Ras inhibitor

Abstract

Provided are a compound having a structure of formula (I) which can be used as an RAS inhibitor, a pharmaceutical composition containing the compound, a method for preparing the compound and the use of the compound in the treatment of cancers.

Description

RAS inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with novel structures that can be used as RAS inhibitors, pharmaceutical compositions containing such compounds, methods for preparing such compounds, and uses of these compounds in treating cancer or tumors. Background Art

[0002] RAS, or rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, RAS is activated by growth factors and various other extracellular signals and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. These regulatory functions of RAS are carried out by switching between the GDP-bound and GTP-bound states, i.e., a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13: 394-401). RAS bound to GDP is in an inactive form and is in a dormant or closed state. At this time, the signaling system is shut down. When it is exposed to some pro-growth stimuli, it will be activated. For example, it can be induced by guanine nucleotide exchange factors (GEFs) to release GDP and bind to GTP. As a result, RAS is "turned on" and converted into the active form of RAS, which recruits and activates various downstream effectors to carry out signal transduction. It can transmit signals from the cell surface to the cytoplasm, thereby controlling many key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

[0003] RAS has GTPase activity, which can cleave the terminal phosphate of GTP and convert it to GDP, that is, convert itself to an inactive state. However, the endogenous GTPase activity of RAS is very low, and the conversion of GTP-RAS to GDP-RAS requires the exogenous protein GAP (GTPase activating protein). GAP interacts with RAS and promotes the conversion of GTP to GDP. Therefore, any RAS gene mutation that affects the interaction between RAS and GAP or affects the conversion of GTP to GDP will cause RAS to be in an activated state for a long time, thereby continuously transmitting growth and division signals to cells, stimulating continuous cell proliferation, and ultimately leading to tumor formation and development.

[0004] Among the genes associated with human tumors, there are three ubiquitously expressed RAS genes, H-RAS, K-RAS, and N-RAS, which encode highly homologous, approximately 21KDa HRAS, NRAS, and KRAS proteins, respectively. In 1982, researchers first discovered that RAS was activated by mutation in cancer cell lines (Chang, EH et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large-scale genome sequencing studies in different cancer types revealed that RAS proteins mutated in more than 30% of cancer types, with the highest mutation rates in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%). Transgenic and genetically engineered mouse models have also revealed that mutated RAS proteins are sufficient to drive and induce various types of cancer, and RAS oncogenes are also crucial for the maintenance and progression of tumors in various cancer types. For example, in RAS mutant cancer cell lines and cancer animal models, RNA intervention has been shown to slow tumor growth. These studies have made RAS oncoproteins widely accepted in the pharmaceutical field as very attractive anti-cancer drug targets.

[0005] Studies have shown that RAS mutations are most common in KRAS, and KRAS mutations can be observed in about 85% of RAS mutation-driven cancers; the vast majority of RAS mutations occur at codons G12, G13, and Q61, of which about 80% of KRAS mutations occur at glycine at codon 12, such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, and Q61H mutation. KRAS mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer, and can also be seen in 25% of non-small cell lung cancer patients (McCormick, F. et al., Clinical Cancer Research 21(8), 1797-1801, 2015). Therefore, KRAS mutant proteins have become the most important branch in the study of Ras drug targets, and the development of its inhibitors is also considered a very promising research and development direction in the development of anti-cancer / tumor drugs.

[0006] However, decades of drug development targeting RAS have shown that due to the smooth surface of the RAS protein, the lack of obvious grooves or pockets for binding small molecule inhibitors, and its very high affinity for guanine substrates (picomolar), the development of small molecule inhibitors has been mired in a difficult dilemma. As a result, RAS has long been considered an "undruggable" target in the industry. At the same time, there is still a great need for compounds with more structural types or patterns as KRAS inhibitors to provide more treatment options or to provide further improved inhibitory activity compared to existing KRAS inhibitors, thereby providing more potent therapeutic drugs for clinical use.

[0007] The present invention addresses these and other needs. It provides novel structural inhibitor compounds with RAS protein inhibitory activity. Due to their improved structural patterns, these compounds exhibit enhanced RAS protein inhibitory activity and tumor-related inhibitory activity compared to existing RAS protein inhibitors. They also possess favorable pharmacokinetic properties, resulting in excellent drugability. For example, they can be conveniently administered for easier absorption in the body, with reduced toxic side effects, improved drug tolerance and safety, and a reduced risk of drug interactions.

[0008] Summary of the Invention

[0009] The present invention provides a compound having structural formula (I) as defined herein below, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0010] The definitions of the various groups are as defined in the detailed description of the invention.

[0011] The present invention also provides a pharmaceutical composition comprising a compound of the present invention or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0012] The present invention also provides a compound of the present invention or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof for use as a medicament.

[0013] The present invention also provides compounds of the present invention or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, for use as inhibitors of RAS proteins, especially KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplified cells.

[0014] The present invention also provides a compound of the present invention or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases mediated by RAS proteins, especially KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplification.

[0015] The present invention also provides the use of a compound of the present invention or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases mediated by RAS proteins, especially KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.

[0016] The present invention also provides the use of a compound of the present invention or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing diseases mediated by RAS proteins, especially KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.

[0017] The present invention also provides a method for treating and / or preventing diseases mediated by RAS proteins, especially KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same.

[0018] The present invention also provides a method for treating tumors or cancers, comprising administering to a patient in need thereof a compound of the present invention or its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same.

[0019] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a RAS inhibitor in research, in particular as a research tool compound for inhibiting KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.

[0020] The present invention also provides pharmaceutical combinations comprising a compound of the present invention, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, and one or more other pharmaceutically active agents.

[0021] The present invention also provides methods for preparing the compounds of the present invention.

[0022] Detailed Description of the Invention

[0023] definition

[0024] Unless otherwise indicated, the various terms used in the specification and claims have the meanings shown below. In the absence of a specific definition of a particular term or phrase, it should be understood according to its ordinary meaning in the art. In the event of a conflict, the present specification (including definitions) will control.

[0025] In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0026] As used herein, the term "RAS mutation" or "RAS mutant protein" refers to a protein encoded and expressed by a RAS gene in which one or more codons are mutated, typically including but not limited to RAS proteins with mutations at glycine at codon 12, glycine at codon 13, or glutamine at codon 61 of RAS, such as mutant HRAS, NRAS, or KRAS. These residues are located in the active site of RAS, and their mutations can impair the intrinsic or GAP-catalyzed GTPase activity of RAS, resulting in the persistence of RAS bound to GTP.

[0027] For the purposes of the present invention, "RAS mutation" or "RAS mutant protein" and "RAS" when describing inhibitory activity are used interchangeably and generally refer to mutant HRAS, NRAS or KRAS, such as but not limited to KRAS-G12C (glycine to cysteine ​​mutation at codon G12), KRAS-G12D (glycine to aspartic acid mutation at codon G12), HRAS-G12D, NRAS-G12D, KRAS- G12V (mutation of glycine to valine at codon G12), KRAS-G13D (mutation of glycine to aspartic acid at codon G13); specifically refers to KRAS mutant protein, more specifically refers to KRAS-G12C mutant protein, KRAS-G12D mutant protein, KRAS-G12V mutant protein, G12A mutant protein, G12R mutant protein, G12S mutant protein, KRAS-G13D mutant protein and Q61H mutant protein.

[0028] As used herein, the term "treatment" refers to administering one or more compounds of the present invention as described herein, or pharmaceutically acceptable salts or solvates thereof, to a subject, such as a mammal, such as a human, suffering from the disease or symptoms of the disease, to cure, alleviate, lessen or affect the disease or symptoms of the disease. Preferably, the treatment is curative or ameliorative.

