Pharmaceutical compositions, their uses and methods for treating cancer

Abstract

The present invention provides a pharmaceutical composition or kit comprising a therapeutically effective amount of a KRAS inhibitor and a therapeutically effective amount of another cancer therapeutic agent, and the use of a KRAS inhibitor and at least one other cancer therapeutic agent in the manufacture of a medicament for treating cancer, wherein the combined use of the KRAS inhibitor and the other cancer therapeutic agent in tumor cells has a relatively good synergistic effect.

Description

[Technical field]

[0001] The present invention relates to the pharmaceutical technical field, specifically to a combined pharmaceutical composition containing a KRAS inhibitor. [Background technology]

[0002] Cancer is one of the major diseases that threaten human health worldwide. Lung cancer is the cancer with the highest incidence rate worldwide, and in China, it ranks first among all cancers, and it is also the cancer with the highest incidence rate and mortality rate in China. According to data published by the American Cancer Society in 2016, approximately 1.8 million people worldwide suffer from lung cancer annually, of which nearly 80% are non-small cell lung cancer (NSCLC).

[0003] RAS is a closely related monomeric globular protein (molecular weight 21 kDa) that has 188-189 amino acids and binds guanosine diphosphate GDP or guanosine triphosphate GTP. RAS subfamily members include HRAS, KRAS, and NRAS. RAS functions as a molecular switch; when RAS contains bound GDP, it is in the resting or off position and is "inactive". When cells are exposed to some growth-promoting stimuli, RAS is induced to convert its bound GDP to GTP; when bound to GTP, RAS is "on" and can interact with and activate other downstream target proteins. RAS protein itself has very low intrinsic ability to hydrolyze GTP back to GDP (thereby converting itself to the off state). An exogenous protein, GTP enzyme-activating protein (GAP), is required to return it to the off state, and interaction of GAP with RAS greatly accelerates the conversion of GTP to GDP. Any mutation in RAS affects the interaction of RAS with GAP and its ability to convert GTP to GDP, and such mutations result in an extended protein activation time, thereby extending cell signaling and further resulting in continued cell growth and division. Since such signaling leads to cell growth and division, overactive RAS signaling can ultimately lead to cancer. In lung cancer, mutations in the RAS gene have been identified in approximately 32% of lung cancers, and mutations in any one of the three main subtypes of RAS (HRAS, NRAS, or KRAS) genes can lead to the development of human tumors. The KRAS gene has the highest mutation frequency in RAS genes, with KRAS mutations reported to be detected in 25-30% of tumors. In comparison, the incidence of oncogenic mutations in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found on residues G12 and G13 in the P loop, and on residue Q61. The G12C mutation is a frequent mutation in the KRAS gene (glycine-12 to cysteine).This mutation is found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-associated polyposis (familial colon cancer syndrome). Therefore, although the development of inhibitors that selectively block KRAS mutations is a relatively good direction, and KRAS inhibitors as monotherapy are effective in some cancers, more effective treatment strategies in cancer are still needed. Summary of the Invention

[0004] The object of the present invention is to provide a pharmaceutical composition or kit comprising a therapeutically effective amount of a KRAS inhibitor and a therapeutically effective amount of another cancer therapeutic agent, and the use of a KRAS inhibitor and at least one other cancer therapeutic agent in the manufacture of a drug for treating cancer, whose combination in tumor cells has a relatively good synergistic effect.

[0005] In one aspect of the invention, a pharmaceutical composition or kit is provided that comprises a therapeutically effective amount of a KRAS inhibitor and at least one therapeutically effective amount of another cancer therapeutic agent and a pharma- ceutically acceptable carrier.

[0006] The KRAS inhibitors include compounds represented by formula (I), or pharma- ceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, wherein R is CH3 or CD3.

[0007] [ka] Formula (I)

[0008] In one embodiment, the other cancer therapeutic agent is selected from a PD-1 pathway inhibitor, a PD-L1 pathway inhibitor, an EGFR targeting agent, a CDK inhibitor, and a PI3K inhibitor.

[0009] In one embodiment, the PD-1 pathway inhibitor is selected from a PD-1 antagonist, a PD-1 binding antagonist, a small molecule PD-1 antagonist, a PD-1 inhibitor, and an anti-PD-1 biological product.

[0010] In one embodiment, the PD-L1 pathway inhibitor is selected from a PD-L1 antagonist, a PD-L1 binding antagonist, a small molecule PD-L1 antagonist, a PD-L1 inhibitor, and an anti-PD-L1 biological product.

[0011] In one embodiment, the EGFR targeting agent is selected from an EGFR inhibitor and an EGFR antibody or antigen-binding fragment thereof.

[0012] In one embodiment, the CDK inhibitor is selected from a CDK4 / 6 inhibitor, a CDK2 / 4 / 6 inhibitor, a CDK7 inhibitor, a CDK8 inhibitor, a CDK9 inhibitor, a CDK10 inhibitor, and a CDK11 inhibitor.

[0013] In one embodiment, the PI3K inhibitor is selected from a PI3K gamma inhibitor, a PI3K delta inhibitor, a PI3K beta inhibitor, a PI3K alpha inhibitor, and a pan-PI3K inhibitor.

[0014] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and a PD-1 inhibitor.

[0015] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and a PD-L1 inhibitor.

[0016] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and an EGFR inhibitor.

[0017] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and an EGFR antibody or antigen-binding fragment thereof.

[0018] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and a CDK7 inhibitor.

[0019] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and a PI3K inhibitor.

[0020] In one embodiment, the PD-1 inhibitor is AMG404, pembrolizumab, nivolumab (MDX 1106), pembrolizumab (MK-3475), pidilizumab (CT-011), cemiplimab (REGN2810), tislelizumab (BGB-A317), spartalizumab (PDR001), RN888, mAb15, MEDI-0680 (AMP-514), BGB-108, spartalizumab (AGEN-2034), IBI-308, mDX-400, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, and biological analogs, biological enhancers and biological equivalents of these inhibitors.

[0021] In one embodiment, the PD-L1 inhibitor is selected from BMS-936559 (MDX-1105), AMP-714, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, avelumab, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, KY-1003, and biological analogs, biological enhancers, and biological equivalents of these inhibitors.

[0022] In one embodiment, the EGFR inhibitor is selected from afatinib, erlotinib, lapatinib, gefitinib, osimertinib, icotinib, pyrotinib, and olmutinib.

[0023] In one embodiment, the EGFR antibody or antigen-binding fragment thereof is selected from Cetuximab, Nimotuzumab, Panitumumab, Zalutumumab, Matuzumab, and Necitumumab, more preferably Cetuximab.

[0024] In one embodiment, the CDK7 inhibitor is selected from SY-5609, SY-1365, CT-7001, and BTX-A51.

[0025] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and SY-5609.

[0026] In one embodiment, the PI3K inhibitor is selected from BYL719, GDC0941, AMG511, LY294002, BEZ235, BKM120, and GSK-2636771.

[0027] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and BYL719.

[0028] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (I) and GDC0941.

[0029] In one embodiment, the cancer is a KRAS G12C mutant cancer.

[0030] In one embodiment, the cancer is a solid tumor or a hematological tumor.

[0031] In one embodiment, the cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, cutaneous melanoma, endometrial carcinoma, uterine carcinoma sarcoma, thyroid cancer, acute myeloid leukemia, bladder urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, hepatic cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenocortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdomyosarcoma, sarcoma, small intestinal neuroendocrine tumor, T-cell prolymphocytic leukemia.

[0032] In one embodiment, the cancer is lung adenocarcinoma, colon cancer, rectal cancer or lung cancer.

[0033] In one embodiment, the cancer is lung adenocarcinoma, rectal adenocarcinoma or lung cancer.

