Pharmaceutical combination product and use thereof

Abstract

Provided are a pharmaceutical combination product and use thereof. The present invention specifically relates to a pharmaceutical combination product comprising a RAS inhibitor and a chemotherapeutic agent and use thereof in treating tumors.

Description

Drug combination products and their uses

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese patent application 202410924310.6, filed on July 10, 2024, and Chinese patent application 202411625438.9, filed on November 13, 2024. The full text of the above two Chinese patent applications is incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of biomedicine and specifically relates to a drug combination product and its uses. Background Technology

[0004] Currently, cancer remains a major public health problem worldwide. The main treatments for cancer include surgery, radiotherapy, and chemotherapy. Microtubule inhibitors are a class of highly effective anti-tumor chemotherapy drugs, with paclitaxel-based drugs being widely used clinically. Docetaxel, a type of paclitaxel, works similarly to paclitaxel by promoting the assembly of microtubule dimers into microtubules and stabilizing microtubules by preventing depolymerization, thus arresting cells in the G2 and M phases and inhibiting cancer cell mitosis and proliferation. Although microtubule inhibitor chemotherapy drugs such as docetaxel are widely used clinically, their efficacy still needs further improvement.

[0005] RAS (including KRAS, NRAS, and HRAS) are downstream of growth factor receptors such as EGFR. They are small GTPases that act as molecular switches, serving as key nodes in the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways, regulating events such as cell proliferation and survival. Mutations in RAS can disrupt GTP hydrolysis, leading to functional activation of the protein. Under normal physiological conditions, RAS typically exists in its inactive form (OFF) bound to GDP; however, in RAS-mutated tumor cells, it primarily exists in its activated form (ON) bound to GTP. Approximately 30% of cancer patients have RAS mutations, with KRAS mutations being the most common, including various types such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, and KRAS G13C. Because RAS mutations are a significant factor in cancer development and progression, mutant RAS has become an important therapeutic target for cancer. Patent publication numbers WO2024067857A1, WO2024153208A1, WO2024060966A1, and WO2024169914A1 disclose a series of RAS inhibitors with macrocyclic structures. Summary of the Invention

[0006] This disclosure aims to provide a pharmaceutical combination product and its use.

[0007] This disclosure provides a pharmaceutical combination product comprising a RAS inhibitor and a chemotherapy drug.

[0008] In some implementations, the drug combination product includes:

[0009] (i) a first pharmaceutical composition comprising the RAS inhibitor; and

[0010] (ii) A second pharmaceutical composition comprising the chemotherapy drug.

[0011] This disclosure also provides the use of a combination of a RAS inhibitor and a chemotherapeutic agent in the preparation of a medicament for treating tumors.

[0012] This disclosure also provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of tumors in combination with chemotherapy drugs.

[0013] This disclosure also provides the use of a chemotherapeutic agent in the preparation of a medicament for the treatment of tumors in combination with a RAS inhibitor.

[0014] This disclosure also provides a method for treating a tumor in a subject, the method comprising administering to the subject a therapeutically effective amount of a RAS inhibitor and a chemotherapy drug.

[0015] This disclosure also provides a method for inhibiting tumor cell growth under in vitro, in vivo, or ex vivo conditions, comprising contacting the tumor cells with a therapeutically effective amount of a RAS inhibitor and a chemotherapeutic agent.

[0016] In some embodiments, the RAS inhibitor is a RAS(ON) inhibitor, such as a RAS(ON) MULTI inhibitor.

[0017] In some embodiments, the RAS inhibitor is a compound of formula (VI) or a pharmaceutically acceptable salt thereof;

[0018] L is R6 or

[0019] L1 is -N(R9)C(=O)-;

[0020] L2 is C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a replace;

[0021] L3 is -CH2- or C 3-6 cycloalkyl;

[0022] L4 is a single bond or -C 1-4 Alkyl-N(R) 10 )C(=O)-;

[0023] Ring A is hexahydropyridazinyl, tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexyl, 5,6-diazaspiro[2.5]octyl, 3,4-diazabicyclo[4.2.0]octyl, or 2,3-diazabicyclo[3.1.1]heptyl;

[0024] Ring B is a 5-membered heteroaryl-6-membered heteroaryl, a 5-membered heteroaryl-5-membered heteroaryl, or an indole group;

[0025] T1, T2, T3, and T4 are independently CH or N;

[0026] R1 is H, F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are independently and optionally surrounded by 1, 2, or 3 R groups. h replace;

[0027] R2 is -O- or -NH-;

[0028] R3 is a phenyl or a 5-6 heteroaryl group, wherein the phenyl and the 5-6 heteroaryl group are each independently selected by 1, 2 or 3 R3 groups. b replace;

[0029] R4 and R5 are independently H and C, respectively. 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are each independently and optionally bound by 1, 2 or 3 R groups. c replace;

[0030] R6 is C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are each independently and optionally bound by 1, 2 or 3 R groups. d replace;

[0031] Each R7 is independently H, halogen, or C. 1-4 Alkyl or C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are independently and optionally surrounded by 1, 2, or 3 R groups. e replace;

[0032] Each R8 is independently H, and the C that is arbitrarily substituted is also independently H. 1-4 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 1-4 Alkoxy group, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-6-membered heteroaryl (the optional substitution may be, for example, by 1, 2, or 3 R groups). g replace);

[0033] R9, R 10 For H or C 1-4 Alkyl, the C 1-4 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. g replace;

[0034] Each R a Each R b Each R c Each R e Each R g and each R h They are, independently, H, D, F, Cl, Br, I, OH, and C. 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0035] Each R d C, each independently 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl or -C(=O)-C 2-4 alkenyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 The alkenyl groups can be independently and optionally substituted by 1, 2 or 3 R groups;

[0036] Each R is independently D, F, Cl, Br, I, OH, CH3, CF3, OCH3, or OCF3;

[0037] n, p, and q are each 0, 1, 2, or 3 independently.

[0038] In some embodiments, the RAS inhibitor is a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof;

[0039] Among them, rings A, T1, T3, R1, R3, R6, R7, R8, L3 and n are defined as in equation (VI).

[0040] In some implementations, in equations (VI) and (VI-1), ring A is... For example

[0041] In some implementations, L3 is -CH2- in formulas (VI) and (VI-1).

[0042] In some implementations, R3 in equations (VI) and (VI-1) is For example

[0043] In some implementations, in equations (VI) and (VI-1), R7 is C. 1-4 alkyl.

[0044] In some implementations, R1 is H in equations (VI) and (VI-1).

[0045] In some implementations, T1 and T3 are CH in equations (VI) and (VI-1).

