

[0153] 61. In any one of items 43 to 60, the patient has not received prior treatment for the use.

[0154] 62. In any one of items 43 to 60, use for which the patient has received prior treatment with one or more chemotherapy agents or immunotherapy agents.

[0155] 63. Use in any one of items 43 to 60 or 62, wherein the patient has received prior treatment with one or more chemotherapy agents or immunotherapy agents, and has developed acquired resistance to treatment, and / or has developed bypass resistance to treatment, and / or has developed bypass resistance to treatment controlled by FAK, SRC, or JAK2.

[0156] 64. A composition comprising, in a therapeutically effective amount, a compound inhibiting FAK, SRC, and JAK2 in combination with at least one substance inhibiting KRAS G12C, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in patients.

[0157] 65. In Item 64, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I

[0158]

[0159] I

[0160] Here

[0161] M is CR 5 or N;

[0162] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0163] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0164] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0165] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0166] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0167] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0168] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0169] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0170] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0171] or a pharmaceutically acceptable salt thereof.

[0172] 66. In item 64 or 65, the compound that inhibits FAK, SRC, and JAK2 is of the formula

[0173]

[0174] A compound of or a pharmaceutically acceptable salt thereof.

[0175] 67. In any one of items 64 to 66, 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, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade brain glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, A composition selected from the group consisting of castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer, and lung cancer.

[0176] 68. A composition in which, in any one of items 64 to 67, 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.

[0177] 69. A composition in which, in any one of items 64 to 68, the cancer is non-small cell lung cancer.

[0178] 70. A composition in which, in any one of items 64 to 68, the cancer is colorectal cancer.

[0179] 71. A composition comprising a compound that inhibits FAK, SRC, and JAK2 in any one of items 64 to 70, which is administered to a patient before or after, simultaneously with at least one substance that inhibits KRAS G12C.

[0180] 72. A composition in which IL-6 secretion from cancer is reduced in any one of items 64 to 71.

[0181] 73. A composition in any one of items 64 to 72, wherein at least one substance inhibiting KRAS G12C is a biological substance inhibiting KRAS G12C or a small molecule inhibitor of KRAS G12C.

[0182] 74. A composition in any one of items 64 to 73, wherein at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C.

[0183] 75. In item 74, the biological material inhibiting KRAS G12C is a composition that is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0184] 76. A composition in any one of items 64 to 73, wherein at least one substance inhibiting KRAS G12C is a small molecule inhibitor of KRAS G12C.

[0185] 77. A composition in which at least one substance inhibiting KRAS G12C in any one of items 64 to 73 or 76 is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0186] 78. A composition in any one of items 64 to 73, 76, or 77, wherein at least one substance inhibiting KRAS G12C is AMG-510 or a pharmaceutically acceptable salt thereof.

[0187] 79. A composition in any one of items 64 to 73, 76, or 77, wherein at least one substance inhibiting KRAS G12C is MRTX849 or a pharmaceutically acceptable salt thereof.

[0188] 80. In any one of items 64 to 79, the compound inhibiting 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; A composition in which at least one substance that inhibits KRAS 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.

[0189] 81. In any one of items 64 to 79, the compound inhibiting 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 the KRAS G12C A composition in which at least one inhibiting substance 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.

[0190] 82. In any one of items 64 to 81, the host animal is a human patient requiring treatment and the composition has not received prior treatment.

[0191] 83. A composition in any one of items 64 to 81, wherein the host animal is a human patient in need of treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents.

[0192] 84. In any one of items 64 to 81 or 83, the host animal is a human patient requiring treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents, and / or has developed acquired resistance to treatment or bypass resistance to treatment, and / or has developed bypass resistance to treatment controlled by FAK, SRC or JAK2.

[0193] 85. A preparation comprising a compound that inhibits FAK, SRC, and JAK2, or a pharmaceutically acceptable salt thereof, combined with at least one substance that inhibits KRAS G12C, either in a fixed or free combination.

[0194] 86. In Item 85, the compound that inhibits FAK, SRC, and JAK2 is the compound of Formula I

[0195]

[0196] I

[0197] Here

[0198] M is CR 5 or N;

[0199] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0200] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, -NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0201] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0202] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0203] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0204] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0205] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0206] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0207] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0208] Or a pharmaceutically acceptable salt thereof.

[0209] 87. In item 85 or 86, the compound that inhibits FAK, SRC and JAK2 is of the formula

[0210]

[0211] A pharmaceutical agent that is a compound of or a pharmaceutically acceptable salt thereof.

[0212] 88. In any one of items 85 to 87, the drug is for ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, A drug that provides a synergistic effect against cancers selected from the group consisting of castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer, and lung cancer.

[0213] 89. A drug in which, in any one of items 85 to 88, 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.

[0214] 90. A drug in which, in any one of items 85 to 89, the cancer is non-small cell lung cancer.

[0215] 91. A drug in which, in any one of items 85 to 89, the cancer is colorectal cancer.

[0216] 92. A drug in which, in any one of items 85 to 89, the cancer is pancreatic cancer.

[0217] 93. A drug that reduces IL-6 secretion from cancer in any one of items 85 to 92.

[0218] 94. In any one of items 85 to 93, at least one substance that inhibits KRAS G12C is a biological substance that inhibits KRAS G12C or a drug that is a small molecule inhibitor of KRAS G12C.

[0219] 95. In any one of items 85 to 94, at least one substance that inhibits KRAS G12C is a drug that is a biological substance that inhibits KRAS G12C.

[0220] 96. In Item 95, the biological substance inhibiting KRAS G12C is a drug that is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0221] 97. In any one of items 85 to 95, at least one substance that inhibits KRAS G12C is a drug that is a small molecule inhibitor of KRAS G12C.

[0222] 98. In any one of items 85 to 95 or 97, at least one substance that inhibits KRAS G12C is a drug that is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0223] 99. In any one of items 85 to 95, 97 or 99, at least one substance that inhibits KRAS G12C is a drug that is AMG-510 or a pharmaceutically acceptable salt thereof.

[0224] 100. In any one of items 85 to 95, 97 or 99, at least one substance that inhibits KRAS G12C is a drug that is MRTX849 or a pharmaceutically acceptable salt thereof.

[0225] 101. In any one of items 85 to 100, the compound inhibiting 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; At least one substance that inhibits KRAS G12C is a drug 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.

[0226] 102. In any one of items 85 to 100, the compound inhibiting 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 the KRAS At least one substance that inhibits G12C is a drug 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.

[0227] 103. A synergistic composition of a compound that inhibits FAK, SRC and JAK2 and a substance that inhibits KRAS G12C, wherein the two components are in contact with each other at one location.

[0228] 104. In Item 103, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I

[0229]

[0230] I

[0231] Here

[0232] M is CR 5 or N;

[0233] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0234] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0235] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1- C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0236] R 4 and R5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0237] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0238] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1- Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0239] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0240] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0241] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0242] Or a synergistic composition which is a pharmaceutically acceptable salt thereof.

[0243] 105. In item 103 or 104, the compound that inhibits FAK, SRC and JAK2 is of the formula

[0244]

[0245] A synergistic composition that is a compound of or a pharmaceutically acceptable salt thereof.

[0246] 106. An synergistic composition in any one of items 103 to 105, wherein the place is cancer or cancer cells.

[0247] 107. In any one of items 103 to 106, the place is ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade brain glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic kidney, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin skin A synergistic composition of cancer selected from the group consisting of melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colorectal cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, gastric cancer and lung cancer.

[0248] 108. An synergistic composition in which the cancer in Item 107 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.

[0249] 109. In item 107, the cancer is a non-small cell lung cancer, and the synergistic composition.

[0250] 110. In item 107, the cancer is a colorectal cancer, and the synergistic composition.

[0251] 111. In item 107, the cancer is pancreatic cancer, a synergistic composition.

[0252] 112. An synergistic composition in which IL-6 secretion from cancer is reduced in any one of items 106 to 111.

[0253] 113. In any one of items 103 to 112, the substance inhibiting KRAS G12C is a biological substance inhibiting KRAS G12C or a synergistic composition that is a small molecule inhibitor of KRAS G12C.

[0254] 114. In any one of items 103 to 113, the substance that inhibits KRAS G12C is a synergistic composition in which the substance inhibiting KRAS G12C is a biological substance that inhibits KRAS G12C.

[0255] 115. In item 114, the biological material inhibiting KRAS G12C is a synergistic composition in which the biological material is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0256] 116. A synergistic composition in which at least one substance inhibiting KRAS G12C is a small molecule inhibitor of KRAS G12C, in any one of items 103 to 112.

[0257] 117. An synergistic composition in which at least one material inhibiting KRAS G12C in any one of items 103 to 112 or 116 is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0258] 118. A synergistic composition in which at least one substance inhibiting KRAS G12C in any one of items 103 to 112, 116, or 117 is AMG-510 or a pharmaceutically acceptable salt thereof.

[0259] 119. A synergistic composition in which at least one substance inhibiting KRAS G12C in any one of items 103 to 112, 116, or 117 is MRTX849 or a pharmaceutically acceptable salt thereof.

[0260] 120. In any one of items 103 to 119, the compound inhibiting 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; The above-mentioned KRAS G12C inhibiting at least one substance is an synergistic composition 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.

[0261] 121. In any one of items 103 to 119, the compound inhibiting 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 the KRAS At least one substance that inhibits G12C is an synergistic composition 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.

[0262] 122. In any one of items 106 to 119, a synergistic composition in which the cancer or cancer cells were previously in contact with at least one prior treatment of a chemotherapy agent or an immunotherapy agent.

[0263] 123. An synergistic composition in any one of items 106 to 119, wherein the cancer or cancer cells have been previously exposed to at least one prior treatment of a chemotherapy agent or an immunotherapy agent, and / or have developed acquired resistance to the treatment, or have developed bypass resistance to the treatment, and / or have developed bypass resistance to the treatment regulated by FAK, SRC, or JAK2.

[0264] 124. A synergistic composition of a compound inhibiting FAK, SRC and JAK2 and a substance inhibiting KRAS G12C, wherein the two components come into contact with each other only within the human body.

[0265] 125. In Item 124, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I

[0266]

[0267] I

[0268] Here

[0269] M is CR 5 or N;

[0270] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0271] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1- C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0272] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -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 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0273] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0274] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0275] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0276] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0277] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0278] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0279] Or a synergistic composition which is a pharmaceutically acceptable salt thereof.

[0280] 126. In item 124 or 125, the compound that inhibits FAK, SRC and JAK2 is of the formula

[0281]

[0282] A synergistic composition that is a compound of or a pharmaceutically acceptable salt thereof.

[0283] 127. In any one of items 124 to 126, the substance inhibiting KRAS G12C is a biological substance inhibiting KRAS G12C or a small molecule inhibitor of KRAS G12C, in a synergistic composition.

[0284] 128. In any one of items 124 to 127, the substance that inhibits KRAS G12C is a synergistic composition in which the substance inhibiting KRAS G12C is a biological substance that inhibits KRAS G12C.