[0034] In one embodiment, the lung cancer is small cell lung cancer or non-small cell lung cancer.

[0035] In one embodiment, the compound of formula (I) is [ka] Formula (II) [ka] Formula (III) [ka] Formula (IV) [ka] Formula (V) is selected from the group consisting of:

[0036] In one embodiment, the KRAS inhibitor is a compound of formula (II) or a pharma- ceutically acceptable salt thereof. [ka] Formula (II)

[0037] In one embodiment, the pharmaceutical composition or kit comprises a compound of Formula (II) and a PD-1 pathway inhibitor.

[0038] In one embodiment, the pharmaceutical composition or kit comprises a compound of Formula (II) and a PD-L1 pathway inhibitor.

[0039] In one embodiment, the pharmaceutical composition or kit comprises a compound of Formula (II) and an EGFR targeting agent.

[0040] In one preferred embodiment, the pharmaceutical composition or kit comprises the compound of formula (II) and cetuximab.

[0041] In one embodiment, the pharmaceutical composition or kit comprises a compound of formula (II) and a CDK7 inhibitor.

[0042] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (II) and SY-5609.

[0043] In one embodiment, the pharmaceutical composition or kit comprises a compound of formula (II) and a PI3K inhibitor.

[0044] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (II) and BYL719.

[0045] In one preferred embodiment, the pharmaceutical composition or kit comprises a compound of formula (II) and GDC0941.

[0046] In one embodiment, the pharmaceutical composition or kit comprises 0.1 to 1000 nM of a KRAS inhibitor and 1 to 10000 nM of another cancer therapeutic agent.

[0047] In one embodiment, the pharmaceutical composition or kit contains 0.32 to 1000 nM of a KRAS inhibitor.

[0048] In one embodiment, the pharmaceutical composition or kit contains 3 to 1000 nM of a KRAS inhibitor.

[0049] In one embodiment, the pharmaceutical composition or kit contains 3.17 to 1000 nM of a KRAS inhibitor.

[0050] In one embodiment, the pharmaceutical composition or kit contains 10 to 1000 nM of a KRAS inhibitor.

[0051] In one embodiment, the pharmaceutical composition or kit contains 0.1 to 100 nM of a KRAS inhibitor.

[0052] In one embodiment, the pharmaceutical composition or kit contains 3.17 to 1000 nM of another cancer therapeutic agent.

[0053] In one embodiment, the pharmaceutical composition or kit contains 31.74 to 10,000 nM of another cancer therapeutic agent.

[0054] In one embodiment, the pharmaceutical composition or kit contains 100 to 10,000 nM of another cancer therapeutic agent.

[0055] In one embodiment, the pharmaceutical composition or kit contains 316.91 to 10,000 nM of another cancer therapeutic agent.

[0056] In one embodiment, the pharmaceutical composition or kit contains 10 mg / mL of the compound of formula (II) and 1 mg / mL of cetuximab.

[0057] In one embodiment, the pharmaceutical composition or kit comprises 1-3 mg / kg of the compound of formula (II) and 10 mg / kg of the PD-1 antibody.

[0058] In one embodiment, said pharmaceutical composition or kit comprises a drug dose equivalent to 10 mpk of the compound of formula (II) and 1 mpk of cetuximab.

[0059] In one embodiment, the pharmaceutical composition or kit contains a drug dose equivalent to 1-3 mpk of the compound of formula (II) and 10 mpk of the PD-1 antibody.

[0060] In one embodiment, the pharmaceutical composition or kit comprises 0.1 to 100 nM of the compound of formula (II) and 1 to 1000 nM of SY-5609.

[0061] In one embodiment, the pharmaceutical composition or kit comprises 0.1 to 100 nM of the compound of formula (II) and 3.17 to 1000 nM of SY-5609.

[0062] In one embodiment, the pharmaceutical composition or kit comprises 1 to 1000 nM of the compound of formula (II) and 100 to 10000 nM of BYL719.

[0063] In one embodiment, the pharmaceutical composition or kit contains 3 to 1000 nM of the compound of formula (II) and 100 to 10000 nM of BYL719.

[0064] In one embodiment, the pharmaceutical composition or kit contains 10 to 1000 nM of the compound of formula (II) and 100 to 10000 nM of BYL719.

[0065] In one embodiment, the pharmaceutical composition or kit contains 0.1 to 1000 nM of the compound of formula (II) and 10 to 10000 nM of GDC0941.

[0066] In one embodiment, the pharmaceutical composition or kit contains 3.17 to 1000 nM of the compound of formula (II) and 31.74 to 10000 nM of GDC0941.

[0067] In one embodiment, the pharmaceutical composition or kit contains 3.17 to 1000 nM of the compound of formula (II) and 100 to 10000 nM of GDC0941.

[0068] In one embodiment, the pharmaceutical composition or kit comprises 10-1000 nM of the compound of formula (II) and 31.74-10000 nM of GDC0941.

[0069] In one embodiment, the pharmaceutical composition or kit comprises 0.32-1000 nM of the compound of formula (II) and 316.91-10000 nM of GDC0941.

[0070] In one embodiment, the mass ratio of the KRAS inhibitor to the other cancer therapeutic agent in the pharmaceutical composition or kit is 0.00001-1000.

[0071] In one embodiment, the pharmaceutical composition or kit contains the compound of formula (II) and cetuximab, and the mass ratio thereof is (1 to 10):1, and may be, for example, 10:1.

[0072] In one embodiment, the pharmaceutical composition or kit comprises the compound of formula (II) and the PD-1 antibody, and the mass ratio thereof is (1-10):10, for example, 1:10 or 3:10.

[0073] In one embodiment, the pharmaceutical composition or kit contains the compound of formula (II) and SY-5609, and the mass ratio thereof is 0.0001 to 31.6.

[0074] In one embodiment, the pharmaceutical composition or kit contains the compound of formula (II) and BYL719, and the mass ratio thereof is 0.0003 to 10, and may be, for example, 0.001 to 10 or 0.0003 to 10.

[0075] In one embodiment, the pharmaceutical composition or kit contains the compound of formula (II) and GDC0941, and the mass ratio thereof may be 0.000032 to 35, for example, 0.001 to 31.5, 0.0003 to 10, 0.0003 to 31.5, or 0.00003 to 3.15.

[0076] In one embodiment, the pharmaceutical composition or kit includes a drug dose equivalent to 0.01-5000 mg / day, preferably 1-1500 mg / day, alternatively 10 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 400 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 8500 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1200 mg / day, 1250 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day of the compound of formula (II).

[0077] In one embodiment, the pharmaceutical composition or kit includes a drug dose equivalent to 0.01-1000 mg / day, preferably 1-500 mg / day, optionally 10 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 400 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 8500 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day of another cancer therapeutic agent.

[0078] In one embodiment, the pharmaceutical composition or kit comprises 1 to 10,000 mg of a KRAS inhibitor and 1 to 10,000 mg of another cancer therapeutic agent.

[0079] In one embodiment, the pharmaceutical composition or kit comprises 1 to 10,000 mg of the compound of formula (II) and 1 to 10,000 mg of cetuximab.

[0080] In one embodiment, the pharmaceutical composition or kit comprises 1-10000 mg of the compound of formula (II) and 1-10000 mg of SY-5609.

[0081] In one embodiment, the pharmaceutical composition or kit comprises 1-10000 mg of the compound of formula (II) and 1-10000 mg of BYL719.

[0082] In one embodiment, the pharmaceutical composition or kit comprises 1-10000 mg of the compound of formula (II) and 1-10000 mg of GDC0941.

