CN117357650A - Pharmaceutical composition comprising SOS1 inhibitor - Google Patents

Pharmaceutical composition comprising SOS1 inhibitor Download PDF

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Publication number
CN117357650A
CN117357650A CN202310836632.0A CN202310836632A CN117357650A CN 117357650 A CN117357650 A CN 117357650A CN 202310836632 A CN202310836632 A CN 202310836632A CN 117357650 A CN117357650 A CN 117357650A
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China
Prior art keywords
cancer
acid
inhibitor
sos1
pharmaceutical composition
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CN202310836632.0A
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Chinese (zh)
Inventor
张学军
臧杨
刘礼飞
李杨
胡文兵
赵心
李莉娥
杨俊�
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Publication of CN117357650A publication Critical patent/CN117357650A/en
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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

Abstract

The invention discloses a pharmaceutical composition containing an SOS1 inhibitor. The pharmaceutical composition containing the SOS1 inhibitor provided by the invention comprises the SOS1 inhibitor and the inhibitor A; the SOS1 inhibitor is a compound shown in formula I, a tautomer, a stereoisomer, a hydrate or a solution thereofA formulation, a pharmaceutically acceptable salt or prodrug. Can be used for preventing or treating diseases with excessive or abnormal cell proliferation, has obvious effect of inhibiting tumor growth, and is obviously superior to single administration.

Description

Pharmaceutical composition comprising SOS1 inhibitor
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing an SOS1 inhibitor and application thereof.
Background
The RAS protein is a membrane-bound protein with intrinsic gtpase activity that is activated by a number of extracellular stimuli, cycling between a GDP-bound (off) state and a GTP-bound (on) state. When it is in GTP-binding (on) state, it can activate downstream channel and promote cell proliferation, differentiation, migration, immunity and other processes.
The RAS protein family includes three highly homologous isomers: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene) and NRAS (Neuroblastoma ras oncogene), KRAS comprises 2 alternative splice variants: KRAS4A and KRAS4B. RAS family proteins have weaker endogenous GTPase activity and slower nucleotide exchange rates.
RAS gene mutation activation is a major cause of tumorigenesis, and RAS mutation occurs in 27% of all tumor patients. Wherein the KRAS mutation frequency is highest, and the ratio is 86%. KRAS-4B mutations are present in about 90% of pancreatic cancers, 30% -40% of colon cancers, and 15% -20% of lung cancers, and also in biliary tract malignancies, endometrial cancers, cervical cancers, bladder cancers, liver cancers, myelogenous leukemias, and breast cancers. The most common modes of KRAS gene mutation are point mutations, commonly known as KRAS-G12D (41%), KRAS-G12V (28%) and KRAS-G12C (14%). Mutated KRAS affects its ability to bind to gtpase-activating proteins (GTPase activating protein, GAP), thereby inhibiting GAP-induced GTP hydrolysis. As the hydrolysis ability of gtpase decreases, GTP gradually accumulates, KRAS is more easily combined with GTP, and KRAS is most in an activated state, thereby inducing the occurrence and development of malignant tumors.
The transition of RAS proteins from inactive to active involves the release of GDP and the binding of GTP, which requires the involvement of guanylate exchange factors (GMP exchange factor, GEF), such as the SOS (Son of Sevenless) protein. SOS proteins were first discovered in drosophila in 1992 as GEFs for RAS and Rac proteins, playing an important role in RAS and Rac signaling pathways. Human beings have two SOS homologs-SOS 1 and SOS2, which are highly similar in structure and sequence, have 70% homology, but differ in biological function to some extent. SOS1 protein consists of 1300 amino acid residues, and contains a proline-rich domain at the C-terminus, which can interact with growth factor receptor binding protein 2 (growth factor receptor-bound protein 2, grb 2) in the RAS pathway, and Grb2 binds to SOS1 to form a complex that brings SOS1 into the vicinity of the cell membrane RAS protein. The interaction of SOS1 with RAS involves two domains of SOS 1: CDC25 domain and REM domain. The CDC25 domain has an active site for nucleotide exchange and the REM domain comprises a site that binds RAS-GTP and results in allosteric activation of the CDC25 domain. SOS1 can convert GDP to GTP by catalytic exchange, GTP is hydrolyzed by RAS, and then downstream signals are activated, causing a corresponding series of biological effects.
Specific SOSl inhibitors may inhibit SOS1 interaction with KRAS-GDP, thereby reducing the formation of activated KRAS-GTP. A decrease in KRAS-GTP levels will result in a decrease in downstream MAPK signaling, which will play a role 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. SOS1 inhibitors BI-3406 and BI-1701963 developed by Boringer John, are capable of binding to the catalytic domain of SOS1, preventing its interaction with KRAS, reducing KRAS-GTP formation, and inhibiting KRAS-driven proliferation of various cancer cells. SOS1 inhibitors, in combination with MEK inhibitors, can significantly reduce KRAS signaling and increase antitumor activity through complementary mechanisms of action. BI-3406 disclosed that it inhibits cytochrome P450A 4 (CYP 3A 4) in a time-dependent manner, and that there is a potential risk of drug-drug interactions (DDI), thus developing a SOS1 inhibitor without cytochrome P450 inhibition has the advantage that SOS1 inhibitors without CYP3A4 inhibition are more clinically valuable, and both BI-1701963 and a combination therapy with MEK inhibitor, trimetinib, have entered clinical research.
In addition to cancer, 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 in about 20% of NS patients with mutations in SOS1, which are distributed over 6 domains of SOS 1. Patients with SOS1 mutations exhibit phenotypic characteristics of curly hair and ectodermal abnormalities. Mutations in the CDC25 domain may directly increase GEF activity of SOS1, inducing superactivation of the RAS/ERK pathway. The cardiodermic syndrome is one of the cardiomyopathy groups of the renin-angiotensin system, and studies have reported that SOS1 mutations exist in this disease. Type 1 hereditary gum fibromatosis is an autosomal dominant genetic disease whose etiology is associated with mutations in the proline-rich domain of SOS 1.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing an SOS1 inhibitor, which can be used for preventing or treating diseases of excessive or abnormal cell proliferation, has a remarkable effect of inhibiting tumor growth and is remarkably superior to single administration.