[0285] 129. In item 128, the biological material inhibiting KRAS G12C is a synergistic composition in which the biological material is an antibody, antibody fragment, peptide, oligonucleotide, ribonucleic acid, or siRNA.

[0286] 130. A synergistic composition in which at least one substance inhibiting KRAS G12C is a small molecule inhibitor of KRAS G12C, in any one of items 124 to 128.

[0287] 131. An synergistic composition in which at least one material inhibiting KRAS G12C in any one of items 124 to 128 or 130 is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007.

[0288] 132. A synergistic composition in which at least one substance inhibiting KRAS G12C in any one of items 124 to 128, 130 or 131 is AMG-510 or a pharmaceutically acceptable salt thereof.

[0289] 133. A synergistic composition in which at least one substance inhibiting KRAS G12C in any one of items 124 to 128, 130 or 131 is MRTX849 or a pharmaceutically acceptable salt thereof.

[0290] 134. In any one of items 124 to 133, the compound inhibiting 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; The above-mentioned KRAS G12C inhibiting at least one substance is an synergistic composition 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.

[0291] 135. In any one of items 124 to 133, the compound inhibiting 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 the above KRAS At least one substance that inhibits G12C is an synergistic composition 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.

[0292] 136. In any one of items 124 to 135, the human body is an synergistic composition that has not received prior treatment.

[0293] 137. In any one of items 124 to 135, a synergistic composition in which the human body has received at least one prior treatment of a chemotherapy agent or an immunotherapy agent.

[0294] 138. An synergistic composition in any one of items 124 to 135 or 137, wherein the host animal has received prior treatment with one or more chemotherapy agents or immunotherapy agents, and / or has developed acquired resistance to treatment, or has developed bypass resistance to treatment, and / or has developed bypass resistance to treatment controlled by FAK, SRC, or JAK2, and is a human patient requiring treatment. Brief explanation of the drawing

[0295] Figure 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 with KRAS G12C mutation after 24 hours. Figure 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 with KRAS G12C mutation after 48 hours. Figure 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 with KRAS G12C mutation after 24 hours. Figure 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 with KRAS G12C mutation after 48 hours. Figure 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 with KRAS G12C mutation after 24 hours. Figure 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 with KRAS G12C mutation after 48 hours. Figure 2a is a chart showing the 2D dose-response matrix of H2122 cells after treatment with compound 1 and KRAS inhibitor AMG-510 at various concentrations of compound 1 from 0 nM to 3000 nM and KRAS inhibitor AMG-510 from 0 nM to 10000 nM. Figure 2b is a chart showing the 2D dose-response matrix of H2122 cells after treatment with compound 1 and KRAS inhibitor MRTX849 at various concentrations of compound 1 from 0 nM to 3000 nM and KRAS inhibitor MRTX849 from 0 nM to 10000 nM. Figure 3a is a graph showing reduced IL-6 secretion in H358 and H2122 NSCLC cell lines treated with a combination of Compound 1 and AMG-510 for 48 h. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. Figure 3b is a chart showing the reduced 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 h. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. Figure 3c is a chart showing the reduced secretion of IL-6, IGFBP-4, and NAP-2 in H2122 cells treated with a combination of Compound 1 and AMG-510 for 48 h. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. Figure 3d is a chart showing the reduced 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 h. (a) Control; (b) AMG-510; (c) Compound 1; (d) Compound 1 + AMG-510. Figure 3e is a graph showing reduced IL-6 secretion in H2122 NSCLC cell lines treated with the combination of Compound 1 and MRTX849 for 48 h. (a) Control; (b) MRTX849; (c) Compound 1; (d) Compound 1 + MRTX849. Figure 3f is an ELISA assay showing reduced IL-6 secretion in H2122 NSCLC cell lines treated with a combination of compound 1 and MRTX849 for 48 h. Figure 3g is a graph showing the effects of compound 1 alone, MRTX849 alone, and a combination of compound 1 and MRTX849 on IL6 mRNA expression in H2122 cells after 24 and 48 hours of treatment. Figure 4a is a chart showing the antitumor effect of Compound 1 combined with AMG-510 in H358 cell-derived xenograft tumors carrying the KRAS G12C mutation. (●) Control group; (▼) 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 is a chart showing the body weight of mice carrying H358 cell-derived tumors with KRAS G12C mutations upon treatment with Compound 1 combined with AMG-510. (●) Control group; (▼) 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 is a chart showing the antitumor effect of Compound 1 combined with AMG-510 in the LU11693 PDX model carrying 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 group; (■) 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 is a chart showing the body weight of LU11693 PDX mice carrying the KRAS G12C mutation upon treatment with Compound 1 combined 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 group; (■) 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 is a chart showing the effect of Compound 1 combined with AMG-510 on survival in an H2122 cell-derived xenograft tumor model carrying a KRAS G12C mutation. The dose level of AMG-510 was 10 mg / kg QD. ( ) Control group; ( ) 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 is a chart showing the effect of Compound 1 combined with AMG-510 on survival in an H2122 cell-derived xenograft tumor model carrying a KRAS G12C mutation. The dose level of AMG-510 was 30 mg / kg QD. ( ) Control group;. ( ) Compound 1 (15 mg / kg BID); ( ) AMG-510 (30 mg / kg QD); ( ) Compound 1 (15 mg / kg BID) + AMG-510 (30 mg / kg QD). Specific details for implementing the invention

[0296] details

[0297] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described and, of course, may be modified. Furthermore, it should be understood that the terms used herein are intended merely to describe specific embodiments and are not intended to be restrictive, and that the scope of the invention is limited only by the appended claims.

[0298] 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 the present invention pertains. All patents, applications, published applications, and other publications mentioned herein are incorporated by reference in their entirety. In the event that the definitions described in this section conflict with or do not align with the definitions described in any patent, application, published application, and other publication incorporated by reference herein, the definitions described in this section shall prevail over the definitions incorporated by reference.

[0299] The single forms "a," "an," and "the" used herein and in the claims include plural references unless the context clearly indicates otherwise. It is further noted that the claims may be drafted to exclude any optional elements. As such, this statement is intended to serve as a precedent for the use of exclusive terms such as "sole," "only," etc., in connection with the citation of claim elements or the use of "negative" limitations.

[0300] The terms "including," "containing," and "including" as used herein are used in an open and non-restrictive sense.

[0301] To provide a more concise explanation, some of the quantitative expressions provided herein are not limited to the term “about.” Regardless of whether the term “about” is explicitly used, all quantities provided herein are understood to mean actual given values, and also to mean approximations of such given values ​​that would be reasonably inferred based on the ordinary knowledge of the art, including equivalents and approximations resulting from experimental and / or measurement conditions for such given values. Whenever a yield is given as a percentage, such yield refers to the mass of the individual for which the yield is given relative to the maximum amount of the same individual that can be obtained under specific stoichiometric conditions. Concentrations expressed as percentages represent mass ratios unless otherwise indicated.

[0302] 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 the present invention pertains. Any methods and materials similar or equivalent to those described herein may also be used to practice or test the present invention, but preferred methods and materials are described hereafter. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials cited therein.

[0303] The methods and techniques of the present embodiment are generally carried out, unless otherwise indicated, in accordance with conventional methods as described in various general and more specific references well known in the art and cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0304] The chemical nomenclature for the compounds described in this specification was generally derived using commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0305] For clarity, it is understood that specific features of the invention described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination. All combinations of embodiments belonging to the chemical group indicated by the variable are specifically included in the invention and are disclosed herein as if each and every combination were individually and explicitly disclosed, and such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all sub-combinations of the chemical group listed in the embodiments describing these variables are specifically included in the invention and are disclosed herein as if all such sub-combinations of the chemical group were individually and explicitly disclosed herein.

[0306] The method described herein is used to treat a “host animal” with cancer requiring such treatment. In one embodiment, the method described herein may be used for both human clinical medicine and veterinary applications. Accordingly, the “host animal” may be administered with the combination described herein, and the host animal may be a human (e.g., a human patient, aka patient), or in the case of veterinary applications, a laboratory, agricultural animal, or livestock. In one aspect, the host animal may be a human, or an experimental animal such as a rodent (e.g., mouse, rat, etc.).

[0307] As used herein, the term “disease” includes, but is not limited to, cancer, pain, inflammatory diseases, e.g., allergy, asthma, autoimmune disease, 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 accompanied by myelofibrosis.

[0308] As used herein, the term "cancer" refers, without limitation, to ALCL, lung cancer, e.g., non-small cell lung cancer (NSCLC) including adenocarcinoma, pulmonary squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine tumor, small cell lung cancer (SCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, e.g., lumen A, lumen B, triple-negative breast cancer, triple-positive breast cancer, HER 2+ etc., colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, thyroid cancer, e.g. anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric cancer, e.g. gastric adenocarcinoma, colorectal cancer (CRC), inflammatory myofibroblastic tumor, angiosarcoma, epithelioid epithelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, papilloma tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, skin cancer such as cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC), pediatric glioma CML, prostate cancer, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, uterine cancer such as serous and clear cell endometrial cancer, endometrial cancer This includes 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 gastric cancer. The term "cancer" is understood to include both primary cancer or primary tumor and metastatic cancer or metastatic tumor, and to include 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, etc. It is understood that the term "cancer" includes cancer involving the upregulation of specific genes or genetic mutations that can cause disease progression, such as small GTPases (e.g., KRAS, etc.) and receptor tyrosine kinases such as EGFR, etc.

[0309] As used herein, the term "substance inhibiting KRAS G12C" includes, but is not limited to, any compound or substance known in the art for selectively inhibiting the KRAS G12C gene, referred herein as K-Ras G12C, or selectively inhibiting the protein encoded by the KRAS G12C gene, in which the K-Ras protein product of the KRAS gene is involved in the RAS / MAPK signaling pathway having a missense mutant G12C. The terms KRAS gene, K-Ras, and RAS / MAPK signaling pathway will be known and understood by those skilled in the art. It will be understood that the KRAS G12C mutation codes for a mutation from glycine to cysteine ​​at position 12 of the K-Ras protein (also known as K-Ras G12C). It will be further understood that the production of the K-Ras G12C protein as the gene product of the KRAS G12C gene may result from a coding sequence mutation, for example, a substitution of guanine to thymine at position 34 of the coding sequence. It will be further understood that the substance inhibiting KRAS G12C may be any substance known in the art that selectively targets the KRAS G12C gene and may include substances such as siRNA, oligonucleotides, ribonucleic acid, etc., which can selectively inhibit or otherwise selectively interfere with the transcription (and / or translation) of the KRAS G12C gene (or the corresponding messenger RNA) into the K-Ras G12C protein. It will be further understood that the substance inhibiting KRAS G12C may be a substance that can selectively inhibit or otherwise selectively interfere with the transcription of KRAS G12C and / or the translation of the corresponding messenger RNA, and the corresponding messenger RNA may be biological substances, for example, siRNA, oligonucleotides, ribonucleic acid, etc.Alternatively, it will be understood that a substance that inhibits KRAS G12C may be a substance that selectively inhibits a protein encoded by the KRAS G12C gene having a coding sequence that produces a K-Ras G12C protein (e.g., 34 of the KRAS coding sequence), and this may be a biological substance, e.g., 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 "substances that inhibit 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 substance inhibiting KRAS G12C is a compound described in U.S. Patent Publication US20180334454, which is incorporated by reference to KRAS G12C (also known as an exemplary small molecule inhibitor of KRAS G12C) and an exemplary substance inhibiting the production thereof. In some embodiments, the substance inhibiting KRAS G12C is AMG510 having the following formula.