[0083] In another aspect of the present invention, there is provided a method of treating cancer comprising administering to a subject in need thereof a KRAS inhibitor as described above and another cancer therapeutic agent, wherein the therapeutically effective amount of the KRAS inhibitor and the therapeutically effective amount of the other cancer therapeutic agent may be administered simultaneously, separately or sequentially.

[0084] In one embodiment, the method of treating cancer further comprises administering to the subject another therapy, the other therapy being one or more selected from radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, and phototherapy. The other therapy may be in the form of an adjunctive therapy or a neo-adjunctive therapy.

[0085] In another aspect of the present invention, there is provided a use of the pharmaceutical composition in the manufacture of a medicament for treating cancer. The therapeutically effective amount of a KRAS inhibitor and the therapeutically effective amount of another cancer therapeutic agent may be administered simultaneously, separately or sequentially.

[0086] In one embodiment, the cancer in said use is a solid tumor or a hematological tumor.

[0087] In one embodiment, the cancer in the above use is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung cancer, skin melanoma, endometrioid carcinoma, uterine carcinoma sarcoma, thyroid cancer, acute myeloid leukemia, bladder urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenocortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdomyosarcoma, sarcoma, small intestinal neuroendocrine tumor, T-cell prolymphocytic leukemia.

[0088] In one embodiment, the cancer in said use is lung adenocarcinoma, colon cancer, rectal cancer or lung cancer.

[0089] In one embodiment, the cancer in said use is lung adenocarcinoma, rectal adenocarcinoma or lung cancer.

[0090] In one embodiment, the cancer in said use is a KRAS G12C mutant cancer.

[0091] In one embodiment, the lung cancer in the above use is small cell lung cancer or non-small cell lung cancer.

[0092] In another aspect of the present invention, there is provided a use of a therapeutically effective amount of a KRAS inhibitor and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a drug, drug combination, or kit for treating cancer, wherein the KRAS inhibitor is one or more selected from the compounds represented by the above formula (I) and the compounds represented by the formulas (II) to (V), or pharma- ceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof. The definitions of the KRAS inhibitor, the other cancer therapeutic agent, and cancer in this use are as defined in the above pharmaceutical composition or kit.

[0093] Specifically, in one aspect, the present invention provides the use of a therapeutically effective amount of a compound of formula (I) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating cancer.

[0094] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of Formula (II) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating cancer.

[0095] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of formula (I) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating lung cancer.

[0096] In one aspect, the invention provides the use of a therapeutically effective amount of a compound of Formula (I) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer or non-small cell lung cancer.

[0097] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of Formula (II) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating lung cancer.

[0098] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of Formula (II) and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer or non-small cell lung cancer.

[0099] In one aspect, the invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of a PD-1 inhibitor in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma.

[0100] In one aspect, the invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of a PD-L1 inhibitor in the manufacture of a medicament, drug combination or kit for the treatment of small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma.

[0101] In one aspect, the invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of an EGFR inhibitor in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma.

[0102] In one aspect, the invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of an EGFR antibody or antigen-binding fragment thereof in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma.

[0103] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of a CDK7 inhibitor in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma.

[0104] In one aspect, the present invention provides the use of a therapeutically effective amount of a compound of Formula (II) and a therapeutically effective amount of a PI3K inhibitor in the manufacture of a medicament, drug combination or kit for treating small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer or rectal adenocarcinoma. [Brief description of the drawings]

[0105] [Figure 1] FIG. 2 is a matrix diagram of the growth inhibition of tumor cells LU99 by the combined use of the compound of formula (II) and BYL719 in Example 1. [Figure 2A] 1 shows the average synergy values ​​calculated from the four statistical models in Example 1. [Figure 2B]1 shows the average synergy values ​​calculated from the four statistical models in Example 1. [Figure 2C] 1 shows the average synergy values ​​calculated from the four statistical models in Example 1. [Figure 2D] 1 shows the average synergy values ​​calculated from the four statistical models in Example 1. [Diagram 3] FIG. 2 is a matrix diagram of the growth inhibition of tumor cells SW837 by the combined use of the compound of formula (II) and BYL719 in Example 2. [Figure 4A] 1 shows the average synergy values ​​calculated from the four statistical models in Example 2. [Figure 4B] 1 shows the average synergy values ​​calculated from the four statistical models in Example 2. [Figure 4C] 1 shows the average synergy values ​​calculated from the four statistical models in Example 2. [Figure 4D] 1 shows the average synergy values ​​calculated from the four statistical models in Example 2. [Diagram 5] FIG. 2 is a matrix diagram of the growth inhibition of tumor cells LU99 by the combined use of the compound of formula (II) and GDC0941 in Example 3. [Figure 6A] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 6B] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 6C] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 6D] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 7] FIG. 1 is a matrix diagram of the growth inhibition of tumor cells SW837 by the combined use of the compound of formula (II) and GDC0941 in Example 4. [Figure 8A] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 8B]1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 8C] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 8D] 1 shows the average synergy values ​​calculated by the four statistical models in Example 4. [Figure 9] FIG. 1 is a matrix diagram of the growth inhibition of tumor cells SW1463 by the combination of the compound of formula (II) and GDC0941 in Example 5. [Figure 10A] 1 shows the average synergy values ​​calculated from the four statistical models in Example 5. [Figure 10B] 1 shows the average synergy values ​​calculated from the four statistical models in Example 5. [Figure 10C] 1 shows the average synergy values ​​calculated from the four statistical models in Example 5. [Figure 10D] 1 shows the average synergy values ​​calculated from the four statistical models in Example 5. [Figure 11] FIG. 1 is a matrix diagram of growth inhibition of tumor cells SW1573 by the combination of the compound of formula (II) and GDC0941 in Example 6. [Figure 12A] 1 shows the average synergy values ​​calculated by the four statistical models in Example 6. [Figure 12B] 1 shows the average synergy values ​​calculated by the four statistical models in Example 6. [Figure 12C] 1 shows the average synergy values ​​calculated by the four statistical models in Example 6. [Figure 12D] 1 shows the average synergy values ​​calculated by the four statistical models in Example 6. [Figure 13] FIG. 13 is a matrix diagram of the growth inhibition of tumor cells NCI-H2122 by the combination of the compound of formula (II) and SY-5609 in Example 7. [Figure 14A] 1 shows the average synergy values ​​calculated by the four statistical models in Example 7. [Figure 14B]1 shows the average synergy values ​​calculated by the four statistical models in Example 7. [Figure 14C] 1 shows the average synergy values ​​calculated by the four statistical models in Example 7. [Figure 14D] 1 shows the average synergy values ​​calculated by the four statistical models in Example 7. [Figure 15] 1 shows tumor growth curves (mean value ± standard error) of tumor-bearing mice in each group in Example 8. [Figure 16] 1 shows the tumor growth curves of single tumor-bearing mice in each group in Example 8. [Figure 17] 1 shows the tumor weight (mean value ± standard error) of tumor-bearing mice in each group in Example 8. [Figure 18] 1 shows the relative animal weight change (mean value ± standard error) of tumor-bearing mice in Example 8. [Figure 19] 1 shows tumor growth curves (mean value ± standard error) of tumor-bearing mice in each group in Example 9. [Figure 20] 1 shows the tumor growth curves of single tumor-bearing mice in each group in Example 9. [Figure 21] 1 shows the tumor weight (mean value ± standard error) of tumor-bearing mice in each group in Example 9. [Figure 22] 13 shows the relative animal weight change (mean value ± standard error) of tumor-bearing mice in Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0106] I. Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein shall have the following meanings. A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood in its general sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0107] As used herein, unless otherwise noted, the terms "comprise," "include," "have," and "contain," including their grammatical equivalents, are generally to be understood as open-ended and open-ended, e.g., not excluding other unrecited elements or steps.