The invention solves the technical problems through the following technical proposal.
The invention provides a pharmaceutical composition, comprising an SOS1 inhibitor and an inhibitor A; the inhibitor A is one or two selected from KRAS inhibitor and EGFR inhibitor;
the SOS1 inhibitor is a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
wherein R is 1 Is 3-6 membered cycloalkyl unsubstituted or substituted by Ra; the Ra is C 1 -C 6 A haloalkyl group.
In a preferred embodiment, R 1 Is cyclopropyl substituted with Ra, which is halogen substituted methyl, ethyl or propyl; preferably, the halogen is fluorine or chlorine.
In a preferred embodiment, the compound of formula I is selected from:
in a preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is a salt of the compound of formula I with an acid; the acid is one or more of 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, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid and benzoic acid.
In a preferred embodiment, the pharmaceutically acceptable salt of the compound of formula I is a salt of the compound of formula I-1 with an acid.
In a preferred embodiment, the mass ratio of 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.
In a preferred embodiment, the SOS1 inhibitor is present in the pharmaceutical composition in an amount of 1mg to 2000mg (e.g., 10mg to 1000mg; or 200mg to 600mg; or 400mg to 500 mg).
In a preferred embodiment, 50mg of SOS1 inhibitor is included.
In a preferred embodiment, 100mg of SOS1 inhibitor is included.
In a preferred embodiment, 200mg of SOS1 inhibitor is included.
In a preferred embodiment, 400mg of SOS1 inhibitor is included.
In a preferred embodiment, 800mg of SOS1 inhibitor is included.
In a preferred embodiment, 1600mg of SOS1 inhibitor is included.
In a preferred embodiment, 2000mg of SOS1 inhibitor is included.
In a preferred embodiment, the mass ratio of SOS1 inhibitor to EGFR inhibitor is from 1:1 to 100:1, preferably from 1:1 to 50:1, 7.5:1 to 25:1, e.g. 7.5:1 or 25:1.
In a preferred embodiment, the EGFR inhibitor is oxatinib, gefitinib.
In a preferred embodiment, the mass ratio of SOS1 inhibitor to KRAS inhibitor is from 1:1 to 100:1, preferably from 1:1 to 50:1, from 7.5:1 to 25:1, for example 7.5:1 or 25:1.
In a preferred embodiment, the KRAS inhibitor is MRTX-849, AMG-510, JDQ443.
MRTX849 has the chemical structure of
AMG-510 has the chemical structure of
The chemical structure of JDQ443 is
In a preferred embodiment, the pharmaceutical composition comprises an SOS1 inhibitor and inhibitor A as active ingredients.
In a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
In a second aspect, the present invention provides a kit comprising
A first pharmaceutical composition or dosage form comprising an SOS1 inhibitor as defined in the first aspect and optionally one or more pharmaceutically acceptable carriers, excipients;
a second pharmaceutical composition or dosage form comprising inhibitor a as defined in the first aspect and optionally one or more pharmaceutically acceptable carriers, excipients.
In a third aspect of the present invention there is provided the use of a pharmaceutical composition as described in the first aspect or a kit as described in the second aspect, the use comprising one or more selected from the group consisting of:
Inhibit SOS1 interaction with RAS family proteins,
Preventing and/or treating SOS1 and RAS family protein related diseases,
Preparation of a medicament, pharmaceutical composition or formulation for inhibiting the interaction of SOS1 with a RAS family protein and/or preventing and/or treating SOS 1-RAS family protein-related diseases,
For example, for the preparation of medicaments for the prophylaxis and/or treatment of cancer and RAS diseases.
In a preferred embodiment, the SOS 1-associated (or mediated) diseases with RAS family proteins include, but are not limited to: cancer and RAS disease.
Preferably, the RAS disease or SOS1 and RAS family protein mediated disease includes noonan syndrome, heart face skin syndrome, hereditary gum fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, costerol syndrome and rice syndrome.
Preferably, the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gall bladder cancer, bile duct cancer, chorionic epithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumor, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, bone tumor, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma, and glioma; the liver cancer is preferably hepatocellular carcinoma; the head and neck tumor is preferably a head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the cancer is preferably non-small cell lung cancer.
The RAS disease is preferably type I neurofibromatosis (NF 1); the lung cancer is preferably non-small cell lung cancer, and more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myelogenous leukemia; the lymphoma 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 a head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer.
Preferably, the SOS 1-related disease of the RAS family protein is colorectal cancer or lung cancer, preferably non-small cell lung cancer.
The RAS family protein may be KRAS, e.g., KRAS G12C, KRAS G12D, KRAS G12V.
The present invention also provides a method of inhibiting SOS1 and a RAS family protein, or preventing and/or treating a SOS1 and RAS family protein-related (or mediated) disease, comprising the steps of: administering to a patient in need thereof a pharmaceutical composition according to the first aspect of the present invention.
The SOS1 inhibitor and inhibitor A may be administered simultaneously or separately.
The "simultaneous administration" of, for example, the SOS1 inhibitor and inhibitor a is comprised in a single pharmaceutical composition; alternatively, "a separate pharmaceutical composition comprising an SOS1 inhibitor" is administered simultaneously with "a separate pharmaceutical composition comprising inhibitor a".
The "separate administration" for example "a separate pharmaceutical composition comprising an SOS1 inhibitor" is administered separately from "a separate pharmaceutical composition comprising inhibitor a" at different times; for example: one of the "individual pharmaceutical compositions comprising SOS1 inhibitor" and "individual pharmaceutical composition comprising inhibitor A" is administered first, the other is administered subsequently. The separate applications may be close in time or remote in time.