[0046] In some embodiments, the RAS inhibitor is any compound selected from the compounds shown in formulas (I), (II), (III), and (IV) or a pharmaceutically acceptable salt thereof;

[0047] In equations (I), (II), (III), and (IV),

[0048] R 1a R 1b R 1c and R 1d Each independently Where R i It is a phenyl or a 5–6-membered heteroaryl group (e.g., pyridyl, pyrimidinyl, pyrazinyl), wherein the phenyl and 5–6-membered heteroaryl group are optionally substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, methyl, methoxy, trifluoromethyl and cyclopropyl.

[0049] R 3a R 3c and R 3d Each is independently ethyl or 2,2,2-trifluoroethyl;

[0050] L 1 It is CH2 or O;

[0051] R 2a R 2b R2c and R 2d Each of the 5–10-membered heterocyclic alkyl groups is independently substituted with one, two, three or four substituents independently selected from methyl, ethyl, cyclopropyl, =O, –CH2OH, –CH2CH2OH, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2 and –CH2CF3.

[0052] In some implementation schemes, R in equations (I), (II), (III), and (IV) 1a R 1b R 1c and R 1d Each independently

[0053] In some implementations, in equations (I), (II), and (III), R 2a R 2b and R 2c Each independently

[0054] In some implementations, in formula (IV), R 2d for

[0055] In some embodiments, the RAS inhibitor is a compound of formula (I). In some embodiments, the RAS inhibitor is a compound of formula (II). In some embodiments, the RAS inhibitor is a compound of formula (III). In some embodiments, the RAS inhibitor is a compound of formula (IV).

[0056] In some embodiments, the RAS inhibitor is RMC-6236 or a pharmaceutically acceptable salt thereof;

[0057] In some embodiments, the RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof;

[0058] In some embodiments, the chemotherapeutic agent is one or a combination of two or more of the following: a microtubule inhibitor, a dihydrofolate reductase inhibitor, a thymidine reductase inhibitor, a purine nucleotide tautomerase inhibitor, a nucleotide reductase inhibitor, a DNA polymerase inhibitor, an alkylating agent, a platinum complex, and a topoisomerase inhibitor. In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In some embodiments, the chemotherapeutic agent is a dihydrofolate reductase inhibitor. In some embodiments, the chemotherapeutic agent is a thymidine reductase inhibitor. In some embodiments, the chemotherapeutic agent is a purine nucleotide tautomerase inhibitor. In some embodiments, the chemotherapeutic agent is a nucleotide reductase inhibitor. In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the chemotherapeutic agent is a platinum complex. In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor.

[0059] In some embodiments, the tubulin inhibitor is one or a combination of two or more of paclitaxel-based tubulin inhibitors and vincristine-based tubulin inhibitors, such as paclitaxel, albumin-bound paclitaxel, docetaxel, vincristine, vinorelbine, vindesine, and vindesine. In some embodiments, the tubulin inhibitor is a paclitaxel-based tubulin inhibitor. In some embodiments, the tubulin inhibitor is paclitaxel, albumin-bound paclitaxel, or docetaxel. In some embodiments, the tubulin inhibitor is docetaxel.

[0060] In some embodiments, the dihydrofolate reductase inhibitor is one or a combination of two or more of pemetrexed, docetaxel, and methotrexate.

[0061] In some embodiments, the thymidine synthase inhibitor is one or a combination of two or more of 5-fluorouracil, tegafur, tegafur, carmoflu, deoxyfluorouracil, difurylfluorouracil, gemcitabine, capecitabine, and vinorelbine.

[0062] In some embodiments, the purine nucleotide tautomerism inhibitor is one or a combination of two or more of mercaptopurine, azathioprine, and 6-thioguanine.

[0063] In some embodiments, the nucleotide reductase inhibitor is hydroxyurea.

[0064] In some embodiments, the DNA polymerase inhibitor is cytarabine.

[0065] In some embodiments, the alkylating agent is one or a combination of two or more of nitrogen mustard, dacarbazine, semustine, carmustine, cyclophosphamide, temozolomide, and ifosfamide.

[0066] In some embodiments, the platinum complex is one or a combination of two or more of cisplatin, carboplatin, nedaplatin, bicyclic platinum, pyridine, oxaliplatin, miplatin, lobaplatin, and levoplatin.

[0067] In some embodiments, the topoisomerase inhibitor is one or a combination of two or more of the following: topotecan, irinotecan, topotecan, etoposide, teniposide, doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin, penoxorubicin, homoharringtonine, and homoharringtonine.

[0068] In some embodiments, the chemotherapeutic agent is a paclitaxel-based microtubule inhibitor, including but not limited to paclitaxel, albumin-bound paclitaxel, and docetaxel. In some embodiments, the chemotherapeutic agent is docetaxel.

[0069] In some embodiments, this disclosure provides a pharmaceutical combination product comprising a RAS inhibitor and a microtubule inhibitor; said RAS inhibitor and microtubule inhibitor may be as described in any of the preceding embodiments.

[0070] In some embodiments, this disclosure provides a pharmaceutical combination product comprising:

[0071] (i) a first pharmaceutical composition comprising a RAS inhibitor; and

[0072] (ii) A second pharmaceutical composition comprising a tubulin inhibitor;

[0073] The RAS inhibitor and tubulin inhibitor can be as described in any of the preceding protocols.

[0074] In some embodiments, this disclosure provides the use of a combination of a RAS inhibitor and a tubulin inhibitor in the preparation of a medicament for treating tumors; said RAS inhibitor and tubulin inhibitor may be as described in any of the preceding embodiments.

[0075] In some embodiments, this disclosure provides the use of a RAS inhibitor in the preparation of a medicament for the treatment of tumors in combination with a microtubule inhibitor; the RAS inhibitor and the microtubule inhibitor may be as described in any of the preceding embodiments.

[0076] In some embodiments, this disclosure provides the use of a microtubule inhibitor in the preparation of a medicament for the treatment of tumors in combination with a RAS inhibitor; the RAS inhibitor and the microtubule inhibitor may be as described in any of the preceding embodiments.

[0077] In some embodiments, this disclosure provides a method for treating tumors, the method comprising administering a therapeutically effective amount of a RAS inhibitor and a microtubule inhibitor to a subject in need; said RAS inhibitor and microtubule inhibitor may be as described in any of the preceding embodiments.

[0078] In some implementations, the tumor is a solid tumor or a hematologic tumor.