[0108] As used herein, the use of the term "inhibition" is relative to a control. One of skill in the art can easily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound. The disclosure of any range in the present invention should be considered as a disclosure of all subranges and all point values ​​within the range. For example, the disclosure of 1-1000 should be considered as also disclosing ranges such as 1-200, 200-300, etc., as well as point values ​​such as 200, 300, 400, 500, 600, 700, 800, 900, and 1000.

[0109] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / hazard ratio.

[0110] The compounds may be present in the pharmaceutical composition as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention prepared from compounds found in the present invention with certain substituents and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic acid salts, such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts, such as, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; and further include salts of amino acids, such as, for example, arginic acid, and salts of organic acids, such as, for example, glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups and may be converted into either base or acid addition salts.

[0111] The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds that contain an acid or base group. In general, such salts are prepared by reacting the compounds in their free acid or base form with the stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0112] In addition to the salt form, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily converted to the compounds of the present invention by chemical changes under physiological conditions. Furthermore, the prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment. For example, the prodrugs may be slowly converted to the compounds of the present invention when placed in a transdermal patch with a suitable enzyme or chemical reagent.

[0113] Some compounds of the present invention may exist in unsolvated or solvated form, including hydrated form. In general, solvated forms are equivalent to unsolvated forms, and both are included within the scope of the present invention. Solvated forms are generally equivalent to unsolvated forms, and should be included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form. In general, for the application considered by the present invention, all physical forms are equivalent and should be included within the scope of the present invention.

[0114] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. All such compounds are contemplated in this invention to include cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic and other mixtures thereof, including enantiomerically or diastereomerically enriched mixtures, and all of these mixtures are within the scope of the present invention.

[0115] The compounds disclosed herein can exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in a molecule is hindered or significantly slowed down due to spatial interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers as preparations of pure individual atropisomers, enriched preparations of each, or unspecified mixtures of each. If the rotation barrier around a single bond is sufficiently high and the tautomerization between conformations is sufficiently slow, separation and resolution of isomeric types may be permitted. Separation and resolution of isomeric types is appropriately represented by the well-known and widely accepted symbols "M" or "P".

[0116] The term "cancer" refers to a disease characterized by the uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Various examples of cancer are described herein, including, but not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, etc. The terms "tumor" and "cancer" may be used interchangeably herein, for example, the two terms include solid and liquid, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes precancerous lesions as well as malignant cancers and tumors.

[0117] The term "antigen-binding fragment" refers to any portion of a full-length antibody that is less than full-length but contains at least a partial variable region of the antibody that binds to an antigen (e.g., one or more CDRs and / or one or more antibody binding sites), and thereby retains the binding specificity and at least partial specific binding ability of the full-length antibody. Thus, an antigen-binding fragment refers to an antibody fragment that contains an antigen-binding portion that binds to the same antigen as the antibody from which the antibody fragment is derived. Antibody fragments include antibody derivatives produced by enzymatic treatment of a full-length antibody, and synthetically produced derivatives, such as recombinantly produced derivatives. Antibodies include antibody fragments. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, single chain Fv (scFv), Fv, dsFv, diabody, Fd and Fd' fragments, and other fragments, including modified fragments. The fragments may contain multiple chains linked together, for example, by disulfide bonds and / or by peptide linkers. Antibody fragments generally contain at least or about 50 amino acids, and typically at least or about 200 amino acids. Antigen-binding fragments include any antibody fragment that, when inserted into an antibody framework (e.g., by replacing the corresponding region), results in an antibody that immunospecifically binds to an antigen (i.e., exhibits a Ka of at least or at least about 107-108 M-1). A "functional fragment" or "analog of an anti-GPC3 antibody" is a fragment or analog that prevents or substantially reduces the ability of the receptor to bind to a ligand or initiate signal transduction. As used herein, a functional fragment is generally synonymous with an "antibody fragment" and can refer to a fragment, such as an Fv, Fab, F(ab')2, that prevents or substantially reduces the ability of the receptor to bind to a ligand or initiate signal transduction, with respect to an antibody. An "Fv" fragment consists of a dimer (VH-VL dimer) formed by non-covalently binding one variable domain of a heavy chain and one variable domain of a light chain. In this configuration, the three CDRs of each variable domain interact to determine a target binding site on the surface of the VH-VL dimer, as in the case of a complete antibody. The six CDRs together confer the target binding specificity of the intact antibody.However, even a single variable domain (or half of an Fv comprising only three target-specific CDRs) can still have the ability to recognize and bind to the target.

[0118] An "effective amount" or "therapeutically effective amount" as described in this disclosure includes an amount sufficient to ameliorate or prevent the symptoms or condition of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount used in a particular patient or veterinary subject can vary depending on factors such as, for example, the condition being treated, the overall health of the patient, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen in which significant side effects or toxic effects are avoided.

[0119] The terms "subject," "individual," or "patient" may be used interchangeably herein and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.

[0120] The amount of compound administered may depend on the subject being treated, the subject's age, health condition, sex and weight, type of concurrent treatment (if any), severity of the condition, the nature of the desired effect, the mode and frequency of treatment, and the judgment of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen tension. However, as will be understood by those skilled in the art and can be determined without undue experimentation, the most suitable dose can be adjusted for each individual subject. This usually involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0121] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds of the present application or their salts with a pharma- ceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism. The pharmaceutical compositions of the invention may also contain one or more pharma- ceutical acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.

[0122] The term "pharmaceutical acceptable carrier" refers to an auxiliary agent that has no obvious irritating effect on the organism and does not impair the biological activity and performance of the active compound. Suitable auxiliary agents are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, liposomes, polymeric micelles or inorganic nanocarriers.

[0123] The pharmaceutical compositions of the present invention may be prepared in any pharma- ceutically acceptable form for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration, such as tablets, lozenges, capsules, pills, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

[0124] The term "anti-PD-L1 biological product" refers to an antibody or antigen-binding fragment thereof that specifically binds to PD-1.

[0125] The term "synergism" refers to the phenomenon whereby the action of two drugs applied in combination is more effective than their action alone, as compared to antagonism.

[0126] The term "treatment" includes prevention and treatment, for example, treatment of a KRAS G12C mutation mediated disease includes prevention and / or treatment of a KRAS G12C mutation mediated disease.

[0127] The PD-1 pathway inhibitors, PD-L1 pathway inhibitors, EGFR targeting agents, CDK inhibitors and PI3K inhibitors described in the present invention are intended to include pharma- ceutically acceptable salts of these compounds when these inhibitors are small molecule compounds. For example, in one embodiment, the pharmaceutical composition described in the present invention includes a compound of formula (II) and GDC0941, which is intended to include a compound of formula (II) and pharma- ceutically acceptable salts of GDC0941 and GDC0941.

[0128] II. Specific Embodiments The KRAS inhibitor disclosed in the present invention has the following structural formula (II), and is named (4aR,8R)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione, and its preparation method is as described in step of Example 25 of the international patent application (PCT / CN2020 / 124226). [ka] Formula (II)

[0129] Materials and Reagents (Examples 1 to 7) NCI-H2122 (ATCC, CRL-5985), LU99 (JCRB, JCRB0080), SW837 (ATCC, CRL-235), SW1463 (ATCC, CRL-234), SW1573 (ATCC, CRL-2170), L-15 (Gibco, 11415-064), RPMI1640 (Gibco, 11875-093), Trypsin-EDTA (Gibco, 25200-072), FBS (Gibco, 10099-141C), CellTiter Glo (Progema, G7573), cell counter (Count star, IC1000), cell counter (CHEMOMETEC, NC-200), microplate reader (PerkinElmer, Envison).