Whether administered simultaneously or separately, the regimen of administration (including route of administration, dosage of administration, interval of administration, etc.) of the SOS1 inhibitor and inhibitor a may be the same or different, which may be adjusted as needed by one skilled in the art to provide optimal therapeutic effect.
According to certain embodiments of the invention, the patient is a mammal, preferably a human.
In a preferred embodiment, the SOS1 inhibitor is administered orally in a dose of 1mg to 2000mg per dose (e.g., 10mg to 1000mg per dose, or 200mg to 600mg per dose, or 400mg to 500mg per dose).
In a preferred embodiment, a single dose comprises 50mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 100mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 200mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 400mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 800mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 1600mg of SOS1 inhibitor.
In a preferred embodiment, a single dose comprises 2000mg of SOS1 inhibitor.
In a preferred embodiment, the SOS1 inhibitor is administered orally at a dose of 400mg to 500mg twice daily, the mass ratio of SOS1 inhibitor to EGFR inhibitor is 7.5:1 or 25:1, and the EGFR inhibitor is administered once daily.
The amounts of SOS1 inhibitor given above all refer to the free base of the SOS1 inhibitor and can be scaled up if a pharmaceutically acceptable salt or other solid form is used.
In a preferred embodiment, the SOS1 inhibitor is administered once daily, twice daily or three times daily.
In a preferred embodiment, the inhibitor a is administered once a day, twice a day, three times a day, or once every two days.
In a preferred embodiment, the EGFR inhibitor of the present invention is oxatinib.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Terminology and definitions
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a conventional formula written from left to right, the substituent also includes the result of writing the formula from right to leftChemically equivalent substituents. For example, CH 2 O is equal to OCH 2 。
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both endpoints of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1, 2, 3, 4, 5, and 6.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, is a hydrate.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms, a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C 1 -C 3 Alkyl "), such as methyl, ethyl, n-propyl or isopropyl. Those skilled in the art will recognize that the term "alkaneThe group "may include an" alkylene "group.
The term "cycloalkyl" or "carbocyclyl" refers to a cyclic alkyl group. The term "m-n membered cycloalkyl" or "Cm-Cn cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-6 membered cycloalkyl" or "C 3 -C 6 Cycloalkyl "refers to a cyclic alkyl group containing 3, 4, 5 or 6 carbon atoms. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "halo" refers to substitution by halogen, wherein "halogen" has the above definition.
The term "haloalkyl" is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw where v=1 to 3,w =1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "single dose" refers to the dose when administered to a patient at one time.
The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed a pathology or symptomatology of the disease. (2) inhibition of disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) alleviation of disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The reaction temperature of each step may be appropriately selected depending on the solvent, starting material, reagent, etc., and the reaction time may be appropriately selected depending on the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is finished, the target compound can be separated and purified from the reaction system according to a common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Under the condition of not influencing the next reaction, the target compound can also directly enter the next reaction without separation and purification.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained. The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the pharmaceutical composition containing the SOS1 inhibitor provided by the invention can be used for preventing or treating diseases of excessive or abnormal cell proliferation, has a remarkable effect of inhibiting tumor growth, and is remarkably superior to single-drug administration.
Drawings
Figure 1, test compounds for tumor suppression capacity at tumor volume level in NCIH1975 in vivo efficacy experiments for non-small cell lung cancer.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that the following description is only of the most preferred embodiments of the present invention and should not be taken as limiting the scope of the invention. Upon a complete understanding of the present invention, experimental methods without specific references in the following examples, generally according to conventional conditions or according to conditions suggested by the manufacturer, may make insubstantial changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of the present invention.
Preparation of intermediate A1
The synthetic route is as follows:
the first step: (Z) -2- ((dimethylamino) methylene) -3-oxoglutarate methyl ester (A1-2)
The compound methyl 3-oxoglutarate (10.0 g,57.4 mmol) was added to 2-methyltetrahydrofuran (100 ml) at room temperature, DMF-DMA (6.8 g,57.1 mmol) was added and stirred at room temperature for 4h. Concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give crude (Z) -2- ((dimethylamino) methylene) -3-oxoglutarate methyl (A1-2) (12 g, yellow liquid, yield 91.1%).
LC-MS,M/Z(ESI):230.2[M+H] + 。
And a second step of: 1- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (A1-4)
The compound (Z) -2- ((dimethylamino) methylene) -3-oxoglutarate methyl ester (2.4 g,10.4 mmol) was added to 2-methyltetrahydrofuran (30 ml), 4N hydrochloric acid (10 ml) was added, and stirred for 3h at room temperature. The aqueous phase was separated, extracted with ethyl acetate (100 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, methanol (30 ml) was added, 1- (fluoromethyl) cyclopropane-1-amino hydrochloride (1.0 g,8.0 mmol) was added, and stirred at room temperature for 16h. Sodium methoxide (1.3 g,24.0 mmol) was added to the system and stirred for 2h. The ph=2 was adjusted with concentrated hydrochloric acid and filtered to give crude 1- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (A1-4) (2.0 g, 79.1% yield).
LC-MS,M/Z(ESI):242.2[M+H] + 。
And a third step of: 1- (1- (fluoromethyl) cyclopropyl) -6-oxo-4- (p-toluenesulfonyloxy) -1, 6-dihydropyridine-3-carboxylic acid methyl ester (A1-5)
Raw material 1- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (2.0 g,8.3 mmol) was added to acetonitrile (20 ml), cooled to 0 ℃, triethylamine (1.68 g,16.6 mmol), tsCl (1.58 g,8.3 mmol) was added, warmed to room temperature and stirred for 2h. The reaction solution was concentrated, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =5:1-1:1) to give methyl 1- (1- (fluoromethyl) cyclopropyl) -6-oxo-4- (p-toluenesulfonyloxy) -1, 6-dihydropyridine-3-carboxylate (A1-5) (1.2 g, yield 36.6%).
