WO2024008185A1 - 包含sos1抑制剂的药物组合物 - Google Patents

包含sos1抑制剂的药物组合物 Download PDF

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WO2024008185A1
WO2024008185A1 PCT/CN2023/106366 CN2023106366W WO2024008185A1 WO 2024008185 A1 WO2024008185 A1 WO 2024008185A1 CN 2023106366 W CN2023106366 W CN 2023106366W WO 2024008185 A1 WO2024008185 A1 WO 2024008185A1
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cancer
inhibitor
acid
sos1
pharmaceutical composition
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PCT/CN2023/106366
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French (fr)
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张学军
臧杨
刘礼飞
李杨
胡文兵
赵心
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine. Specifically, the present invention relates to a pharmaceutical composition containing an SOS1 inhibitor and its use.
  • RAS protein is a membrane-bound protein with intrinsic GTPase activity that can be activated by many extracellular stimuli and cycles between a GDP-bound (off) state and a GTP-bound (on) state. When it is in the GTP-bound (on) state, it can activate downstream pathways and promote a series of processes such as cell proliferation, differentiation, migration, and immunity.
  • the RAS protein family includes three highly homologous isoforms: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene) and NRAS (Neuroblastoma ras oncogene).
  • KRAS contains 2 alternative splicing variants: KRAS4A and KRAS4B.
  • RAS family proteins have weak endogenous GTPase activity and slow nucleotide exchange rates.
  • KRAS mutation frequency is the highest, accounting for 86%.
  • KRAS-4B mutations are present in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. The mutations are also present in biliary malignancies, endometrial cancer, cervical cancer, and bladder cancer. , liver cancer, myeloid leukemia and breast cancer.
  • the most common way of KRAS gene mutation is point mutation, and the common ones are KRAS-G12D (41%), KRAS-G12V (28%) and KRAS-G12C (14%) mutations.
  • Mutated KRAS affects its ability to bind to GTPase activating protein (GAP), thus inhibiting GTP-induced hydrolysis of GTP. As the hydrolysis ability of GTPase decreases, GTP gradually accumulates, and KRAS is more likely to combine with GTP, thus leaving KRAS mostly in an activated state, inducing the occurrence and development of malignant tumors.
  • GAP GTPase activating protein
  • GTP exchange factor guanylate exchange factor
  • SOS Session of Sevenless protein
  • SOS protein was first discovered in Drosophila in 1992. It is the GEF of RAS and Rac proteins and plays an important role in the RAS and Rac signaling pathways. Humans have two SOS homologues - SOS1 and SOS2. They are highly similar in structure and sequence, with 70% homology, but there are certain differences in biological functions.
  • the SOS1 protein consists of 1,300 amino acid residues and contains a proline-rich domain at the C-terminus, which may be associated with growth in the RAS pathway.
  • Grb2 Growth factor receptor-bound protein 2
  • Rhb2 interacts with each other.
  • Grb2 combines with SOS1 to form a complex, which can bring SOS1 to the cell membrane near the RAS protein.
  • the interaction of SOS1 with RAS involves two domains of SOS1: CDC25 domain and REM domain.
  • the CDC25 domain has an active site for nucleotide exchange
  • the REM domain contains a site that can bind RAS-GTP and lead to allosteric activation of the CDC25 domain.
  • SOS1 can convert GDP into GTP through catalytic exchange.
  • GTP is hydrolyzed by RAS and then activates downstream signals, causing a series of corresponding biological effects.
  • Specific SOS1 inhibitors inhibit the interaction between SOS1 and KRAS-GDP, thereby reducing the formation of activated KRAS-GTP. Reduced KRAS-GTP levels lead to reduced downstream MAPK signaling in both wild-type and multiple KRAS mutant types.
  • the SOS1 small molecule inhibitor BAY-293 can effectively reduce the activity of mutated KRAS and wild-type KRAS in tumor cells.
  • the SOS1 inhibitors BI-3406 and BI-1701963 developed by Boehringer Ingelheim can bind to the catalytic domain of SOS1, prevent its interaction with KRAS, reduce the formation of KRAS-GTP, and inhibit the proliferation of various cancer cells driven by KRAS. .
  • SOS1 inhibitors and MEK inhibitors can significantly reduce KRAS signaling and improve anti-tumor activity through complementary mechanisms of action.
  • BI-3406 inhibits cytochrome P450 3A4 (CYP3A4) in a time-dependent manner, and there is a potential risk of drug-drug interaction (DDI). Therefore, it has been developed without cytochrome P450 inhibition.
  • DCI drug-drug interaction
  • SOS1 inhibitors have more clinical value, and BI-1701963 and combination therapy with the MEK inhibitor trametinib have entered clinical research.
  • SOS1 gene mutations and abnormal expression are also closely related to the occurrence of some genetic diseases.
  • Noonan syndrome (NS) is an autosomal dominant genetic disease. SOS1 mutations occur in approximately 20% of NS patients. These mutations are distributed in 6 domains of SOS1. Patients with SOS1 mutations exhibit phenotypic features of curly hair and ectodermal abnormalities. Mutations in the CDC25 domain can directly increase the GEF activity of SOS1 and induce hyperactivation of the RAS/ERK pathway.
  • Cardiofaciocutaneous syndrome is a type of cardiomyopathies of the renin-angiotensin system. Studies have reported that SOS1 mutations exist in this disease. Hereditary gingival fibromatosis type 1 is an autosomal dominant disease caused by mutations in the proline-rich domain of SOS1.
  • the purpose of the present invention is to provide a pharmaceutical composition containing an SOS1 inhibitor, which can be used to prevent or treat diseases of excessive or abnormal cell proliferation, and has a significant effect on inhibiting tumor growth, which is significantly better than single drug administration.
  • the present invention solves the above technical problems through the following technical solutions.
  • the invention provides a pharmaceutical composition, including a SOS1 inhibitor and inhibitor A; the inhibitor A is selected from one or both of KRAS inhibitors and EGFR inhibitors;
  • the SOS1 inhibitor is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • R 1 is a 3-6-membered cycloalkyl group that is unsubstituted or substituted by Ra; the Ra is a C 1 -C 6 haloalkyl group.
  • R 1 is a cyclopropyl group substituted by Ra, and the Ra is a methyl, ethyl or propyl group substituted by a halogen; preferably, the halogen is fluorine or chlorine.
  • the compound represented by formula I is selected from:
  • the pharmaceutically acceptable salt of the compound represented by formula I is a salt formed by the compound represented by formula I and an acid; the acid is hydrochloric acid, sulfuric acid, maleic acid, aspartic acid , phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippuric acid, gluconic acid, lactic acid, succinic acid, ascorbic acid, adipic acid, p-toluenesulfonic acid, methanesulfonic acid, benzene sulfonate One or more of acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid, and benzoic acid.
  • the acid is hydrochloric acid, sulfuric acid, maleic acid, aspartic acid , phosphoric acid, fumaric acid, tartaric acid, citric acid, glucuronic acid, glycolic acid, malic acid, hippur
  • the pharmaceutically acceptable salt of the compound represented by Formula I is a salt formed by the compound represented by Formula I-1 and an acid.
  • the mass ratio of the SOS1 inhibitor to inhibitor A is 1:1 to 500:1, preferably 1:1 to 50:1, 7.5:1 to 25:1; for example, 7.5 :1 or 25:1.
  • the content of the SOS1 inhibitor in the pharmaceutical composition is 1 mg to 2000 mg (for example, 10 mg to 1000 mg; or 200 mg to 600 mg; or 400 mg to 500 mg).
  • 50 mg of SOS1 inhibitor is included.
  • 100 mg of SOS1 inhibitor is included.
  • 200 mg of SOS1 inhibitor is included.
  • 400 mg of SOS1 inhibitor is included.
  • 800 mg of SOS1 inhibitor is included.
  • 1600 mg of SOS1 inhibitor is included.
  • 2000 mg of SOS1 inhibitor is included.
  • the mass ratio of the SOS1 inhibitor to the EGFR inhibitor is 1:1 to 100:1, preferably 1:1 to 50:1, 7.5:1 to 25:1, such as 7.5 :1 or 25:1.
  • the EGFR inhibitor is osimertinib or gefitinib.
  • the mass ratio of the SOS1 inhibitor to the KRAS inhibitor is 1:1 to 100:1, preferably 1:1 to 50:1, 7.5:1 to 25:1, such as 7.5 :1 or 25:1.
  • the KRAS inhibitor is MRTX-849, AMG-510 or JDQ443.
  • the active ingredients of the pharmaceutical composition are composed of SOS1 inhibitor and inhibitor A.
  • the pharmaceutical composition further includes pharmaceutically acceptable carriers and/or excipients.
  • the present invention provides a medicine box, including
  • a first pharmaceutical composition or dosage form which includes an SOS1 inhibitor as defined in the first aspect and optionally one or more pharmaceutically acceptable carriers and excipients;
  • the second pharmaceutical composition or dosage form includes inhibitor A as defined in the first aspect and optionally one or more pharmaceutically acceptable carriers and excipients.
  • a third aspect of the present invention provides the use of the pharmaceutical composition as described in the first aspect or the pharmaceutical kit as described in the second aspect, and the use includes one or more selected from the following:
  • Preparation of drugs for example, preparation of drugs for the prevention and/or treatment of cancer and RAS disease.