[0310]

[0311] Or it is a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the substance inhibiting KRAS G12C is a compound described in U.S. Patent Publications US20190270743 and US20190144444, which are incorporated by reference to KRAS G12C (also known as an exemplary small molecule inhibitor of KRAS G12C) and exemplary substances inhibiting the production thereof. In some embodiments, the substance inhibiting KRAS G12C is MRTX849 having the following formula

[0313]

[0314] Or it is a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the substance that inhibits KRAS G12C is AMG-510, MRTX849, or ARS-1620, or a pharmaceutically acceptable salt thereof.

[0316] Chemical definition

[0317] As used herein, the term "alkyl" comprises a chain of carbon atoms that is optionally branched and contains 1 to 20 carbon atoms. In certain embodiments, the alkyl is advantageously C1-C 12 , C1-C 10 , C1-C9, C1-C8, C1-C7, It may be a limited length including C1-C6 and C1-C4, and exemplary, C1-C8, C1-C7, It should be further understood that such particularly limited length alkyl groups, including C1-C6, and C1-C4, etc., may be referred to as “lower alkyls.” Exemplary 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, etc. Alkyls may be substituted or unsubstituted. Representative substituents include cycloalkyl, aryl, heteroaryl, heteroallic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, aryltio, 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 those as described in the various embodiments provided herein. It is understood that "alkyl" may be combined with other groups, e.g. provided above, to form a functionalized alkyl group. As an example, a combination of a "carboxy" group and an "alkyl" group as described herein may be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, etc.

[0318] As used herein, the term “alkenyl” comprises a chain of carbon atoms that is optionally branched and contains 2 to 20 carbon atoms, and also comprises at least one carbon-carbon double bond (i.e., C=C). In certain embodiments, the alkenyl is advantageously C2-C 12 It is understood that the alkenyl group may be of a limited length including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Exemplarily, such a particularly limited length alkenyl group including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as a lower alkenyl. The alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butynyl, etc.

[0319] As used herein, the term "alkynyl" comprises a chain of carbon atoms that is optionally branched and contains 2 to 20 carbon atoms, and also comprises at least one carbon-carbon triple bond (i.e., C≡C). In certain embodiments, the alkynyl is each advantageously C2-C 12 It is understood that the alkenyl group may be of a limited length including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Exemplarily, such a particularly limited length alkenyl group including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as a lower alkenyl. The alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary alkenyl groups include, but are not limited to, ethinyl, 1-procinyl, 2-procinyl, 1-, 2-, or 3-butynyl, etc.

[0320] 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 fully conjugated pi-electron system. In certain embodiments, the aryl is advantageously of a limited size, e.g., C6-C 10 It is understood that it may be an aryl. Exemplary 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.

[0321] As used herein, the term “cycloalkyl” refers to a 3 to 15-membered all-carbon monocyclic ring comprising an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring or a multicyclic fused ring (a “fused” ring system means that each ring of the system shares a pair of adjacent carbon atoms of the system), wherein one or more of the rings may comprise one or more double bonds, but the cycloalkyl does not comprise a fully conjugated pi-electron system. In certain embodiments, the cycloalkyl is advantageously of a limited size, e.g., C3-C 13 It is understood that they may be C3-C9, C3-C6, and C4-C6. The cycloalkyl group may be unsubstituted or substituted as described for the alkyl or as described in the various embodiments provided herein. Exemplary cycloalkyl groups are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norborneyl, norbornenyl, 9 H Includes -fluorene-9-yl, etc. An exemplary example of a cycloalkyl group shown in the graphic representation includes the following entities in the form of a suitably bonded moiety:

[0322]

[0323]

[0324]

[0325] As used herein, the term “heterocycloalkyl” refers to a monocyclic or fused ring group having 3 to 12 ring atoms in the ring(s), wherein at least one ring atom is a heteroatom such as nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon atoms. Heterocycloalkyl may optionally contain 1, 2, 3, or 4 heteroatoms. Heterocycloalkyl may also have one or more double bonds, including a double bond to nitrogen (e.g., C=N or N=N), but does not contain a fully conjugated pi-electron system. In certain embodiments, it is understood that heterocycloalkyl may advantageously be of a limited size, e.g., 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, etc. Heterocycloalkyl may be unsubstituted or substituted as described for the alkyl or as described in the various embodiments provided herein. Exemplary heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxephanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, etc. Exemplary examples of heterocycloalkyl groups shown in the graphic representation include the following entities in the form of appropriately bonded moieties:

[0326]

[0327] 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, and the remaining ring atom being a carbon atom, and also having a fully conjugated pi-electron system. In certain embodiments, it will be understood that the heteroaryl may advantageously be of a limited size, such as 3- to 7-membered heteroaryls, 5- to 7-membered heteroaryls, etc. The heteroaryl may be unsubstituted or substituted as described for the alkyl or as described in the various embodiments provided herein. Exemplary heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, furinyl, tetrazolyl, triazinyl, tetrazolyl, triazolyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisosoxazolyl, benzisothiazolyl, and carbazoloyl, etc. Exemplary examples of heteroaryl groups shown in the graphic representation include the following entities in the form of appropriately combined moieties:

[0328]

[0329] As used herein, "hydroxy" or "hydroxyl" refers to the -OH group.

[0330] As used herein, "alkoxy" refers to both -O-(alkyl) and -O-(unsubstituted cycloalkyl) groups. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0331] 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, etc.

[0332] As used in this text, "mercapto" refers to the -SH group.

[0333] 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, etc.

[0334] 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, etc.

[0335] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0336] As used in this text, "cyano" refers to the -CN group.

[0337] The term "oxo" refers to a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0338] As used herein, "bond" refers to a covalent bond.

[0339] The term "substituted" means that a specified group or moiety has one or more substituents. The term "non-substituted" means that a specified group has no substituents. When the term "substituted" is used to describe a structural system, substitution means that an atom of the system occurs at an allowed position. In some embodiments, "substituted" means that a specified group or moiety has one, two, or three substituents. In other embodiments, "substituted" means that a specified group or moiety has one or two substituents. In yet another embodiment, "substituted" means that a specified group or moiety has one substituent.

[0340] As used herein, “arbitrary” or “arbitrary” means that an event or situation described below may occur but is not necessarily required to occur, and this includes cases where the event or situation occurs and cases where it does not occur. For example, “wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, or mono- or bicyclic heteroaryl, is independently optionally substituted with a C1-C6 alkyl group, and C is substituted by the substitution of a hydrogen atom for each alkyl group. 1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 This means that it is either an aryl, or a mono- or bicyclic heteroaryl, but does not necessarily have to occur, which here refers to C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Situations in which an aryl, or a mono- or bicyclic heteroaryl, is substituted with an alkyl group, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10This includes situations where an aryl, or mono- or bicyclic heteroaryl, is not substituted with an alkyl group.

[0341] As used herein, "independently" means that an event or situation subsequently described is read as independent in relation to other similar events or situations. For example, in a situation where several equivalent hydrogen groups are arbitrarily substituted with other groups described in that situation, the use of "independently arbitrarily" means that each case of a hydrogen atom in the group can be substituted with a different group. The substitution of each hydrogen atom may be the same or different. Or, for example, where there are several groups that can all be selected from a set of possibilities, the use of "independently" means that each group can be selected from a set of possibilities separate from the other groups, and that the group selected in that situation may be the same or different.

[0342] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt that opposes an ion that can be used in a pharmaceutical. Generally, see SM Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. A preferred pharmaceutically acceptable salt is a salt that is pharmacologically effective and suitable for contact with the tissues of a target without excessive toxicity, irritation, or allergic reaction. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, functional groups of both types, or one or more of each type, and thus react with a number of inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts. Such salts include:

[0343] (1) an acid addition salt that can be obtained by reacting a free base of a parent compound with an inorganic acid such as hydrochloric acid, hydrobromide, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, etc., or an organic acid 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, etc.; or

[0344] (2) A salt formed when an acidic proton present in a parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucarmine, etc.

[0345] Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be considered in connection with the embodiments described herein. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, caproate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, Includes sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetate, phenylpropionate, phenylbutyrate, citrates, lactates, γ-hydroxybutyrate, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0346] Any formulas provided herein are intended to represent not only the compound of the structural formula but also specific variations or forms. For example, a formula provided herein is intended to represent a racemic form, or one or more enantiomers, diastereomers, or geometric isomers, or a mixture thereof. Additionally, any formula provided herein is also intended to refer to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. For example, the symbol " Compounds depicted by structural formulas containing " are symbol " It includes both stereoisomers for the carbon atom to which " is attached, specifically bonding " " and " Both of them It will be understood that this is included in the meaning of ". For example, in some exemplary embodiments, certain compounds provided herein may be described by the following chemical formulas and

[0347] ,

[0348] This formula is understood to include compounds having all stereochemical arrangements at the relevant carbon atoms, including the following.

[0349] and .

[0350] Specific example

[0351] In some embodiments, the method described herein relates to the treatment of cancer comprising administering a therapeutically effective amount of one or more compounds that inhibit FAK, SRC, and / or JAK2 in combination with a substance that inhibits KRAS G12C to a patient in need of treatment. In some embodiments, the method described herein relates to the treatment of cancer comprising administering a therapeutically effective amount of compounds that inhibit FAK, SRC, and JAK2 in combination with a substance that inhibits KRAS G12C to a patient in need of treatment. It will be understood that an inhibitor is a substance that reduces or inhibits cell surface receptors (i.e., receptor tyrosine kinases) or kinases (i.e., non-receptor tyrosine kinases) or and / or gene transcription and / or translation. It will be understood that a “compound that inhibits FAK, SRC, and JAK2” is a compound having affinity for all three biological targets FAK, SRC, and JAK2.