LC-MS,M/Z(ESI):396.3[M+H] + 。
Fourth step: 4-acetamido-1- (1- (fluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester (A1-6)
1- (1- (fluoromethyl) cyclopropyl) -6-oxo-4- (p-toluenesulfonyloxy) -1, 6-dihydropyridine-3-carboxylic acid methyl ester (1.2 g,3.0 mmol) was added to dioxane (50 ml) at room temperature, potassium phosphate (700 mg,3.3 mmol), xantphos (173 mg,0.3 mmol), palladium chloride (pi-cinnamyl) dimer (212 mg,0.3 mmol), N 2 Heating, refluxing and stirring for 2h under protection. Cooled to room temperature, the reaction solution was concentrated, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =3:1-1:1) to give methyl 4-acetamido-1- (1- (fluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (A1-6) (680 mg, yield 79.3%)
LC-MS,M/Z(ESI):283.2[M+H] + 。
Fifth step: 6- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one (A1)
The starting material, methyl 4-acetamido-1- (1- (fluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (680 mg,2.41 mmol), was added to 7mol/L ammonia methanol solution (10 ml) and stirred at room temperature for 5d. Concentrate (3 ml) to filter to give 6- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one (460 mg, 16.4% yield)
1 H 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] + 。
Example 1: synthesis of Compound I-1
The synthetic route is as follows:
the first step: synthesis of 1- (3- (pentafluorosulfanyl) phenyl) ethan-1-one (B1-2)
The compound 3-bromo- (pentafluorosulfanyl) benzene (B1-1) (3.00 g,10.6 mmol) was added to dioxane (100 mL) at room temperature, and ditolylphosphine palladium dichloride (744 mg,1.06 mmol), tributyl (1-ethoxyethylene) tin (4.20 g,11.7 mmol), N 2 Heating to 90 ℃ under protection, and stirring for 14h. Cooled to room temperature, 2N hydrochloric acid (100 mL) was added and stirred for 4h. Extraction with ethyl acetate (200 ml×3), separation, combining the organic phases, drying the organic phases over anhydrous sodium sulfate, filtration, concentration, and purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =8:1) afforded 1- (3- (pentafluorosulfanyl) phenyl) ethan-1-one (B1-2, yellow liquid, 2.4g, 89% yield).
LC-MS,M/Z(ESI):247.0[M+H] + 。
And a second step of: synthesis of (S, E) -2-methyl-N- (1- (3- (pentafluorosulfanyl) phenyl) ethylene) propane-2-sulfinamide (B1-3)
The compound 1- (3- (pentafluorosulfanyl) phenyl) ethan-1-one (B1-2, 1.0g,4.06 mmol) was added to THF (150 mL) at room temperature, and (S) -tert-butylsulfinamide (492 mg,4.06 mmol) and tetraethyltitanate (1.14 g,5.0 mmol) were added and heated to 70℃and stirred for 16h. Cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 ml×3), separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =4:1) to give (S, E) -2-methyl-N- (1- (3- (pentafluorosulfanyl) phenyl) ethylene) propane-2-sulfinamide (B1-3, 1.42g, 100% yield).
LC-MS,M/Z(ESI):350.2[M+H] + 。
And a third step of: synthesis of (S) -2-methyl-N- ((R) -1- (3- (pentafluorosulfanyl) phenyl) ethyl) propane-2-sulfinamide (B1-4)
Raw material (S, E) -2-methyl-N- (1- (3- (pentafluorosulfanyl) phenyl) ethylene) propane-2-sulfinamide (B1-3, 1.5g,4.3 mmol) was added to methanol (30 mL) at room temperature, cooled to 0deg.C, naBH was added 4 (744 mg,20.1 mmol) was added in portions to methanol, warmed to room temperature, and stirred for 3h. The reaction solution was concentrated, and purified by thin layer preparation to give (S) -2-methyl-N- ((R) -1- (3- (pentafluorosulfanyl) phenyl) ethyl) propane-2-sulfinamide (B1-4, 600mg, 40.0% yield).
LC-MS,M/Z(ESI):352.1[M+H] + 。
Fourth step: synthesis of (R) -1- (3- (pentafluorosulfanyl) phenyl) ethane-1-amine hydrochloride (B1-5)
Raw material (R) -2-methyl-N- ((R) -1- (3- (pentafluorosulfanyl) phenyl) ethyl) propane-2-sulfinamide (B1-4, 600mg,1.70 mmol) was added to 4mol/L dioxane hydrochloride solution (10 mL) at room temperature and stirred for 4h. The reaction solution was concentrated, methyl t-butyl ether (20 mL) was added thereto, stirred for 1h, and filtered to give (R) -1- (3- (pentafluorosulfanyl) phenyl) ethane-1-amine hydrochloride (B1-5, 350mg, yield 72.7%).
LC-MS,M/Z(ESI):248.2[M+H] + 。
Fifth step: synthesis of (R) -6- (1- (fluoromethyl) cyclopropyl) -2-methyl-4- ((1- (3- (pentafluorosulfanyl) phenyl) ethyl) amino) pyrido [4,3-d ] pyrimidin-7 (6H) -one (I-1)
6- (1- (fluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyridin [4,3-d ] pyrimidin-7 (6H) -one (A1) (200 mg,0.80 mmol) was added to acetonitrile (20 mL) at room temperature, potassium phosphate (678 mg,3.20 mmol) was added, phosphazene trichloride (416 mg,1.20 mmol) was stirred at room temperature for 16H. Raw material (R) -1- (3- (pentafluorosulfanyl) phenyl) ethane-1-amine hydrochloride (B1-5, 160mg,0.56 mmol) was added to methylene chloride (10 mL), diisopropylethylamine (2 mL) was added, stirring was performed for 0.5h, and this solution was added to the above system and stirring was performed at room temperature for 6h. The reaction solution was concentrated and purified to give (R) -6- (1- (fluoromethyl) cyclopropyl) -2-methyl-4- ((1- (3- (pentafluorosulfanyl) phenyl) ethyl) amino) pyrido [4,3-d ] pyrimidin-7 (6H) -one (I-1, 44mg, 16.4% yield).