[0079] In some implementations, the tumor is brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer (e.g., non-small cell lung cancer, including but not limited to lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, lung carcinoid; small cell lung cancer), liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, or bladder cancer. Anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia (e.g., acute myeloid leukemia, including but not limited to acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia; acute lymphoblastic leukemia, including but not limited to precursor B-cell acute lymphoblastic leukemia, precursor T-cell acute lymphoblastic leukemia, etc.). Acute lymphoblastic leukemia, Burkitt cell leukemia; chronic myeloid leukemia, including but not limited to chronic myeloid leukemia, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, and chronic neutrophilic leukemia; chronic lymphocytic leukemia; acute mixed cell leukemia); lymphoma (e.g., Hodgkin's lymphoma); B-cell lymphoma, including but not limited to diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and B-lymphoblastic lymphoma; T-cell lymphoma, including but not limited to peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and T-lymphoblastic lymphoma; NK-cell lymphoma); myeloma (e.g., multiple myeloma); skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma (e.g., neuroblastoma of the brain), glioblastoma, and neuroendocrine tumors, one or more of these.

[0080] In some embodiments, the tumor is lung cancer. In some embodiments, the tumor is non-small cell lung cancer, such as lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, or lung carcinoid.

[0081] In some implementations, the tumor is colon cancer and / or rectal cancer.

[0082] In some implementations, the tumor is pancreatic cancer.

[0083] In some implementations, the tumor is cholangiocarcinoma.

[0084] In some implementations, the tumor is ovarian cancer.

[0085] In some implementations, the tumor is gastric cancer.

[0086] In some implementations, the tumor is leukemia, lymphoma, or myeloma, such as acute promyelocytic leukemia, acute monocytic leukemia, or multiple myeloma.

[0087] In some implementations, the tumor contains RAS mutations.

[0088] In some embodiments, the tumor comprises one or a combination of two or more of the following: KRAS mutation, NRAS mutation, and HRAS mutation. In some embodiments, the tumor comprises a KRAS mutation. In some embodiments, the tumor comprises an NRAS mutation. In some embodiments, the tumor comprises an HRAS mutation.

[0089] In some embodiments, the tumor contains one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H. In some embodiments, the tumor contains a KRAS G12A mutation. In some embodiments, the tumor contains a KRAS G12C mutation. In some embodiments, the tumor contains a KRAS G12D mutation. In some embodiments, the tumor contains a KRAS G12V mutation. In some embodiments, the tumor contains a KRAS G12R mutation. In some embodiments, the tumor contains a KRAS G12S mutation. In some embodiments, the tumor contains a KRAS G13C mutation. In some embodiments, the tumor contains a KRAS G13D mutation. The tumor contains a KRAS Q61R mutation. In some embodiments, the tumor contains a KRAS Q61K mutation. In some embodiments, the tumor contains a KRAS Q61H mutation. In some embodiments, the tumor contains an NRAS G12D mutation. In some embodiments, the tumor contains an NRAS Q61K mutation. In some embodiments, the tumor contains an NRAS Q61L mutation. In some embodiments, the tumor contains an HRAS Q61H mutation.

[0090] In some implementations, the tumor does not contain RAS mutations.

[0091] In some embodiments, the tumor is a KRAS-mutated lung cancer. In some embodiments, the tumor is a KRAS G12V-mutated lung cancer.

[0092] In some embodiments, the tumor is pancreatic cancer, which comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0093] In some embodiments, the tumor is colon cancer and / or rectal cancer, which comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0094] In some embodiments, the tumor is non-small cell lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma, lung large cell carcinoma, lung adenosquamous carcinoma, lung carcinoid), the non-small cell lung cancer comprising one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, HRAS Q61H.

[0095] In some embodiments, the tumor is cholangiocarcinoma, which comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0096] In some embodiments, the tumor is ovarian cancer, which comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0097] In some embodiments, the tumor is gastric cancer, which comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0098] In some embodiments, the tumor is leukemia, lymphoma, or myeloma (e.g., acute promyelocytic leukemia, acute monocytic leukemia, or multiple myeloma), wherein the leukemia, lymphoma, or myeloma comprises one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

[0099] In some embodiments, the tumor is resistant to at least one chemotherapy drug, which may be one of the types of chemotherapy drugs described above. In some embodiments, the tumor is resistant to the combination drug product or the chemotherapy drugs included in the combination.

[0100] In some implementations, the RAS inhibitor and the chemotherapy drug are administered simultaneously or sequentially.

[0101] In this disclosure, the RAS inhibitors and chemotherapeutic drugs can be administered by any suitable method, such as oral, intravenous, intramuscular, subcutaneous, or intravenous infusion. Depending on the method of administration, the RAS inhibitors and chemotherapeutic drugs can be formulated into various conventional dosage forms, such as, but not limited to, tablets, capsules, granules, syrups, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, and injections.

[0102] In some implementations, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered orally.

[0103] The RAS inhibitor can be administered at a fixed dose or based on the individual's weight or body surface area.

[0104] In some embodiments, the single-dose administration of the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is from 0.01 mg to 1000 mg, for example 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, etc. 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg.

[0105] In some embodiments, the single-dose administration of the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg. / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, based on the body weight of the individual receiving the medication. In some embodiments, the single-dose administration of the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is from 0.1mg / kg to 20mg / kg.

[0106] In some embodiments, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may be administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly (QW), twice weekly (BIW), three times weekly (TIW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily. In some embodiments, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the RAS inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered three times daily.

[0107] In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is administered via intravenous injection, intramuscular injection, subcutaneous injection, or intravenous infusion. In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is administered via intravenous injection or intravenous infusion. In some embodiments, the chemotherapeutic agent is administered orally.

[0108] The chemotherapy drugs can be administered at a fixed dose or based on the individual's weight or body surface area.

[0109] In some embodiments, the single-dose administration of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is from 0.01 mg to 1000 mg, for example 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 6 0mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg. In some implementations, the single dose of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is 100 mg to 500 mg.

[0110] In some embodiments, the single-dose administration of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg. / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, based on the individual's body weight. In some embodiments, the single-dose administration of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is from 0.1mg / kg to 10mg / kg.