[0130] Calculation method for cell survival ratio in the combination group The % cell survival rate after the combination of two drugs was calculated as follows: % cell survival rate = (1-(DMSO control RLU-drug RLU) / (DMSO control RLU-blank control RLU)) x 100%. The DMSO control was a solvent control without any drug, and the blank control was a medium control without any drug or solvent.

[0131] Interpreting the results of cell survival ratio calculations In the cell survival ratio calculation results diagrams (Figure 1, Figure 3, Figure 5, Figure 7, Figure 9, Figure 11, Figure 13), the ordinate is the concentration of the compound of the present application's KRAS inhibitor formula (II) (effective concentration of the drug in the well solution), and the abscissa is the concentration of the combined drug (effective concentration of the drug in the well solution). A perpendicular line is drawn with the concentration scale of the abscissa and the ordinate as the perpendicular point, and the value in the grid where the two perpendicular lines intersect is the cell survival ratio of the drug combination group using the two concentrations. For example, in Figure 1, the reading value of the abscissa is 0nM, the reading value of the ordinate is 10.03nM, and the reading value of the ordinate is 10.03nM. A perpendicular line is drawn with the two concentration scales as the perpendicular point, and the value in the grid where the two perpendicular lines intersect is 86.1. When the cell survival ratio is 86.1%, and the concentration of BYL719 is 0nM, that is, when the compound of formula (II) is administered alone, the cell survival ratio is 86.1%.

[0132] Synergy evaluation method Statistical methods were used to evaluate the combined effect of the two drugs on tumor cells. The statistical software used was R systems, and the statistical models were Bliss, HSA, Loewe, and ZIP. A synergistic value of >5 indicates synergistic effect, a synergistic value of >10 indicates obvious synergistic effect, a synergistic value of <-5 indicates antagonistic effect, and a synergistic value of <-10 indicates obvious antagonistic effect. The synergistic value was used to further determine the final efficacy of the combined administration of the two drugs.

[0133] Example 1: Effect of the combination of the compound of formula (II) and BYL719 (Alpelisib) on tumor cells LU99 Human non-small cell lung cancer cells LU99 were seeded in a 384-well plate at 600 cells per well, and after the cells were attached (24h), the compound of formula (II) and BYL719 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0134] The calculation results of the cell viability ratio are shown in Figure 1. For example, in human non-small cell lung cancer cells LU99, the cell viability was 83% in the case of 100 nM of the compound of formula (II), 62.6% in the case of 1000 nM of BYL719, and 33.8% in the case of the combination of 100 nM of the compound of formula (II) and 1000 nM of BYL719.

[0135] The combination effect is shown in Figure 2. In human non-small cell lung cancer cells LU99, 10 nM to 1000 nM of the compound of formula (II) was combined with 100 nM to 10000 nM of BYL719. The average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 2A), HSA (Figure 2B), Loewe (Figure 2C), and ZIP (Figure 2D) were 8.622, 18.377, 17.27, and 8.959, respectively, all of which were greater than 5. This shows that the combination of the compound of formula (II) and BYL719 in tumor cells has excellent synergistic effect.

[0136] Example 2: Effect of the combination of the compound of formula (II) and BYL719 on tumor cells SW837 Human rectal adenocarcinoma cells SW837 were seeded in 384-well plates at 800 cells per well, and after cell attachment (24h), the compound of formula (II) and BYL719 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0137] The calculation results of the cell viability ratio are shown in Figure 3. For example, in human rectal adenocarcinoma cells SW837, the cell viability was 60.2% in the case of 31.69 nM of the compound of formula (II), 62.9% in the case of 10,000 nM of BYL719, and 20.6% in the case of the combination of 31.69 nM of the compound of formula (II) and 10,000 nM of BYL719.

[0138] The combination effect is shown in Figure 4. In human rectal adenocarcinoma cells SW837, the compound of formula (II) at 3.17 nM to 1000 nM was combined with BYL719 at 100 nM to 10000 nM. The average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 4A), HSA (Figure 4B), Loewe (Figure 4C), and ZIP (Figure 4D) were 10.586, 18.221, 15.149, and 10.857, respectively, all of which were greater than 5. This shows that the combination of the compound of formula (II) and BYL719 in tumor cells has excellent synergistic effect.

[0139] Example 3: Effect of the combination of the compound of formula (II) and GDC0941 (Pictilisib) on tumor cells LU99 Human non-small cell lung cancer cells LU99 were seeded in a 384-well plate at 600 cells per well, and after the cells attached (24h), the compound of formula (II) and GDC0941 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0140] The calculation results of the cell viability ratio are shown in Figure 5. For example, in human non-small cell lung cancer cells LU99, the cell viability was 83.8% in the case of 100 nM of the compound of formula (II), 85.4% in the case of 100 nM of GDC0941, and 58% in the case of the combination of 100 nM of the compound of formula (II) and 100 nM of GDC0941.

[0141] The combination effect is shown in Figure 6. In human non-small cell lung cancer cells LU99, 10 nM to 1000 nM of the compound of formula (II) was combined with 31.74 nM to 10000 nM of GDC0941. The average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 6A), HSA (Figure 6B), Loewe (Figure 6C), and ZIP (Figure 6D) were 8.876, 13.71, 8.626, and 7.761, respectively, all of which were greater than 5. It was shown that the combination of the compound of formula (II) and GDC0941 in tumor cells has excellent synergistic effect.

[0142] Example 4: Effect of the combination of the compound of formula (II) and GDC0941 on tumor cells SW837 Human rectal adenocarcinoma cells SW837 were seeded in 384-well plates at 800 cells per well, and after cell attachment (24h), the compound of formula (II) and GDC0941 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0143] The calculation results of the cell viability ratio are shown in Figure 7. For example, in human rectal adenocarcinoma cells SW837, the cell viability was 56.2% in the case of 31.69 nM of the compound of formula (II), 67.6% in the case of 1000 nM of GDC0941, and 23.4% in the case of the combination of 31.69 nM of the compound of formula (II) and 1000 nM of GDC0941.

[0144] The combination effect is shown in Figure 8. In human rectal adenocarcinoma cells SW837, the compound of formula (II) at 3.17 nM to 1000 nM was combined with GDC0941 at 100 nM to 10000 nM. The average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 8A), HSA (Figure 8B), Loewe (Figure 8C), and ZIP (Figure 8D) were 8.733, 20.115, 18.31, and 9.181, respectively, all of which were greater than 5. This shows that the combination of the compound of formula (II) and GDC0941 in tumor cells has excellent synergistic effect.

[0145] Example 5: Effect of the combination of the compound of formula (II) and GDC0941 on tumor cells SW1463 Human rectal adenocarcinoma cells SW1463 were seeded in 384-well plates at 1200 cells per well, and after cell attachment (24h), the compound of formula (II) and GDC0941 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0146] The calculation results of the cell viability ratio are shown in Figure 9. For example, in human rectal adenocarcinoma cells SW1463, the cell viability was 43.2% in the case of 31.69 nM of the compound of formula (II), 64.6% in the case of 1000 nM of GDC0941, and 8.9% in the case of the combination of 31.69 nM of the compound of formula (II) and 1000 nM of GDC0941.

[0147] The combination effect is shown in Figure 10. In human rectal adenocarcinoma cells SW1463, the compound of formula (II) at 3.17nM-1000nM was combined with GDC0941 at 31.74nM-10000nM, and the average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 10A), HSA (Figure 10B), Loewe (Figure 10C), and ZIP (Figure 10D) were 5.76, 12.967, 10.21, and 6.077, respectively, all of which were greater than 5. It was shown that the combination of the compound of formula (II) and GDC0941 in tumor cells has excellent synergistic effect.