1 H 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] + 。
Example 2: synthesis of Compound I-2
The synthetic route is as follows:
the first step: synthesis of methyl 1- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-1)
The compound (Z) -2- ((dimethylamino) methylene) -3-oxoglutarate dimethyl ester (A1-2, 5.0g,21.81 mmol) and 1- (difluoromethyl) cyclopropane-1-amine hydrochloride (3.44 g,23.99 mmol) were dissolved in methanol (50.0 mL) and the reaction was stirred at room temperature for 16 hours. Sodium methoxide (1.76 g,32.58 mmol) was then added to the reaction solution, and the reaction system was stirred at 25℃for 0.5 hours. HCl (1.0N, 15.0 mL) was added to the reaction system, pH was adjusted to 1-2, filtration was performed, the cake was washed with 10.0mL of methanol, and the cake was dried to give methyl 1- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-1) (2.4 g, yield 42.5%).
LC-MS,M/Z(ESI):260.3[M+H] +
And a second step of: synthesis of methyl 1- (1- (difluoromethyl) cyclopropyl) -6-oxo-4- (tosyloxy) -1, 6-dihydropyridine-3-carboxylate (B2-2)
Methyl 1- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-1, 2.4g,9.26 mmol) was dissolved in acetonitrile (24.0 mL), then triethylamine (1.41 g,13.89 mmol) was added to the reaction system, and p-toluenesulfonyl chloride (1.77 g,9.26 mmol) was added in slow portions and the reaction system was stirred at 25℃for 2 hours. Methylene chloride (20.0 mL) was added to the reaction mixture to dilute it, the pH was adjusted to 2-3 with 1N HCl (10.0 mL), the mixture was extracted, and the organic phase was dried by spinning to give methyl 1- (1- (difluoromethyl) cyclopropyl) -6-oxo-4- (tosyloxy) -1, 6-dihydropyridine-3-carboxylate (B2-2) (3.4 g, yield 89%).
LC-MS,M/Z(ESI):414.5[M+H] +
And a third step of: synthesis of methyl 4-acetamido-1- (1- (difluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-3)
1- (1- (difluoromethyl) cyclopropyl) -6-oxo-4- (tosyloxy) -1, 6-dihydropyridine-3-carboxylic acid methyl ester (B2-2) (3.3 g,7.98 mmol), acetamide (707.0 mg,11.97 mmol), xantphos (924.0 mg,1.60 mmol), potassium phosphate (3.39 g,15.97 mmol), palladium chloride (pi-cinnamyl) dimer (1.46 g,1.60 mmol) were sequentially added to a 100mL single-port bottle, and after three substitutions in a nitrogen atmosphere, the system was warmed to 115℃and stirred for 16 hours. The reaction solution was cooled, filtered, and the obtained mother liquor was dried by spin-drying and stirred, and purified by silica gel column (petroleum ether: ethyl acetate (V/V) =10:1-1:1) to give methyl 4-acetamido-1- (1- (difluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-3) (1.6 g, yield 67%).
Fourth step: 6- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one (B2-4)
In a 50.0mL pot, methyl 4-acetamido-1- (1- (difluoromethyl) cyclopropyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (B2-3, 1.6g,5.33 mmol) was dissolved in methanolic ammonia (7N, 15.0 mL) and the reaction was warmed to 50deg.C and stirred for 12 hours. After the reaction solution was cooled, it was filtered, and the filter cake was rinsed with methanol (15.0 mL) to give 6- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one (B2-4) as a pale yellow solid (900 mg, 63% yield).
LC-MS,M/Z(ESI):268.2[M+H] + 。
Fifth step: (R) -6- (1- (difluoromethyl) cyclopropyl) -2-methyl-4- ((1- (3- (pentafluorosulfanyl) phenyl) ethyl) amino) pyrido [4,3-d ] pyrimidin-7 (6H) -one (I-2)
6- (1- (difluoromethyl) cyclopropyl) -4-hydroxy-2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one (300.0 mg,1.12 mmol) was dissolved in acetonitrile (15.0 mL), potassium phosphate (596.0 mg,2.81 mmol) was added followed by hexachlorocyclotriphosphazene (585.0 mg,1.68 mmol), after stirring at room temperature for 2 hours, (R) -1- (3- (pentafluorosulfanyl) phenyl) ethan-1-amine hydrochloride (B1-5, 318.0mg,1.12 mmol) was added, the reaction stirred overnight at room temperature, the reaction mixture was first filtered, the filter cake was washed with acetonitrile (15.0 mL), the filtrate was dried to give crude product by silica gel column chromatography (petroleum ether: ethyl acetate=10:1-1:1) to give (R) -6- (1- (difluoromethyl) cyclopropyl) -2-methyl-4- ((1- (3- (pentafluorosulfanyl) phenyl) ethyl) pyrido [4,3-d ] pyrimidin-7 (I) 6.166.0 g, yield.
1 H NMR(400MHz,DMSO-d 6 )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] + 。
In the test examples of the present invention, the preparation of the control compound I is referred to in WO2019122129A1 and the preparation of the control compound II is referred to in WO2019122129A1. The structure is as follows:
test example 1: SOS1 binding inhibition assay for KRAS G12C
Test compounds were formulated as 10mM stock solutions using DMSO and the compounds were serially diluted using 1X test buffer. Transfer 0.1. Mu.L of the compound solution of different concentrations into 384 well plates, add 5. Mu.L of GST-KRAS G12C to 384 well plates and centrifuge at 1000rpm for 1 minute. mu.L of His-SOS1 was added to 384 well plates, centrifuged at 1000rpm for 1 min and incubated at room temperature for 15 min.