[0111] In some embodiments, the single-dose administration of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is 0.01 mg / m². 2 Up to 1000 mg / m 2 For example, 0.01 mg / m³ 2 0.02 mg / m 2 0.03 mg / m 2 0.04 mg / m 2 0.05mg / m 2 0.06 mg / m 2 0.07 mg / m 2 0.08 mg / m 2 0.09 mg / m 2 0.1 mg / m 2 0.2 mg / m 2 0.3 mg / m 2 0.4 mg / m 2 0.5 mg / m 2 0.6 mg / m 2 0.7 mg / m 2 0.8 mg / m 2、0.9mg / m 2 、1mg / m 2 、2mg / m 2 、3mg / m 2 、4mg / m 2 、5mg / m 2 、6mg / m 2 、7mg / m 2 、8mg / m 2 、9mg / m 2 、10mg / m 2 、15mg / m 2 、20mg / m 2 、25mg / m 2 、30mg / m 2 、35mg / m 2 、40mg / m 2 、45mg / m 2 、50mg / m 2 、55mg / m 2 、60mg / m 2 、65mg / m 2 、70mg / m 2 、75mg / m 2 、80mg / m 2 、85mg / m 2 、90mg / m 2 、95mg / m 2 、100mg / m 2 、125mg / m 2 、150mg / m 2 、175mg / m 2 、200mg / m 2 、225mg / m 2 、250mg / m 2 、275mg / m 2 、300mg / m 2 、325mg / m 2 、350mg / m 2 、375mg / m 2 、400mg / m 2 、425mg / m 2 、450mg / m 2 、475mg / m 2 、500mg / m 2 、525mg / m 2 、550mg / m 2 、575mg / m 2 、600mg / m 2 、625mg / m2 650mg / m 2 675mg / m 2 700mg / m 2 725mg / m 2 750mg / m 2 775mg / m 2 800mg / m 2 825mg / m 2 850mg / m 2 875mg / m 2 900mg / m 2 925mg / m 2 950mg / m 2 975mg / m 2 Or 1000mg / m 2 Based on the body surface area of ​​the individual to whom the medication is administered. In some embodiments, the single dose of the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is 10 mg / m². 2 Up to 500mg / m 2 .

[0112] In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, such as docetaxel) may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, such as docetaxel) is administered once daily. In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, such as docetaxel) is administered twice daily. In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, such as docetaxel) is administered three times daily. In some embodiments, the chemotherapeutic agent (e.g., docetaxel) is administered once every three weeks.

[0113] In some embodiments, the chemotherapeutic agent (e.g., a microtubule inhibitor, or docetaxel) is administered at the standard dose and frequency when the chemotherapeutic agent is used alone, such as the recommended dose and frequency in the drug's package insert (e.g., the generally recommended dose of docetaxel is 75 mg / m²). 2 Or 100mg / m 2 (once every three weeks). In some embodiments, the chemotherapy drug may be administered at 5% to 95% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the standard dose when the chemotherapy drug is used alone.

[0114] The combination of RAS inhibitors and chemotherapy drugs disclosed herein can be administered in one or more cycles, wherein each cycle can be longer than one week, for example, one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer; optionally, the duration of each cycle can be the same or different, and the interval between each cycle can be the same or different. Within any treatment cycle, the dosage and frequency of administration of the RAS inhibitors and chemotherapy drugs can be adjusted according to the actual situation; for example, after using an initial dose, subsequent doses can be 10% to 300% of the initial dose, such as 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%.

[0115] In some implementations, the combination of the RAS inhibitor and the chemotherapeutic drug achieves a synergistic effect.

[0116] In some embodiments, administration of the drug combination of this disclosure to a subject with a tumor results in complete tumor remission. In some embodiments, administration of the drug combination of this disclosure to a subject with a tumor results in a reduction of tumor volume by 30% or more, such as 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more. The reduction in tumor volume can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytological, histological, or molecular genetic analysis.

[0117] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0118] The terms "drug combination product" or "combination" can refer to a fixed combination of products administered in a single dosage unit (e.g., a single dosage form containing all active pharmaceutical ingredients) or a kit, or to a combination of a drug and a package insert indicating that the drug can be used in combination with one or more other drugs. For example, in some embodiments, the drug combination product of this disclosure may include: a pharmaceutical composition containing a RAS inhibitor; and a package insert indicating that the RAS inhibitor is for use in combination with a chemotherapy drug (e.g., for the treatment of cancer). In other embodiments, the drug combination product of this disclosure may include: a pharmaceutical composition containing a chemotherapy drug; and a package insert indicating that the chemotherapy drug is for use in combination with a RAS inhibitor (e.g., for the treatment of cancer). In some embodiments, the drug combination product of this disclosure may include: (i) a first pharmaceutical composition containing a RAS inhibitor; and (ii) a second pharmaceutical composition containing a chemotherapy drug (defined as a second pharmaceutical composition to indicate another pharmaceutical composition independent of the first pharmaceutical composition). In other embodiments, the pharmaceutical combination products disclosed herein may include: a single pharmaceutical composition comprising a RAS inhibitor and a chemotherapeutic agent (i.e., a unit dosage form comprising both a RAS inhibitor and a chemotherapeutic agent).

[0119] In some embodiments, this disclosure provides a commercial package containing a RAS inhibitor and instructions for using the RAS inhibitor in combination with a chemotherapy drug to treat a tumor, wherein the RAS inhibitor, the chemotherapy drug, and the tumor can be as described in any of the preceding embodiments.

[0120] The term "pharmaceuticalally acceptable" refers to something that is non-toxic, biologically tolerable, and suitable for administration to subjects.

[0121] The term “optional” or “optionally” means that the event or condition described below is possible but not required; that is, the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0122] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0123] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0124] The term "RAS inhibitor" refers to any inhibitor that targets the RAS protein (e.g., a small molecule inhibitor with a molecular weight less than 1000 Daltons). In various embodiments, RAS inhibitors include RAS(OFF) and RAS(ON) inhibitors. In some embodiments, the RAS inhibitor is a KRAS inhibitor.

[0125] The term "KRAS inhibitor" refers to any inhibitor that targets the KRAS protein (e.g., a small molecule inhibitor with a molecular weight of less than 1,000 Daltons). In various embodiments, KRAS inhibitors include KRAS(OFF) and KRAS(ON) inhibitors.

[0126] The term "RAS(ON) inhibitor" refers to an inhibitor that selectively binds to or inhibits the active state of RAS that binds to GDP (e.g., selectivity relative to the inactive state of RAS that binds to GTP). In some embodiments, the RAS(ON) inhibitor may also bind to or inhibit the inactive state of RAS that binds to GTP (e.g., its affinity or inhibition constant is lower than that of the active state of RAS that binds to GDP). Examples of RAS(ON) inhibitors include, but are not limited to, patent applications WO2020132597A1, WO2021091956A1, WO2021091967A1, WO2021091982A1, WO2022060836A1, WO2022235864A1, WO2022235870A1, WO2023060253A1, WO2023133543A1, WO2023240263A1, WO2024060966A1, and WO2024104364A1. The RAS(ON) inhibitors disclosed in WO2023025832A1, WO2023232776A1, WO2024008610A1, WO2024008834A1, WO2024017859A1, WO2023208005A1, WO2023086341A1, WO2023039240A1, WO2024067857A1, WO2024169914A1, and WO2024208934A1 are incorporated herein by reference in their entirety.