[0148] Example 6: Effect of the combination of the compound of formula (II) and GDC0941 on tumor cells SW1573 Human non-small cell lung cancer cells SW1573 were seeded in a 384-well plate at 600 cells per well, and after the cells were attached (24h), the compound of formula (II) and GDC0941 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0149] The calculation results of the cell viability ratio are shown in Figure 11. For example, in human non-small cell lung cancer cells SW1573, the cell viability was 86.4% in the case of 100 nM of the compound of formula (II), 46% in the case of 3164 nM of GDC0941, and 23.6% in the case of the combination of 100 nM of the compound of formula (II) and 3164 nM of GDC0941.

[0150] The combination effect is shown in Figure 12. In human non-small cell lung cancer cells SW1573, the compound of formula (II) at 0.32nM-1000nM was combined with GDC0941 at 316.91nM-10000nM, and the average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 12A), HSA (Figure 12B), Loewe (Figure 12C), and ZIP (Figure 12D) were 12.227, 19.12, 17.997, and 13.191, respectively, all of which were greater than 5. It was shown that the combination of the compound of formula (II) and GDC0941 in tumor cells has excellent synergistic effect.

[0151] Example 7: Effect of the combination of the compound of formula (II) and SY-5609 (Synonyms) on tumor cells NCI-H2122 Human non-small cell lung cancer cells NCI-H2122 were seeded in a 384-well plate at 600 cells per well, and after the cells were attached (24h), the compound of formula (II) and SY-5609 drug were added and diluted to a certain gradient concentration, and the drug was added to two duplicate wells for each concentration. After 120h, the cell activity was detected using the Cell Titer-Glo method, 30μL of Cell Titer-Glo reagent was added to each well, the plate was shaken for 2 minutes, left to stand for 10 minutes, and the RLU value was read on the Envision instrument.

[0152] The calculation results of the cell viability ratio are shown in Figure 13. For example, in human non-small cell lung cancer cells NC-H2122, the cell viability was 60.7% in the case of 3.17 nM of the compound of formula (II), 57.5% in the case of 31.69 nM of SY-5609, and 3.9% in the case of the combination of 3.17 nM of the compound of formula (II) and 31.69 nM of SY-5609.

[0153] The combination effect is shown in Figure 14. In human non-small cell lung cancer cells NC-H2122, the compound of formula (II) at 0.1 nM to 100 nM was combined with SY-5609 at 3.17 nM to 1000 nM. The average synergistic effect values ​​calculated by the four statistical models of Bliss (Figure 14A), HSA (Figure 14B), Loewe (Figure 14C), and ZIP (Figure 14D) were 8.249, 12.89, 10.518, and 8.805, respectively, all of which were greater than 5. It was shown that the combination of the compound of formula (II) and SY-5609 in tumor cells has excellent synergistic effect.

[0154] Example 8: In vivo antitumor pharmacodynamic evaluation of the combination of compound of formula (II) with Cetuximab in the NCI-H2122 human non-small cell lung cancer model Materials and Reagents: NCI-H2122 (ATCC, CRL-5807), penicillin-streptomycin (Gibco, 15140-122), RPMI 1640 (Gibco, 11875-093), Trypsin-EDTA (Gibco, 25200-072), FBS (Gibco, 10099-141C), Solutol HS 15 (Sigma, 42966-1kg), HP-β-CD (Shaoyuan, SY004863 100g).

[0155] During the experiment, the health status of the animals was observed daily. For example, if the animal lost 10% of its body weight, the administration dose was halved; if the animal lost 15% of its body weight, the administration was stopped until the body weight recovered, or if the tumor volume of the animal reached 2000 mm 3 If any of the following health conditions occurred, the veterinarian was notified and the animal was euthanized: Obvious weight loss, weight loss of more than 20%. No free access to food or water. Animals may develop infections, severe tumor ulcerations or hematomas. Animals develop and continue to deteriorate with clinical signs including piloerection, arching, blanching of the ears, nose, eyes or legs, shortness of breath, convulsions, diarrhea, pain, dehydration and moribundity.

[0156] Experimental animals: BALB / c nude mouse, 6-8 weeks old, female, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., Animal Qualification Certificate No. 20170011008676, rearing environment SPF grade.

[0157] Experimental Drugs: Cetuximab was purchased from MERCK under lot number G00XED.

[0158] Preparation method: The compound of formula (II) was prepared using a solvent of 5% DMSO+10% Solutol HS 15+85% (6% HP-β-CD), and Cetuximab was prepared using 0.9% sodium chloride injection.

[0159] Experimental Method and Steps NCI-H2122 was cultured in RPMI 1640 medium supplemented with 10% FBS and 1% penicillin-streptomycin in an incubator at 37°C and 5% CO2. The cells were passaged by routine digestion with 0.25% trypsin-EDTA. When the cells were in the exponential growth phase and the saturation was 80%-0%, the cells were harvested and counted. The cells were harvested and the final cell concentration was 2.0 × 10 6 Mice were inoculated subcutaneously on the right dorsal side, with an inoculation volume of 0.15 mL per animal and an inoculum dose of 3 × 10 per animal. 5 The tumors averaged approximately 242 mm 3 When the mice had grown to 100 mg / kg (D5 after inoculation), 32 tumor-bearing mice were selected from the group and randomly divided into 4 groups according to the tumor volume and animal weight, with 8 mice per group. The administration was started according to the experimental protocol in Table 1. The dose of each mouse was 10 mL / kg. The animals were weighed twice a week with an electronic balance, and the tumor volume was measured twice a week with a vernier caliper. D17 after inoculation was the end point of the study, and the mice were euthanized after measuring the tumor volume for each group.

[0160] [Table 1]

[0161] Key evaluation indicators: Tumor volume: Tumor volume (TV) = (L × W 2 ) / 2, where L is the longest diameter of the tumor and W is the width of the tumor.

[0162] Tumor growth inhibition (TGI): TGI(%)=[1-(avT i-0 / avC i-0)] × 100%, where avTi-0 is the mean tumor volume of the treatment group on a particular day minus the mean tumor volume of the treatment group on the day treatment began, and avCi-0 is the mean tumor volume of the vehicle control group on a particular day minus the mean tumor volume of the vehicle control group on the day treatment began.

[0163] Tumor weight inhibition (TWI): TWI=(1-TW treatment / Dx / TW control / Dx )×100%, where TW control : Mean tumor weight in the control group (g), TW treatment : Mean tumor weight (g) of treatment group.

[0164] Relative change of body weight (RCBW): RCBW(%)=(BW i -BW0) / BW0×100%, where BW i is the body weight of the animal on a particular day, and BW0 is the body weight of the animal on the day treatment began.

[0165] Data analysis, experimental results and conclusions All experimental data were analyzed and plotted using GraphPad Prism software. Tumor volumes and animal weights of each group were statistically compared using two-way ANOVA (Dunnett's multiple comparisons test), and tumor weights of each group at the end point were statistically compared using one-way ANOVA (Dunnett's multiple comparisons test). P<0.05 indicates statistically significant differences. Tumor volumes, weights, and animal weights are expressed as mean ± standard error of the mean (SEM). The results are shown in Table 2 below.

[0166] [Table 2]

[0167] The effect of tumor growth in NCI-H2122 tumor-bearing mice by each treatment group (see Figures 15 and 16); tumor weight of each tumor-bearing mouse in each treatment group at the endpoint (Figure 17); at the endpoint, animals were euthanized and dissected to collect tumor tissues, which were weighed and photographed; the relative weight changes of tumor-bearing mice in each group are shown in Figure 18.