[0029] The term "prevention" as used herein is well known in the art and refers to administering one or more compounds described herein, or pharmaceutically acceptable salts or solvates thereof, to a subject, such as a mammal, such as a human, suspected of suffering from or susceptible to a Ras-mediated disease as defined herein, particularly cancer or tumor, so as to reduce the risk of developing the defined disease or prevent the onset of the disease. The term "prevention" includes the use of the compounds of the present invention before the diagnosis or confirmation of any clinical and / or pathological symptoms.

[0030] As used herein, the terms "inhibit" and "reduce" or any variants of these terms refer to the ability of a bioactive agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target, and refer to any measurable reduction or complete inhibition of the activity of the target of interest. For example, compared to normal, the activity (e.g., KRAS activity) can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.

[0031] As used herein, the term "RAS-mediated disease" refers to a disease in which RAS contributes to the onset and progression of the disease, or in which inhibition of RAS reduces the incidence, ameliorate, or eliminates disease symptoms. For purposes of the present invention, "RAS-mediated disease" preferably refers to a KRAS-mediated disease, and more preferably, a cancer or tumor mediated by a KRAS mutation.

[0032] As used herein, the term "cancer" or "tumor" refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. For purposes of the various aspects of the present invention, the cancer or tumor includes, but is not limited to, lung adenocarcinoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma, or pituitary adenoma.

[0033] For various aspects of the present invention, preferably, the cancer or tumor is associated with RAS, especially KRAS mutation and amplification, including but not limited to the above-mentioned tumor types and their preferred ranges. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, leukemia and ovarian cancer.

[0034] As used herein, the terms "subject," "individual," or "patient" refer to a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (e.g., cattle), sports animals, pets (e.g., guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human.

[0035] As used herein, the term "therapeutically effective amount" refers to an amount or dosage generally sufficient to produce a beneficial therapeutic effect in a patient with a "RAS-mediated disease" such as cancer or tumor in need of treatment. Those skilled in the art can determine the effective amount or dosage of the active ingredients of the present invention using conventional methods and in combination with conventional factors.

[0036] The term "drug combination" as used herein means that the compounds of the present invention can be combined with other active agents to achieve the purpose of the present invention. The other active agents may be one or more additional compounds of the present invention, or may be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activity, such as these active agents are known to regulate other biologically active pathways, or regulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention. Such active agents are suitably combined in an effective amount to achieve the intended purpose. The other active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or administered separately from the compounds of the present invention in different discrete units, and when administered separately, may be performed simultaneously or sequentially. The sequential administration may be close or distant in time.

[0037] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable, including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" can be formed by compounds having a basic group with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like, as well as salts derived from pharmaceutically acceptable organic non-toxic bases including, but not limited to, primary, secondary, and tertiary amines, substituted ammoniums including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0039] The term "isomer" as used herein refers to any stereoisomer, enantiomeric mixture, including racemates, diastereomeric mixtures, geometric isomers, atropisomers and / or tautomers that may exist in the structure of a compound. The determination and separation of the stereochemistry of the isomers are well known to those skilled in the art (SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994).

[0040] Certain compounds of the present invention contain at least one asymmetric center and may thus give rise to stereoisomers. The present invention therefore encompasses all possible isomeric forms of the compounds defined herein, and pharmaceutically acceptable salts or solvates thereof, unless otherwise indicated.

[0041] The compound structural formula or structural fragments used herein Indicates the absolute configuration of a stereocenter, i.e., a chiral center. Accordingly, in the names of the compounds or intermediates provided by the present invention, R or S represents the absolute configuration about the chiral center. In the definitions of some compounds of the present invention, axial chirality may also be used to represent the configuration of the compound. These configurations are determined using the Cahn-Ingold-Prelog rules well known to those skilled in the art.

[0042] It should be understood that when a person skilled in the art can determine, based on the structure of the compound shown herein, that the compound exists and only exists as a pair of chiral isomers, and that the compound can be easily separated based on conventional methods in the art, then the disclosure of the racemate of the compound herein (whether in terms of structural formula or chemical name) should be deemed to have disclosed each isomer of the compound separately.

[0043] The structural fragments used in this article The bonds indicated to be cross-linked are the bonds connecting the structural fragment to the rest of the molecule.

[0044] Unless otherwise defined, substituents shown as spanning chemical bonds in cyclic structure fragments as referred to herein, for example -(R3) m , means that the defined number of substituents can replace one or more feasible positions in the ring, wherein when m is 0, it means that the ring does not carry non-H substituents, but the ring atoms still carry hydrogen atoms with chemical valence.

[0045] The compounds of the present invention include unlabeled forms of the compounds of the present invention and isotopically labeled forms thereof. Isotopically labeled forms of compounds are compounds that differ only in that one or more atoms are replaced by corresponding isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 37 Cl and 125 I. Such isotopically labeled compounds are useful, for example, as probes in biological assays, analytical tools, or as therapeutic agents. In certain embodiments, the compounds of the present invention are provided in unlabeled form.

[0046] In some embodiments, the compounds of the present invention are provided in unlabeled form. In other embodiments, the compounds of the present invention are provided in isotopically labeled form, for example, compounds in which one or more H atoms are replaced by deuterium atoms (D), for example, fragments In the above, two R2 can each independently be D, or can be each defined group substituted by D; R4 can be each defined group substituted by D; for example, each group defined as R7 can each independently be optionally substituted by one or more isotopes, for example, substituted by D.

[0047] As used herein, the term "solvate" refers to a solvent addition form of a compound containing a stoichiometric or non-stoichiometric amount of a solvent, including any solvated form of a compound of the invention, including, for example, solvates with water, such as hydrates, or solvates with organic solvents, such as methanol, ethanol, or acetonitrile, i.e., as methanolate, ethanolate, or acetonitrile, respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.

[0048] As used herein, the term "metabolite" refers to a product produced by the metabolism of a compound in vivo. Such products may be derived, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Identification and analysis of metabolite products are performed in a manner well known to those skilled in the art.

[0049] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and have sufficient purity and sufficiently low toxicity. Examples include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, etc.

[0050] The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-substituted" group as used herein when defining a group is intended to include monohalogenated or polyhalogenated groups in which one or more identical or different halogens replace one or more hydrogens in the corresponding group.

[0051] The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Typically, an alkyl group has 1-10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and "C 1-3 In some embodiments, the term "C 0-6 The term "alkyl" refers to a saturated hydrocarbon group having 1 to 6 carbon atoms, which is a straight or branched chain, and is exemplified by methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), n-hexyl and 2-methylpentyl.

[0052] In the compound definitions herein, "alkyl" as a single substituent, such as -C 1-6 Alkyl or "alkyl" as part of a substituent, such as -OC 1-6 The alkyl group in the alkyl group is optionally substituted, wherein one or more (e.g. 1, 2, 3, 4 or 5) hydrogen atoms, when present, are optionally replaced by a substituent as defined, and when there are more than one substituent, each may be the same or different and may be located on the same or different C atoms, and the substituent is selected from one or more of the following: D, OH, NH2, halogen, CN, -OC 1-6 Alkyl, -O-CON(H) or -C optionally substituted by halogen 1-6 Alkyl)2, wherein -C 1-6The alkyl group is further optionally substituted with halogen or D. Examples of optionally substituted alkyl groups include, but are not limited to, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -CF(CF3)2, -CH2CN, -CH2CH2CN, -CH2D, -CHD2, -C D3, -CH2CD3, -CH2-OCH3, -CH2CH2-OCH3, -CH2-OCF3, -CH2-OCD3, -CH2-OCH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2 CH3, -CH2-OCONH2, -CH2-OCONH(CH3), -CH2-OCON(CH3)2, -CH2-OCON(CH2CH3)(CH3), -CH2-OCON(CH2CH3)(CF3).