  • diseases related (or mediated) by SOS1 and RAS family proteins include but are not limited to: cancer and RAS disease.
  • the RAS diseases or diseases mediated by SOS1 and RAS family proteins include Noonan syndrome, cardiofaciocutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation- Arteriovenous malformation syndrome, Costello syndrome, and Legers syndrome.
  • the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma, pancreatic cancer, polycythemia vera diseases, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminomas, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma tumor, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the liver cancer is preferably hepatocellular carcinoma; the head and neck The tumor is preferably head and neck squamous cell carcinoma; the sarcom
  • the RAS disease is preferably neurofibromatosis type I (NF1); the lung cancer is preferably non-small cell lung cancer, and further preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute lymphoblastic leukemia.
  • Myeloid leukemia is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma ;
  • the head and neck tumor is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer.
  • the disease mediated by SOS1 and RAS family proteins is colorectal cancer or lung cancer, preferably non-small cell lung cancer.
  • Cell lung cancer preferably non-small cell lung cancer.
  • the RAS family protein may be KRAS, such as KRAS G12C, KRAS G12D, and KRAS G12V.
  • the present invention also provides a method for inhibiting SOS1 and RAS family proteins, or preventing and/or treating diseases related to (or mediated by) SOS1 and RAS family proteins, including the steps of: administering the first aspect of the present invention to a patient in need.
  • the pharmaceutical composition described above is described above.
  • the SOS1 inhibitor and inhibitor A may be administered simultaneously or separately.
  • Said "simultaneous administration”, for example, the SOS1 inhibitor and inhibitor A include simultaneous administration in separate pharmaceutical compositions; or, "a separate pharmaceutical composition containing a SOS1 inhibitor” and a “separate pharmaceutical composition containing inhibitor A" simultaneously Apply.
  • Said “separate administration”, for example, "a separate pharmaceutical composition containing an SOS1 inhibitor” and “a separate pharmaceutical composition containing an inhibitor A” are administered separately at different times; for example: “a separate pharmaceutical composition containing an SOS1 inhibitor” and One of the “separate pharmaceutical compositions comprising inhibitor A” is administered first, the other subsequently.
  • the separate administrations may be close in time or far apart in time.
  • the administration regimen (including administration route, administration dose, administration interval, etc.) of the SOS1 inhibitor and inhibitor A can be the same or different, which can be adjusted by those skilled in the art as needed to provide the optimal Excellent therapeutic effect.
  • the patient is a mammal, preferably a human.
  • the oral dosage of the SOS1 inhibitor is 1 mg to 2000 mg per dose (for example, 10 mg to 1000 mg per dose; or 200 mg to 600 mg per dose; or 400 mg per dose). to 500mg).
  • a single dose contains 50 mg of SOS1 inhibitor.
  • a single dose contains 100 mg of SOS1 inhibitor.
  • a single dose contains 200 mg of SOS1 inhibitor.
  • a single dose contains 400 mg of SOS1 inhibitor.
  • a single dose contains 800 mg of SOS1 inhibitor.
  • a single dose contains 1600 mg of SOS1 inhibitor.
  • a single dose contains 2000 mg of SOS1 inhibitor.
  • the SOS1 inhibitor is administered orally at a dose of 400 mg to 500 mg twice a day, the mass ratio of the SOS1 inhibitor to the EGFR inhibitor is 7.5:1 or 25:1, and the The EGFR inhibitor is administered once daily.
  • SOS1 inhibitor refers to the free base of the SOS1 inhibitor and are pharmaceutically acceptable if used.
  • the amount of salt or other solid form may be increased proportionally.
  • the SOS1 inhibitor is administered once a day, twice a day or three times a day.
  • the inhibitor A is administered once a day, twice a day, three times a day or once every two days.
  • the EGFR inhibitor of the present invention is osimertinib.
  • the present invention also provides a method for treating cancer, which includes the steps of: administering the pharmaceutical composition according to the first aspect of the present invention to a patient in need; the cancer is selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, and nasal cancer.
  • Pharyngeal cancer gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer , ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, bone marrow tumor, astrocytoma, glioblastoma and glioma; the liver cancer is preferably hepatocellular carcinoma; the head and neck tumor is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma; the colorectal cancer
  • the cancer is preferably colon cancer or rectal cancer; the lung cancer
  • the cancer is colorectal cancer or lung cancer, preferably non-small cell lung cancer.
  • the administration regimen of the SOS1 inhibitor and inhibitor A may be the same or different, which can be adjusted by those skilled in the art as needed to provide optimal therapeutic effects.
  • the SOS1 inhibitor and inhibitor A may be administered simultaneously or separately.
  • Said "simultaneous administration”, for example, the SOS1 inhibitor and inhibitor A include simultaneous administration in separate pharmaceutical compositions; or, "a separate pharmaceutical composition containing a SOS1 inhibitor” and a “separate pharmaceutical composition containing inhibitor A" simultaneously Apply.
  • Said “separate administration”, for example, "a separate pharmaceutical composition containing an SOS1 inhibitor” and “a separate pharmaceutical composition containing an inhibitor A” are administered separately at different times; for example: “a separate pharmaceutical composition containing an SOS1 inhibitor” and One of the “separate pharmaceutical compositions comprising inhibitor A” is administered first, the other subsequently.
  • the separate administrations may be close in time or far apart in time.
  • the administration regimen (including administration route, administration dose, administration interval, etc.) of the SOS1 inhibitor and inhibitor A can be the same or different, which can be adjusted by those skilled in the art as needed to provide the optimal Excellent therapeutic effect.
  • the patient is a mammal, preferably a human.
  • the oral dosage of the SOS1 inhibitor is 1 mg to 2000 mg per dose (for example, 10 mg to 1000 mg per dose; or 200 mg to 600 mg per dose; or 400 mg per dose). to 500mg).
  • a single dose contains 50 mg of SOS1 inhibitor.
  • a single dose contains 100 mg of SOS1 inhibitor.
  • a single dose contains 200 mg of SOS1 inhibitor.
  • a single dose contains 400 mg of SOS1 inhibitor.
  • a single dose contains 800 mg of SOS1 inhibitor.
  • a single dose contains 1600 mg of SOS1 inhibitor.
  • a single dose contains 2000 mg of SOS1 inhibitor.
  • the SOS1 inhibitor is administered orally at a dose of 400 mg to 500 mg twice a day, the mass ratio of the SOS1 inhibitor to the EGFR inhibitor is 7.5:1 or 25:1, and the The EGFR inhibitor is administered once daily.
  • SOS1 inhibitor refers to the free base of the SOS1 inhibitor and may be scaled up if a pharmaceutically acceptable salt or other solid form is used.
  • the SOS1 inhibitor is administered once a day, twice a day or three times a day.
  • the inhibitor A is administered once a day, twice a day, three times a day or once every two days.
  • the EGFR inhibitor of the present invention is osimertinib.
  • the KRAS inhibitor is MRTX-849, AMG-510 or JDQ443.
  • the pharmaceutical composition includes the SOS1 inhibitor and the EGFR inhibitor; the cancer is colorectal cancer or lung cancer;
  • the cancer is non-small cell lung cancer;
  • the SOS1 inhibitor is the compound represented by Formula I-1;
  • the EGFR inhibitor is osimertinib; the compound represented by Formula I-1 and osimertinib
  • the mass ratio of Ni is 7.5:1 or 25:1.
  • the compound represented by Formula I-1 is administered once a day, twice a day, or three times a day; osimertinib is administered once a day, twice a day, three times a day, or once every two days.
  • the pharmaceutical composition includes the SOS1 inhibitor and the KRAS inhibitor; the cancer is colorectal cancer or lung cancer; preferably, the cancer is non-small cell lung cancer.
  • the SOS1 inhibitor is the compound represented by the formula I-1 or the compound represented by the formula I-2; the KRAS inhibitor is MRTX-849, AMG-510 or JDQ443.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • pharmaceutical composition refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of pharmaceutical compositions is to facilitate administration to organisms and facilitate the absorption of active ingredients to exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authorities as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying the functional groups in the compound, and the modifications can be removed by conventional procedures or in vivo to obtain the parent compound.
  • Prodrugs include compounds in which a hydroxyl group or amino group in the compound of the present invention is connected to any group.
  • excipient means a pharmaceutically acceptable inert ingredient.
  • examples of types of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling properties of pharmaceutical formulations, i.e. make the formulation more suitable for direct compression by increasing flowability and/or viscosity.
  • C 1 -C 6 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms or a branched chain having 3 to 6 carbon atoms. Saturated monovalent hydrocarbon group.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.
  • alkyl may include “alkylene” groups.
  • cycloalkyl or “carbocyclyl” refers to a cyclic alkyl group.
  • mn-membered cycloalkyl or “Cm-Cn cycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
  • 3-6 membered cycloalkyl or “C 3 -C 6 cycloalkyl” refers to a cyclic alkyl group containing 3, 4, 5 or 6 carbon atoms.
  • unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • halo means substituted by halogen, where "halogen” has the above definition.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
  • single dose refers to a dose administered to a patient in one sitting.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human, and includes one of the following or more of: (1) Prevention of disease: e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibition of disease: e.g., inhibition of a disease, disorder, or condition (i.e., preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing pathology or symptoms of the disease, disorder, or condition.