[0127] The term "RAS(OFF) inhibitor" refers to an inhibitor that selectively binds to or inhibits the inactive state of RAS binding to GDP (e.g., selectivity relative to the active state of RAS binding to GTP).

[0128] The term "KRAS(OFF) inhibitor" refers to any inhibitor that selectively binds to or inhibits the inactive state of KRAS by binding to GDP. Examples of KRAS(OFF) inhibitors include, but are not limited to, sotorasib and adagrasib.

[0129] The term "RAS(ON)MULTI inhibitor" refers to a RAS(ON) inhibitor capable of inhibiting at least three RAS variants having a missense mutation at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON)MULTI inhibitor refers to a RAS(ON) inhibitor capable of inhibiting at least three RAS variants having a missense mutation at one of the following positions: 12, 13, and 61.

[0130] Term "C" 1-6 "alkyl" on its own or in combination with other terms is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, etc. Unless otherwise specified, the term "C" refers to... 1-4 The term "alkyl" alone, or in combination with other terms, is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0131] Term "C"2-4 "Alkenyl" refers to a straight-chain or branched hydrocarbon group consisting of 1 to 4 carbon atoms and containing at least one carbon-carbon double bond; it can be monovalent, divalent, or polyvalent. 2-4 Examples of alkenyl groups include vinyl, allyl, and propenyl groups.

[0132] Term "C" 1-4 "Alkoxy" on its own, or in combination with other terms, refers to alkyl groups comprising 1 to 4 carbon atoms that are attached to the remainder of the molecule by an oxygen atom. The C 1-4 Alkoxy groups include C 1-3 C 1-2 C 2-4 C4 and C3 alkoxy groups, etc. They can be monovalent, divalent, or polyvalent. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), etc.

[0133] Term "C" 3-6 "Cycloalkyl" on its own or in combination with other terms respectively represents a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms. The C 3-6 Cycloalkyl groups include monocyclic and polycyclic compounds, with polycyclic compounds comprising spirocyclic, fused, and bridged rings. The C 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, etc.

[0134] The term "3-10 membered heterocyclic alkyl" or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). The 3-10 membered heterocyclic alkyl groups include monocyclic and polycyclic groups, wherein the polycyclic groups include spirocyclic, fused, and bridged rings. Furthermore, with respect to the "3-10 membered heterocyclic alkyl group", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-10 membered heterocyclic alkyl groups include 3-6, 4-6, 5-6, 4-7, 5-7, 5-8, 6-8, 6-9, 6-10, 4, 5, 6, 7, 8, 9, and 10 membered heterocyclic alkyl groups, etc. They can be monovalent, divalent, or polyvalent. Examples of 3-10 membered heterocyclic alkyl groups include, but are not limited to, azahexacyclic butyl, oxacyclobutyl, thiohexacyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, tetrahydropyridinyl, etc. wait.

[0135] The term "3-6 membered heterocyclic alkyl" or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 3-6 membered heterocyclic alkyl group includes monocyclic and polycyclic groups, wherein the polycyclic group includes spirocyclic, fused, and bridged rings. Furthermore, with respect to the "3-6 membered heterocyclic alkyl group", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-6 membered heterocyclic alkyl group includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. It can be monovalent, divalent, or polyvalent. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl or piperidinylene, etc.

[0136] The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p (where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes both 5- and 6-membered heteroaryl groups. It can be monovalent, divalent, or polyvalent. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0137] The term "5-membered heteroaryl-5-membered heteroaryl" indicates that one 5-membered heteroaryl group is fused to another 5-membered heteroaryl group through two adjacent atoms. Examples of "5-membered heteroaryl-5-membered heteroaryl" include, but are not limited to, those mentioned above.

[0138] The term "5-membered heteroaryl-6-membered heteroaryl" indicates that a 5-membered heteroaryl group is fused to another 6-membered heteroaryl group through two adjacent atoms. Examples of "5-membered heteroaryl-5-membered heteroaryl" include, but are not limited to, those mentioned above.

[0139] C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0140] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups by chemical bonds.

[0141] The term "treatment" refers to the application of one or more pharmaceutical substances to a person suffering from or having symptoms of a disease in order to cure, alleviate, reduce, alter, treat, improve, enhance, or affect the disease or its symptoms.

[0142] The term "therapeutic effective amount" refers to the amount of medicine that is sufficient to effectively treat a disease or condition when administered to a subject. The therapeutic effective amount of medicine administered to a subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the age and condition of the subject being treated, etc., but can still be routinely determined by those skilled in the art.

[0143] The term "subject" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and so on. Examples of non-mammals include, but are not limited to, birds. The term "subject" is not limited to a specific age or sex. In some implementations, the subject is a human.

[0144] The term "simultaneous or sequential administration" refers to the simultaneous or sequential administration of two or more drugs within a single dosing cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours) at certain time intervals, so that they can work together to achieve the desired therapeutic effect. The method of administration for each drug (e.g., oral, intravenous, intramuscular, or subcutaneous) can be the same or different, and the dosing frequency / cycle can be the same or different.

[0145] The term "synergy" refers to an effect achieved by using the drug combination of this disclosure that is greater than the sum of the effects of using them individually. The evaluation of synergy can be carried out using the methods reported in the literature Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010, 15; 70(2):440-6 (the full text of which is incorporated herein by reference) and Clarke R. Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models[J]. Breast Cancer Research & Treatment, 1997, 46(2-3):255-278 (the full text of which is incorporated herein by reference).

[0146] The term "drug resistance" refers to the tolerance of cancer patients or cancer cells to the effects of a drug. For example, after cancer cells develop resistance to a particular chemotherapy drug, the effectiveness of that drug decreases significantly. Cancer cells may acquire resistance through a series of mechanisms, including mutations or overexpression of the drug target, drug inactivation, or elimination of the drug from the cells. Drug resistance can be classified into primary resistance and acquired resistance based on its cause. Primary resistance refers to cancer cells being insensitive to the drug at the start of treatment, while acquired resistance refers to cancer cells that were initially sensitive to the drug but became insensitive after repeated exposure during treatment.

[0147] The names of chemotherapy drugs listed in this disclosure include both the free form of the active ingredient and its salt form. For example, vindesine includes the free vindesine compound and its clinically used vindesine sulfate; irinotecan includes the free irinotecan compound and its clinically used irinotecan hydrochloride.

[0148] The compounds mentioned in this disclosure also include their isotopic derivatives. All forms of the compounds, isotopic derivatives, and pharmaceutically acceptable salts of this disclosure, including various solid forms and mixtures thereof, such as crystalline, amorphous, solvates (e.g., hydrates), or any mixtures thereof, are included within the scope of this disclosure.