[0053] The term "alkylene" as used herein means a linear or branched divalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably a linear divalent saturated hydrocarbon group. Generally, an alkylene group has 1 to 10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "-C 1-3 Alkylene-" or "-(CH2) n -, wherein n is an integer from 0 to 3" means that the alkylene group does not exist or is a straight or branched divalent saturated hydrocarbon group having 1 to 3 carbon atoms; the term "-C 1-6 "Alkylene-" refers to a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. Unless otherwise specified, the "alkylene" in the compound definitions herein is optionally substituted, for example, by one or more D, OH, NH2, halogen, CN or -C optionally substituted by halogen. 1-6 Alkyl or -OC 1-6 Alkyl substitution.

[0054] The term "alkoxy" as used herein means an alkyl group as defined herein that is attached to the rest of the molecule via an oxygen atom. Specifically, the alkoxy group has 1-10, e.g., 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 Alkoxy" or "-OC 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom, and more preferably "-C 1-3 Alkoxy" or "-OC 1-3"alkyl", examples of which are -O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O-n-hexyl, 2-methylpentyl-O-, etc. Unless otherwise defined, the "alkoxy" as a substituent in the definition of the compound herein is optionally substituted, that is, the alkyl part thereof is optionally substituted, for example, by one or more D, OH, NH2, halogen, CN or -OC which is optionally substituted by halogen or D. 1-6 Alkyl substitution, examples include but are not limited to -OCH3, -OCH2CH3, -OCD3, -OCH2CD3, -OCH2CH2CN, -OCH2CH2CH3, -OCH(CH3)(CH3), -OCH2Cl, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2 , -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -O-CH2-OCH3, -OCH2CH2-OCH3, -OCH2-OCF3, -OCH2-OCD3, -OCH2-OCH2CH3, -OCH2CH2-O-CH2CH3.

[0055] The term "alkenyl" as used herein refers to a linear or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one double bond. Specifically, the alkenyl group has 2-8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 "Alkenyl" refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, and "C 2-4 "Alkenyl", such as vinyl, propenyl, allyl, butenyl, pentenyl, etc., the carbon atom in the alkenyl group connected to the rest of the molecule can be saturated or an olefinic carbon atom.

[0056] The term "alkynyl" as used herein refers to a linear or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one triple bond. Specifically, the alkynyl group has 2-8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, and "C 2-4 Alkynyl", such as ethynyl, propynyl, propargyl, butynyl, etc., the carbon atom in the alkynyl group connected to the rest of the molecule can be saturated or an acetylenic bond carbon atom.

[0057] Unless otherwise defined, the "alkenyl" and "alkynyl" groups as substituents in the compound definitions herein are optionally substituted, and the substituents may be selected from one or more of the following: D, halogen, CN, OH, -OC 1-6 Alkyl, -O-CON(H) or -C optionally substituted by halogen 1-6 alkyl)2, wherein the alkyl is further optionally substituted with halogen or D. Examples include, but are not limited to, -CH=CH2, -CH=CHF, -CH=CF2, -CF=CF2, -CH=CHCN, -CH2CH=CH2, -CH2CH=CHCN, -CH2CH=CF2, -CH2CF=CF2, -C(CH3)=CH2, -C(CF3)=CH2, -C(CH3)=CF2, -CH=CHCF3, -CH=CHCH2O-CH3, -C(CH3)=CHCF3, -CH2CH=CHCF3, -C≡C(CF3), -CH2C≡C(CF3),

[0058] As used herein, the term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic saturated monovalent hydrocarbon ring structure having a specified number of ring carbon atoms. A cycloalkyl group may have 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), for example, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 4, 5 to 6 carbon atoms. Examples of suitable cycloalkyls include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or polycyclic (e.g., bicyclic) structures, including spiro, fused, or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octanyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[3.2.1]octanyl. The term "C 3- 6 cycloalkyl" or "C 3-4 "Cycloalkyl" refers to a monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0059] Unless otherwise specified, the "cycloalkyl" as a substituent in the compound definitions herein, such as -C 3-6 Cycloalkyl or spiro-C 3-4 Cycloalkyl or "cycloalkyl" as part of a substituent such as -(CH2) n -C 3-6 The cycloalkyl group in the cycloalkyl group is optionally substituted, and the substituent group may be selected from one or more of the following: D, OH, NH2, halogen, CN, -C optionally substituted by halogen or D 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl, -O-CON(H) or -C optionally substituted by halogen1-6 alkyl)2, wherein the alkyl is further optionally substituted by halogen or D. Optionally substituted -C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Examples of cycloalkyl groups include, but are not limited to: where * represents the atom in the spirocycloalkyl group that is attached to the rest of the molecule.

[0060] The term "heterocycloalkyl" as used herein means a monocyclic, fused polycyclic, spirocyclic or bridged polycyclic non-aromatic saturated or unsaturated ring structure comprising one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from O, N, P, Se and S and the specified number of ring atoms, or an N-oxide, or an S-oxide or S-dioxide thereof. The heterocycloalkyl group may have 3 to 12 ring members (which may be referred to as a 3-12 membered heterocyclyl), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 7 ring members, 5 to 6 ring members, 6 to 10 ring members, 6 to 12 ring members, for example, a 4- to 7-membered monocyclic heterocycloalkyl group such as a 4- to 7-membered monocyclic saturated heterocycloalkyl group, a 4- to 7-membered monocyclic unsaturated heterocycloalkyl group; or a 6- to 12-membered polycyclic heterocycloalkyl group, such as a 6- to 10-membered spiroheterocycloalkyl group, a 6- to 10-membered fused heterocycloalkyl group, and a 6- to 10-membered bridged heterocycloalkyl group. The heterocycloalkyl group usually contains at least 1 and at most 4 (e.g., 1, 2, 3 or 4) heteroatoms, for example, a 4-7 membered monocyclic heterocycloalkyl group such as a 4-7 membered monocyclic saturated heterocycloalkyl group or a 4-7 membered monocyclic unsaturated heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, P, Se and S (preferably O, N, S), for example, a 4-7 membered monocyclic saturated heterocycloalkyl group or a bridged heterocycloalkyl group containing 1 or 2 N atoms, or a 6-12 membered polycyclic heterocycloalkyl group (preferably a 6-10 membered polycyclic heterocycloalkyl group) containing 1 to 4 (preferably 1 to 3, more preferably 1 to 2) heteroatoms independently selected from N, O, P, Se and S (preferably O, N, S), for example, a 6-10 membered spiroheterocycloalkyl group, a fused heterocycloalkyl group or a bridged heterocycloalkyl group containing 1-3 N atoms and 0-1 O atoms. For example, these exemplified heterocycloalkyl groups may be saturated or unsaturated.Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, dihydropyrrolyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, partially or fully hydrogenated forms of triazolyl, partially or fully hydrogenated forms of tetrazole, partially or fully hydrogenated forms of furanyl such as dihydrofuranyl, tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), partially or fully hydrogenated forms of thienyl such as dihydrothienyl, tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), thiazolyl, or isothiazolyl. partially or fully hydrogenated forms such as dihydrothiazolyl, thiazolidinyl, thiadiazolyl or partially or fully hydrogenated forms thereof, partially or fully hydrogenated forms of oxazolyl or isoxazolyl such as dihydrooxazolyl, oxazolidinyl, oxadiazolyl or dioxazolyl, partially or fully hydrogenated forms of pyridyl such as dihydropyridyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), partially or fully hydrogenated forms of pyranyl such as dihydropyranyl, tetrahydropyranyl (e.g., 4-tetrahydropyranyl), dihydrothiopyranyl, tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxinyl, dioxenyl, dioxanyl, piperazinyl, aza. Partially or fully hydrogenated forms of the alkyl groups such as azepanyl, diazepine Partially or fully hydrogenated forms of diazepanyl such as 1,4-diazepanyl, oxazepine Partially or fully hydrogenated forms of oxazacycloheptane, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl, Partially or fully hydrogenated forms of indolyl or isoindole, etc. The atom in a heterocycloalkyl group that is attached to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible. As long as the ring attached to the rest of the molecule is a non-aromatic saturated or unsaturated ring, even if the ring fused to it is aromatic, the fused ring is still within the scope of "heterocycloalkyl" herein. In a preferred embodiment of the present invention, the heterocycloalkyl group is saturated.