  • Prevention of disease e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease.
  • Inhibition of disease e.g., inhibition of a disease, disorder
  • Disease amelioration e.g., alleviation of a disease, disorder, or condition (i.e., reversal of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature can be appropriately selected based on the solvent, starting materials, reagents, etc.
  • the reaction time can also be appropriately selected based on the reaction temperature, solvent, starting materials, reagents, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step of the reaction, the target compound can also directly enter the next step of the reaction without separation and purification.
  • Figure 1 Inhibition of tumor volume levels by test compounds in NCIH1975 non-small cell lung cancer in vivo efficacy experiments. tumor ability.
  • Step 2 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (A1-4)
  • Step 3 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (A1- 5)
  • Step 4 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (A1-6)
  • the raw material 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (1.2g) was prepared at room temperature. , 3.0mmol) was added to dioxane (50ml), potassium phosphate (700mg, 3.3mmol), Xantphos (173mg, 0.3mmol), palladium chloride ( ⁇ -cinnamyl) dimer (212mg, 0.3mmol) ), heated to reflux and stirred for 2 h under N2 protection.
  • Step 5 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one (A1)
  • Step 1 Synthesis of 1-(3-(pentafluorosulfanyl)phenyl)ethane-1-one (B1-2)
  • Step 2 (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylene)propane-2-sulfinamide (B1-3) synthesis
  • Step 4 Synthesis of (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (B1-5)
  • Step 5 (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl) Synthesis of amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-1)
  • Step 1 Synthesis of 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (B2-1)
  • Step 2 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (B2 -2) synthesis
  • Step 3 Synthesis of 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (B2-3)
  • reaction solution was cooled and then filtered.
  • Step 4 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one (B2-4)
  • Step 5 (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl) )Amino)pyrido[4,3-d]pyrimidin-7(6H)-one(I-2)
  • Test Example 1 Compound binding inhibition test on KRAS G12C::SOS1
  • the compound to be tested was prepared into a 10mM stock solution using DMSO, and the compound was serially diluted using 1X test buffer. Transfer 0.1 ⁇ L of compound solutions of different concentrations to a 384-well plate, add 5 ⁇ L of GST-KRAS G12C to the 384-well plate, and centrifuge at 1000 rpm for 1 minute. Add 5 ⁇ L His-SOS1 to the 384-well plate, centrifuge at 1000rpm for 1 minute, and incubate at room temperature for 15 minutes.
  • the fluorescence signal ratio at 665nm and 615nm wavelengths was read on a multifunctional microplate reader (Perkin Elmer, Envision 2104), and the IC 50 value was calculated using Graphpad 5 software.
  • Test Example 2 Inhibition test of compounds on ERK phosphorylation level in DLD-1 cells
  • Intracellular western blot quantitative analysis was used to detect the inhibitory level of compounds on ERK phosphorylation in DLD-1 cells.
  • DLD-1 cells (ATCC, CCL-221) were inoculated into T75 culture flask at 2.5 ⁇ 10 6 cells/flask, and cultured in RPMI 1640 medium containing 10% FBS for 2 days. On the 3rd day, the cells were seeded on a 384-well plate and cultured overnight at 37°C and 5% CO2 . After overnight, add serially diluted compounds (final DMSO content is 0.5%), and add DMSO to the negative group. Incubate in a 37 °C, 5% CO2 incubator.
  • Relative signal 800 channel signal value/700 channel signal value.
  • IC 50 values were calculated using Graphpad 5 software.
  • Test Example 3 Compound Inhibition of 3D Cell Proliferation Test
  • H358 cells were inoculated into T75 culture flasks and cultured in RPMI 1640 medium containing 10% FBS for 2 days in preparation for subsequent culture or inoculation into 384-well plates for experiments.
  • IC 50 values were calculated using Graphpad 5 software.
  • the stability test of human liver microsomes is performed by co-incubation of compounds and human liver microsomes in vitro.
  • the compound to be tested was first prepared as a 10mM stock solution in DMSO solvent, and then the compound was diluted to 0.5mM using acetonitrile.
  • the concentration of the compound in the working solution is 1.5 ⁇ M, and the concentration of human liver microsomes is 0.75mg/mL. .
  • Test Example 5 Inhibition test of cytochrome P450 by compounds
  • CYP450 cytochrome P450
  • ketoconazole 10mM, 2.5mM, and 2.5mM stock solutions in DMSO solvent.
  • the compound to be tested and ketoconazole were diluted to 400 times final concentration with acetonitrile (compound: 10 ⁇ M, ketoconazole: 2.5 ⁇ M).
  • potassium phosphate buffer 0.1M, pH 7.4 to prepare 4 times the final concentration of NADPH cofactor (add 66.7mg NADPH to 10mL potassium phosphate buffer) and substrate.
  • the final concentration of CYP3A4 substrate midazolam is 320 ⁇ M, CYP3A4 The final concentration of substrate testosterone was 20 ⁇ M.
  • the reaction was stopped by adding 120 ⁇ L of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS 2/4) for 10 min (600 rpm/min), and then centrifuged for 15 min. After centrifugation, take the supernatant, add purified water at a ratio of 1:1 and perform LC-MS/MS detection to obtain the ratio of the peak area of the compound to the peak area of the internal standard. The peak area ratio of the compound is compared with the peak area ratio of the control inhibitor to calculate the inhibition. Rate.
  • Equilibrium dialysis method (HTDialysis, HTD 96b) was used to detect the plasma protein binding rate of the compound.
  • % binding rate 100 ⁇ ([supply side concentration] 5h - [receiving side concentration] 5h )/[supply side concentration] 5h .
  • % free fraction 100-% bound
  • ICR mice 20-25g, fasted overnight. Take 3 mice and administer 10 mg/kg orally. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. The blood sample was centrifuged at 6800g for 6 minutes at 2-8°C, and the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard, mix, vortex and mix for 1 minute, 13000 rpm, centrifuge at 4°C for 10 minutes, take the supernatant, add 3 times the amount of water, mix, take an appropriate amount and mix The liquid was analyzed by LC-MS/MS. The main pharmacokinetic parameters were analyzed using WinNonlin 7.0 software non-compartmental model.
  • mice pharmacokinetic experiments show that compounds I-1 and I-2 of the present invention have high oral exposure, good pharmacokinetic properties and good druggability.
  • Test Example 8 In vivo drug efficacy experiment of LOVO for colorectal cancer
  • mice After the mice were adaptively raised for one week, the LOVO cells in the logarithmic phase were resuspended in serum-free F12K, and 5 x 10 6 LOVO cells were inoculated subcutaneously into the right flank of the mice at 100 ⁇ L/mouse, and tumor growth was observed regularly.
  • the mice when the tumor grows to an average volume of 150-200mm3 , the mice will be randomly divided into a model group and a drug administration group according to the tumor size and weight of the mice. Measure and record the tumor size and animal weight before and during drug administration. After treatment, The difference in tumor size between the model group and the drug treatment group was compared to determine the drug efficacy.
  • Test Example 9 NCI-H1975 non-small cell lung cancer in vivo drug efficacy experiment
  • Test Example 10 In vivo drug efficacy experiment of H2122 non-small cell lung cancer
  • mice Cultivate H2122 tumor cells in an incubator at 37°C and 5% CO2 until the cell confluence reaches 80-90% and then pass them into bottles.
  • NCI-H1975 in the logarithmic phase was inoculated subcutaneously on the right flank of the mice.
  • the tumors grew to a certain volume, they were randomly divided into model groups and drug administration groups based on tumor size and mouse weight. group (combined with KRAS inhibitors, KRAS inhibitors are MRTX849, AMG-510, JDQ443), measure and record the tumor size and animal weight before and during administration, and compare the tumors in the model group and the administration group after treatment Difference in size to determine potency.