[0352] The specific compounds described herein have been found to be, surprisingly, inhibitors of FAK, SRC, and JAK2, and have been discovered to be usable in combination with substances that inhibit KRAS G12C to treat cancer in patients requiring such treatment. In some embodiments, a combination of one or more compounds that inhibit FAK, SRC, and / or JAK2 and substances that inhibit KRAS G12C may provide a synergistic response in patients requiring cancer treatment. In some embodiments, a combination of compounds that inhibit FAK, SRC, and JAK2 and substances that inhibit KRAS G12C may provide a synergistic response in patients requiring cancer treatment. In some embodiments, a method for treating cancer comprises administering a combination of a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2 and a therapeutically effective amount of a substance that inhibits KRAS G12C. In some embodiments, the compound inhibiting FAK, SRC, and JAK2 and the substance inhibiting KRAS G12C are co-formulated. In some embodiments, the compound inhibiting FAK, SRC, and JAK2 and the substance inhibiting KRAS G12C are administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC, and JAK2 and the substance inhibiting KRAS G12C are formulated individually and administered simultaneously. In some embodiments, the compound inhibiting FAK, SRC, and JAK2 and the substance inhibiting KRAS G12C are formulated individually and administered sequentially. In some embodiments, sequential administration of the compound inhibiting FAK, SRC, and JAK2 and the substance inhibiting KRAS G12C can be achieved by administering the compound inhibiting FAK, SRC, and JAK2 first, and the substance inhibiting KRAS G12C second.In some embodiments, sequential administration of a compound that inhibits FAK, SRC, and JAK2 and a substance that inhibits KRAS G12C can be achieved by administering the substance that inhibits KRAS G12C first, and then administering the compound that inhibits FAK, SRC, and JAK2 second.

[0353] In some embodiments, the compound inhibiting FAK, SRC, and JAK2 is the compound of Formula I.

[0354]

[0355] I

[0356] Here

[0357] M is CR 5 or N;

[0358] X 1 and X 2 is independently -C(R 7 )(R 8 )-, -S-, -S(O)-, -S(O)2-, -O- or -N(R 9 )-;

[0359] Each R 1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 6- C 10 Aril, -C(O)OR 7 or -C(O)NR 7 R 8 ; Here, C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl and C6-C 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC 1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- Optionally substituted with 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;

[0360] Each R 2 and R 3 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aril, -C(O)OR 7or -C(O)NR 7 R 8 ; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C6-C 10 Each hydrogen atom within the aryl is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC1-C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C 1- C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C1-C6alkyl)S(O)2(C1-C6alkyl) , -NHS(O)NH2, NHS(O)2NH2, -N(C 1- C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C 1- C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -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 optionally substituted with 3- to 7-membered heterocycloalkyl;

[0361] R 4 and R 5 Is Each independently H, fluoro, chloro, bromo, C1-C6 alkyl, -OH, -CN, -OC 1- C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2 or -CF3;

[0362] R 6 is H, C1-C6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl or 3- to 7-membered heterocycloalkyl is independently a halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -CO2H, -CO2C 1- Optionally substituted with C6 alkyl, -CONH2, -CONH(C1-C6 alkyl), CON(C1-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0363] Each R 7 and R 8 is 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; wherein C1-C6 alkyl, C2-C6 alkenyl, C 2- C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in an aryl, or a 5- to 7-membered heteroaryl, is independently deuterium, halogen, -OH, -CN, -OC1-C6alkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -NHC(O)C1-C6alkyl, -N(C1-C6alkyl)C(O)C1-C6alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6alkyl, -N(C1-C6alkyl)C(O)NH2, -N(C1-C6alkyl)C(O)NHC 1- C6alkyl, -NHC(O)N(C1-C6alkyl)2, -N(C 1- C6alkyl)C(O)N(C1-C6alkyl)2, -NHC(O)OC1-C6alkyl, -N(C1-C6alkyl)C(O)OC1-C6alkyl, -NHS(O)(C1-C6alkyl), -NHS(O)2(C1-C6alkyl), -N(C1-C6alkyl)S(O)(C1-C6alkyl), -N(C 1- C6alkyl)S(O)2(C1-C6alkyl) , - NHS(O)NH2, NHS(O)2NH2, -N(C1-C6alkyl)S(O)NH2, -N(C1-C6alkyl)S(O)2NH2, -NHS(O)NH(C1-C6alkyl), -NHS(O)2NH(C1-C6alkyl), -NHS(O)N(C1-C6alkyl)2, -NHS(O)2N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)2NH(C1-C6alkyl), -N(C1-C6alkyl)S(O)N(C1-C6alkyl)2, -N(C1-C6alkyl)S(O)2N(C1-C6alkyl)2, -CO2H, -C(O)OC1-C6alkyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, - S(O)NH(C 1- C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C 1-Optionally substituted with C6alkyl)2, -S(O)2N(C1-C6alkyl)2, -P(C1-C6alkyl)2, -P(O)(C1-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[0364] Each R 9 is 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 mono- or bicyclic heteroaryl; wherein 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 a 5- to 7-membered heteroaryl, is independently a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR 7 Arbitrarily replaced with;

[0365] Each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is independently N, NH, or C(R 10 ), where each R 10 is independently H, deuterium, halogen, C1-C6 alkyl, -O- C1-C6 alkyl, -OH, -NH2, NH(C1-C6 alkyl), -NH(phenyl), -NH(heteroaryl), -CN, or -CF3, and

[0366] Single Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 At least one of them is N or NH;

[0367] Or it is a pharmaceutically acceptable salt thereof.

[0368] In some specific examples, R1 is H or C1-C6 alkyl. In some embodiments, R 1 is H or methyl. In some embodiments, R 1 One of them is H and R 1 The other one is methyl. In some embodiments, R 2 is H. In some embodiments, R 2 is a C1-C6 alkyl. In some embodiments, R 2 One of them is H and R 2 The other one is methyl. In some embodiments, X 1 is -NR 9 -is. In some specific examples, R 9 is H. In some embodiments, X 1 is CHR 7 is. In some embodiments, R 7 is H. In some embodiments, X 2 is -O-. 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.

[0369] The macrocyclic compound disclosed herein as a potent small molecule multi-target kinase inhibitor exhibiting activity against FAK, SRC, and JAK2 is, without limitation, (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-etenopyrazolo[4,3- f ][1,4,8,10]Benzoxatria cyclotridecin-4(5 H It includes )-on (also referred to herein as "Compound 1")).

[0370] .

[0371] Compound 1 possesses properties including pharmacologically mediated antitumor properties through the inhibition of receptor and non-receptor tyrosine kinases. Compound 1 is disclosed in International Patent Publication WO2015 / 112806, which is incorporated herein by reference regarding the preparation of Compound 1.

[0372] In some specific embodiments of the above aspects, the compound inhibiting FAK, SRC, and JAK2 is of the formula

[0373]

[0374] Or it is a pharmaceutically acceptable salt thereof.

[0375] Cancer is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple-negative breast, colorectal adenocarcinoma, glioblastoma, glioblastoma pleomorphic, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioma, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade cerebral glioma, secretory breast carcinoma, mammary gland analog carcinoma, acute myeloid leukemia, congenital mesoblastic renal cell, congenital fibrosarcoma, pH-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, pulmonary squamous carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous and It will be understood that clear cell cancer may be any cancer mediated by or associated with KRAS G12C, or KRAS G12C upregulation, including 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, gastric cancer, and lung cancer.

[0376] In some embodiments, the present disclosure provides a method for treating a disease in a patient who has not received prior treatment. In some embodiments, the present disclosure provides a method for treating a disease in a patient who has received prior treatment with one or more therapeutic agents. In some embodiments, the patient has previously been treated with one or more chemotherapy agents. In another embodiment, the patient has previously been treated with one or more chemotherapy agents or immunotherapy and has developed acquired resistance to treatment. In another embodiment, the patient has previously been treated with one or more chemotherapy agents or immunotherapy and has developed bypass resistance to treatment. In another embodiment, the patient has previously been treated with one or more chemotherapy agents or immunotherapy and has developed bypass resistance to treatment controlled by FAK, SRC, or JAK2 and / or FAK.

[0377] Other chemotherapeutic agents that may treat a patient prior to treatment with one or more of the compounds or biological substances described herein include, but are not limited to, kinase inhibitors, adrenocorticoids and corticosteroids, alkylating agents, peptides and peptide-mimicking signaling inhibitors, anti-androgens, anti-estrogens, androgens, aclamycin and aclamycin derivatives, estrogens, antimetabolites, platinum compounds, amanitin, plant alkaloids, mitomycin, discodermolid, microtubule inhibitors, epotillone, anti-inflammatory and pro-inflammatory agents, purine analogs, pyrimidine analogs, camptothecin, dolastatin, or immunotherapy. In some embodiments, the patient received prior treatment for NSCLC such as pembrolizumab, platinum, platinum doublet, pemetrexid, carboplatin, paclitaxel, bevacizumab, atezolizumab, Abraxane, and combinations thereof. In some embodiments, the patient received prior treatment for NSCLC, which is a standard of care using one or more substances selected from the group consisting of pembrolizumab, platinum, platinum doublet, pemetrexid, carboplatin, paclitaxel, bevacizumab, atezolizumab, and abraxane.

[0378] In some embodiments, patients received prior treatment for colorectal cancer such as fluorouracil (5-FU), leucovorin, irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, pemborizumab, nivolumab, ipilimumab, encorafenib, binimetinib, and combinations thereof. In some embodiments, the patient receives a prior standard treatment for colorectal cancer using one or more substances selected from the group consisting of 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-aflibercept, or ramucirumab; FOLFOXIRI (i.e., irinotecan, irinotecan, leucovorin, 5-FU), irinotecan + cetuximab, panitumumab, or amucirumab, pemborizumab, nivolumab, nivolumab + ipilimumab, encorafenib, and binimetinib. Received treatment.

[0379] In some embodiments, the patient received prior treatment for pancreatic cancer such as fluorouracil (5-FU), leucovorin, irinotecan, liposomal irinotecan, oxaliplatin, gemcitabine, abraxane, erlotinib, capecitabine, and combinations thereof. In some embodiments, the patient received prior treatment for pancreatic cancer that is standard treatment using one or more substances 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.

[0380] In some embodiments, the patient received prior treatment for uterine cancer (also known as endometrial cancer), such as carboplatin, cisplatin, paclitaxel, docetaxel, doxorubicin, liposomal doxorubicin, trastuzumab, topotecan, bevacizumab, temsirolimus tamoxifen, fulvestrant, aromatase inhibitors, and combinations thereof. In some embodiments, the patient received prior treatment for pancreatic cancer, which is standard treatment using one or more substances selected from the group consisting of carboplatin + paclitaxel + / - trastuzumab, carboplatin or cisplatin + docetaxel, doxorubicin, or paclitaxel, liposomal doxorubicin, topotecan, bevacizumab, temsirolimus tamoxifen, fulvestrant, and aromatase inhibitors.

[0381] It will be understood that a substance inhibiting KRAS G12C for use in connection with the combination therapy described herein may be any substance inhibiting KRAS G12C as defined herein. Suitable examples of substances inhibiting KRAS G12C include antibodies against KRAS G12C, siRNA, ribonucleic acid, peptides, oligonucleotides, small molecule inhibitors of KRAS G12C (as described herein), etc. In some embodiments, the substance inhibiting KRAS G12C may be AMG-510, MRTX849, JNJ-74699157 (also known as ARS-3248), ARS-1620, MRTX1257, RM-007, or ADT-007.

[0382] Pharmaceutical composition

[0383] For therapeutic purposes, a pharmaceutical composition comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic and biologically suitable for administration to a target body. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, volume enhancers, emulsifiers, or flavor modifiers. In a preferred embodiment, the pharmaceutical composition according to the present invention is a sterile composition. The pharmaceutical composition may be prepared using known or available formulation techniques.