[0061] The term "saturated" as used herein in defining cyclic groups means a monocyclic or polycyclic saturated ring containing at least one (preferably 1 to 4, more preferably 1 to 3) heteroatom selected from N, O, S, P and Se, examples of which include aziridinyl, azetidinyl, oxetanyl, imidazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydrothienyl, thiazolidinyl, oxazolidinyl and the like.

[0062] As used herein, the term "unsaturated" when defining cyclic groups refers to monocyclic or polycyclic non-aromatic partially unsaturated ring groups. Examples of unsaturated rings include, but are not limited to, partially hydrogenated forms of the following aromatic rings: imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, 1,2,3,4-tetrahydroisoquinolyl, and the like.

[0063] As used herein, the term "hydroxy" refers to an -OH group.

[0064] As used herein, the term "cyano" refers to a -CN group.

[0065] The term "amino" as used herein refers to -NH2.

[0066] The compounds defined herein also include substituted amino groups, such as -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, wherein -C 1-6 Alkyl groups may be further optionally substituted as shown below the definitions of the respective groups. In some embodiments, the substituted amino group is in the form of -CON(R b )2 in -N(R b )2, where R b is -C optionally substituted by halogen 1-6 Alkyl. Examples of substituted amino groups include, but are not limited to, -NH2, -NH-CH3, -NH-CH2CH3, -NH-CF3, -NH-CH2CF3, -NH-CH2CN, -NH-CH2CH2CN, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH3)(CF3), -N(CH3)(CH2CF3), -N(CH3)(CH2CH2CN), -NHCH2-OCH3, N(CH3)(CH2CH2-OCH3.

[0067] As used herein, the term "optionally substituted" means, unless otherwise indicated, that a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5 or more, or any range derivatizable therein) of the substituents listed for that group, wherein when multiple substituents are present, each substituent may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents that are the same or different. In another embodiment, the optionally substituted group has 3 substituents that are the same or different. In another embodiment, the optionally substituted group has 4 substituents that are the same or different. In another embodiment, the optionally substituted group has 5 substituents that are the same or different.

[0068] In the compound definitions herein, the H groups carried by saturated carbon atoms may not be shown. A person skilled in the art can easily determine the number of H or non-H substituents carried by the target atom, such as the structural fragment In the case where m is 1 and R3 is not H, there is an unshown H on the ring carbon atom to which it is attached or when R3 is =C(R c )2 when H does not exist; when m is 2 and R3 is not H, the ring carbon atom to which it is connected does not carry an H atom, and the two R3 it carries can be separately connected to the ring carbon atom shown by a single bond, or together with the carbon atom shown to form a spiro ring.

[0069] In the compound definition herein, the CH2 or NH defined for the ring atoms are not limited to the unsubstituted state, and their actual existence is determined by the overall definition of the ring group. In the fragment, X may be CH2, but according to the overall definition of the fragment, it also includes, for example, the case where R8 and R8' are both connected to X that is CH2 and together form a spiro ring, for example, the case where one of R8 and R8' is connected to X that is CH2 and the other is connected to an adjacent ring atom and the two together form a fused ring, for example, the case where one of R8 and R8' is connected to X that is CH2 and the other is connected to a non-adjacent ring atom and the two together form an intra-ring bridge, and the case where it is substituted by a substituent defined for the fragment. For another example, the structural fragment In the above, each G variable is defined as CH2 or NH. This includes the case where both are unsubstituted, and also includes the case where either CH2 or NH is substituted with a defined substituent, according to the overall definition of the fragment. For example,

[0070] Many of the groups defined herein are optionally substituted, and the list of substituents given in this definitions section is merely exemplary and is not intended to limit the substituents defined elsewhere in the specification and claims.

[0071] Unless otherwise specified, C in the definition of compounds of the present invention is n-n+m or C n -C m Including various cases from n to n+m carbons, such as C 1-6 Including C1, C2, C3, C4, C5 and C6, and also including any range from n to n+m, such as C 0-6 Including C1, C2, C3, C4, C5, C6, C 0-1 、C 0-2 、C 0-3 、C 0-4 、C 0-5 、C 1-2 、C 1-3 、C 1-4 、C 2-3 etc., C. 1-6 Including C 1-2 、C 1-3 、C 1-4 、C 2-6 、C 3-6 Etc. Similarly, the n-membered to n+m-membered in the definition of the compounds of the present invention means that the number of ring atoms is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 12-membered ring, etc., and also includes any range of n to n+m-membered, for example, 3-12-membered ring includes 3-6-membered ring, 3-8-membered ring, 3-9-membered ring, 4-10-membered ring, 4-7-membered ring, 4-5-membered ring, 5-6-membered ring, 5-7-membered ring, 5-8-membered ring, 5-9-membered ring, 6-7-membered ring, 6-8-membered ring, 6-10-membered ring and 6 to 12-membered ring, etc.

[0072] It is understood by those skilled in the art of organic synthesis that the various groups carried in the structure of the compounds of the present invention, whether unsubstituted or substituted by various defined substituents, are all based on the premise that the compound molecules are chemically feasible and stable, wherein the type and number of substituents are determined by the number and chemical valence of atoms in the group.

[0073] As used in this specification and the claims that follow, the word "comprise" and variations of the word such as "include" and "comprising" mean "including but not limited to," and are not intended to exclude, for example, other additives, ingredients, integers, or steps. When an element is described as comprising a plurality of ingredients, steps, or conditions, it should be understood that the element may also be described as comprising any combination of the plurality of ingredients, steps, or conditions, or "consisting of" or "consisting essentially of" the plurality or combination of ingredients, steps, or conditions.

[0074] It should be understood that the dosages referred to herein when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits containing the same, and related uses and methods are based on the weight of the free form and do not include any salts, hydrates or solvates thereof, unless the description indicates that the dosage is based on the weight of the salt, hydrate or solvate.

[0075] Problems to be solved by the present invention

[0076] As described above, compounds that can inhibit RAS proteins, especially KRAS mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS wild-type amplified cells can be used to treat or prevent diseases mediated by the protein (such as cancer or tumors). Therefore, in this field, a variety of structural types of RAS inhibitors have been developed. However, the existing KRAS inhibitors still have problems that need to be solved, including, for example, many inhibitors have unsatisfactory anti-tumor activity, or have toxic side effects that lead to poor drug resistance, or pharmacokinetic properties that are not sufficient to allow convenient administration, i.e., poor "drugability", or due to the inhibitory effect on the cytochrome P450 enzyme system, resulting in undesirable drug interactions, etc. Furthermore, even for inhibitors with good anti-tumor activity, people still hope to further enhance their selective inhibitory activity against target proteins in vivo, further improve their drug resistance (fewer toxic side effects or better safety) and further improve their pharmacokinetic properties through structural optimization, so as to provide more and better treatment options in clinical practice.

[0077] Solutions to the Problem

[0078] Through extensive and in-depth research, the inventors have developed a group of compounds with significant inhibitory activity against RAS proteins, particularly KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, and Q61H mutant proteins), and KRAS-amplified cells. Through structural modification and activity verification, the inventors discovered that by modifying the benzopyrimidine ring and quinazoline ring of the KRAS inhibitor structure with specific types of substituents, the specific combination of substitution sites and substituent types achieved further enhanced inhibitory activity against KRAS mutant proteins compared to prior art inhibitors. Furthermore, the modified compounds exhibited a good safety profile, reduced risk of drug interactions, and good, or even improved, pharmacokinetic properties, enabling convenient administration.