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Abstract

公开了一种包含SOS1抑制剂的药物组合物。提供的包含SOS1抑制剂的药物组合物包括SOS1抑制剂和抑制剂A；所述SOS1抑制剂为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。可以用于预防或治疗过度或者异常细胞增殖的疾病，具有显著的抑制肿瘤生长的作用，显著优于单药给药。

Description

包含SOS1抑制剂的药物组合物
本申请要求申请日为2022/7/7的中国专利申请2022108036059、申请日为2022/8/8中国专利申请2022109460378和申请日为2023/6/29中国专利申请2023107928693的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体地，本发明涉及到一种包含SOS1抑制剂的药物组合物和用途。
背景技术
RAS蛋白是一种具有固有GTP酶活性的膜结合蛋白，可被许多细胞外刺激激活，在GDP结合(关)的状态与GTP结合(开)的状态间循环。当其处于GTP结合(开)状态时能激活下游通路，促进细胞增殖、分化、迁移、免疫等一系列过程。
RAS蛋白家族包括三种高度同源的异构体：KRAS(Kirsten rat sarcoma virus oncogene)、HRAS(Harvey rat sarcoma virus oncogene)和NRAS(Neuroblastoma ras oncogene)，KRAS包含2种可变剪接变异体：KRAS4A和KRAS4B。RAS家族蛋白具有较弱的内源性GTPase活性和较慢的核苷酸交换率。
RAS基因突变激活是肿瘤发生的重要原因，在所有肿瘤患者中有27％患者发生RAS突变。其中KRAS突变频率最高，占比为86％。大约90％的胰腺癌、30％-40％的结肠癌和15％-20％的肺癌中都存在KRAS-4B突变，该突变也存在于胆道恶性肿瘤、子宫内膜癌、宫颈癌、膀胱癌、肝癌、骨髓性白血病和乳腺癌中。KRAS基因突变的最常见方式是点突变，常见的有KRAS-G12D(41％)、KRAS-G12V(28％)和KRAS-G12C(14％)突变。突变的KRAS会影响其与GTP酶活化蛋白(GTPase activating protein，GAP)的结合能力，从而抑制GAP诱导的GTP水解。随着GTP酶水解能力下降，GTP逐渐积累，KRAS更易与GTP结合，进而使KRAS大多处于激活状态，诱发恶性肿瘤的发生与发展。
RAS蛋白从失活态到活化态的转变，涉及GDP的释放和GTP的结合，GDP的释放需要鸟苷酸交换因子(GMP exchange factor，GEF)的参与，如SOS(Son of Sevenless)蛋白。SOS蛋白于1992年在果蝇中首次发现，是RAS和Rac蛋白的GEF，在RAS和Rac信号通路中发挥重要作用。人类有两种SOS同源体——SOS1和SOS2，两者在结构和序列上高度相似，有70％的同源性，但在生物功能上存在一定的差异。SOS1蛋白由1300个氨基酸残基组成，C端含有一个富含脯氨酸的结构域，该结构域可与RAS通路中的生长 因子受体结合蛋白2(growth factor receptor-bound protein 2,Grb2)相互作用，Grb2与SOS1相结合形成复合物后可将SOS1带至细胞膜RAS蛋白附近。SOS1与RAS的相互作用涉及SOS1的两个结构域：CDC25结构域和REM结构域。CDC25结构域具有核苷酸交换的活性位点，REM结构域包含一个能结合RAS-GTP并导致CDC25结构域变构激活的位点。SOS1可通过催化交换将GDP转化为GTP，GTP通过RAS发生水解，然后激活下游信号，引起相应的一系列生物学效应。
特异性SOSl抑制剂可抑制SOS1与KRAS-GDP的相互作用，从而减少活化状态的KRAS-GTP的形成。KRAS-GTP水平的减少会导致下游MAPK信号的减少，在野生型和多种KRAS突变类型中均起作用。SOS1小分子抑制剂BAY-293能有效降低肿瘤细胞中的突变的KRAS和野生型KRAS活性。勃林格殷格翰开发的SOS1抑制剂BI-3406和BI-1701963，能够与SOS1的催化结构域结合，阻止其与KRAS的相互作用，减少KRAS-GTP的形成，抑制KRAS驱动的多种癌症细胞增殖。SOS1抑制剂与MEK抑制剂联用，能够显著降低KRAS信号传导，并通过互补作用机制提高抗肿瘤活性。据勃林格殷格翰公司披露BI-3406以时间依赖性的抑制细胞色素P450 3A4(CYP3A4)，存在潜在的药物药物相互作用(DDI)风险，因此开发无细胞色素P450抑制，优势是无CYP3A4抑制的SOS1抑制剂更有临床价值，BI-1701963及与MEK抑制剂曲美替尼联合疗法均已进入临床研究。
除癌症以外，SOS1基因突变和表达异常也与一些遗传性疾病的发生密切相关。努南综合征(Noonan syndrome,NS)是一种常染色体显性遗传病，在约20％的NS患者中SOS1出现突变，这些突变分布在SOS1的6个结构域。SOS1突变的患者表现出卷发和外胚层异常的表型特征。CDC25结构域中的突变可直接增加SOS1的GEF活性，诱导RAS/ERK通路的超活化。心面皮肤综合征是肾素-血管紧张素系统心肌病群的一种，有研究报道在该病中存在SOS1的突变。1型遗传性齿龈纤维瘤病是一种常染色体显性遗传病，其病因与SOS1的富含脯氨酸的结构域突变有关。
发明内容
本发明的目的是提供一种包含SOS1抑制剂的药物组合物，可以用于预防或治疗过度或者异常细胞增殖的疾病，具有显著的抑制肿瘤生长的作用，显著优于单药给药。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种药物组合物，包括SOS1抑制剂和抑制剂A；所述抑制剂A选自KRAS抑制剂和EGFR抑制剂中的一种或两种；
所述SOS1抑制剂为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
其中，R1为未取代或被Ra取代的3-6元环烷基；所述Ra为C1-C6卤代烷基。
在一优选实施方式中，R1为被Ra取代的环丙基，所述Ra为卤素取代的甲基、乙基或丙基；较佳地，所述卤素为氟或氯。
在一优选实施方式中，所述式I所示化合物选自：
在一优选实施方式中，所述的式I所示化合物药学上可接受的盐为式I所示化合物与酸形成的盐；所述的酸为盐酸、硫酸、马来酸、天冬氨酸、磷酸、富马酸、酒石酸、柠檬酸、葡萄糖醛酸、乙醇酸、苹果酸、马尿酸、葡萄糖酸、乳酸、琥珀酸、抗坏血酸、己二酸、对甲苯磺酸、甲磺酸、苯磺酸、草酸、2-羟基乙磺酸、乙磺酸、龙胆酸、苯甲酸中的一种或多种。
在一优选实施方式中，所述式I所示化合物药学上可接受的盐为式I-1所示化合物与酸形成的盐。
在一优选实施方式中，所述SOS1抑制剂与抑制剂A的质量比为1:1～500:1，较佳地为1:1～50:1、7.5:1～25:1；例如7.5:1或25:1。
在一优选实施方式中，所述的药物组合物中，SOS1抑制剂的含量为1mg至2000mg(例如，10mg至1000mg；或200mg至600mg；或400mg至500mg)。
在一优选实施方式中，包含50mg的SOS1抑制剂。
在一优选实施方式中，包含100mg的SOS1抑制剂。
在一优选实施方式中，包含200mg的SOS1抑制剂。
在一优选实施方式中，包含400mg的SOS1抑制剂。
在一优选实施方式中，包含800mg的SOS1抑制剂。
在一优选实施方式中，包含1600mg的SOS1抑制剂。
在一优选实施方式中，包含2000mg的SOS1抑制剂。
在一优选实施方式中，所述SOS1抑制剂与EGFR抑制剂的质量比为1:1～100:1，较佳地为1:1～50:1、7.5:1～25:1，例如7.5:1或25:1。
在一优选实施方式中，所述EGFR抑制剂为奥西替尼、吉非替尼。
在一优选实施方式中，所述SOS1抑制剂与KRAS抑制剂的质量比为1:1～100:1，较佳地为1:1～50:1、7.5:1～25:1，例如7.5:1或25:1。
在一优选实施方式中，所述KRAS抑制剂为MRTX-849、AMG-510或JDQ443。
MRTX849的化学结构为
AMG-510的化学结构为
JDQ443的化学结构为
在一优选实施方式中，所述药物组合物，其活性成分由SOS1抑制剂和抑制剂A组成。
在一优选实施方式中，所述药物组合物还包括药学上可接受的载体和/或赋形剂。
本发明第二方面，提供了一种药盒，包括
第一药物组合物或剂型，其包含如第一方面所定义的SOS1抑制剂及任选地一种或多种药学上可接受的载体、赋形剂；
第二药物组合物或剂型，其包含如第一方面所定义的抑制剂A及任选地一种或多种药学上可接受的载体、赋形剂。
本发明第三方面，提供了如第一方面所述的药物组合物或如第二方面所述的药盒的用途，所述用途包括选自下列的一种或多种：
抑制SOS1与RAS家族蛋白的相互作用、
预防和/或治疗SOS1与RAS家族蛋白相关的疾病、
制备用于抑制SOS1与RAS家族蛋白的相互作用，和/或预防和/或治疗SOS1与RAS家族蛋白相关的疾病的药物、药物组合物或制剂、
制备药物，例如制备用于预防和/或治疗癌症、RAS病的药物。
在一优选实施方式中，所述SOS1与RAS家族蛋白相关的(或介导的)疾病包括但不限于：癌症、RAS病。
较佳地，所述RAS病或者SOS1与RAS家族蛋白介导的疾病包括努南综合征、心面皮肤综合征、1型遗传性齿龈纤维瘤病、1型神经纤维瘤病、毛细血管畸形-动静脉畸形综合征、科斯特洛综合症和莱格斯综合征。
较佳地，癌症选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述肝癌优选为肝细胞癌；所述头颈瘤优选为头颈鳞状细胞癌；所述肉瘤优选为骨肉瘤；所述结肠直肠癌优选为结肠癌或直肠癌；所述癌症优选为非小细胞肺癌。
所述的RAS病优选为I型神经纤维瘤病(NF1)；所述的肺癌优选为非小细胞肺癌，进一步优选为转移性非小细胞肺癌；所述的白血病优选为慢性淋巴细胞白血病或急性髓性白血病；所述的淋巴瘤优选为弥漫性大B细胞淋巴瘤；所述的骨髓瘤优选为多发性骨髓瘤；所述的骨瘤优选为骨软骨瘤；所述肝癌优选为肝细胞癌；所述头颈瘤优选为头颈鳞状细胞癌；所述肉瘤优选为骨肉瘤；所述结肠直肠癌优选为结肠癌或直肠癌。
较佳地，所述SOS1与RAS家族蛋白介导的疾病为结肠直肠癌或肺癌，优选为非小 细胞肺癌。
所述的RAS家族蛋白可为KRAS，例如KRAS G12C、KRAS G12D、KRAS G12V。
本发明还提供一种抑制SOS1与RAS家族蛋白，或预防和/或治疗SOS1与RAS家族蛋白相关的(或介导的)疾病的方法，包括步骤：给需要的患者施用本发明第一方面所述的药物组合物。
所述SOS1抑制剂和抑制剂A可同时施用或分开施用。
所述“同时施用”例如SOS1抑制剂和抑制剂A包含在单独药物组合物中同时施用；或者，“包含SOS1抑制剂的单独药物组合物”与“包含抑制剂A的单独药物组合物”同时施用。
所述“分开施用”例如“包含SOS1抑制剂的单独药物组合物”与“包含抑制剂A的单独药物组合物”在不同时间分开施用；例如：“包含SOS1抑制剂的单独药物组合物”和“包含抑制剂A的单独药物组合物”其中之一首先施用，另一个随后施用。所述的分开施用可在时间上距离接近或时间上距离较远。
无论同时施用还是分开施用，所述SOS1抑制剂和抑制剂A的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同，其可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
根据本发明的某些实施例，所述患者是哺乳动物，优选是人。