[0149] Without violating common sense in the field, the various implementation schemes and preferred conditions described herein can be combined arbitrarily to obtain various preferred examples of this disclosure. Detailed Implementation

[0150] The present disclosure is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present disclosure. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0151] In the following examples, the raw materials and reagents used are commercially available, or can be prepared by those skilled in the art by referring to known methods or by conventional modifications based on known methods.

[0152] Example 1:

[0153] 1. Experimental Objective: To evaluate the antitumor effect of compound 1 in combination with docetaxel in a human lung cancer NCI-H727 cell CB-17SCID mouse subcutaneous xenograft tumor model.

[0154] 2. Experimental materials:

[0155] 1) Compound 1:

[0156] 2) Docetaxel (Isox, batch number: 220519BV).

[0157] 3) NCI-H727 cells (human lung cancer cells, KRAS G12V mutation): purchased from ECACC, cultured in RPMI 1640 medium containing 10% fetal bovine serum, cultured at 37°C with 5% carbon dioxide.

[0158] 4) Experimental animals: CB-17SCID mice (purchased from Zhejiang Vital River Laboratory Animal Co., Ltd.), female, 7 weeks old at the time of tumor inoculation.

[0159] 3. Experimental Methods

[0160] NCI-H727 tumor transplantation model construction: NCI-H727 cells were cultured in RPMI 1640 medium (GIBCO, catalog number 22400-089) containing 10% fetal bovine serum at 37°C and 5% carbon dioxide. The cells were passaged 2-3 times per week, at passage 15. One hundred female CB-17SCID mice were inoculated axillary with NCI-H727 cells at a dose of 1 × 10⁶ cells / mL. 6 Cells, mixed with Matrigel (Matrigel: CONRING, catalog number 354230) for injection.

[0161] When the tumor reaches a size of approximately 120 mm 3 Around day 11 post-inoculation, 24 animals were selected and administered the drug in a group. The mean tumor volume of these 24 animals was 121.17 ± 1.58 mm. 3Animals were randomly grouped according to their tumor volume and body weight, and each group was given the prescribed dose on the day of administration (D1) (as shown in Table 1).

[0162] Table 1: Grouping and Dosing Regimens

[0163] Note:

[0164] Solvent control group: 5% DMSO + 10% Solutol + 85% water; (Solutol: Sigma Aldrich, catalog number 42966-1KG)

[0165] Compound 1 solvent: 5% DMSO+10% solutol+85% water;

[0166] Docetaxel solvent: physiological saline.

[0167] Tumor volume:

[0168] Tumor volume was measured twice weekly. Relative tumor volume (RTV), tumor inhibition rate (TGI%), and relative tumor proliferation rate (T / C%) were calculated based on the tumor volume.

[0169] The formula for calculating tumor volume (TV) is: TV = 1 / 2 × a × b 2 Where a and b represent the long and short diameters of the tumor mass, respectively.

[0170] The formula for calculating relative tumor volume is: RTV = TV n / TV1×100%; where TV1 is the tumor volume on the day of administration, and TV n To measure the tumor volume on that day.

[0171] Tumor inhibition rate (TGI) (%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the start of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0172] Relative tumor proliferation rate (T / C%) = RTV t / RTV c ×100%

[0173] Among them, RTV t RTV represents the average relative tumor volume in the treatment group. c The average relative tumor volume is the solvent control group.

[0174] Data processing and statistical analysis:

[0175] All data are presented as (mean ± SEM). Statistical analysis was performed on the grouped D22 data using GraphPad Prism 8.3.0 software, and one-way ANOVA was used for inter-group comparisons. If variances were homogeneous, Turkey's analysis was used; if variances were unequal, Dunnett's T3 method was used.

[0176] 5. Experimental Results

[0177] 5.1 The average weight changes of each group of animals during the drug administration period are shown in Table 2 below.

[0178] Table 2: Mean body weight change (Mean ± SEM) of animals in each group during drug administration.

[0179] During the experiment, the docetaxel monotherapy group showed significant weight loss two weeks after administration, and the drug was discontinued on day 14. The remaining animals maintained normal weight and tolerated the drug well.

[0180] 5.2 The changes in tumor volume in each group of animals during the drug administration period are shown in Table 3 below.

[0181] Table 3: Tumor volume changes in each group of animals during drug administration (Mean±SEM)

[0182] 5.3 Tumor-inhibiting effect

[0183] As shown in Table 4, on day 22 (D22), the TGI of the docetaxel monotherapy group was 39.22%; the TGI of the compound 1 monotherapy group was 86.37%; and the TGI of the compound 1 combined with docetaxel group was 100.87%, showing a significant tumor-suppressing effect compared with the solvent control group (p = 0.0079). Furthermore, the mean tumor volume in the compound 1 combined with docetaxel group was significantly smaller than that in the two monotherapy groups, indicating that the tumor-suppressing efficacy of the compound combined with docetaxel was superior to that of docetaxel or compound 1 alone.

[0184] Table 4: Antitumor effects of the compounds

[0185] 5.4 Evaluation of the combined effects of compound 1 and docetaxel

[0186] The interaction between the two drugs was evaluated using the following formula described in Clarke R. Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res Treat. 1997, 46(2-3): 255-78.

[0187] Collaborative score = ((A / C) × (B / C)) / (AB / C)

[0188] Where A is the RTV value of drug A; B is the RTV value of drug B; C is the RTV value of the control group; and AB is the RTV value of the combination therapy of A and B. A synergy score > 1 indicates that the two drugs have a synergistic effect; a synergy score = 1 indicates that the two drugs have an additive effect; and a synergy score < 1 indicates that the two drugs have an antagonistic effect.

[0189] Since the docetaxel group stopped taking the drug on day 14, the synergy score of the two drugs was calculated using the data from day 12 and was 1.28 (as shown in Table 5 below), indicating that compound 1 and docetaxel have a synergistic effect.

[0190] Table 5: Synergistic scores of compound 1 and docetaxel

[0191] Example 2

[0192] The purpose of this experiment was to evaluate the inhibitory effects of compound 1 in combination with different chemotherapeutic drugs on different cell lines and their xenograft mouse models.

[0193] 1) The inhibitory effects of compound 1 in combination with irinotecan, gemcitabine, 5-fluorouracil, capecitabine or tegafur on RAS mutant pancreatic cancer cell lines (PK-59, PSN-1, AsPC-1, Panc 04.03, KP4, MIA PaCa-2) and their xenograft mouse models.