[0079] The present invention mainly provides effective RAS inhibitors, specifically KRAS inhibitors (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS expansion inhibitors); pharmaceutical compositions containing such compounds as active ingredients; and pharmaceutical compositions for treating or preventing RAS, specifically KRAS (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS expansion inhibitors). mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification) mediated or benefited from the inhibition of RAS, specifically KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification); and using the compound for treating or preventing tumors or cancers caused by RAS, specifically KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification). D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification) mediated or benefited from the inhibition of RAS, specifically KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification); and the use of the compound in the preparation of a method for treating or preventing a disease mediated or benefited from the inhibition of RAS, specifically KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification); The invention also relates to a method for treating a disease mediated by or benefiting from the inhibition of RAS, particularly KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification), such as a medicament for treating a tumor or cancer.

[0080] The present invention therefore provides the following technical solutions.

[0081] Compounds of the present invention

[0082] The terms "inventive compound" and "compound of the present invention" and the like as used throughout this application, unless otherwise limited, encompass the compounds defined in each embodiment herein and preferred embodiments thereof, or various specific embodiments thereof, including isomers, including atropisomers, enantiomeric mixtures, in particular racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopic variants and salts (e.g., pharmaceutically acceptable salts) thereof.

[0083] Therefore, the above-mentioned various isomers and derivatives of the compounds of the present invention are thus encompassed within the scope of the present invention, and their respective meanings, preparations and specific examples are as defined in the "Definitions" section above, or are well known in the art. However, preferably, it is the compound of the present invention and / or its pharmaceutically acceptable salt or solvate.

[0084] The present invention also encompasses N-oxides of the compounds of this invention, as long as these compounds contain a basic nitrogen atom such as the nitrogen atom present in a nitrogen-containing heterocycle and are chemically and biologically feasible. Some compounds of the present invention can exist in polymorphic or amorphous form, so they also fall within the scope of the present invention.

[0085] In a first aspect, the present invention provides the following compound embodiments.

[0086] Embodiment 1: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0087] in:

[0088] M is selected from N or C-R9;

[0089] W is selected from N or CR 10 ;

[0090] R9 is selected from H, halogen, CN, NO2 and -C 1-6 alkyl;

[0091] R 10 is selected from H, halogen, CN, OH, -C 1-6 Alkyl and optionally halogen-substituted -OC 1-6 alkyl;

[0092] Z is selected from H, OH and NH2;

[0093] X is selected from CH2 and O, provided that when k is 0, X is CH2;

[0094] Y is selected from O, S, Se and NR a ;

[0095] R1 is selected from H and optionally substituted -C 1-6 Alkyl, wherein the substituents are selected from halogen, D and -OC optionally substituted by halogen or D 1-6 alkyl;

[0096] R2 are each independently selected from H, D and optionally substituted -C 1-6 Alkyl, wherein the substituents are selected from halogen, D and -OC optionally substituted by halogen or D 1-6 alkyl;

[0097] R3 is selected from H, D, halogen, -CN, -OH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -(CH2) n -C 3-6 Cycloalkyl and =C(R c )2, where each occurrence of C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl is optionally substituted with substituents selected from halogen, CN, D and -OC optionally substituted with halogen. 1-6 Alkyl, where C 3-6 The cycloalkyl group is optionally substituted, and the substituents are selected from halogen, CN, D, -C 1-6 Alkyl and optionally halogen-substituted -OC 1-6 Alkyl, or

[0098] Two R3 attached to the same ring carbon atom together with the carbon atom to which they are attached form a spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with halogen or -C 1-6 Alkyl substitution;

[0099] R4 is selected from H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 Cycloalkyl, wherein -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl is optionally substituted with a substituent selected from D, halogen, CN, OH, -OC optionally substituted with halogen or D 1-6 Alkyl and -OCON(R b )2, where C 3-6 The cycloalkyl group is optionally substituted, and the substituents are selected from D, halogen, CN, OH, -C 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl and -OCON(R b )2;

[0100] R5 is selected from H, halogen, -CN, -NO2;

[0101] R6 is selected from halogen, CN, -C 1-6 Alkyl and -C 2-6 Alkynyl, where -C 1-6 Alkyl and -C 2-6 each alkynyl group is independently optionally substituted with halogen;

[0102] R7 is selected from H, halogen, CN, -C optionally substituted by halogen or D 1-6 alkyl, -OC optionally substituted by halogen or D 1- 6 alkyl and optionally substituted by halogen or D -C 2-6 Alkynyl;

[0103] R8 and R8' attached to non-adjacent ring carbon atoms together form an intracyclic bridge -(CH2) 1-2 - or -CH2=CH2-,

[0104] or R8 and R8' attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a 4-6 membered spirocycloalkyl or a 4-6 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S,

[0105] Or R8 and R8' attached to adjacent ring carbon atoms together with the ring carbon atoms to which they are attached form a fused C 3-6 cycloalkyl or a 4-6 membered fused heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S,

[0106] wherein the bridged ring, spiro ring or fused ring are each independently optionally substituted, and the substituent is selected from OH, oxo, -OC optionally substituted by halogen 1-6 Alkyl and optionally substituted by halogen -C 1-6 alkyl;

[0107] R a and R b are each independently selected from H and -C 1-6 alkyl;

[0108] R c are each independently selected from H, halogen and -C 1-6 alkyl;

[0109] k and n are each independently selected from integers from 0 to 3; and

[0110] m is selected from integers of 0 to 6.

[0111] Embodiment 1.1: A compound of Formula (I) according to Embodiment 1, wherein M is N, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0112] Embodiment 1.2: A compound of Formula (I) according to Embodiment 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-R9.

[0113] Embodiment 1.2.1: A compound of Formula (I) according to Embodiment 1.2, wherein R9 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0114] Embodiment 1.2.2: A compound of Formula (I) according to Embodiment 1.2, wherein R9 is halogen, eg, F, Cl, Br, I, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0115] Embodiment 1.2.3: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is CN; or R9 is NO2.

[0116] Embodiment 1.2.4: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, preferably substituted by halogen, more preferably substituted by F.

[0117] Embodiment 1.3: A compound of formula (I) of Embodiment 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is selected from any one or any combination of Embodiments 1.1 to 1.2.4; for example, M is selected from N, C-halogen (e.g., CF, C-Cl), C-CN, C-NO2, C-halogen substituted C 1-6 Alkyl (eg C-CF3); preferably M is N.

[0118] Embodiment 2.1: A compound of formula (I) according to any one of Embodiments 1 to 1.3, wherein W is N, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0119] Embodiment 2.2: A compound of formula (I) according to any one of Embodiments 1 to 1.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is CR 10 .

[0120] Embodiment 2.2.1: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 For H.

[0121] Embodiment 2.2.2: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 is halogen, such as F, Cl, Br, I, preferably F; or R 10 For CN.

[0122] Embodiment 2.2.3: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 For OH.

[0123] Embodiment 2.2.4: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen.

[0124] Embodiment 2.2.5: A compound of Formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 For-OC 1-6 Alkyl, preferably -OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by halogen.

[0125] Embodiment 2.3: A compound of formula (I) according to any one of Embodiments 1 to 1.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is selected from any one of Embodiments 2.1 to 2.2.5 or any combination thereof; for example, W is selected from N, C-halogen, C-CN, C-substituted-C 1-6 Alkyl, C-substituted-OC 1-6 Alkyl, such as N, CF, C-Cl, C-CN, C-CF3; preferably W is C-halogen, more preferably CF.