在一优选实施方式中，所述的药物组合物中，SOS1抑制剂的经口使用的剂量为每剂1mg至2000mg(例如，每剂10mg至1000mg；或每剂200mg至600mg；或每剂400mg至500mg)。
在一优选实施方式中，单一剂量包含50mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含100mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含200mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含400mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含800mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含1600mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含2000mg的SOS1抑制剂。
在一优选实施方式中，所述SOS1抑制剂经口按照400mg至500mg的剂量每日两次施用，所述SOS1抑制剂与EGFR抑制剂的质量比为7.5:1或25:1，且所述EGFR抑制剂每日一次施用。
以上所有给出的SOS1抑制剂的量是指SOS1抑制剂的游离碱且若使用药物学上可接 受的盐或其他固体形式，则可按比例增加。
在一优选实施方式中，所述SOS1抑制剂是每天一次、每天两次或每天三次给药。
在一优选实施方式中，所述抑制剂A是每天一次、每天两次、每天三次或每两天一次给药。
在一优选实施方式中，本发明所述EGFR抑制剂为奥西替尼。
本发明还提供一种治疗癌症的方法，包括步骤：给需要的患者施用本发明第一方面所述的药物组合物；所述癌症选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述肝癌优选为肝细胞癌；所述头颈瘤优选为头颈鳞状细胞癌；所述肉瘤优选为骨肉瘤；所述结肠直肠癌优选为结肠癌或直肠癌；所述肺癌优选为非小细胞肺癌。
较佳地，所述癌症为结肠直肠癌或肺癌，优选为非小细胞肺癌。
所述SOS1抑制剂和抑制剂A的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同，其可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
所述SOS1抑制剂和抑制剂A可同时施用或分开施用。
所述“同时施用”例如SOS1抑制剂和抑制剂A包含在单独药物组合物中同时施用；或者，“包含SOS1抑制剂的单独药物组合物”与“包含抑制剂A的单独药物组合物”同时施用。
所述“分开施用”例如“包含SOS1抑制剂的单独药物组合物”与“包含抑制剂A的单独药物组合物”在不同时间分开施用；例如：“包含SOS1抑制剂的单独药物组合物”和“包含抑制剂A的单独药物组合物”其中之一首先施用，另一个随后施用。所述的分开施用可在时间上距离接近或时间上距离较远。
无论同时施用还是分开施用，所述SOS1抑制剂和抑制剂A的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同，其可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
根据本发明的某些实施例，所述患者是哺乳动物，优选是人。
在一优选实施方式中，所述的药物组合物中，SOS1抑制剂的经口使用的剂量为每剂1mg至2000mg(例如，每剂10mg至1000mg；或每剂200mg至600mg；或每剂400mg至500mg)。
在一优选实施方式中，单一剂量包含50mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含100mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含200mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含400mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含800mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含1600mg的SOS1抑制剂。
在一优选实施方式中，单一剂量包含2000mg的SOS1抑制剂。
在一优选实施方式中，所述SOS1抑制剂经口按照400mg至500mg的剂量每日两次施用，所述SOS1抑制剂与EGFR抑制剂的质量比为7.5:1或25:1，且所述EGFR抑制剂每日一次施用。
以上所有给出的SOS1抑制剂的量是指SOS1抑制剂的游离碱且若使用药物学上可接受的盐或其他固体形式，则可按比例增加。
在一优选实施方式中，所述SOS1抑制剂是每天一次、每天两次或每天三次给药。
在一优选实施方式中，所述抑制剂A是每天一次、每天两次、每天三次或每两天一次给药。
在一优选实施方式中，本发明所述EGFR抑制剂为奥西替尼。
在一优选实施方式中，所述KRAS抑制剂为MRTX-849、AMG-510或JDQ443。
在一优选实施方式中，所述药物组合物包括所述SOS1抑制剂和所述EGFR抑制剂；所述癌症为结肠直肠癌或肺癌；
优选的，所述癌症为非小细胞肺癌；所述SOS1抑制剂为所述式I-1所示化合物；所述EGFR抑制剂为奥西替尼；所述式I-1所示化合物与奥西替尼的质量比为7.5:1或25:1。优选地，所述式I-1所示化合物是每天一次、每天两次或每天三次给药；奥西替尼是每天一次、每天两次、每天三次或每两天一次给药。
在一优选实施方式中，所述药物组合物包括所述SOS1抑制剂和所述KRAS抑制剂；所述癌症为结肠直肠癌或肺癌；优选的，所述癌症为非小细胞肺癌。优选地，所述SOS1抑制剂为所述式I-1所示化合物或所述式I-2所示化合物；所述KRAS抑制剂为MRTX-849、AMG-510或JDQ443。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发 生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基具有3至6个碳原子的支链的饱和单价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。本领域技术人员将认识到，术语“烷基”可包括“亚烷基”基团。
术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-6元环烷基”或者“C3-C6环烷基”是指含有3、4、5或6个碳原子的环状烷基。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基。
术语“卤代”是指被卤素取代，其中“卤素”具有上述定义。
术语“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
术语“单一剂量”是指患者一次施用时的剂量。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。本发明所用试剂和原料均市售可得。
附图说明
图1、测试化合物在NCIH1975非小细胞肺癌体内药效实验中的肿瘤体积水平的抑 瘤能力。
具体实施方式
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。
中间体A1的制备
合成路线如下所示：
第一步：(Z)-2-((二甲基氨基)亚甲基)-3-氧代戊二甲酸甲酯(A1-2)
室温下，将化合物3-氧代戊二甲酸甲酯(10.0g,57.4mmol)加入到2-甲基四氢呋喃(100ml)中，加入DMF-DMA(6.8g,57.1mmol)，室温搅拌4h。浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)得粗品(Z)-2-((二甲基氨基)亚甲基)-3-氧代戊二甲酸甲酯(A1-2)(12g,黄色液体，产率91.1％)。
LC-MS,M/Z(ESI):230.2[M+H]+。
第二步：1-(1-(氟甲基)环丙基)-4-羟基-6-氧-1,6-二氢吡啶-3-甲酸甲酯(A1-4)
室温下将化合物(Z)-2-((二甲基氨基)亚甲基)-3-氧代戊二甲酸甲酯(2.4g,10.4mmol)加入到2-甲基四氢呋喃(30ml)中，加入4N盐酸(10ml)，搅拌3h。分液，水相用乙酸乙酯(100ml×3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，加入甲醇(30ml)，加入1-(氟甲基)环丙烷-1-氨基盐酸盐(1.0g,8.0mmol)，室温搅拌16h。在体系中加入甲醇 钠(1.3g,24.0mmol)，搅拌2h。用浓盐酸调节pH＝2，过滤，得粗品1-(1-(氟甲基)环丙基)-4-羟基-6-氧-1,6-二氢吡啶-3-甲酸甲酯(A1-4)(2.0g,产率79.1％)。
LC-MS,M/Z(ESI):242.2[M+H]+。
第三步：1-(1-(氟甲基)环丙基)-6-氧-4-(对甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(A1-5)
室温下将原料1-(1-(氟甲基)环丙基)-4-羟基-6-氧-1,6-二氢吡啶-3-甲酸甲酯(2.0g,8.3mmol)加入到乙腈(20ml)中，冷却至0℃，加入三乙胺(1.68g,16.6mmol)，TsCl(1.58g,8.3mmol)，升至室温，搅拌2h。反应液浓缩，经硅胶柱纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)得1-(1-(氟甲基)环丙基)-6-氧-4-(对甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(A1-5)(1.2g,产率36.6％)。
LC-MS,M/Z(ESI):396.3[M+H]+。
第四步：4-乙酰氨基-1-(1-(氟甲基)环丙基)-6-氧-1,6-二氢吡啶-3-甲酸甲酯(A1-6)
室温下将原料1-(1-(氟甲基)环丙基)-6-氧-4-(对甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(1.2g,3.0mmol)加入到二氧六环(50ml)中，加入磷酸钾(700mg,3.3mmol)，Xantphos(173mg,0.3mmol)，氯化钯(π-肉桂基)二聚物(212mg,0.3mmol)，N2保护下加热回流搅拌2h。冷却至室温，反应液浓缩，经硅胶柱纯化(石油醚:乙酸乙酯(V/V)＝3:1-1:1)得4-乙酰氨基-1-(1-(氟甲基)环丙基)-6-氧-1,6-二氢吡啶-3-甲酸甲酯(A1-6)(680mg,产率79.3％)
LC-MS,M/Z(ESI):283.2[M+H]+。
第五步：6-(1-(氟甲基)环丙基)-4-羟基-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮(A1)
室温下将原料4-乙酰氨基-1-(1-(氟甲基)环丙基)-6-氧-1,6-二氢吡啶-3-甲酸甲酯(680mg,2.41mmol)加入到7mol/L的氨气甲醇溶液(10ml)中，室温搅拌5d。浓缩(3ml)至过滤，得6-(1-(氟甲基)环丙基)-4-羟基-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮(460mg,产率16.4％)
1H NMR(400mHz,DMSO-d6)δ11.8(s,1H),8.36(s,1H),6.17(s,1H),4.62(d,2H),2.24(s,3H),1.27(s,4H).