[0168] The results showed that in the NCI-H2122 human non-small cell lung cancer model, once-day oral administration of compound of formula (II) and twice-weekly intraperitoneal injection of Cetuximab could significantly inhibit NCI-H2122 tumor growth, and had a certain combination enhancing effect. Compared with the weight loss of the solvent control group, the weight loss of animals in the 10mpk group of compound of formula (II), the 1mpk group of Cetuximab, and the combined administration group of compound of formula (II) 10mpk and Cetuximab 1mpk was not significantly decreased, and the difference was statistically significant.

[0169] Example 9: In vivo antitumor pharmacodynamic evaluation of the combination of compound of formula (II) and mPD1 in a mouse CT-26 cell model The experimental animals and main evaluation indices were the same as in Example 8.

[0170] Experimental Drugs: Mouse PD1 antibody (mPD1) was purchased from BioXcell-BE0146, lot number 810421D1.

[0171] Preparation method: The compound of formula (II) was prepared using a solvent of 5% DMSO + 10% Solutol HS 15 + 85% (6% HP-β-CD), and mPD1 was prepared using PBS.

[0172] Experimental Method and Steps Mice were subcutaneously inoculated with CT26 KRASG12C KI cells (KRASG12C mutant CT26 cells) on the right dorsal side, with an inoculation volume of 0.1 mL per animal. On day 12 (D0) after cell inoculation, the mean tumor volume was 69 mm 3 After reaching the target mass, group administration was started, and 32 tumor-bearing mice were selected from them and randomly divided into 4 groups according to tumor volume and animal weight, with 8 mice per group, and the administration method was performed according to the experimental protocol in Table 3. The administration volume for mice was 10 mL / kg in all cases. The animals were weighed twice a week with an electronic balance, and the tumor volumes were measured twice a week with a vernier caliper.

[0173] [Table 3]

[0174] The main evaluation indexes were tumor volume, TGI, TWI and RCBW, and the calculation formulas and data analysis were the same as in Example 8. The results are shown in Table 4 below.

[0175] [Table 4]

[0176] The results showed that in mouse CT26 KRASG12C KI cell model, administration of the compound of formula (II) and mouse PD1 antibody (mPD1) could significantly inhibit tumor growth, and had a certain combination enhancing effect.

[0177] The effect of tumor growth in CT26 KRAS G12C KI tumor-bearing mice by each treatment group (see Figures 19 and 20); tumor weight of each tumor-bearing mouse in each treatment group at the endpoint (see Figure 21); at the endpoint, animals are euthanized and dissected to collect and weigh tumor tissues; the relative weight change of tumor-bearing mice in each group is shown in Figure 22.

[0178] The results showed that in a mouse colon cancer CT26 KRAS G12C KI cell subcutaneous tumor model, both the compound of formula (II) and mPD1 monotherapy groups showed mild tumor inhibitory effects, with the mean tumor volume reaching 1,065 mm 3 (T / C=54.92%, TGI=46.74%, p=0.1640) and 968mm 3 (T / C=49.91%, TGI=51.94%, p=0.1094). The combined treatment group of the compound of formula (II) and mPD1 showed a significant tumor inhibitory effect, with the mean tumor volume being 632 mm 3 (T / C=32.56%, TGI=69.92%, p=0.0223). At the end of the experiment, the tumor volume of one mouse in the group was 50 mm 3 During the treatment, the tumor-bearing mice all showed good tolerance to the test drugs, and no obvious drug-related weight loss or death was observed in any of the mice in any of the treatment groups.

[0179] From the above experimental results, it was found that the KRAS inhibitor represented by formula (I), as well as cancer therapeutic agents such as PI3K inhibitors represented by BYL719 and GDC0941, EGFR antibodies represented by cetuximab, CDK7 inhibitors represented by SY-5609, and PD-1 antibodies represented by mPD1 antibodies all have obvious synergistic effects when used in the treatment of cancers such as lung adenocarcinoma, rectal adenocarcinoma, or lung cancer.

[0180] The foregoing descriptions of specific, exemplary embodiments of the present invention are for purposes of explanation and illustration. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many modifications and variations can be made in light of the above teachings. The purpose of selecting and describing the exemplary examples is to interpret certain principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments and various different options and modifications of the present invention. It is intended that the scope of the present invention be limited by the claims and their equivalents.

Claims

1. A pharmaceutical composition or kit comprising a therapeutically effective amount of a KRAS inhibitor, a therapeutically effective amount of at least one other cancer therapeutic agent, and a pharma- ceutically acceptable carrier, The KRAS inhibitor comprises a compound of formula (I) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof: 【Chemistry 1】 Formula (I) where R is CH ３ or CD ３ is A pharmaceutical composition or kit comprising:

2. the other cancer therapeutic agent is selected from a PD-1 pathway inhibitor, a PD-L1 pathway inhibitor, an EGFR targeting agent, a CDK inhibitor, and a PI3K inhibitor; Preferably, the PD-1 pathway inhibitor is selected from a PD-1 antagonist, a PD-1 binding antagonist, a small molecule PD-1 antagonist, a PD-1 inhibitor, and an anti-PD-1 biological product; Preferably, the PD-L1 pathway inhibitor is selected from a PD-L1 antagonist, a PD-L1 binding antagonist, a small molecule PD-L1 antagonist, a PD-L1 inhibitor, and an anti-PD-L1 biological product; Preferably, the EGFR targeting agent is selected from an EGFR inhibitor and an EGFR antibody or antigen-binding fragment thereof; Preferably, the CDK inhibitor is selected from a CDK4 / 6 inhibitor, a CDK2 / 4 / 6 inhibitor, a CDK7 inhibitor, a CDK8 inhibitor, a CDK9 inhibitor, a CDK10 inhibitor and a CDK11 inhibitor; Preferably, the PI3K inhibitor is selected from a PI3Kγ inhibitor, a PI3Kδ inhibitor, a PI3Kβ inhibitor, a PI3Kα inhibitor, and a pan-PI3K inhibitor. The pharmaceutical composition or kit according to claim 1 .

3. the other cancer therapeutic agent is selected from a PD-1 inhibitor, a PD-L1 inhibitor, an EGFR inhibitor, an EGFR antibody or an antigen-binding fragment thereof, a CDK7 inhibitor, and a PI3K inhibitor; Preferably, the PD-1 inhibitor is selected from AMG404, pembrolizumab, nivolumab, pembrolizumab, pidilizumab, cemiplimab, tislelizumab, spartalizumab, RN888, mAb15, MEDI-0680, BGB-108, spartalizumab, IBI-308, mDX-400, SHR-1210, PF-06801591, PDR-001, GB-226 and STI-1110, and biological analogs, biological enhancers and biological equivalents of these inhibitors; Preferably, the PD-L1 inhibitor is selected from BMS-936559, AMP-714, atezolizumab, durvalumab, avelumab, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014 and KY-1003, and biological analogues, biological enhancers and bioequivalents of these inhibitors; Preferably, the EGFR inhibitor is selected from afatinib, erlotinib, lapatinib, gefitinib, osimertinib, icotinib, pyrotinib and olmutinib; Preferably, the EGFR antibody or antigen-binding fragment thereof is selected from Cetuximab, Nimotuzumab, Panitumumab, Zalutumumab, Matuzumab, and Necitumumab, more preferably Cetuximab; Preferably, the CDK7 inhibitor is selected from SY-5609, SY-1365, CT-7001 and BTX-A51, more preferably SY-5609; Preferably, the PI3K inhibitor is selected from BYL719, GDC0941, AMG511, LY294002, BEZ235, BKM120 and GSK-2636771, more preferably, BYL719 and GDC0941. The pharmaceutical composition or kit according to claim 1 .