[0194] 2) The inhibitory effects of compound 1 in combination with gemcitabine, taxanes, vinorelbine or docetaxel on RAS-mutant non-small cell lung cancer cell lines (NCI-H727, Calu-6, NCI-H460, NCI-H1915, NCI-H1355, A549, NCI-H441, LU99, H358, EBC-1, NCI-H1975) and their xenograft mouse models.

[0195] 3) The inhibitory effects of compound 1 in combination with irinotecan or capecitabine on RAS mutant colon cancer cell lines (SW620, GP2D, SW480, HCT116, LOVO) and their xenograft mouse models.

[0196] 4) The inhibitory effect of compound 1 in combination with platinum complexes, taxanes, docetaxel or gemcitabine on RAS mutant cervical cancer cell line (SW756) and its xenograft mouse model.

[0197] 5) The inhibitory effect of compound 1 in combination with platinum complexes or gemcitabine on RAS mutant cholangiocarcinoma cell lines (SNU869, G415, HUCCTI, TKKK, KKU-M213) and their xenograft mouse models.

[0198] 6) The inhibitory effects of compound 1 in combination with platinum complexes, taxanes, docetaxel or gemcitabine on RAS mutant ovarian cancer cell lines (SNU8, OVCAR8, MCAS, OV55, OVK18, TOV21G) and their xenograft mouse models.

[0199] 7) The inhibitory effects of compound 1 in combination with daunorubicin, cytarabine or homoharringtonine on RAS mutant hematologic malignancy cell lines (RPMI 8226, HL-60, THP1) and their xenograft mouse models.

[0200] 8) The inhibitory effect of compound 1 in combination with thiabendazole compounds or platinum complexes on RAS mutant hematologic malignancy cell lines (AGS, SNU-1) and their xenograft mouse models.

[0201] Cell experiments

[0202] Using Promega's CellTiter-Glo method ( (Luminescent Cell Viability Assay). The experimental steps are as follows:

[0203] 1) Tumor cells are passaged regularly, and cells in the logarithmic growth phase are used for plating;

[0204] 2) Use trypan blue to stain cells and count viable cells, adjust the cell concentration to a suitable level, and seed the cells into a plate;

[0205] 3) Cells were treated with drugs (Compound 1 as a single agent, chemotherapy drug as a single agent, and Compound 1 in combination with chemotherapy drugs) after serial dilution;

[0206] 4) Add Promega CellTiter-Glo working solution to the cell culture plate and wrap the plate with aluminum foil to protect it from light. After the culture plate has been incubated for a period of time and the luminescence signal has stabilized, detect the luminescence signal using a microplate reader.

[0207] The Combination Index (CI) of drugs was calculated using CompuSyn software, as shown in Table 6, and the synergistic effect of the drugs was evaluated. CompuSyn is a commonly used software for drug combination effect analysis. It is based on the classic Chou-Talalay method (Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010, 15; 70(2):440-6), which calculates the Combination Index by analyzing the dose-response curves of the drugs. The Combination Index reflects the synergistic effect when drugs are used in combination.

[0208] Table 6: Combination Index of Drugs

[0209] Xenograft tumor mouse model experiment

[0210] The experiment was conducted according to the method described in Example 1.

[0211] While specific embodiments of this disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of this disclosure. Therefore, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. Use of a combination of a RAS inhibitor and a chemotherapy drug in the preparation of a medicament for treating tumors.

2. The use as described in claim 1, characterized in that, The RAS inhibitor is any compound selected from the compounds shown in formulas (I), (II), (III), and (IV) or a pharmaceutically acceptable salt thereof; In equations (I), (II), (III), and (IV), R 1a R 1b R 1c and R 1d Each independently Where R i It is a phenyl or a 5–6-membered heteroaryl group, wherein the phenyl and the 5–6-membered heteroaryl group are optionally substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, methyl, methoxy, trifluoromethyl and cyclopropyl; R 3a R 3c and R 3d Each is independently ethyl or 2,2,2-trifluoroethyl; L 1 It is CH2 or O; R 2a R 2b R 2c and R 2d Each is independently a 5–10-membered heterocyclic alkyl group, which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from methyl, ethyl, cyclopropyl, =O, –CH2OH, –CH2CH2OH, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2 and –CH2CF3.

3. The use as described in claim 2, characterized in that, R 1a R 1b R 1c and R 1d Each independently 4. The use as described in claim 2 or 3, characterized in that, R 2a R 2b and R 2c Each independently 5. The use as described in any one of claims 2–4, characterized in that, R 2d for 6. The use as described in claim 1, characterized in that, The RAS inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; 7. The use as described in claim 1, characterized in that, The RAS inhibitor is RMC-6236 or a pharmaceutically acceptable salt thereof; 8. The use as described in any one of claims 1–7, characterized in that, The chemotherapeutic drugs are one or a combination of two or more of the following: microtubule inhibitors, dihydrofolate reductase inhibitors, thymidylate synthase inhibitors, purine nucleotide tautomerase inhibitors, nucleotide reductase inhibitors, DNA polymerase inhibitors, alkylating agents, platinum complexes, and topoisomerase inhibitors.

9. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a microtubule inhibitor.

10. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a dihydrofolate reductase inhibitor.

11. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a thymidine synthase inhibitor.

12. The use as claimed in any one of claims 1–7, characterized in that, The chemotherapy drug is a purine nucleotide tautomerism inhibitor.

13. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a nucleotide reductase inhibitor.

14. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a DNA polymerase inhibitor.

15. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is an alkylating agent.

16. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a platinum-based complex.

17. The use as described in any one of claims 1–7, characterized in that, The chemotherapy drug is a topoisomerase inhibitor.

18. The use as described in claim 8 or 9, characterized in that, The microtubule inhibitor is one or a combination of two or more of the following: paclitaxel-based microtubule inhibitors and vincristine-based microtubule inhibitors, such as paclitaxel, albumin-bound paclitaxel, docetaxel, vincristine, vinorelbine, and vindesine.

19. The use as described in claim 8 or 10, characterized in that, The dihydrofolate reductase inhibitor is one or a combination of two or more of pemetrexed, docetaxel, and methotrexate.

20. The use as described in claim 8 or 11, characterized in that, The thymidine synthase inhibitor is one or a combination of two or more of the following: 5-fluorouracil, tegafur, tegafur, carmoflu, deoxyfluorouracil, difurylfluorouracil, gemcitabine, capecitabine, and vinorelbine.

21. The use as described in claim 8 or 12, characterized in that, The purine nucleotide tautomerism inhibitor is one or a combination of two or more of mercaptopurine, azathioprine, and 6-thioguanine.