[0384] Sterilization compositions comprising compositions that comply with national and regional regulations governing such compositions are also considered by the present invention.

[0385] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in a suitable pharmaceutical solvent or carrier, or as pills, tablets, lozenges, suppositories, sachets, coated tablets, granules, powders, reconstitution powders, or capsules with a solid carrier according to conventional methods known in the art for the preparation of various dosage forms. The pharmaceutical compositions of the present invention may be administered by an appropriate delivery route such as oral, parenteral, rectal, nasal, topical, or ocular routes, or inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0386] For oral administration, the compounds of the present invention may be provided in solid forms, such as tablets or capsules, or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of the present invention may be formulated in dosages, for example, about 0.1 mg to 2 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Alternative exemplary 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 comprise active ingredient(s) mixed with suitable pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorings, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugars, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginate are exemplary disintegrants. Binders may include starch and gelatin. Lubricants may be magnesium stearate, stearic acid, or talc, if present. If desired, tablets may be coated with a substance such as glyceryl monostearate or glyceryl distearate, or coated with an enteric coating, to delay absorption in the gastrointestinal tract.

[0387] Oral capsules include hard and soft gelatin capsules. To manufacture hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be manufactured by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and di-glycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0388] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be provided as lyophilized or as dry products to be reconstituted with water or other suitable vehicles before use. These liquid compositions may contain pharmaceutically acceptable excipients, e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.; non-aqueous vehicles, e.g., 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); humectants such as lecithin; and optionally flavorings or colorings if desired.

[0389] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the material of the present invention may be provided as a sterile aqueous solution or suspension or a parenterally acceptable oil buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Gorger solution and isotonic sodium chloride. These forms may be provided in unit-dose forms, such as ampoules or single-use injection devices; multi-dose forms, such as vials from which an appropriate dose can be withdrawn; or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion doses of the agent mixed with the pharmaceutical carrier range from about 1 to 1000 µg / kg / min over a period ranging from minutes to days.

[0390] For nasal, inhalation, or oral administration, the pharmaceutical composition of the present invention may be administered, for example, using a spray formulation also containing a suitable carrier. The composition of the present invention may be formulated for rectal administration as a suppository.

[0391] For topical application, the compounds of the present invention are preferably formulated as a cream, ointment, or similar vehicle suitable for topical administration. For topical administration, the compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of the drug to the vehicle. Another method of administering the material of the present invention may utilize a patch formulation that affects transdermal delivery.

[0392] Medication and administration

[0393] In some embodiments of the methods and compositions described herein, one or more compounds that inhibit FAK, SRC, and / or JAK2 in combination with at least one substance that inhibits KRAS G12C in a therapeutically effective amount are administered to a host animal, such as a human patient requiring cancer treatment. In some embodiments of the methods and compositions described herein, compounds that inhibit FAK, SRC, and JAK2 in combination with at least one substance that inhibits KRAS G12C in a therapeutically effective amount, particularly compound 1, are administered to a host animal, such as a human patient requiring cancer treatment.

[0394] As used herein, the term “combined with” refers to the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly Compound 1, together with at least one substance that inhibits KRAS G12C. It will be understood that the administration of at least one substance that inhibits KRAS G12C is “combined with” the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly Compound 1, simultaneously, wherein the one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly Compound 1, are administered prior to the at least one substance that inhibits KRAS G12C, or wherein the one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly Compound 1, are administered after the at least one substance that inhibits KRAS G12C. In addition, when the administration of one or more compounds that inhibit FAK, SRC, and / or JAK2, particularly compound 1, occurs simultaneously with the administration of one or more substances that inhibit KRAS G12C, the administered compound may be co-formulated into a composition or medicine, or administered simultaneously with a separate composition or medicine.

[0395] As used herein, the term "therapeutic effective dose" refers to the amount of an active compound or agent that induces a biological or medical response in a patient, including the alleviation of symptoms of the disease or disorder being treated. In one aspect, a therapeutic effective dose is an amount capable of treating or alleviating a disease or symptom. The specific therapeutic effective dose level for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, the route of administration, and the elimination rate of the specific compound used; between treatment groups; drugs used with or simultaneously with the specific compound used; and similar factors.

[0396] In some embodiments, the therapeutically effective dose of the combination may be a synergistic combination that provides an enhanced response to treatment compared to when one or more compounds inhibiting FAK, SRC, and / or JAK2 and at least one substance inhibiting KRAS G12C are administered individually. In some embodiments, the synergistic effect provided by the administration of a therapeutically effective dose of a combination of one or more compounds inhibiting FAK, SRC, and / or JAK2 and at least one substance inhibiting KRAS G12C is a dose response greater than the additive response compared to the response of each component of the combination administered individually.

[0397] In some embodiments, the therapeutically effective dose of the combination may be a synergistic combination that provides an enhanced response to treatment compared to when the compounds inhibiting FAK, SRC, and JAK2, in particular compound 1 and at least one substance inhibiting KRAS G12C are administered individually. In some embodiments, the synergistic effect provided by the administration of the therapeutically effective dose of the combination of compounds inhibiting FAK, SRC, and JAK2, in particular compound 1 and at least one substance inhibiting KRAS G12C, is a dose response greater than the additive response compared to the response of each component of the combination administered individually.

[0398] In some embodiments, exemplary doses for each compound or substance in the various methods and compositions described herein are individually 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 understood that all possible sub-ranges within the dose ranges described above are considered and described herein. For example, the dose range of about 150 to about 500 mg for compounds inhibiting FAK, SRC, and JAK2, particularly Compound 1, provided in the methods and compositions described herein, includes all doses and ranges that may be necessary based on such factors for determining the therapeutically effective dose as described herein, such as about 150 mg, about 160 mg, 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 It includes doses of 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, and about 500 mg. In some embodiments, the FAK, SRC, and JAK2 inhibiting compound provided in the method and composition described herein, particularly compound 1, may be administered at about 40 mg, about 80 mg, about 120 mg, or about 160 mg.

[0399] In some embodiments, exemplary doses for each compound or substance in the various methods and compositions described herein are individually 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 understood that all possible sub-ranges within the daily dose ranges described above are considered and described herein. For example, the dose range of about 150 to about 500 mg daily for compounds inhibiting FAK, SRC, and JAK2, particularly Compound 1, provided in the methods and compositions described herein, includes all doses and ranges that may be necessary based on such factors for determining the therapeutically effective dose as described herein, such as about 150 mg daily, about 160 mg daily, 170 mg daily, about 180 mg daily, about 190 mg daily, about 200 mg daily, about 210 mg daily, about 220 mg daily, about 230 mg daily, about 240 mg daily, about 250 mg daily, about 260 mg daily, about 270 mg daily, about 280 mg daily, about 290 mg daily, about 300 mg daily, about 310 mg daily, about 320 mg daily, about 330 mg daily, about 340 mg daily, about 350 mg daily, about 360 mg daily, It includes doses of about 370 mg daily, about 380 mg daily, about 390 mg daily, about 400 mg daily, about 410 mg daily, about 420 mg daily, about 430 mg daily, about 440 mg daily, about 450 mg daily, about 460 mg daily, about 470 mg daily, about 480 mg daily, about 490 mg daily, and about 500 mg daily.In some embodiments, the FAK, SRC, and JAK2 inhibiting compound provided in the method and composition described herein, particularly compound 1, may be administered at about 40 mg per day, about 80 mg per day, about 120 mg per day, or about 160 mg per day.

[0400] In some embodiments, alternative exemplary doses for each compound or substance in the various methods and compositions described herein are within the range of about 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 understood that all possible sub-ranges within the dose ranges described above are considered and described herein. For example, the dose range of about 1.0 mg / kg to about 10 mg / kg for compounds inhibiting 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 doses and ranges that may be required based on such factors for determining the therapeutically effective dose as described herein.

[0401] In some embodiments, alternative exemplary doses for each compound or substance in the various methods and compositions described herein are within the range of about 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 understood that all possible sub-ranges within the dose ranges described above are considered and described herein. For example, the dose range of about 1.0 mg / kg to about 10 mg / kg per day for compounds inhibiting FAK, SRC, and JAK2, particularly compound 1, provided in the methods and compositions described herein, includes all doses and ranges that may be required based on such factors for determining the therapeutically effective dose as described herein, such as 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.

[0402] It will be understood that various administration schedules for the administration of each compound or substance administered individually (or together) may be applied to the methods and compositions described herein. It will be understood that the administration schedule for each compound or substance administered individually (or together) in the various methods and compositions described herein may be defined by the cycle of the administration schedule, wherein such cycle is defined by the number of days of treatment, the number of administrations of each compound or substance individually (or together), the total dose of each compound or substance individually (or together), etc. In some embodiments, a host animal, such as a human patient requiring treatment, may be administered each compound or substance administered individually (or together) for at least one cycle, at least two cycles, at least three cycles, at least four cycles, etc. Alternatively, a host animal, such as a human patient requiring treatment, may be administered each compound or substance 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, etc. In some embodiments, it will be understood that the administration schedule for each compound or substance administered individually (or together) in the various methods and compositions described herein may include a rest period during which the compound or substance is not administered, and that such rest period may be measured in days. In some embodiments, the administration schedule for each compound or substance 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 rest period as described herein, followed by another number of cycles.

[0403] In some embodiments, an exemplary administration schedule for each compound or substance individually in the various methods and compositions described herein may include a once-daily 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 administration schedule for each compound or substance in the various methods and compositions described herein may be the same, for example, all compounds or substances in the various methods and compositions described herein are administered as QD, BID, etc. In some embodiments, the administration schedule for each compound or substance in the various methods and compositions described herein may differ from one another, for example, one compound or substance in the various methods and compositions described herein is administered as QD, and another compound or substance in the various methods and compositions described herein is administered as BID. In some embodiments, the administration schedule for each compound or substance in the various methods and compositions described herein may vary within a cycle, for example, one compound or substance of the various methods and compositions described herein is administered as QD for a set number of days (e.g., QD for 1, 2, 3, 4 days, etc.) and then as BID for a set number of days (e.g., BID for 1, 2, 3, 4 days, etc.). In some embodiments, the administration schedule for each compound or substance in the various methods and compositions described herein may be the same or different within a cycle, for example, to match the length of the cycle and to match the length of the cycle, one compound or substance of the various methods and compositions described herein is administered as QD for a set number of days (e.g., QD for 1, 2, 3, 4 days, etc.) and then administered as BID for a set number of days (e.g., BID for 1, 2, 3, 4 days, etc.).