LC-MS,M/Z(ESI):250.2[M+H]+。
实施例1：化合物I-1的合成
合成路线如下所示:
第一步：1-(3-(五氟硫烷基)苯基)乙烷-1-酮(B1-2)的合成
室温下将化合物3-溴-(五氟硫烷基)苯(B1-1)(3.00g,10.6mmol)加入到二氧六环(100mL)中，加入二三苯基膦二氯化钯(744mg,1.06mmol)，三丁基(1-乙氧基乙烯)锡(4.20g,11.7mmol)，N2保护下加热至90℃，搅拌14h。冷却至室温，加入2N盐酸(100mL)，搅拌4h。用乙酸乙酯(200mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝8:1)得1-(3-(五氟硫烷基)苯基)乙烷-1-酮(B1-2，黄色液体，2.4g，产率89％)。
LC-MS,M/Z(ESI):247.0[M+H]+。
第二步：(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(B1-3)的合成
室温下将化合物1-(3-(五氟硫烷基)苯基)乙烷-1-酮(B1-2，1.0g,4.06mmol)加入到THF(150mL)中，加入(S)-叔丁基亚磺酰胺(492mg,4.06mmol)，钛酸四乙酯(1.14g,5.0mmol)，加热至70℃，搅拌16h。冷却至室温，加入水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝4:1)得(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(B1-3,1.42g，产率100％)。
LC-MS,M/Z(ESI):350.2[M+H]+。
第三步：(S)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(B1-4)的合成
室温下将原料(S,E)-2-甲基-N-(1-(3-(五氟硫烷基)苯基)亚乙基)丙烷-2-亚硫酰胺(B1-3，1.5g,4.3mmol)加入到甲醇(30mL)中，冷却至0℃，将NaBH4(744mg,20.1mmol)分批加入到甲醇中，升至室温，搅拌3h。反应液浓缩，经薄层制备板纯化得(S)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(B1-4，600mg，产率40.0％)。
LC-MS,M/Z(ESI):352.1[M+H]+。
第四步：(R)-1-(3-(五氟硫烷基)苯基)乙烷-1-胺盐酸盐(B1-5)的合成
室温下将原料(R)-2-甲基-N-((R)-1-(3-(五氟硫烷基)苯基)乙基)丙烷-2-亚硫酰胺(B1-4，600mg,1.70mmol)加入到4mol/L的盐酸二氧六环溶液(10mL)中，搅拌4h。反应液浓缩，加入甲基叔丁基醚(20mL)，搅拌1h，过滤，得(R)-1-(3-(五氟硫烷基)苯基)乙烷-1-胺盐酸盐(B1-5，350mg，产率72.7％)。
LC-MS,M/Z(ESI):248.2[M+H]+。
第五步：(R)-6-(1-(氟甲基)环丙基)-2-甲基-4-((1-(3-(五氟硫烷基)苯基)乙基)氨基)吡啶并[4,3-d]嘧啶-7(6H)-酮(I-1)的合成
室温下将6-(1-(氟甲基)环丙基)-4-羟基-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮(A1)(200mg,0.80mmol)加入到乙腈(20mL)中，加入磷酸钾(678mg,3.20mmol)，三聚氯化磷腈(416mg,1.20mmol)，室温搅拌16h。将原料(R)-1-(3-(五氟硫烷基)苯基)乙烷-1-胺盐酸盐(B1-5，160mg,0.56mmol)加入到二氯甲烷(10mL)中，加入二异丙基乙胺(2mL)，搅拌0.5h，将此溶液加入到上述体系中，室温搅拌6h。将反应液浓缩，经纯化制备得到(R)-6-(1-(氟甲基)环丙基)-2-甲基-4-((1-(3-(五氟硫烷基)苯基)乙基)氨基)吡啶并[4,3-d]嘧啶-7(6H)-酮(I-1，44mg，产率16.4％)。
1H NMR(400m Hz,DMSO-d6)δ9.18(s,1H),8.87(d,1H),7.96(s,1H),7.78(d,1H),7.71(d,1H),7.60(t,1H),6.08(s,1H),5.60(q,1H),4.68-4.56(m,2H),2.21(s,3H),1.61(d,3H),1.32-1.28(m,4H)。
LC-MS,M/Z(ESI):479.4[M+H]+。
实施例2：化合物I-2的合成
合成路线如下所示:
第一步：1-(1-(二氟甲基)环丙基)-4-羟基-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-1)的合成
将化合物(Z)-2-((二甲氨基)亚甲基)-3-氧代戊二酸二甲酯(A1-2,5.0g，21.81mmol)和1-(二氟甲基)环丙烷-1-胺盐酸盐(3.44g,23.99mmol)溶解在甲醇(50.0mL)中，反应体系于室温条件下搅拌16小时。然后向反应液中加入甲醇钠(1.76g,32.58mmol)，反应体系在25℃下搅拌0.5小时。向反应体系中加入HCl(1.0N,15.0mL)，调节pH至1-2，过滤，滤饼用10.0mL甲醇洗涤，滤饼干燥，得到化合物1-(1-(二氟甲基)环丙基)-4-羟基-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-1)(2.4g，产率42.5％)。
LC-MS,M/Z(ESI):260.3[M+H]+
第二步：1-(1-(二氟甲基)环丙基)-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(B2-2)的合成
将1-(1-(二氟甲基)环丙基)-4-羟基-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-1,2.4g,9.26mmol)溶于乙腈(24.0mL)中，随后向反应体系中加入三乙胺(1.41g,13.89mmol),缓慢分批次加入对甲苯磺酰氯(1.77g,9.26mmol),反应体系在25℃下搅拌2小时。向反应液中加入二氯甲烷(20.0mL)稀释，并用1N HCl(10.0mL)调节pH至2-3，萃取，有机相旋干后得到1-(1-(二氟甲基)环丙基)-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(B2-2)(3.4g，产率89％)。
LC-MS,M/Z(ESI):414.5[M+H]+
第三步：4-乙酰氨基-1-(1-(二氟甲基)环丙基)-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-3)的合成
在100mL单口瓶中依次按顺序加入1-(1-(二氟甲基)环丙基)-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-甲酸甲酯(B2-2)(3.3g,7.98mmol),乙酰胺(707.0mg,11.97mmol), Xantphos(924.0mg,1.60mmol),磷酸钾(3.39g,15.97mmol),氯化钯(π-肉桂基)二聚物(1.46g,1.60mmol)溶于二氧六环(30.0mL)，氮气氛围置换三次后，将体系升温至115℃搅拌16小时。将反应液冷却后进行过滤，所得母液旋干后拌样，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)得到4-乙酰氨基-1-(1-(二氟甲基)环丙基)-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-3)(1.6g，产率67％)。
第四步：6-(1-(二氟甲基)环丙基)-4-羟基-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮(B2-4)
在50.0mL焖罐中加入4-乙酰氨基-1-(1-(二氟甲基)环丙基)-6-氧代-1,6-二氢吡啶-3-甲酸甲酯(B2-3,1.6g,5.33mmol)溶于氨甲醇溶液(7N,15.0mL)中，反应体系升温至50℃搅拌12小时。待反应液冷却后，过滤，滤饼用甲醇(15.0mL)淋洗，得到浅黄色固体6-(1-(二氟甲基)环丙基)-4-羟基-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮(B2-4)(900mg，产率63％)。
LC-MS,M/Z(ESI):268.2[M+H]+。
第五步：(R)-6-(1-(二氟甲基)环丙基)-2-甲基-4-((1-(3-(五氟硫烷基)苯基)乙基)氨基)吡啶并[4,3-d]嘧啶-7(6H)-酮(I-2)