4. The compound of formula (I) is 【Chemistry 2】 Formula (II) 【Chemistry 3】 Formula (III) 【Chemistry 4】 Formula (IV) 【Chemistry 5】 Formula (V) Selected from the group consisting of The pharmaceutical composition or kit according to claim 1 .

5. The KRAS inhibitor is a compound of formula (II) or a pharma- ceutically acceptable salt thereof: 【Chemistry 6】 Formula (II) Preferably, the pharmaceutical composition or kit comprises a compound of formula (II) and a PD-1 pathway inhibitor, Preferably, the pharmaceutical composition or kit comprises a compound of formula (II) and a PD-L1 pathway inhibitor, Preferably, the pharmaceutical composition or kit comprises a compound of formula (II) and an EGFR targeting agent, more preferably, a compound of formula (II) and cetuximab; Preferably, the pharmaceutical composition or kit comprises a compound of formula (II) and a CDK7 inhibitor, more preferably, a compound of formula (II) and SY-5609; Preferably, the pharmaceutical composition or kit comprises a compound of formula (II) and a PI3K inhibitor, more preferably, a compound of formula (II) and BYL719, or a compound of formula (II) and GDC0941. A pharmaceutical composition or kit according to claim 1 or 2.

6. 0.1-1000 nM of a KRAS inhibitor and 1-10000 nM of another cancer therapeutic agent; Preferably, the pharmaceutical composition or kit comprises 10 mg / mL of the compound of formula (II) and 1 mg / mL of cetuximab; Preferably, the pharmaceutical composition or kit comprises 1-3 mg / kg of the compound of formula (II) and 10 mg / kg of the PD-1 antibody; Preferably, the pharmaceutical composition or kit comprises a drug dose equivalent to 10 mpk of the compound of formula (II) and 1 mpk of cetuximab, Preferably, the pharmaceutical composition or kit comprises a drug dose equivalent to 1-3 mpk of the compound of formula (II) and 10 mpk of the PD-1 antibody; Preferably, the pharmaceutical composition or kit comprises 0.1-100 nM of the compound of formula (II) and 3.17-1000 nM of SY-5609; Preferably, the pharmaceutical composition or kit comprises 1-1000 nM of the compound of formula (II) and 100-10000 nM of BYL719, 3-1000 nM of the compound of formula (II) and 100-10000 nM of BYL719, 10-1000 nM of the compound of formula (II) and 100-10000 nM of BYL719, Preferably, the pharmaceutical composition or kit comprises 0.1-1000 nM of the compound of formula (II) and 10-10000 nM of GDC0941, 3.17-1000 nM of the compound of formula (II) and 31.74-10000 nM of GDC0941, 3.17-1000 nM of the compound of formula (II) and 100-10000 nM of GDC0941, 10-1000 nM of the compound of formula (II) and 31.74-10000 nM of GDC0941 or 0.32-1000 nM of the compound of formula (II) and 316.91-10000 nM of GDC0941. A pharmaceutical composition or kit according to claim 5.

7. 13. A method of treating cancer comprising administering to a subject in need thereof a KRAS inhibitor of claim 1 and other cancer therapeutic agents, wherein the therapeutically effective amount of a KRAS inhibitor and the therapeutically effective amount of another cancer therapeutic agent may be administered simultaneously, separately or sequentially; Preferably, the method of treating cancer further comprises administering to the subject another therapy, the other therapy being one or more selected from radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, and phototherapy, and the other therapy may be in the form of an adjunctive therapy or a novel adjunctive therapy. The method according to claim 1,

8. Use of the pharmaceutical composition or kit according to any one of claims 1 to 6 in the manufacture of a medicament for treating cancer, wherein a therapeutically effective amount of a KRAS inhibitor and a therapeutically effective amount of another cancer therapeutic agent may be administered simultaneously, separately or sequentially; Preferably, the cancer is a solid tumor or a hematological tumor; Preferably, the cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, skin melanoma, endometrial carcinoma, uterine sarcoma, thyroid cancer, acute myeloid leukemia, bladder urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdomyosarcoma, sarcoma, small intestinal neuroendocrine tumor, T-cell prolymphocytic leukemia; Preferably, the cancer is lung adenocarcinoma, colon cancer, rectal cancer or lung cancer; Preferably, the cancer is lung adenocarcinoma, rectal adenocarcinoma or lung cancer; Preferably, the lung cancer is small cell lung cancer or non-small cell lung cancer; Preferably, the cancer is a KRAS G12C mutant cancer. use.

9. 1. Use of a therapeutically effective amount of a KRAS inhibitor and at least one therapeutically effective amount of another cancer therapeutic agent in the manufacture of a drug, drug combination, or kit for treating cancer, comprising: The KRAS inhibitor is one or more selected from the compound represented by formula (I) according to claim 1 and the compounds represented by formulas (II) to (V) according to claim 4, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; Preferably, the other cancer therapeutic agent is selected from a PD-1 pathway inhibitor, a PD-L1 pathway inhibitor, an EGFR targeting agent, a CDK inhibitor, and a PI3K inhibitor; use.

10. the PD-1 pathway inhibitor is selected from a PD-1 antagonist, a PD-1 binding antagonist, a small molecule PD-1 antagonist, a PD-1 inhibitor, and an anti-PD-1 biological product; Preferably, the PD-L1 pathway inhibitor is selected from a PD-L1 antagonist, a PD-L1 binding antagonist, a small molecule PD-L1 antagonist, a PD-L1 inhibitor, and an anti-PD-L1 biological product; Preferably, the EGFR targeting agent is selected from an EGFR inhibitor and an EGFR antibody or antigen-binding fragment thereof; Preferably, the CDK inhibitor is selected from a CDK4 / 6 inhibitor, a CDK2 / 4 / 6 inhibitor, a CDK7 inhibitor, a CDK8 inhibitor, a CDK9 inhibitor, a CDK10 inhibitor and a CDK11 inhibitor; Preferably, the PI3K inhibitor is selected from a PI3Kγ inhibitor, a PI3Kδ inhibitor, a PI3Kβ inhibitor, a PI3Kα inhibitor, and a pan-PI3K inhibitor; 10. The use according to claim 9.

11. the other cancer therapeutic agent is selected from a PD-1 inhibitor, a PD-L1 inhibitor, an EGFR inhibitor, an EGFR antibody or an antigen-binding fragment thereof, a CDK7 inhibitor, and a PI3K inhibitor; Preferably, the PD-1 inhibitor is selected from AMG404, pembrolizumab, nivolumab, pembrolizumab, pidilizumab, cemiplimab, tislelizumab, spartalizumab, RN888, mAb15, MEDI-0680, BGB-108, spartalizumab, IBI-308, mDX-400, SHR-1210, PF-06801591, PDR-001, GB-226 and STI-1110, and biological analogs, biological enhancers and biological equivalents of these inhibitors; Preferably, the PD-L1 inhibitor is selected from BMS-936559, AMP-714, atezolizumab, durvalumab, avelumab, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014 and KY-1003, and biological analogues, biological enhancers and bioequivalents of these inhibitors; Preferably, the EGFR inhibitor is selected from afatinib, erlotinib, lapatinib, gefitinib, osimertinib, icotinib, pyrotinib and olmutinib; Preferably, the EGFR antibody or antigen-binding fragment thereof is selected from Cetuximab, Nimotuzumab, Panitumumab, Zalutumumab, Matuzumab, and Necitumumab, more preferably Cetuximab; Preferably, the CDK7 inhibitor is selected from SY-5609, SY-1365, CT-7001 and BTX-A51, more preferably SY-5609; Preferably, the PI3K inhibitor is selected from BYL719, GDC0941, AMG511, LY294002, BEZ235, BKM120 and GSK-2636771, more preferably, BYL719 and GDC0941; 10. The use according to claim 9.

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