[0126] Embodiment 3.1: The compound of formula (I) of Embodiment 1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the fused parent ring containing M and W includes but is not limited to: wherein R9 is as defined in any one of Embodiments 1.2.1 to 1.3, R 10 As defined in any one of Embodiments 2.2.1 to 2.3, for example but not limited to:

[0127] Embodiment 4.1: A compound of formula (I) according to any one of Embodiments 1 to 3.1, wherein R7 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0128] Embodiment 4.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 3.1, wherein R7 is halogen; or R7 is CN.

[0129] Embodiment 4.3: A compound of formula (I) according to any one of Embodiments 1 to 3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -C optionally substituted with halogen or D 1-6 Alkyl, preferably -C optionally substituted by halogen or D 1-3 Alkyl, such as -CH3, -CD3.

[0130] Embodiment 4.4: A compound of formula (I) according to any one of Embodiments 1 to 3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -OC optionally substituted with halogen or D 1-6 Alkyl, preferably -OC optionally substituted by halogen or D 1-3 Alkyl, such as -O-CH3, -O-CD3; in a specific embodiment, M is N.

[0131] Embodiment 4.5: A compound of formula (I) according to any one of Embodiments 1 to 3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -C optionally substituted with halogen or D 2-6 Alkynyl, preferably -C optionally substituted by halogen or D 2-4 Alkynyl groups, such as, but not limited to, ethynyl and prop-1-ynyl.

[0132] Embodiment 4.6: A compound of formula (I) according to any one of Embodiments 1 to 3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is selected from any one of Embodiments 4.1 to 4.5 or any combination thereof, for example, R7 is selected from H, -OC optionally substituted with halogen or D 1-6 Alkyl and optionally substituted by halogen or D-C 2-6 Alkynyl, for example R7 is selected from H and -OC optionally substituted by halogen or D 1-6 Alkyl, more particularly selected from H and -OC optionally substituted by D 1-6 alkyl.

[0133] Embodiment 5.1: A compound of Formula (I) according to any one of Embodiments 1 to 4.6, wherein R5 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0134] Embodiment 5.2: A compound of formula (I) according to any one of Embodiments 1 to 4.6, wherein R5 is halogen, preferably F, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0135] Embodiment 5.3: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 4.6, wherein R5 is -CN; or R5 is -NO2.

[0136] Embodiment 5.4: A compound of formula (I) according to any one of Embodiments 1 to 4.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is selected from any one of Embodiments 5.1 to 5.3 or any combination thereof; for example, R5 is selected from H and halogen (preferably F), for example, R5 is selected from halogen (preferably F).

[0137] Embodiment 6.1: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 5.4, wherein R6 is halogen, eg, F or Cl.

[0138] Embodiment 6.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 5.4, wherein R6 is CN.

[0139] Embodiment 6.3: A compound of formula (I) according to any one of Embodiments 1 to 5.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C optionally substituted with halogen1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as -C 1-3 Alkyl groups, such as ethyl groups.

[0140] Embodiment 6.4: A compound of formula (I) according to any one of Embodiments 1 to 5.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C 2-6 Alkynyl, preferably -C optionally substituted by halogen 2-4 Alkynyl, for example ethynyl.

[0141] Embodiment 6.5: A compound of formula (I) according to any one of Embodiments 1 to 5.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is selected from any one of Embodiments 6.1 to 6.4 or any combination thereof, for example, R6 is selected from halogen, -C 1-6 Alkyl and optionally substituted by halogen -C 2-6 Alkynyl, for example R6 is selected from halogen, -C 1-3 Alkyl and -C 2-4 Alkynyl groups, such as F, Cl, ethyl and ethynyl.

[0142] Embodiment 7.1: A compound of formula (I) according to any one of Embodiments 1 to 6.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is H; in a specific embodiment, Z is H, R5 is H and R6 is a halogen, such as F or Cl.

[0143] Embodiment 7.2: A compound of formula (I) according to any one of Embodiments 1 to 6.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is OH, or Z is NH 2 In one embodiment, Z is OH, R5 is selected from halogen, R6 is selected from halogen, -C 1-6 Alkyl and optionally substituted by halogen -C 2-6 Alkynyl, for example R6 is selected from halogen, -C 1-3 Alkyl and -C 2-4 Alkynyl.

[0144] Embodiment 8: A compound of formula (I) according to any one of Embodiments 1 to 7.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment wherein R5 is selected from H and halogen, preferably halogen (more preferably F); R6 is selected from halogen, -C 1-6Alkyl and optionally substituted by halogen -C 2- 6 alkynyl, preferably R6 is selected from halogen, -C 1-3 Alkyl and -C 2-4 Alkynyl; Z is selected from H and OH, preferably OH; specific examples include but are not limited to:

[0145] Embodiment 9.1: A compound of formula (I) according to any one of Embodiments 1 to 8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment middle,

[0146] When k is 0, the fragment has an intracyclic bridge -(CH2) 1-2 - or -CH2=CH2- azetidine, azetidine spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), or azetidine fused (C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S);

[0147] When k is 1, the fragment has an intracyclic bridge -(CH2) 1-2 - or -CH2=CH2-, aziridine or azoxolane, (aziridine or azoxolane)spiro(4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), or (aziridine or azoxolane)fused(C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S);

[0148] When k is 2, the fragment has an intracyclic bridge -(CH2) 1-2 - or -CH2=CH2-, azacyclohexane or azacyclohexane, (azacyclohexane or azacyclohexane)spiro(4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), or (azacyclohexane or azacyclohexane)fused(C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S);

[0149] When k is 3, the fragment has an intra-ring bridge -(CH2) 1-2 - or -CH2=CH2- azepane or azacycloheptane, (azepane or azacycloheptane) spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), or (azepane or azacycloheptane) fused (C 3-6cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S);

[0150] The common ring carbon atom of the spiro ring can be in the meta or para position relative to the nitrogen heteroatom, preferably in the meta position;

[0151] wherein the bridged ring, spiro ring or fused ring are each independently optionally substituted, and the substituent is selected from OH, oxo, -OC optionally substituted by halogen 1-6 Alkyl and optionally substituted by halogen -C 1-6 Alkyl, for example, selected from OH and oxo;

[0152] Preferably, the structural fragment is the above-mentioned spiro ring or fused ring structure.

[0153] Embodiment 9.2: A compound of formula (I) according to any one of Embodiments 1 to 9.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for That is, k is 0; That is, k is 1; That is, k is 2 or 3.

[0154] Embodiment 9.2.1: A compound of formula (I) according to Embodiment 9.1 or 9.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment is azetidine spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), (azacyclopentane or azaoxetane) spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), (azacyclohexane or azaoxetane) spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S), cycloalkyl) or (azepane or azacycloheptan) spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S); preferably (azacyclohexane) spiro (4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S); the common ring carbon atom of the spiro ring can be in the para position or meta position with respect to the nitrogen heteroatom attached to the rest of the molecule as appropriate; for example but not limited to

[0155] In one embodiment, R8 and R8' form a spiro 4-6 membered cycloalkyl or a spiro 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S with the ring carbon atom at the position meta to the N heteroatom of the azacyclohexane, that is, wherein G1 is selected from CH2, NH, O and S, at least one of G2, G3 and G4 is selected from CH2, NH, O and S, and the others are each independently selected from not present, CH2, NH, O and S;

[0156] In a more specific embodiment, G3 and G4 do not exist, that is, Wherein G1 and G2 are both CH2, or one of them is CH2 and the other is selected from NH, O and S (preferably NH and O); wherein the common ring carbon atoms marked with an asterisk may have chirality as appropriate, and accordingly the fragment may be in racemic form, or may exist isomeric forms of

[0157] In a more specific embodiment, G4 does not exist in wherein G1, G2 and G3 are each independently selected from CH2, NH, O and S;