After the incubation, 10. Mu.L of a mixed solution of anti-6 his-Tb mab (Cisbio, cat. No.61HI2 TLA) and anti-GST-XL 665 mab (Cisbio, cat. No.61 GSTXLA) was added to the test wells, centrifuged at 1000rpm for 1 min and incubated at room temperature for 1 hr.
After incubation, the ratio of fluorescence signals at 665nm and 615nm wavelengths was read on a multifunctional microplate reader (Perkin Elmer, envision 2104) and the IC was calculated using Graphpad 5 software 50 Values.
TABLE 1 test compound vs KRAS G12C: SOS1 binding inhibition results
Test compounds IC 50 (nM)
Control Compound I 8.58
Control Compound II 8.15
I-1 3.94
I-2 4.9
Experimental results show that the compounds I-1 and I-2 have remarkable inhibition effect on KRAS G12C-SOS 1.
Test example 2: inhibition assay of DLD-1 cell ERK phosphorylation level by Compounds
And detecting the ERK phosphorylation inhibition level of the compound on the DLD-1 cells by using an intracellular western blot quantitative analysis method.
DLD-1 cells (ATCC, CCL-221) were cultured at a rate of 2.5X10 6 Individual cells/flask were inoculated in T75 flasks and cultured in RPMI 1640 medium containing 10% fbs for 2 days. Day 3 cells were seeded on 384 well plates at 37℃with 5% CO 2 Culturing overnight. Serial dilutions of compound (final DMSO content 0.5%) and DMSO were added overnight, negative groups at 37 ℃,5% co 2 Incubation in incubator.
Cells were fixed, washed once with PBS, membrane broken, and blocked for 1 hour at room temperature. Removing the blocking solution, adding primary antibody (CST, cat. No. # 4370S), and incubating overnight at 4 ℃. PBST (PBS solution with 0.05% tween 20) was used for 3 washes, each for 2 minutes. Secondary antibody (LI-COR, cat.no. 926-32211) was added and incubated at room temperature protected from light. PBST was used for 3 washes, each for 2 minutes. The culture plate is centrifugated for 1 minute at the rotation speed of 1000rpm, and the culture plate is arranged in a bicolor infrared laser imaging systemCLX), reads the signal.
Relative signal = 800 channel signal values/700 channel signal values.
ERK phosphorylation relative expression level= (test compound-control compound I)/(DMSO group-control compound I)
Calculation of IC using Graphpad 5 software 50 Values.
TABLE 2 test compounds for inhibition of ERK phosphorylation levels in DLD-1 cells
Test compounds IC 50 (nM)
Control Compound I 72
I-1 56
Experimental results show that the compounds in the invention have remarkable inhibition effect on the ERK phosphorylation level of DLD-1 cells.
Test example 3: compound inhibition 3D cell proliferation assay
The H358 cells were inoculated into T75 flasks and cultured in RPMI 1640 medium containing 10% FBS for 2 days for subsequent culture or inoculated into 384-well plates for experiments.
On day 1 cells were seeded on 384 well plates with 40 μl of medium per well, gradient diluted compound or DMSO per well, and wells without cells added medium were set as blank. 37 ℃,5% CO 2 The culture was performed for 7 days, and 3D CellTiter-Glo reagent (Promega, cat. No. G9683) was added on day 8, and the mixture was shaken at 320rpm for 20 minutes and left at room temperature for 2 hours. The luminescence signal was read on a multifunctional microplate reader. Calculating the inhibition rate of cell viability:
cell viability inhibition ratio = (DMSO group-test compound)/(DMSO group-blank control group) ×100%
Calculation of IC using Graphpad 5 software 50 Values.
TABLE 3 test compounds for inhibition of H358 cell 3D proliferation
Test compounds IC 50 (nM)
Control Compound I 13
I-1 11.5
I-2 12.0
Experimental results show that the compounds I-1 and I-2 in the invention have strong inhibition effect on the 3D proliferation of H358 cells.
Test example 4: human liver microsome stability test
The stability test of the human liver microsome is carried out by adopting the co-incubation of the compound and the human liver microsome in vitro. Test compounds were first formulated as a 10mM stock solution in DMSO solvent, followed by dilution of the compounds to 0.5mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to a microsome/buffer solution, and 0.5mM of the compound was diluted with the solution to a working solution having a compound concentration of 1.5. Mu.M and a human liver microsome concentration of 0.75mg/mL. The reaction was started by taking a deep well plate, adding 30. Mu.L of working solution per well, then adding 15. Mu.L of pre-warmed 6mM NADPH solution, and incubating at 37 ℃. At 0, 5, 15, 30, 45 minutes of incubation, the reaction was terminated by adding 135 μl acetonitrile to the corresponding wells. After the reaction was terminated with acetonitrile at the last 45 min time point, the deep-well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. Taking supernatant after centrifugation, adding purified water 1:1, performing LC-MS/MS detection to obtain the ratio of the peak area of the compound to the internal standard peak area at each time point, comparing the ratio of the peak area of the compound at 5, 15, 30 and 45 minutes with the ratio of the peak area at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T by using Graphpad 5 software 1/2 。
TABLE 4 results of human liver microsome stability test
Experimental results show that the compound of the invention has better liver metabolism stability, slower metabolism in human body and higher exposure. Wherein the metabolic stability of compound I-1 is significantly improved compared to control compound I.
Test example 5: test for inhibition of cytochrome P450 by Compounds
The inhibitory potential of the compounds against cytochrome P450 (CYP 450) subtype CYP3A4 (2 substrates midazolam and testosterone) was examined. Firstly, preparing a compound to be tested into a 10mM stock solution in a DMSO solvent, and preparing a CYP3A4 inhibitor ketoconazole into a 10mM stock solution, a 2.5mM stock solution and a 2.5mM stock solution in the DMSO solvent. The test compound and ketoconazole were diluted to 400-fold final concentration (compound: 10. Mu.M, ketoconazole: 2.5. Mu.M) with acetonitrile.