[0404] In some embodiments, compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, and a substance that inhibits KRAS G12C are administered simultaneously. In some embodiments, compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, and a substance that inhibits KRAS G12C are formulated individually and administered simultaneously. In some embodiments, compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, and a substance that inhibits KRAS G12C are formulated individually and administered sequentially. In some embodiments, sequential administration of compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, and a substance that inhibits KRAS G12C can be achieved by administering the compounds that inhibit FAK, SRC, and JAK2, particularly compound 1, first (e.g., in the morning), and the substance that inhibits KRAS G12C second (e.g., in the afternoon or evening). In some embodiments, sequential administration of a compound that inhibits FAK, SRC, and JAK2, particularly compound 1, and a substance that inhibits KRAS G12C can be achieved by administering the substance that inhibits KRAS G12C first (e.g., in the morning), and administering the compound that inhibits FAK, SRC, and JAK2, particularly compound 1, second (e.g., in the afternoon or evening).

[0405] In some embodiments, an exemplary dosing schedule for each compound or substance in the various methods and compositions individually described herein may include administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, for at least one day at a dose level of about 100 mg to about 300 mg QD, followed by administration of a substance 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 the compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, and the substance that inhibits KRAS G12C, particularly AMG510, for the above-described dosing schedule may be performed for 1 to about 20 cycles, wherein each cycle is about 5 to about 20 days. In some embodiments, the administration of compounds inhibiting FAK, SRC, and JAK2, particularly compound 1, and substances inhibiting KRAS G12C, particularly AMG510, according to the above-described dosage schedule may be provided for a set number of days, for example, for about 20 days to about 200 days, permanently, or until the treating physician stops treatment.

[0406] In some embodiments, an exemplary dosing schedule for each compound or substance in the various methods and compositions individually described herein may include administration of a compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, for at least one day at a dose level of about 100 mg to about 300 mg QD, followed by administration of a substance that inhibits KRAS G12C, particularly MRTX849, at a dose level of about 500 mg to about 1 g BID. In some embodiments, administration of the compound that inhibits FAK, SRC, and JAK2, particularly Compound 1, and the substance that inhibits KRAS G12C, particularly MRTX849, for the above-described dosing schedule may be performed for 1 to about 20 cycles, wherein each cycle is about 5 to about 20 days. In some embodiments, the administration of compounds inhibiting FAK, SRC, and JAK2, particularly compound 1, and substances inhibiting KRAS G12C, particularly MRTX849, according to the above-described dosage schedule may be provided for a set number of days, for example, for about 20 days to about 200 days, permanently, or until the treating physician stops treatment.

[0407] Examples

[0408] Chemicals and reagents

[0409] Compound 1 was prepared according to the method described in WO2015 / 112806, specifically refer to Example 90 described herein. WO2015 / 112806 is incorporated herein by reference for the preparation of Compound 1.

[0410] AMG510 was purchased from Active Biochem (catalog number A-9132). The drug was prepared in dimethyl sulfoxide (DMSO) at a concentration of 10-100 mmol / L stock solution and stored at -20°C. Before use, it was further diluted in culture medium to the final concentration. Phospho-STAT3 (Tyr705), phospho-AKT (Ser473), phospho-ERK1 / 2 (Thr202 / Tyr204), phospho-FAK (Tyr576 / 577), STAT3, FAK, SRC, AKT, ERK, PARP, cleaved caspase-3, tubulin, and actin were purchased from Cell Signaling Technology (Beverly, MA).

[0411] cell line

[0412] Human NSCLC cell lines H358, H23, H2122, H1373, and H1792 carrying the KRAS G12C mutation were purchased from the American Type Culture Collection (ATCC). All cell lines were maintained in Roswell Park Memorial Institute medium (RPMI) 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 were routinely evaluated for Mycoplasma contamination.

[0413] In vitro test

[0414] Example 1: Cell viability test

[0415] 2,000 cells per well were seeded into 96- or 384-well white plates and then treated with the indicated compounds for 72 hours (37°C, 5% CO2). Cell proliferation was measured using the CellTiter-Glo luciferase-based ATP detection assay (Promega) according to the manufacturer's protocol. IC50 50 Measurements were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).

[0416] The results regarding cell viability (%) of the KRAS G12C inhibitor (AMG510), Compound 1, and the combination of KRAS inhibitor AMG510 and Compound 1 (1 μM) in KRAS G12C mutant H358, H23, H2122, H1373, and H179 are summarized in Table 1. Although H358, H23, H2122, H1373, and H1792 NSCLC cell lines endogenously express the KRAS G12C mutant, the KRAS G12C inhibitor AMG510 demonstrated moderate to weak inhibition of cell proliferation. The inventors investigated the synergistic effect of Compound 1 (1 μM) combined with AMG510 on cell proliferation in H358, H23, H2122, H1373, and H1792 NSCLC cell lines with KRAS G12C mutants. Compound 1 alone had weak inhibitory activity against H358, H23, H2122, H1373, and H1792 NSCLC cell lines, and IC 50 The range is 1.9–5 μM. A strong synergistic effect was observed with the combination of AMG510 and Compound 1. Compound 1 at a concentration of 1 μM [relative to] H358 cell proliferation, the IC of AMG510 50 The concentration was shifted from 213 nM to 3 nM. This combination caused much more complete inhibition of cell proliferation compared to AMG510 treatment alone in H23, H2122, H1372, and H1792 NSCLC cell lines carrying KRAS G12C mutations.

[0417] Table 1

[0418]

[0419] We also determined the results representing cell viability (%) of the KRAS G12C inhibitor MRTX849, Compound 1, and the combination of KRAS inhibitor MRTX849 and Compound 1 (1 μM) in KRAS G12C mutant H358 and H2122 cells. We investigated the effect of Compound 1 (1 μM) combined with MRTX849 on cell proliferation in H358 and H2122 NSCLC cell lines with KRAS G12C mutations. Compound 1 at a concentration of 1 μM corresponds to the IC50 of MRTX849. 50 It was shifted from 75nM to 11nM for H358 cell proliferation and from 182nM to 42nM for H2122 cell proliferation.

[0420] We determined the results representing cell viability (%) of the KRAS G12C inhibitor ARS-1620, Compound 1, and the combination of the KRAS inhibitor ARS-1620 and Compound 1 (1 μM) in KRAS G12C mutant H358 and H2122 cells. We investigated the effect of Compound 1 (1 μM) combined with ARS-1620 on cell proliferation in H358 and H2122 NSCLC cell lines with KRAS G12C mutations. Compound 1 at a concentration of 1 μM [demonstrates] the IC50 of ARS-1620. 50 It was shifted from 488 nM to 88 nM for H358 cell proliferation and from 1287 nM to 52 nM for H2122 cell proliferation.

[0421] Example 2: Apoptosis Test

[0422] 2,000 cells per well were seeded into 384-well white plates and then treated with compounds for 24 or 48 hours (37°C, 5% CO2). Cellular caspase-3 / 7 activity, a key characteristic of apoptosis, was measured using the CaspaseGlo® 3 / 7 detection assay (Promega) according to the manufacturer's protocol. Results showing the increase in caspase-3 / 7 activity when NSCLC cell lines carrying KRAS G12C mutations (H358, H2122, H1373) were treated with AMG510 (50 nM), Compound 1 (1 μM), and a combination of AMG510 (50 nM) and Compound 1 (1 μM) for 24 and 48 hours are shown in Figures 1a-1f. Compound 1 alone increased caspase-3 / 7 activity in H358 and H2122 NSCLC cell lines (Figs. 1a-1d). AMG510 alone increased caspase-3 / 7 activity in H358, H2122, and H1373 NSCLC cell lines (Figs. 1a-1f). The combination of Compound 1 and AMG510 caused greater caspase-3 / 7 activation in NSCLC cells with the G12C mutation at both 24 and 48 hours compared to treatment with AMG510 alone (Figs. 1a-1f).

[0423] Cleaved PARP and cleaved caspase-3 were evaluated as biomarkers of apoptosis. 500,000 cells per well were seeded into 24-well plates for 24 hours, and then treated with compounds for 4, 24, or 48 hours. After treatment, cells were collected 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 a phosphatase inhibitor (Thermo Scientific). Protein lysates (approx. 20 μg) were digested on a 4-12% Bolt Bis-Tris precast gel containing MES execution buffer (Life Technologies), transferred to a nitrocellulose membrane using a Trans-Blot Turbo Transfer System (Bio-Rad), and detected with antibodies targeting PARP, cleaved Caspase-3, tubulin, and actin (Cell Signaling Technology). The antibodies were typically 4 oThe membranes were gently shaken overnight in C, washed, and incubated with an appropriate HRP-conjugated secondary antibody. The membranes were incubated with a chemiluminescent substrate at room temperature for 5 minutes (SuperSignal West Femto, Thermo Scientific). Chemiluminescent images were acquired using a C-DiGit Imaging system (LI-COR Biosciences). Results for the H358 KRAS G12C NSCLC cell line demonstrated a significant increase in cleaved PARP and cleaved Caspase-3 after 24 and 48 hours of treatment with a 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 slight increase in cleaved PARP and cleaved Caspase-3 proteins. Activation of apoptosis was demonstrated by cleaved PARP and cleaved Caspase-3 in H358 mutant KRAS G12C NSCLC cells after 24 or 48 hours with AMG510 (100 nM), Compound 1 (1 μM), and a combination of AMG510 (100) and Compound 1 (1 μM) after 48 hours. The results in H2122 KRAS G12C NSCLC demonstrated a large increase in cleaved PARP and cleaved Caspase-3 after 48 hours of treatment with the combination of AMG510 (100 nM) and Compound 1 (1 μM). Treatment with AMG510 (100 nM) alone or Compound 1 (1 μM) alone resulted in minimal or no increase in cleaved PARP, and cleaved Caspase-3 was significantly lower than with 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 a combination of AMG510 (100 nM) and compound 1 (1 μM).

[0424] Example 3. Immunoblotting for Cell Kinase Phosphorylation Assay

[0425] 500,000 cells per well were seeded into 6-well or 24-well plates for 24 hours, followed by treatment with compounds for 4, 24, or 48 hours. After treatment, cells were collected 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 a phosphatase inhibitor (Thermo Scientific). Protein lysates (approx. 20 μg) were digested on a 4-12% Bolt Bis-Tris precast gel containing MES run buffer (Life Technologies), transferred to a nitrocellulose membrane using a Trans-Blot Turbo Transfer System (Bio-Rad), and treated with phosphorylated STAT3, FAK, SRC, and HER2. 2 , AKT, ERK, S6 (Cell Signaling Technology), total STAT3, FAK, SRC, HER 2 , AKT, S6 ERK, and cleaved caspase 3 (Cell Signaling Technology) were detected with antibodies targeting these targets. Antibodies are typically 4 o Gently shaken overnight in C, washed, and incubated with an appropriate HRP conjugated secondary antibody. The membrane was incubated with a chemiluminescent substrate at room temperature for 5 minutes (SuperSignal West Femto, Thermo Scientific). Chemiluminescent images were acquired using a C-DiGit Imaging system (LI-COR Biosciences). Inhibition of phosphorylation of STAT3, ERK, AKT, and FAK by Compound 1 (1 μM), AMG510 (100 nM), and Compound 1 (1 μM) + AMG510 (100 nM) was measured after 4, 24, and 48 hours.