[0158] The spiro ring in each of the above embodiments is optionally substituted at any chemically feasible position, for example, on the spiro ring formed by R8 and R8' together with the ring carbon atoms to which they are attached, and the substituent is selected from OH, oxo, -OC optionally substituted by halogen 1- 6 alkyl and optionally substituted by halogen -C 1-6 Alkyl, for example, selected from OH and oxo;

[0159] Specific examples include but are not limited to

[0160] Embodiment 9.2.2: A compound of formula (I) according to Embodiment 9.1 or 9.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment For azetidine fused (C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S), (azacyclopentane or azacyclopentane) fused (C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S), (azacyclohexane or azacyclohexane) fused (C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S) or (azepane or azacycloheptane) fused (C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S); preferably (azepane or azacycloheptane) fused (C 3-6cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S); more preferably (azacycloheptane) fused (C 3-6 Cycloalkyl); for example but not limited to

[0161] In a specific embodiment, the ring containing N and X is azepane or azacycloheptane, and R8 and R8' attached to adjacent ring carbon atoms together with the atoms to which they are attached form C 3-6 Cycloalkyl;

[0162] A specific implementation method is More specifically As appropriate Existence, preferred

[0163] The fused rings in each of the above embodiments are optionally substituted at any chemically feasible position, with the substituents selected from OH, oxo, -OC optionally substituted by halogen, 1-6 Alkyl and optionally substituted by halogen -C 1-6 Alkyl; preferably unsubstituted.

[0164] Embodiment 9.2.3: A compound of formula (I) according to Embodiment 9.1 or 9.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment wherein k is an integer from 1 to 3, preferably from 2 to 3, X is selected from CH2 and O, preferably selected from CH2, R8 and R8' are attached to non-adjacent carbon atoms and together form an intracyclic bridge -(CH2) 1-2 - or -CH2=CH2-, preferably -(CH2) 1-2 -; Specific examples include but are not limited to The bridged ring is optionally substituted with OH, oxo, -OC optionally substituted with halogen 1-6 Alkyl and optionally substituted by halogen -C 1-6 Alkyl, such as -OC substituted by OH or optionally halogen 1-6 The alkyl group is substituted, for example, by OH.

[0165] Embodiment 9.3: A compound of formula (I) according to any one of Embodiments 1 to 9.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment As defined in any one of Embodiments 9.2 to 9.2.2 or any combination thereof, for example, selected from optionally substituted (azacyclohexane)spiro(4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S) and (azacycloheptane)fused(C 3-6 Cycloalkyl), specifically as defined above

[0166] or as defined in Embodiment 9.2.3, for example with an intra-ring bridge -(CH2) 1-2 - or -CH2=CH2-, preferably -(CH2) 1-2 - optionally substituted 5- to 7-membered heterocycloalkyl.

[0167] Embodiment 10.1: A compound of Formula (I) according to any one of Embodiments 1 to 9.3, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0168] Embodiment 10.2: A compound of Formula (I) according to any one of Embodiments 1 to 9.3, wherein Y is S, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0169] Embodiment 10.3: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 9.3, wherein Y is Se.

[0170] Embodiment 10.4: A compound of formula (I) according to any one of Embodiments 1 to 9.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Y is NR a , R a is H; or Y is NR a , R a is -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 alkyl.

[0171] Embodiment 11.1: A compound of formula (I) according to any one of Embodiments 1 to 10.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Preferred More preferred The ring carbon atom to which R3 is attached may be chiral as appropriate, so that R3 is in the R or S stereoconfiguration.

[0172] Embodiment 11.2: A compound of formula (I) according to Embodiment 11.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is selected from H or D, for example, both R2 are H; or both R2 are D; or one of R2 is H and the other is D.

[0173] Embodiment 11.2.1: A compound of formula (I) according to Embodiment 11.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one R2 is H or D and the other R2 is -C 1-6 Alkyl (preferably -C 1-3 alkyl), optionally substituted by halogen, D, -OC optionally substituted by halogen or D 1-6 Alkyl substituted, or two R2 are each independently -C 1-6 Alkyl (preferably -C 1-3 alkyl), optionally substituted by halogen, D, -OC optionally substituted by halogen or D 1-6 Alkyl substitution.

[0174] Embodiment 11.3: A compound of formula (I) according to any one of Embodiments 11.1 to 11.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is H; or R1 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, D, or -OC optionally substituted by halogen or D 1-6 Alkyl substituted; preferably R1 is -C 1- 3-alkyl or -deuterated C 1-3 Alkyl groups, such as -CH3, -CH2D, -CHD2, -CD3.

[0175] Embodiment 11.4: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is H; or R3 is D.

[0176] Embodiment 11.4.1: A compound of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is halogen, such as F, Cl, Br, I, preferably F; or R3 is CN.

[0177] Embodiment 11.4.2: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is -OH.

[0178] Embodiment 11.4.3: A compound of formula (I) according to any one of Embodiments 11.1 to 11.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, wherein -C 1-6 Alkyl optionally substituted with halogen, CN, D and -OC optionally substituted with halogen 1-6 Alkyl substitution.

[0179] Embodiment 11.4.4: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, or -C 2-6 Alkenyl, preferably -C 2-4 Alkenyl, or -C 2-6 Alkynyl, preferably -C 2-4 Alkynyl; each optionally substituted by halogen, CN, D and -OC 1-6 Alkyl is substituted, eg optionally substituted by halogen, eg substituted by halogen, eg substituted by F.

[0180] Embodiment 11.4.5: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is -OC 1-6 Alkyl, preferably -OC 1- 3 alkyl, wherein the alkyl is optionally substituted by halogen, CN, D and -OC optionally substituted by halogen 1-6 Alkyl is substituted, for example optionally substituted by halogen.

[0181] Embodiment 11.4.6: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is -OC 3-6 Cycloalkyl, or R3 is -(CH2) 0-3 -C 3-6 Cycloalkyl, preferably -(CH2) 0-3 -C 3-4 Cycloalkyl, wherein C 3-6 Cycloalkyl is each optionally substituted by halogen, CN, D, -C 1-6 Alkyl and optionally halogen-substituted -OC 1-6 Alkyl is substituted, for example optionally substituted by halogen.

[0182] Embodiment 11.4.7: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.3, wherein R3 is =C(R c )2, where R c are each independently selected from H, halogen, -C 1-6 Alkyl, preferably selected from H and halogen (preferably F); R3, for example but not limited to, =CH2, =CHF, =CF2, =CHCl, =CCl2, =C(CH3)2, =CHCH3, =CHCF3, =C(CF3)2.

[0183] Embodiment 11.4.8: A compound of formula (I) according to any one of Embodiments 11.1 to 11.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two R3 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, S, each optionally substituted with halogen and -C 1-6 Alkyl substituted, for example but not limited to spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spiroazetidine, spiroazetidine, each optionally substituted with halogen (preferably F) or C optionally substituted with halogen 1-6 Alkyl (preferably -CF3) substitution; for example but not limited to Wherein * represents the common carbon atom of the spiro ring.

[0184] Embodiment 11.4.9: A compound of formula (I) according to any one of Embodiments 11.1 to 11.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is selected from any one of Embodiments 11.4 to 11.4.8 or any combination thereof; for example, R3 is selected from halogen (preferably F); -C 1-6 Alkyl (preferably C 1-3 alkyl), wherein the alkyl is optionally substituted by halogen, preferably substituted by halogen, more preferably substituted by F; or =C(R c )2, where R c are each independently selected from H, halogen (preferably F), -C 1-6 Alkyl (preferably -C 1-3 Alkyl), preferably R c is selected from H and halogen (preferably F); preferably, R3 is substituted in the para position of the ring N atom;

[0185] The ring carbon atom para to the ring N atom is chiral as appropriate and may be in R or S configuration;

[0186] wherein the para-ring carbon atom of the ring nitrogen atom is substituted with =C(R c )2, the double bond may be in the form of cis-trans isomers, including E or Z type, preferably E type.