NADPH cofactor (66.7 mg NADPH in 10mL potassium phosphate buffer) and substrate were formulated at 4-fold final concentration with potassium phosphate buffer (0.1M, pH 7.4), the CYP3A4 substrate was midazolam at 320. Mu.M, and the CYP3A4 substrate was testosterone at 20. Mu.M.
Human liver microsome solution was prepared with potassium phosphate buffer at a concentration of 0.2mg/mL on ice. Test compound and control inhibitor (control compound) solutions were prepared at 2-fold final concentrations on ice using human liver microsome solutions. To the test wells, 30mL of test compound and control inhibitor solution were added, respectively, and 15mL of substrate was added, and the multiplex well operation was performed. The 96-well assay plate and NADPH solution were incubated at 37 ℃ for 5 minutes, and 15 μl of pre-warmed 8mM NADPH solution was added to the assay plate to initiate the reaction. The CYP3A4 assay plate was pre-incubated for 5 minutes at 37 ℃. The reaction was quenched by the addition of 120. Mu.L of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS 2/4) for 10 minutes (600 rpm/min), and then centrifuged for 15 minutes. And taking the supernatant after centrifugation, adding purified water in a ratio of 1:1, performing LC-MS/MS detection to obtain the ratio of the peak area of the compound to the peak area of the internal standard, comparing the ratio of the peak area of the compound to the ratio of the peak area of the control inhibitor, and calculating the inhibition rate.
Table 5 test compounds for inhibition assay results on CYP450 enzymes
Experimental results show that the compound has weak or no inhibition effect on CYP3A4 enzyme at 10 mu M, and the potential drug-drug interaction risk is low. Among them, the compound I-1 has obvious advantages in the aspect of inhibiting the CYP3A4 enzyme.
Test example 6: plasma protein binding Rate of Compounds
The plasma protein binding rate of the compounds was measured using equilibrium dialysis (HTDialysis, HTD 96 b). Compounds were formulated as 0.5nM stock in DMSO and diluted 25-fold with 0.05M sodium phosphate buffer as working solution. A blank 96-well plate was prepared, and 380. Mu.L of plasma was pre-loaded into each well, followed by adding 20. Mu.L/well of working fluid to the plasma and mixing well, with a final concentration of 1. Mu.M compound, and 0.2% DMSO per well.
100. Mu.L of 0.05M sodium phosphate buffer was added to the receiving side of each dialysis cell (HTD 96 b), and 100. Mu.L of the compound-containing plasma was added to the supply side. After the plastic cover was closed, the mixture was left to incubate with shaking at 37℃for 5 hours.
After the incubation, 25. Mu.L of each of the supply side and the receiving side of the dialysis cell was placed in a blank 96-well plate, and an equal volume of plasma was added to each of the supply side samples, and an equal volume of 0.05M sodium phosphate buffer was added to each of the receiving side samples, and mixed well. After 200. Mu.L of acetonitrile solution containing an internal standard was added to each well, the 96-well plate was vortexed at 600rpm for 10 minutes, 5594g was centrifuged for 15 minutes (Thermo Multifuge. Times.3R), 50. Mu.L of the supernatant was transferred to a new 96-well plate, and the sample was mixed with 50. Mu.L of ultrapure water for LC-MS/MS analysis.
The plasma protein binding rate and the free fraction were calculated using the following formulas: % binding ratio = 100× ([ supply side concentration ]] 5h - [ receiver side concentration ]] 5h ) Concentration at the supply side] 5h . % free fraction = 100-% binding rate
Table 6 free fraction of test compounds in plasma
Experimental results show that the compound has higher free drug ratio in human and mouse plasma and good patentability. Wherein, the compound I-1 has higher ratio of free drug in human and mouse plasma relative to the control drug, and has better patentability.
Test example 7: pharmacokinetic test in mice
Male ICR mice, 20-25g, were used, fasted overnight. 3 mice were taken and orally administered with 10mg/kg by intragastric administration. Blood was collected 15, 30 minutes and 1, 2, 4, 8, 24 hours before and after dosing. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min, centrifugation is carried out at 4 ℃ for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.
TABLE 7 results of test compounds in mouse pharmacokinetic experiments
The results of the mice pharmacokinetics experiments show that the compounds I-1 and I-2 of the invention have high oral exposure, good pharmacokinetic properties and good patentability.
Test example 8: in vivo efficacy experiment of LOVO colorectal cancer
After one week of adaptive feeding, LOVO cells in log phase were resuspended in serum-free F12K at 100. Mu.L/5X 10 only 6 LOVO cells are inoculated under the right flank of a mouse, the growth condition of the tumor is observed periodically, and the tumor grows to an average volume of 150-200mm 3 At the time, the tumor size and the weight of the mice are randomly divided into a model group and an administration group according to the tumor size and the weight of the mice, and the tumor size and the weight of the animals are measured and recorded before and during the administration, so that the animals are treatedThe model and drug administration groups were compared for tumor size differences after the end of treatment to determine efficacy.
Table 8 test compounds for their tumor inhibiting ability at tumor weight level
In the table "-" indicates no test.
Experimental results show that the compounds I-1 and I-2 have remarkable effect of inhibiting the growth of LOVO tumor tissues, and have better effect than the control compound II.
Test example 9: NCI-H1975 in vivo efficacy experiment for non-small cell lung cancer
With medium containing inactivated RPMI 1640+10% FBS at 37deg.C, 5% CO 2 NCI-H1975 tumor cells were cultured in the incubator of (E), and the cell confluence rate reached 80-90% for passage, and then the culture was split into flasks for passage. After one week of adaptive feeding, NCI-H1975 in log phase was carried out at 5X 10 6 Inoculating 100 μl of the strain into the right flank of the mouse subcutaneously, periodically observing tumor growth, and keeping the average volume of tumor growth 100-150mm 3 When the tumor size and the body weight of the mice were randomly divided into a model group and a dosing group (used in combination with oxatinib), the tumor size and the body weight of animals were measured before and during the dosing, the model group and the dosing group were compared for tumor size difference to determine the drug effect, and the significant difference between the combination dosing group and the oxatinib single drug group was compared in Graph Pad 8.0 by using Mann Whitney test test method, and the results are shown in fig. 1.