[0426] The results for H358 KRAS G12C NSCLC showed that Compound 1 alone inhibited protein levels of phospho-STAT3 (pSTAT3) and phospho-FAK (pFAK) 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 phospho-ERK (pERK) at any time point. AMG510 did not inhibit pERK at 4 hours of treatment but inhibited it after 24 and 48 hours of treatment. The combination of Compound 1 and AMG510 inhibited pERK at all time points. Treatment with Compound 1 alone or AMG510 alone showed minimal or no inhibition of phospho-AKT (pAKT) up to 24 hours of treatment. 48-hour treatment with AMG510 alone increased pAKT, whereas 48-hour treatment with compound 1 alone decreased pAKT compared to the control group. The combination of compound 1 and AMG510 significantly inhibited pAKT after 24 and 48 hours of treatment, which supports significantly increased apoptotic activation in combination therapy.

[0427] FAK, STAT3, SRC, HER by caspase-3 cleaved by compound 1 (1 μM), MRTX849 (100 nM), and compound 1 (1 μM) + MRTX849 (100 nM) 2The inhibition of phosphorylation of ERK, AKT, and S6, and the activation of apoptosis were evaluated in H2122 mutant KRAS G12C NSCLC cells after 4 hrs, 24 hrs, and 48 hrs. The results for H2122 KRAS G12C NSCLC indicate that Compound 1 alone inhibited protein levels of phospho-STAT3 (pSTAT3), phospho-FAK (pFAK), and phospho-SRC at 4, 24, and 48 hours. MRTX849 did not inhibit protein levels of pSTAT3, pFAK, or pSRC at any time point. The combination of Compound 1 and MRTX849 inhibited protein levels of pFAK, pSTAT3, and pSRC at all time points. Compound 1 alone did not inhibit phospho-ERK (pERK) at any time point, whereas MRTX849 inhibited pERK at all time points. The combination of compound 1 and MRTX849 inhibited pERK at all time points. Treatment with compound 1 alone or MRTX849 alone inhibited phospho-AKT (pAKT) at all time points. 48-hour treatment with MRTX849 alone increased pHER2. The combination of compound 1 and MRTX849 showed enhanced inhibition of pAKT and p-S6 at 4, 24, and 48 hours after treatment compared to each substance alone, and inhibited pHER2 at 48 hours, which supports the significantly increased activation of apoptosis, as evidenced by cleaved caspase-3 in combination therapy.

[0428] The 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 hrs, 24 hrs, and 48 hrs. The results for H358 KRAS G12C NSCLC indicate that Compound 1 alone inhibited protein levels of phospho-STAT3 (pSTAT3), phospho-FAK (pFAK), and phospho-SRC at 4, 24, and 48 hours. ARS1620 did not inhibit protein levels of pSTAT3, pFAK, or pSRC at any time point. The combination of Compound 1 and ARS1620 inhibited protein levels of pFAK, pSTAT3, and pSRC at all time points. The combination of compound 1 and ARS1620 inhibited pERK at all time points. Treatment with compound 1 alone or ARS1620 alone inhibited phospho-AKT (pAKT) for up to 24 hours. Treatment with ARS1620 alone for 48 hours increased pAKT, whereas treatment with compound 1 alone for 48 hours decreased pAKT compared to the control group. The combination of ARS1620 and compound 1 significantly inhibited pAKT and p-S6.

[0429] The results for H2122 KRAS G12C NSCLC indicate that Compound 1 alone inhibited protein levels of phospho-STAT3 (pSTAT3), phospho-FAK (pFAK), and phospho-SRC at 4, 24, and 48 hours. ARS1620 did not inhibit protein levels of pSTAT3, pFAK, or pSRC at any time point. The combination of Compound 1 and ARS1620 inhibited protein levels of pFAK, pSTAT3, and pSRC at all time points. Compound 1 alone did not inhibit phospho-ERK (pERK) at any time point, whereas ARS1620 inhibited pERK at 4 and 24 hours. The combination of Compound 1 and ARS1620 inhibited pERK at 4 and 24 hours. Treatment with Compound 1 alone or ARS1620 alone inhibited phospho-AKT (pAKT) at all time points. The combination of ARS1620 and compound 1 showed significantly enhanced pAKT and p-S6 inhibition compared to ARS1620 treatment alone.

[0430] Example 4: H2122 NSCLC KRAS G12C 2D Test

[0431] H2122 NSCLC cells were used to confirm a synergistic combination between AMG-510 or MRTX-849 and Compound 1. They were seeded at 2000 cells / well in a single 96-well plate in a total volume of 80 μl of RPMI supplemented with 10% fetal bovine serum (FBS). The following day, a combination matrix was prepared containing horizontal dilution drug titration of AMG-510 or MRTX-849 (three-fold dilution from a final concentration of 10 μM to 1.5 nM) and vertical titration of Compound 1 (three-fold dilution from a final concentration of 3 μM to 37 nM). Cells were incubated at 37°C and 5% CO2 for 96 hours. Subsequently, 36 μl of cell-Titer Glo reagent (Promega) was added to each well, and the plate was incubated at 37°C for 10 minutes. Luminescence was quantified using a Synergy H1 microplate reader (Biotek) according to the manufacturer's instructions. Synergy was evaluated by BLISS independent analysis on the Synergyfinder website (Ianevski A, He L, Aittokallio T, Tang J. Synergyfinder: Web application for drug combination dose-response matrix data analysis. Bioinformatics. 2017 Aug 1;33(15): 2413-2415).

[0432] In an in vitro combination screen, KRAS inhibitors (AMG-510 and MRTX-849) and Compound 1 demonstrated synergy in H2122 cells. Visualization of the dose-response matrix is ​​shown in Figures 2a-2b. Table 2 shows the Bliss synergy scores for the relevant drug doses.

[0433] Table 2

[0434]

[0435] Example 5: The combination of Compound 1 and AMG510 alters the secretion of cytokines and growth factors from mutant KRAS tumor cells

[0436] Evaluated cytokines and growth factors

[0437] 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, Fractalkin (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), osteopropenerin (TNFRSF11B), PARC (CCL18), PLGF, TGF beta 2, TGF beta 3, TIMP-1, TIMP-2.

[0438] Experimental method

[0439] Cytokine array

[0440] Cytokines present in NCI-H358 and NCI-H2122 conditioned media were identified and quantitatively compared using the human cytokine antibody array C5 (AAH-CYT-5-8, RayBiotech). Treatments were performed for 24 or 48 hours with combinations of AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM), or AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM). The antibody arrays were blocked at room temperature for 30 minutes and incubated overnight at 4°C with the conditioned media of H358 and H2122 cells. The antibody arrays were then washed, re-incubated overnight at 4°C with a biotinylated antibody cocktail, and then re-incubated at room temperature for 2 hours with HRP-conjugated streptavidin. After the final washing step, a 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 using iBright analysis software and compared using the RayBiotech analysis tool for AAH-CYT-5.

[0441] ELISA

[0442] 500,000 cells per well were seeded into 6-well plates and allowed to attach for 24 hours, after which they were treated for 48 hours with a combination of AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM) or AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM). To evaluate IL-6 secretion by tumor cells, supernatants were collected, and a human IL-6 ELISA assay was performed according to the manufacturer's instructions (R&D Biosystems). Briefly, microplate wells were incubated at room temperature for 2 hours with sample supernatants from standard, control, and H358 and H2122 cells. The microplates were then washed and incubated with the human IL-6 conjugate at room temperature for 2 hours, followed by washing and the addition of the substrate solution for 20 minutes. Finally, stop solution was added, and the optical density was evaluated using a microplate reader set to 450 nm. To correct optical defects in the plate, the reading at 540 nM was subtracted.

[0443] qPCR

[0444] 500,000 cells per well were seeded into 6-well plates and allowed to adhere for 24 hours, after which they were treated for 24 and 48 hours with a combination of AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM) or AMG-510 (100 nM) / MRTX849 (100 nM) and Compound 1 (1 μM). mRNA was prepared using the Rneasy Mini Kit (Qiagen), and cDNA was synthesized using SuperScript IV VILO (Invitrogen). qPCR was performed using a QuantStudio 5 Thermal Cycler (Applied Biosystems) with diluted cDNA, appropriate Taqman probes, and Taqman Fast Advanced Master mix (Applied Biosystems). Relative mRNA levels were calculated using the 2-Ct method with RPL32 as an internal control.

[0445] KRAS cell lines H358 and H2122 were shown to secrete IL-6, and IL-6 was inhibited by compound 1 alone and in the presence of AMG510, where the inhibition of IL-6 secretion was found to be greater in the combination of compound 1 and AMG-510 than when the two compounds were used individually. The results are shown in Figures 3a-3d.

[0446] Cytokine data in H2122 NSCLC cell lines treated with the combination of Compound 1 and MRTX849 for 48 h were also generated. (a) Control; (b) MRTX849; (c) Compound 1; (d) Compound 1 + MRTX849 (Fig. 3e).

[0447] KRAS cell line H2122 was shown to secrete IL-6, and IL-6 was inhibited by compound 1 alone and in the presence of MRTX849, where the inhibition of IL-6 secretion was found to be greater in the combination of compound 1 and MRTX849 than when the two compounds were used individually (Fig. 3f-3g).

[0448] In vivo research

[0449] Method 1: Subcutaneous xenograft model in immunocompromised mice

[0450] Female thymic 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 were subcutaneously transplanted into the right flank region of each host mouse in 100 μL of serum-free medium supplemented with 50% Matrigel (Corning, Inc). For the subcutaneous patient-derived xenograft model, tumor fragments from the host mouse were subcutaneously transplanted into the flank region of each host mouse. Tumor size and body weight were measured on specified dates. Tumor size was measured using electronic calipers, and tumor volume was calculated as length * width. 2 * The result was calculated using a formula of 0.5 or similar. When the average tumor volume reached a specific size, mice were randomized into treatment groups according to tumor size. Compound 1 was administered orally twice daily at a fixed dose, and AMG-510 was administered orally once daily at a fixed dose. In the case of the stereotactic brain model, approximately 80,000 cells were implanted into the brain, and treatment of mice with either the control or test product was started on day 7 after implantation.

[0451] Method 2: Tumor treatment and immunoblotting for in vivo pharmacodynamic studies

[0452] Mice with xenograft tumors were humanely euthanized, the tumors were resected, rapidly frozen in liquid nitrogen, and stored at -80°C. Proteins were extracted from frozen tumor samples by treating them in RIPA buffer at 4°C. Protein concentrations in the lysates were determined by the Rapid Gold BCA Protein Assay (Life Technologies, Inc.), and the lysates were diluted to ensure uniform protein concentrations throughout the samples. SDS loading samples were prepared by adding 1 volume of 4X LDS Sample Buffer (Life Technologies, Inc.) to 3 volumes of diluted protein lysates. Tumor SDS protein samples were processed by SDS-PAGE, immunoblotted with appropriate primary antibodies, and detected using HRP-conjugated secondary antibodies. Immunoblotting signals were detected by the LI-COR C-DiGit Blot Scanner using Image Studio Digit software (LI-COR).