将6-(1-(二氟甲基)环丙基)-4-羟基-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮(300.0mg,1.12mmol)溶于乙腈(15.0mL)中，加入磷酸钾(596.0mg,2.81mmol),随后加入六氯环三磷氰(585.0mg,1.68mmol),室温搅拌2小时后，加入(R)-1-(3-(五氟硫烷基)苯基)乙-1-胺盐酸盐(B1-5，318.0mg,1.12mmol)，室温条件下反应搅拌过夜，将反应液先进行过滤，滤饼用乙腈(15.0mL)洗涤，滤液旋干后得粗品，通过硅胶柱层析(石油醚：乙酸乙酯＝10:1-1:1)得到(R)-6-(1-(二氟甲基)环丙基)-2-甲基-4-((1-(3-(五氟硫烷基)苯基)乙基)氨基)吡啶并[4,3-d]嘧啶-7(6H)-酮(I-2,166.0mg，产率30％)。
1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.91(d,J＝7.1Hz,1H),7.95(s,1H),7.77(dd,J＝8.2,2.1Hz,1H),7.71(d,J＝7.7Hz,1H),7.59(t,J＝8.0Hz,1H),6.31(t,J＝57.1Hz,1H),6.10(s,1H),5.60(t,J＝6.9Hz,1H),2.18(d,J＝26.4Hz,3H),1.60(d,J＝7.1Hz,3H),1.48(s,2H),1.37(s,2H)。
LC-MS,M/Z(ESI):497.2[M+H]+。
在本发明的测试例中，对照化合物I的制备参考专利WO2019122129A1，对照化合物II的制备参考专利WO2019122129A1。其结构如下：
测试例1：化合物对KRAS G12C::SOS1结合抑制试验
待测化合物使用DMSO配制成10mM的储备液，并使用1X测试缓冲液将化合物进行梯度稀释。转移0.1μL不同浓度的化合物溶液至384孔板中，加入5μL GST-KRAS G12C至384孔板，以1000rpm的转速离心1分钟。加入5μL His-SOS1至384孔板，以1000rpm的转速离心1分钟，室温孵育15分钟。
孵育结束向测试孔中加入10μL抗6his-Tb单抗(Cisbio,Cat.No.61HI2TLA)和抗GST-XL665单抗(Cisbio,Cat.No.61GSTXLA)混合溶液，以1000rpm的转速离心1分钟，室温孵育1小时。
孵育结束后在多功能酶标仪(Perkin Elmer,Envision 2104)上读取665nm和615nm波长的荧光信号比值，采用Graphpad 5软件计算IC50值。
表1测试化合物对KRAS G12C::SOS1结合抑制结果
实验结果表明，本发明中的化合物I-1和I-2对KRAS G12C-SOS1具有显著的抑制作用。
测试例2：化合物对DLD-1细胞ERK磷酸化水平的抑制试验
采用细胞内western blot定量分析法检测化合物对DLD-1细胞ERK磷酸化抑制水平。
将DLD-1细胞(ATCC,CCL-221)按2.5×106个细胞/瓶接种于T75培养瓶中，在含10％FBS的RPMI 1640培养基中培养2天。第3天将细胞接种于384孔板上，37℃，5％CO2培养过夜。过夜后加入系列稀释的化合物(DMSO终含量为0.5％)、阴性组加入DMSO， 在37℃，5％CO2培养箱中孵育。
固定细胞，使用PBS清洗一遍，给细胞破膜，室温下封闭1小时。去除封闭液加入一抗(CST,Cat.No.#4370S)，4℃孵育过夜。使用PBST(PBS溶液加入0.05％吐温20)清洗3次，每次浸泡2分钟。加入二抗(LI-COR,Cat.No.926-32211)，室温避光孵育。使用PBST清洗3次，每次浸泡2分钟。培养板以1000rpm的转速离心1分钟，在双色红外激光成像系统(CLX)上扫描，读取信号。
相对信号＝800通道信号值/700通道信号值。
ERK磷酸化相对表达水平＝(测试化合物-对照化合物I)/(DMSO组-对照化合物I)
采用Graphpad 5软件计算IC50值。
表2测试化合物对DLD-1细胞ERK磷酸化水平抑制结果
实验结果表明，本发明中的化合物对DLD-1细胞ERK磷酸化水平显示显著的抑制作用。
测试例3：化合物抑制3D细胞增殖试验
将H358细胞接种于T75培养瓶中，在含10％FBS的RPMI 1640培养基中培养2天，以备后续培养或接种于384孔板进行实验。
第1天将细胞接种于384孔板上，每孔加入40μL培养基，每孔加入梯度稀释的化合物或DMSO，另设置不接种细胞加入培养基的孔作为空白对照。37℃，5％CO2培养7天，第8天加入3D CellTiter-Glo试剂(Promega,Cat.No.G9683)，以320rpm的速度震荡20分钟，室温放置2小时。在多功能酶标仪上读取luminescence信号。计算细胞活力抑制率：
细胞活力抑制率＝(DMSO组-测试化合物)/(DMSO组-空白对照组)×100％
采用Graphpad 5软件计算IC50值。
表3测试化合物对H358细胞3D增殖抑制结果
实验结果表明，本发明中的化合物I-1和I-2对H358细胞3D增殖显示出较强的抑 制作用。
测试例4：人肝微粒体稳定性试验
人肝微粒体稳定性试验采用化合物与人肝微粒体体外共孵育进行检测。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，随后使用乙腈将化合物稀释至0.5mM。使用PBS稀释人肝微粒体(Corning)成微粒体/缓冲液溶液，并使用该溶液稀释0.5mM的化合物成为工作溶液，工作溶液中化合物浓度为1.5μM，人肝微粒体浓度为0.75mg/mL。取深孔板，每孔加入30μL工作溶液，然后加入15μL预热好的6mM NADPH溶液启动反应，37℃孵育。在孵育的0、5、15、30、45分钟时，加入135μL乙腈至相应的孔中终止反应。在最后45分钟时间点用乙腈终止反应后，深孔板涡旋振动10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得每个时间点化合物峰面积与内标峰面积比值，将5、15、30、45分钟时化合物的峰面积比值与0分钟时的峰面积比值进行比较，计算每个时间点化合物的剩余百分比，使用Graphpad 5软件计算T1/2。
表4人肝微粒体稳定性试验结果
实验结果表明，本发明化合物表现出更为优良的肝代谢稳定性，在人体内代谢更慢，暴露量更高。其中化合物I-1的代谢稳定性与对照化合物I相比显著提高。
测试例5：化合物对细胞色素P450的抑制试验
检测化合物对细胞色素P450(CYP450)亚型CYP3A4(2种底物咪达唑仑和睾酮)的抑制潜力。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，CYP3A4抑制剂酮康唑在DMSO溶剂中配制成10mM、2.5mM、2.5mM的储备液。用乙腈将待测化合物和酮康唑稀释至400倍终浓度(化合物：10μM，酮康唑：2.5μM)。
用磷酸钾缓冲液(0.1M，pH 7.4)配制4倍终浓度的NADPH辅因子(10mL磷酸钾缓冲液中加入66.7mg NADPH)和底物，CYP3A4底物咪达唑仑终浓度为320μM，CYP3A4底物睾酮终浓度为20μM。
在冰上用磷酸钾缓冲液配制人肝微粒体溶液，浓度为0.2mg/mL。在冰上用人肝微粒体溶液配制2倍终浓度的待测化合物和对照抑制剂(对照化合物)溶液。向测试孔中分别加入30mL的待测化合物和对照抑制剂溶液，并加入15mL底物，进行复孔操作。在37℃ 下孵育96孔测定板和NADPH溶液5分钟，将15μL预热的8mM NADPH溶液添加到测定板中以启动反应。CYP3A4测定板37℃下预孵育5分钟。加入120μL乙腈终止反应，淬灭后，在振动器(IKA，MTS 2/4)上摇动平板10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得化合物峰面积与内标峰面积比值，化合物的峰面积比值与对照抑制剂的峰面积比值进行比较，计算抑制率。
表5测试化合物对CYP450酶抑制试验结果
实验结果表明，本发明中的化合物在10μM时对CYP3A4酶抑制作用较弱或没有抑制作用，潜在的药物药物相互作用风险低。其中，化合物I-1对CYP3A4酶的抑制作用方面具有明显的优势。
测试例6：化合物的血浆蛋白结合率
采用平衡透析法(HTDialysis，HTD 96b)检测化合物的血浆蛋白结合率。用DMSO将化合物配制为0.5nM的储备液，再用0.05M磷酸钠缓冲液稀释25倍为工作液。取空白96孔板，每孔预装入380μL血浆，随后在血浆中加入20μL/孔工作液并混匀，化合物终浓度为1μM，每孔含有0.2％DMSO。
分别加入100μL 0.05M磷酸钠缓冲液至各透析小室(HTD 96b)的接收侧，再加入100μL含有化合物的血浆到供给侧。盖好塑料盖后，放置于37℃中摇晃孵育5小时。
孵育结束后，从透析小室的供给侧和接受侧各取25μL样品，置于空白96孔板中，并在供给侧样品中各加入等体积的血浆，在接受侧样品中各加入等体积的0.05M磷酸钠缓冲液，混合均匀。每孔加入200μL含有内标的乙腈溶液后，将96孔板以600rpm的速度涡旋振荡10分钟，5594g离心15分钟(Thermo Multifuge×3R)后，取50μL上清液转移至新的96孔板中，并将样品与50μL超纯水混合后进行LC-MS/MS分析。