Table 9 test Compound and oxatinib synergistic antitumor effect
Compared with the single-drug group of the oxatinib, the average tumor volume of animals is obviously reduced at the end of treatment when the compound I-1 (7.5 mg/kg, BID or 25mg/kg, BID) is combined with the oxatinib (1 mg/kg, QD), the P value is respectively smaller than 0.01 and 0.001, and the difference is statistically significant. The results show that the tumor inhibition effect of the combination of the compound I-1 and the oxatinib is obviously superior to that of single administration.
Test example 10: in vivo efficacy experiment of H2122 non-small cell lung cancer
At 37℃with 5% CO 2 H2122 tumor cells are cultured in the incubator, and the cell confluence rate reaches 80-90% for passage, and then the culture is divided into bottles for passage. Mice were acclimatized for one week, NCI-H1975 in log phase was inoculated under the right flank of mice, tumors were grown to a certain volume, and then randomly divided into model groups and dosing groups (in combination with KRAS inhibitor MRTX849, AMG-510, JDQ 443) according to tumor size and mouse weight, tumor size and animal weight were measured and recorded before and during dosing, and the difference in tumor size between model groups and dosing groups was compared after the end of treatment to determine drug efficacy.
Experimental results show that the compounds I-1 and I-2 of the invention have obvious effect of inhibiting NCI-H1975 cancer growth when used singly or in combination with KRAS inhibitor, and the combination effect is better than that of the single use.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (14)

1. A pharmaceutical composition comprising an SOS1 inhibitor and an inhibitor a;
the inhibitor A is one or two selected from KRAS inhibitor and EGFR inhibitor;
the SOS1 inhibitor is a compound shown in a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
wherein R is 1 Is a 3-6 membered cycloalkane unsubstituted or substituted by RaA base; the Ra is C 1 -C 6 A haloalkyl group.
2. The pharmaceutical composition of claim 1, wherein the compound of formula I is selected from the group consisting of:
3. the pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a salt of the compound of formula I with an acid; the acid is one or more of 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, benzenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, gentisic acid and benzoic acid;
preferably, the pharmaceutically acceptable salt of the compound shown in the formula I is a salt formed by the compound shown in the formula I-1 and acid.
4. Pharmaceutical composition according to claim 1, wherein the mass ratio of SOS1 inhibitor to inhibitor a is 1:1 to 500:1, preferably 1:1 to 50:1, 7.5:1 to 25:1, such as 7.5:1 or 25:1.
5. Pharmaceutical composition according to claim 1, wherein the mass ratio of SOS1 inhibitor to 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.
6. The pharmaceutical composition of claim 1 or 5, wherein the EGFR inhibitor is oxatinib, gefitinib.
7. Pharmaceutical composition according to claim 1, wherein the mass ratio of SOS1 inhibitor to 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.
8. The pharmaceutical composition of claim 1 or 7, wherein the KRAS inhibitor is MRTX-849, AMG-510, JDQ443.
9. The pharmaceutical composition of claim 1, wherein the SOS1 inhibitor is orally administered at a dose of 1mg to 2000mg per dose (e.g., 10mg to 1000mg per dose; or 200mg to 600mg per dose; or 400mg to 500mg per dose);
preferably, the SOS1 inhibitor is administered once daily, twice daily or three times daily;
Preferably, the inhibitor a is administered once a day, twice a day, three times a day, or once every two days;
preferably, the SOS1 inhibitor is administered orally twice daily at a dose of 400mg to 500mg, the mass ratio of the SOS1 inhibitor to EGFR inhibitor is 7.5:1 or 25:1, and the EGFR inhibitor is administered once daily;
preferably, the EGFR inhibitor is oxatinib.
10. The pharmaceutical composition of any one of claims 1-9, further comprising a pharmaceutically acceptable carrier and/or excipient.
11. A kit, comprising
A first pharmaceutical composition or dosage form comprising an SOS1 inhibitor as defined in any one of claims 1 to 3 and optionally one or more pharmaceutically acceptable carriers, excipients;
a second pharmaceutical composition or dosage form comprising inhibitor a as defined in claim 1 and optionally one or more pharmaceutically acceptable carriers, excipients.
12. Use of a pharmaceutical composition according to claims 1-10 or a kit according to claim 11, comprising one or more selected from the group consisting of:
inhibit SOS1 interaction with RAS family proteins,
Preventing and/or treating SOS1 and RAS family protein related diseases,
Preparation of a medicament, pharmaceutical composition or formulation for inhibiting the interaction of SOS1 with a RAS family protein and/or preventing and/or treating SOS 1-RAS family protein-related diseases,
For example, for the preparation of medicaments for the prophylaxis and/or treatment of cancer and RAS diseases.
13. The use according to claim 12, wherein the SOS 1-related disease with RAS family proteins comprises: cancer, RAS disease;
preferably, the RAS disease comprises noonan syndrome, heart-face skin syndrome, hereditary gum fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, costerol syndrome and leggus syndrome;
preferably, the RAS family protein is KRAS, e.g., KRAS G12C, KRAS G12D, KRAS G12V;
preferably, the cancer is selected from the group consisting of melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gall bladder cancer, bile duct cancer, chorionic epithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumor, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma, and glioma; the liver cancer is preferably hepatocellular carcinoma; the head and neck tumor is preferably a head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the lung cancer is preferably non-small cell lung cancer.
14. Use according to claim 12, wherein the SOS 1-related disease of the RAS family protein is colorectal or lung cancer, preferably non-small cell lung cancer.
CN202310836632.0A 2022-07-07 2023-07-07 Pharmaceutical composition comprising SOS1 inhibitor Pending CN117357650A (en)

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