[0453] Example 6: Effect of Compound 1 combined with AMG-510 in H358 cell-derived xenograft tumors

[0454] H358 cells harbor the KRAS G12C mutation. SCID / beige mice harboring H358 cell-derived tumors were treated with vehicle BID combined with AMG-510, Compound 1 BID at 15 mg / kg, AMG-510 QD at 10 mg / kg, and Compound 1 BID at 15 mg / kg, respectively. Tumor volume (TMV) versus time data are shown in Figure 4a as mean ± sem. After 26 days of treatment, Compound 1 combined 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, Tukey's post-hoc multiple comparison test after two-way repeated measures ANOVA analysis). Mouse body weight was measured during treatment and is shown in Figure 4b as mean ± sem. There was no statistical significance between the treatment groups (p = 0.4233, two-way repeated measures ANOVA), which suggests that the combined treatment of compound 1 and AMG-510 did not result in weight loss or apparent abnormalities under these experimental conditions.

[0455] Example 7: Pharmacodynamic effects of Compound 1 combined with AMG510 in H358 cell-derived xenograft tumors

[0456] To evaluate the pharmacodynamic effects of Compound 1 combined with AMG-510 in H358 cell-derived xenograft tumors, tumor lysates were prepared and analyzed by immunoblotting using antibodies against selected candidate molecules from signaling pathways that could potentially be modified by Compound 1 and / or AMG-510. The inhibitory activity of Compound 1 against SRC and JAK2 was demonstrated by a reduction in phosphorylated SRC (Y416) and STAT3 (Y705) signals in tumors treated with Compound 1 as a single substance or in combination with AMG-510, compared to vehicle treatment. Additionally, the activity of Compound 1 against FAK was indicated by a reduction in phosphorylated FAK signals in the Compound 1 and AMG-510 combination treatment group. Furthermore, the activity of AMG-510 toward KRAS was explained by reduced levels of phosphorylated ERK (T202 / Y204) signaling, a major downstream effector of KRAS signaling, in mice treated with AMG-510 as a single substance or in combination with Compound 1. Finally, the combination of Compound 1 and AMG-510 also reduced phosphorylated AKT (S473) signaling, a key factor involved in cell survival and proliferation. Thus, combination therapy with Compound 1 and AMG-510 inhibits the activity of AKT, a key factor in the PI3K-AKT oncogenic pathway, as well as Compound 1 and AMG-510 targets including SRC, FAK, JAK2, and KRAS.

[0457] Example 8: Effects of Compound 1 combined with AMG-510 in a LU11693 patient-derived xenograft model carrying the NSCLC KRAS G12C mutation

[0458] LU11693 PDX tumors harbor the KRAS G12C mutation. NOD / SCID mice harboring LU11693 PDX tumors were treated with Vehicle BID combined with AMG-510 QD 100 mg / kg, Compound 1 BID at 15 mg / kg, AMG-510 QD at 100 mg / kg, and Compound 1 BID at 15 mg / kg, respectively. Tumor volume versus time data are presented as mean ± sem in Figure 5a. Mouse body weight was measured during treatment and is shown as mean ± sem in Figure 5b. Treatment with AMG-510, either as a single substance or at 100 mg / kg QD combined with Compound 1, significantly reduced mouse body weight. On day 13, two mice in the combination treatment group were euthanized due to body weight loss, and the dose of AMG-510 was reduced to 30 mg / kg QD starting on day 14 in both AMG-510 monotherapy and compound 1 AMG-510 combination therapy. After 21 days of treatment, compound 1 combined with AMG-510 significantly reduced tumor volume compared to treatment with vehicle, compound 1 alone, or AMG-510 alone (p=0.0002 for vehicle, p=0.0181 for compound 1, p=0.0003 for AMG-510, post-hoc Dunnett's multiple comparison test according to the mixture-effect model). As mentioned above, body weight loss was observed in mice treated with AMG-510 at 100 mg / kg QD as a single substance or in combination with compound 1. After dose reduction, the body weight of the compound 1 + AMG-510 combination group began to recover, and on day 21, the body weight of the combination group was not significantly different from the vehicle treatment group (p=0.5487 for vehicle, Dunnett's multiple comparison test after one-way ANOVA).

[0459] Example 9: Improvement in survival rate of mice carrying H2122 cell-derived xenograft tumors by Compound 1 combined with AMG-510

[0460] Effects of combination therapy of Compound 1 and AMG-510 on the survival of tumor-bearing mice KRAS G12CEvaluation was performed using a mutant H2122 cell-derived xenograft tumor model. Starting on day 5 after tumor cell transplantation, SCID / Beige mice carrying H2122 cell-derived xenograft tumors were randomized into groups based on tumor size (n=10 for each group) and treated with vehicle BID combined with AMG-510 QD at 30 mg / kg, compound 1 BID 15 mg / kg, AMG-510 QD 10 mg / kg, compound 1 BID 15 mg / kg combined with AMG-510 QD at 10 mg / kg, AMG-510 QD 30 mg / kg, and compound 1 BID 15 mg / kg combined with AMG-510 QD at 30 mg / kg, respectively. To evaluate the survival effect, individual mice were considered dead if they reached one of the humane endpoints: necrotic state, tumor volume greater than 2000 mm³, body weight loss greater than 20% compared to baseline, open tumor lesions, and inability to eat or drink. The study was terminated on day 101 after tumor cell transplantation. The median survival was 34, 45, 52, 77, and 76.5 days for the groups treated with vehicle BID, compound 1 BID at 15 mg / kg, AMG-510 QD at 10 mg / kg, compound 1 BID at 15 mg / kg combined with AMG-510 QD at 10 mg / kg, and AMG-510 at 30 mg / kg, respectively, while the group treated with compound 1 BID at 15 mg / kg combined with AMG-510 QD at 101 days after tumor cell transplantation did not reach the median survival. At the 10 mg / kg dose level of AMG-510, treatment with compound 1 combined with AMG-510 statistically significantly increased median survival compared to treatment with AMG-510 alone (p<0.0019, log-rank test, combination of compound 1 and AMG-510 versus AMG-510, Fig. 6a).At a dose level of 30 mg / kg of AMG-510, treatment with compound 1 combined with AMG-510 statistically significantly increased median survival compared to treatment with AMG-510 alone (p<0.0138, log-rank test, combination of compound 1 and AMG-510 versus AMG-510, Fig. 6b). These findings suggest that combination treatment of compound 1 and AMG-510 extends the survival of mice harboring H2122 cell-derived tumors compared to treatment with AMG-510 monotherapy.

Claims

Claim 1 A pharmaceutical composition for use in the treatment of human cancer, wherein the composition comprises a compound that inhibits FAK, SRC, and JAK2, and the composition is used in combination with at least one substance that inhibits KRAS G12C at a therapeutically effective amount, wherein the compound is the following compound A pharmaceutical composition wherein at least one substance inhibiting KRAS G12C is AMG-510, MRTX849, or ARS-1620 or a pharmaceutically acceptable salt thereof, and the cancer is colorectal cancer, pancreatic cancer, or lung cancer. Claim 2 A pharmaceutical composition in which the cancer is pancreatic cancer, as described in claim 1. Claim 3 A pharmaceutical composition in which the cancer is lung cancer, as described in claim 1. Claim 4 A pharmaceutical composition according to claim 1, wherein the cancer is non-small cell lung cancer. Claim 5 A pharmaceutical composition in which the cancer is colorectal cancer, wherein, in claim 1. Claim 6 A pharmaceutical composition according to claim 1, wherein the compound inhibiting FAK, SRC, and JAK2 is administered simultaneously, prior to, or subsequently with at least one substance inhibiting KRAS G12C. Claim 7 A pharmaceutical composition according to claim 1, wherein IL-6 secretion from cancer is reduced. Claim 8 A pharmaceutical composition according to claim 1, wherein at least one substance inhibiting KRAS G12C is ARS-1620 or a pharmaceutically acceptable salt thereof. Claim 9 A pharmaceutical composition according to claim 1, wherein at least one substance inhibiting KRAS G12C is AMG-510 or a pharmaceutically acceptable salt thereof. Claim 10 A pharmaceutical composition according to claim 1, wherein at least one substance inhibiting KRAS G12C is MRTX849 or a pharmaceutically acceptable salt thereof. Claim 11 In claim 1, the compound inhibiting FAK, SRC, and JAK2 is administered at a dose of 0.1 mg to 3 g, or 1 mg to 50 mg, or 50 to 250 mg, or 150 to 500 mg, or 150 to 250 mg, or 250 mg to 1 g, or 100 mg to 2 g, or 500 mg to 2 g, or 500 mg to 1 g, or 100 mg to 300 mg, or 160 mg; A pharmaceutical composition wherein at least one substance inhibiting KRAS G12C is administered at a dose of 0.1 mg to 3 g, or 1 mg to 50 mg, or 50 to 250 mg, or 150 to 500 mg, or 150 to 250 mg, or 250 mg to 1 g, or 100 mg to 2 g, or 500 mg to 2 g, or 500 mg to 1 g, or 800 mg to 1.5 g, or at least 800 mg, or at least 600 mg, or 960 mg, or 600 mg. Claim 12 In claim 1, the compound inhibiting FAK, SRC, and JAK2 is administered at a dose of 0.1 mg / kg to 1 g / kg, or 0.5 mg / kg to 50 mg / kg, or 0.5 mg / kg to 25 mg / kg, or 1.0 mg / kg to 10 mg / kg, or 1.0 mg / kg to 5 mg / kg, or 0.1 mg / kg to 5 mg / kg, or 0.1 mg / kg to 1 mg / kg, or 0.1 mg / kg to 0.6 mg / kg, or 1.25 mg / kg to 3.75 mg / kg, or 1.0 mg / kg, 2.0 mg / kg, or 3.0 mg / kg, or 4.0 mg / kg, and at least one substance inhibiting KRAS G12C is administered at a dose of 0.1 mg / kg to 1 g / kg, or 0.5 mg / kg to 50 A pharmaceutical composition administered at a dose of mg / kg, or 0.5 mg / kg to 25 mg / kg, or 1.0 mg / kg to 10 mg / kg, or 1.0 mg / kg to 5 mg / kg, or 0.1 mg / kg to 5 mg / kg, or 0.1 mg / kg to 1 mg / kg, or 0.1 mg / kg to 0.6 mg / kg, or 1.25 mg / kg to 3.75 mg / kg, or 1.0 mg / kg, 2.0 mg / kg, or 3.0 mg / kg, or 4.0 mg / kg. Claim 13 A pharmaceutical composition according to claim 1, wherein the human being is a patient in need of treatment who has not received prior treatment. Claim 14 A pharmaceutical composition according to claim 1, wherein the human being is a patient in need of treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents. Claim 15 A pharmaceutical composition according to claim 1, wherein the human being is a patient requiring treatment who has received prior treatment with one or more chemotherapy agents or immunotherapy agents and has developed acquired resistance to treatment, or has developed bypass resistance to treatment, or has developed bypass resistance to treatment controlled by FAK, SRC, or JAK2. Claim 16 In paragraph 15, the compound is A pharmaceutical composition. Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete

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