使用以下公式对血浆蛋白结合率及游离分数进行计算：％结合率＝100×([供给侧浓度]5h-[接收侧浓度]5h)/[供给侧浓度]5h。％游离分数＝100-％结合率
表6测试化合物在血浆中的游离分数

实验结果表明，本发明化合物在人和小鼠血浆中游离药物的比率较高，成药性好。其中，本发明化合物I-1相对于对照药在人和小鼠血浆中游离药物的比率更高，成药性更好。
测试例7：小鼠药代动力学试验
使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟，4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表7测试化合物的小鼠药代动力学试验结果
小鼠药代动力学实验结果表明，本发明化合物I-1和I-2口服暴露量高,药代动力学性质佳，成药性好。
测试例8：LOVO结直肠癌体内药效实验
小鼠适应性饲养一周后，将处于对数期的LOVO细胞重悬于无血清F12K，按100μL/只将5 x 106LOVO细胞接种于小鼠右侧胁肋部皮下，定期观察肿瘤生长情况，待肿瘤生长至平均体积150-200mm3时，根据肿瘤大小和小鼠体重随机分为模型组和给药组，给药前和给药过程中测量、记录肿瘤大小和动物体重，治疗结束后比较模型组和给药组肿瘤大小差异以确定药效。
表8测试化合物在肿瘤重量水平的抑瘤能力

表中“--”表示没有测试。
实验结果表明，本发明化合物I-1和I-2具有显著的抑制LOVO瘤组织生长的作用，比对照化合物II的效果更优。
测试例9：NCI-H1975非小细胞肺癌体内药效实验
用含有灭活的RPMI 1640+10％FBS培养基，在37℃、5％CO2的培养箱中培养NCI-H1975肿瘤细胞，细胞汇合率达到80-90％传代后分瓶传代。鼠适应性饲养一周后，将处于对数期的NCI-H1975，以5 x 106/100μL接种浓度接种于小鼠右侧胁肋部皮下，定期观察肿瘤生长情况，待肿瘤生长至平均体积100-150mm3时，根据肿瘤大小和小鼠体重随机分为模型组和给药组(与奥西替尼联用)，给药前和给药过程中测量、记录肿瘤大小和动物体重，比较模型组和给药组肿瘤大小差异以确定药效，在Graph Pad 8.0中用Mann Whitney test检验方法比较联合给药组和奥西替尼单药组之间的显著性差异，结果如图1所示。
表9测试化合物与奥西替尼协同抗肿瘤作用
与奥西替尼单药组相比，化合物I-1(7.5mg/kg，BID或25mg/kg，BID)与奥西替尼(1mg/kg，QD)联合给药在治疗结束时，动物的平均肿瘤体积均有明显减小，P值分别小于0.01和0.001，差异有统计学意义。结果表明，化合物I-1与奥西替尼联用的抑瘤药效都显著优于单药给药。
测试例10：H2122非小细胞肺癌体内药效实验
在37℃、5％CO2的培养箱中培养H2122肿瘤细胞，细胞汇合率达到80-90％传代后分瓶传代。鼠适应性饲养一周后，将处于对数期的NCI-H1975，接种于小鼠右侧胁肋部皮下，肿瘤生长到一定体积后，根据肿瘤大小和小鼠体重随机分为模型组和给药组(与KRAS抑制剂联用，KRAS抑制剂为MRTX849、AMG-510、JDQ443)，给药前和给药过程中测量、记录肿瘤大小和动物体重，治疗结束后比较模型组和给药组肿瘤大小差异以确定药效。
实验结果表明，本发明化合物I-1和I-2单用或与KRAS抑制剂联用都具有显著的抑制NCI-H1975癌生长的作用，联用比单用的效果更优。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (15)

  1. 一种药物组合物，包括SOS1抑制剂和抑制剂A；
    所述抑制剂A选自KRAS抑制剂和EGFR抑制剂中的一种或两种；
    所述SOS1抑制剂为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    其中，R1为未取代或被Ra取代的3-6元环烷基；所述Ra为C1-C6卤代烷基。
  2. 如权利要求1所述的药物组合物，其特征在于，所述式I所示化合物选自：
  3. 如权利要求1所述的药物组合物，其特征在于，所述式I所示化合物药学上可接受的盐为式I所示化合物与酸形成的盐；所述的酸为盐酸、硫酸、马来酸、天冬氨酸、磷酸、富马酸、酒石酸、柠檬酸、葡萄糖醛酸、乙醇酸、苹果酸、马尿酸、葡萄糖酸、乳酸、琥珀酸、抗坏血酸、己二酸、对甲苯磺酸、甲磺酸、苯磺酸、草酸、2-羟基乙磺酸、乙磺酸、龙胆酸、苯甲酸中的一种或多种；
    较佳地，所述式I所示化合物药学上可接受的盐为式I-1所示化合物与酸形成的盐。
  4. 如权利要求1所述的药物组合物，其特征在于，所述SOS1抑制剂与抑制剂A的质量比为1:1～500:1，较佳地为1:1～50:1、7.5:1～25:1，例如7.5:1或25:1。
  5. 如权利要求1所述的药物组合物，其特征在于，所述SOS1抑制剂与EGFR抑制剂的质量比为1:1～100:1，较佳地为1:1～50:1、7.5:1～25:1，例如7.5:1或25:1。
  6. 如权利要求1或5所述的药物组合物，其特征在于，所述EGFR抑制剂为奥西替尼、吉非替尼。
  7. 如权利要求1所述的药物组合物，其特征在于，所述SOS1抑制剂与KRAS抑制剂的质量比为1:1～100:1，较佳地为1:1～50:1、7.5:1～25:1，例如7.5:1或25:1。
  8. 如权利要求1或7所述的药物组合物，其特征在于，所述KRAS抑制剂为MRTX-849、AMG-510、JDQ443。
  9. 如权利要求1所述的药物组合物，其特征在于，SOS1抑制剂的经口使用的剂量为每剂1mg至2000mg(例如，每剂10mg至1000mg；或每剂200mg至600mg；或每剂400mg至500mg)；
    较佳地，所述SOS1抑制剂是每天一次、每天两次或每天三次给药；
    较佳地，所述抑制剂A是每天一次、每天两次、每天三次或每两天一次给药；
    较佳地，所述SOS1抑制剂经口按照400mg至500mg的剂量每日两次施用，所述SOS1抑制剂与EGFR抑制剂的质量比为7.5:1或25:1，且所述EGFR抑制剂每日一次施用；
    较佳地，所述EGFR抑制剂为奥西替尼。
  10. 如权利要求1-9任一所述的药物组合物，其特征在于，所述药物组合物还包括药学上可接受的载体和/或赋形剂。
  11. 一种药盒，其特征在于，包括
    第一药物组合物或剂型，其包含如权利要求1-3任一所定义的SOS1抑制剂及任选地一种或多种药学上可接受的载体、赋形剂；
    第二药物组合物或剂型，其包含如权利要求1所定义的抑制剂A及任选地一种或多种药学上可接受的载体、赋形剂。
  12. 如权利要求1-10所述的药物组合物或如权利要求11所述的药盒的用途，所述用途包括选自下列的一种或多种：
    抑制SOS1与RAS家族蛋白的相互作用、
    预防和/或治疗SOS1与RAS家族蛋白相关的疾病、
    制备用于抑制SOS1与RAS家族蛋白的相互作用，和/或预防和/或治疗SOS1与RAS家族蛋白相关的疾病的药物、药物组合物或制剂、
    制备药物，例如制备用于预防和/或治疗癌症、RAS病的药物。
  13. 如权利要求12所述的用途，其特征在于，所述SOS1与RAS家族蛋白相关的疾病包括：癌症、RAS病；
    较佳地，所述RAS病包括努南综合征、心面皮肤综合征、1型遗传性齿龈纤维瘤病、1型神经纤维瘤病、毛细血管畸形-动静脉畸形综合征、科斯特洛综合症和莱格斯综合征；
    较佳地，所述的RAS家族蛋白为KRAS，例如KRAS G12C、KRAS G12D、KRAS  G12V；
    较佳地，所述的癌症选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述肝癌优选为肝细胞癌；所述头颈瘤优选为头颈鳞状细胞癌；所述肉瘤优选为骨肉瘤；所述结肠直肠癌优选为结肠癌或直肠癌；所述肺癌优选为非小细胞肺癌。
  14. 一种治疗癌症的方法，包括步骤：给需要的患者施用如权利要求1-10中任一项所述的药物组合物；
    所述癌症选自黑色素瘤、皮肤癌、肝癌、肾癌、肺癌、鼻咽癌、胃癌、食道癌、结肠直肠癌、胆囊癌、胆管癌、绒毛膜上皮癌、胰腺癌、真性红细胞增多症、儿科肿瘤、宫颈癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、输尿管肿瘤、前列腺癌、精原细胞瘤、睾丸肿瘤、白血病、头颈瘤、子宫内膜癌、甲状腺癌、淋巴瘤、肉瘤、骨瘤、成神经细胞瘤、神经母细胞瘤、脑瘤、骨髓瘤、星形细胞瘤、胶质母细胞瘤和胶质瘤；所述肝癌优选为肝细胞癌；所述头颈瘤优选为头颈鳞状细胞癌；所述肉瘤优选为骨肉瘤；所述结肠直肠癌优选为结肠癌或直肠癌；所述肺癌优选为非小细胞肺癌。
  15. 如权利要求14所述的方法，其特征在于，所述癌症为结肠直肠癌或肺癌，优选为非小细胞肺癌。
PCT/CN2023/106366 2022-07-07 2023-07-07 包含sos1抑制剂的药物组合物 WO2024008185A1 (zh)

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