22. The use as described in claim 8 or 13, characterized in that, The nucleotide reductase inhibitor is hydroxyurea.

23. The use as described in claim 8 or 14, characterized in that, The DNA polymerase inhibitor is cytarabine.

24. The use as described in claim 8 or 15, characterized in that, The alkylating agent is one or a combination of two or more of nitrogen mustard, dacarbazine, semustine, carmustine, cyclophosphamide, temozolomide, and ifosfamide.

25. The use as described in claim 8 or 16, characterized in that, The platinum complex is one or a combination of two or more of the following: cisplatin, carboplatin, nedaplatin, bicycloplatin, pyridine, oxaliplatin, miplatin, lobaplatin, and levoplatin.

26. The use as described in claim 8 or 17, characterized in that, The topoisomerase inhibitor is one or a combination of two or more of the following: topotecan, irinotecan, topotecan, etoposide, teniposide, doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin, penoxorubicin, homoharringtonine, and homoharringtonine.

27. The use as described in any one of claims 1–26, characterized in that, The tumors mentioned are one or more of the following: brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, glioblastoma, and neuroendocrine tumors.

28. The use as described in claim 27, characterized in that, The tumor is lung cancer, such as non-small cell lung cancer.

29. The use as described in claim 27, characterized in that, The tumor is colon cancer and / or rectal cancer.

30. The use as described in claim 27, characterized in that, The tumor is pancreatic cancer.

31. The use as described in claim 27, characterized in that, The tumor is bile duct cancer.

32. The use as described in claim 27, characterized in that, The tumor is ovarian cancer.

33. The use as described in claim 27, characterized in that, The tumor is stomach cancer.

34. The use as described in claim 27, characterized in that, The tumor is leukemia, lymphoma, or myeloma, such as acute promyelocytic leukemia, acute monocytic leukemia, or multiple myeloma.

35. The use as described in any one of claims 1–34, characterized in that, The tumor contains RAS mutations.

36. The use as described in any one of claims 1–35, characterized in that, The tumor contains one or a combination of two or more of the following: KRAS mutation, NRAS mutation, and HRAS mutation.

37. The use as described in any one of claims 1–36, characterized in that, The tumor contains one or a combination of two or more of the following mutations: KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61R, KRAS Q61K, KRAS Q61H, NRAS G12D, NRAS Q61K, NRAS Q61L, and HRAS Q61H.

38. The use as described in any one of claims 1–34, characterized in that, The tumor does not contain RAS mutations.

39. The use as described in any one of claims 1–38, characterized in that, The RAS inhibitors and chemotherapy drugs are administered simultaneously or sequentially.

40. The use as described in any one of claims 1–39, characterized in that, The RAS inhibitor is administered orally.

41. The use as described in any one of claims 1–40, characterized in that, The single-dose administration of the RAS inhibitor is from 0.01 mg to 1000 mg, for example, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg. 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg.

42. The use as described in any one of claims 1–40, characterized in that, The single-dose administration of the RAS inhibitor is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, etc. g / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, based on the individual's body weight.

43. The use as described in any one of claims 1–42, characterized in that, The RAS inhibitor is administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once every four weeks, for example, once daily, twice daily, or three times daily.

44. The use as described in any one of claims 1–43, characterized in that, The chemotherapy drugs are administered orally, intravenously, intramuscularly, subcutaneously, or via intravenous infusion.

45. The use as described in any one of claims 1–44, characterized in that, The single-dose administration of the chemotherapy drug is from 0.01 mg to 1000 mg, for example 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg. 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg.

46. ​​The use as described in any one of claims 1–44, characterized in that, The single-dose administration of the chemotherapy drug is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, etc. / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, based on the individual's body weight.

47. The use as described in any one of claims 1–44, characterized in that, The single-dose administration of the chemotherapy drug is 0.01 mg / m². 2 Up to 1000 mg / m 2 For example, 0.01 mg / m³ 2 0.02 mg / m 2 0.03 mg / m 2 0.04 mg / m 2 0.05mg / m 2 0.06 mg / m 2 0.07 mg / m 2 0.08 mg / m 2 0.09 mg / m 2 0.1 mg / m 2 0.2 mg / m 2 0.3 mg / m 2 0.4 mg / m 2 0.5 mg / m 2 0.6 mg / m 2 0.7 mg / m 2 0.8 mg / m 2 0.9 mg / m 2 1mg / m 2 2mg / m 2 3mg / m 2 4mg / m 2 5mg / m 2 6mg / m 2 7mg / m 2 8mg / m 2 9mg / m 2 10mg / m 2 15mg / m 2 20mg / m 2 25mg / m 2 30mg / m 2 35mg / m 2 40mg / m 2 45mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 125mg / m 2 150mg / m 2 175mg / m 2 200mg / m 2 225mg / m 2 250mg / m 2 275mg / m 2 300mg / m 2 325mg / m 2 350mg / m 2 375mg / m 2 400mg / m 2 425mg / m 2 450mg / m 2 475mg / m 2 500mg / m 2 525mg / m 2 550mg / m 2 575mg / m 2 600mg / m 2 625mg / m 2 650mg / m 2 675mg / m 2 700mg / m 2 725mg / m 2 750mg / m 2 775mg / m 2 800mg / m 2 825mg / m 2 850mg / m 2 875mg / m 2 900mg / m 2 925mg / m 2 950mg / m 2 975mg / m 2 Or 1000mg / m 2 Based on the body surface area of ​​the individual to which the treatment is applied.

48. The use as described in any one of claims 1–47, characterized in that, The chemotherapy drugs are administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once every four weeks.

49. The use as described in any one of claims 1–48, characterized in that, The combination of the RAS inhibitor and the chemotherapy drug achieved a synergistic effect.

50. Use of a RAS inhibitor in the preparation of a medicament for the treatment of tumors in combination with a chemotherapy drug, wherein the RAS inhibitor, the chemotherapy drug, and the tumor are as described in any one of claims 1-49.

51. A pharmaceutical combination product comprising a RAS inhibitor and a chemotherapy drug; said RAS inhibitor and chemotherapy drug as described in any one of claims 1-26.

52. The pharmaceutical combination product as described in claim 51, characterized in that, The pharmaceutical combination product includes: (i) a first pharmaceutical composition comprising the RAS inhibitor; and (ii) a second pharmaceutical composition comprising the chemotherapeutic agent; Alternatively, the pharmaceutical combination product may include: (i) a pharmaceutical composition comprising a RAS inhibitor; and a description indicating that the RAS inhibitor is used in combination with a chemotherapy drug for the treatment of a tumor as described in any one of claims 1-49.

53. A commercial package comprising a RAS inhibitor and instructions for using the RAS inhibitor in combination with a chemotherapy drug to treat tumors, wherein, The RAS inhibitor, chemotherapy drug, and tumor are as described in any one of claims 1-49.

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