[0187] Embodiment 11.5: A compound of Formula (I) according to any one of Embodiments 11.4 to 11.4.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, wherein m is an integer from 0 to 6, preferably an integer from 1 to 4, more preferably an integer from 1 to 2, and R3 can be selected from any of the aforementioned R3 embodiments or any combination thereof;

[0188] More specifically, m is 1, R3 is selected from C 1-3 Alkyl, substituted by halogen, preferably by F; and =C(R c )2, where R c are each independently selected from H and halogen (preferably F).

[0189] Embodiment 11.6: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.5, wherein R4 is H.

[0190] Embodiment 11.6.1: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof, according to any one of Embodiments 11.1 to 11.5, wherein R4 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl; or R4 is -C 2-6 Alkenyl, preferably -C 2-4 Alkenyl; or R4 is -C 2-6 Alkynyl, preferably -C 2-4 Alkynyl; each optionally substituted by D, halogen, CN, OH, -OC 1-6 Alkyl and -OCON(R b )2 is substituted, preferably optionally substituted by halogen or D.

[0191] Embodiment 11.6.2: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 11.1 to 11.5, wherein R4 is -(CH2) 0-3 -C 3-6 Cycloalkyl, the -C 3-6 Cycloalkyl optionally substituted by D, halogen, CN, OH, -C 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl and -OCON(Rb )2 replaced.

[0192] Embodiment 11.6.3: A compound of Formula (I) according to any one of Embodiments 11.1 to 11.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R4 is selected from any one of Embodiments 11.6 to 11.6.2 or any combination thereof; for example, R4 is selected from -C 1-6 Alkyl and -C 3-6 Cycloalkyl, optionally substituted by D, halogen, CN, OH, -C 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl and -OCON(R b )2 substituted; preferably R4 is selected from -C 1-3 Alkyl and deuterated C 1-3 Alkyl groups include, but are not limited to, -CH3, -CD3, -CH2CH3, and -CD2CD3.

[0193] Embodiment 11.7: A compound of Formula (I) according to Embodiment 11.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0194] R3 is selected from halogen (preferably F); -C 1-6 Alkyl (preferably C 1-3 alkyl), wherein the alkyl is optionally substituted by halogen, preferably substituted by halogen, more preferably substituted by F; or =C(R c )2, where R c are each independently selected from H, halogen (preferably F), -C 1-6 Alkyl (preferably -C 1-3 Alkyl), preferably R c is selected from H and halogen (preferably F);

[0195] Preferably:

[0196] R2 are each independently selected from H and D; R1 is selected from optionally deuterated -C 1-6 Alkyl; m is 1 or 2; R3 is selected from halogen, -C 1-6 Alkyl and =C(R c )2, where -C 1-6 The alkyl group is optionally substituted with halogen, wherein R c are each independently selected from H, halogen, -C 1-6 Alkyl, preferably, R3 is substituted in the para position of the ring N atom; R4 is selected from optionally deuterated -C 1-6 alkyl;

[0197] More preferably:

[0198] R2 are each independently selected from H and D;

[0199] R1 is selected from -C optionally substituted with one or more deuterium 1-3 alkyl;

[0200] m is 1 or 2, for example, 1;

[0201] R3 is substituted at the para position of the ring N atom and is selected from halogen, substituted by halogen (preferably F) -C 1-3 Alkyl and =C(R c )2, where R c are each independently selected from H, halogen, -C 1-3 Alkyl, specific examples of R3 include but are not limited to fluorine, difluorine, fluoromethyl, difluoromethyl, fluoromethylene, difluoromethylene;

[0202] R4 is selected from -C optionally substituted with one or more deuterium 1-3 Alkyl, such as -CH3, -CH2CH3, -CD3, -CD2CD3; wherein the ring carbon atom para to the ring N atom to which R3 is attached is chiral as appropriate and may be in R or S configuration.

[0203] Embodiment 11.8: A compound of formula (I) according to embodiment 11.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Examples include but are not limited to

[0204] Preferred

[0205] More preferred

[0206] Embodiment 12: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which has the following sub-formula:

[0207] wherein each sub-formula and each substituent in its examples each has the general or preferred meaning defined in the corresponding embodiment above or any combination thereof; wherein each sub-formula also covers compounds formed by any combination of the general or preferred meaning of each substituent with the general or preferred meaning of the remaining substituents;

[0208] In one group of embodiments, in each of the above sub-formulas and examples thereof, M is N, W is C-halogen, preferably CF;

[0209] In one embodiment, in each of the above sub-formulas and examples thereof, M is selected from C-halogen (e.g., CF, C-Cl), C-CN, C-NO2, C-halogen substituted C 1-6 Alkyl (eg C-CF3), W is C-halogen, preferably CF.

[0210] Embodiment 13: A compound selected from the group consisting of the compounds of the Examples below, stereoisomers, pharmaceutically acceptable salts or solvates thereof.

[0211] It should be noted that the compounds of the present invention encompass the above independent embodiments or specific embodiments, and also encompass embodiments consisting of any combination or sub-combination of the above embodiments or specific embodiments, and also encompass embodiments consisting of any combination of any preferred or exemplary embodiments above.

[0212] Advantageous Effects of the Invention

[0213] As mentioned above, RAS proteins, especially KRAS mutant proteins, are known to play a role in tumorigenesis and a variety of other diseases. We have surprisingly found that the compounds of the present invention having the above-mentioned structural characteristics can potently inhibit cell proliferation in cell lines carrying KRAS mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS wild-type amplification, thereby having potential value as anti-proliferative, pro-apoptotic and / or anti-invasive drugs in preventing, suppressing and / or treating related tumor diseases. In particular, the compounds of the present invention are expected to be useful for preventing or treating diseases or conditions mediated by or inhibited by RAS mutations, particularly KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) or KRAS wild type amplification, such as cancer or tumors as defined herein.

[0214] Specifically, it has been found through research that the compounds of the present invention can achieve one or more of the following technical effects:

[0215] High mutant protein inhibitory activity: The compounds of the present invention, especially the compounds specifically exemplified herein, show proliferation inhibitory activity in RAS-related cells, particularly KRAS mutant cells (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, and Q61H mutation) and KRAS amplified cell proliferation inhibition assays, with IC50 values ​​in the range of 0.0001-10 μM, preferably in the range of 0.0001-1 μM, as demonstrated in Activity Examples 1, 2, 5-6;

[0216] · Have good pharmacokinetic properties, such as a long t 1 / 2 , which can, for example, increase the dosing interval, extend the half-life, and enable better patient compliance; have the best AUC for the safety / activity combination effect 0-t data, has better drugability, higher bioavailability, and can be conveniently administered orally, as verified in Active Example 3; and / or

[0217] It has a significantly satisfactory safety profile, a reduced risk of drug interactions, and no significant inhibitory effect on key CYP isoforms of drug metabolism, as demonstrated in Example 4.

[0218] Based on the beneficial effects of the above compounds of the present invention, the present invention also provides the following technical solutions in various aspects.

[0219] Compounds of the invention for use in therapy or as medicine

[0220] In one aspect, the present invention provides a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

[0221] On the other hand, the present invention provides compounds of the present invention, preferably pharmaceutically acceptable salts or solvates thereof, for use as RAS inhibitors, particularly KRAS mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS wild-type amplified cell inhibitors.

[0222] On the other hand, the present invention provides a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use in treating and / or preventing diseases or conditions mediated by RAS protein, particularly KRAS mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification or benefiting from the inhibition of RAS mutation, particularly KRAS mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.

[0223] In a specific embodiment, the present invention provides a method for treating and / or preventing a disease in which RAS protein, specifically KRAS mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification promote the occurrence and development of the disease or inhibit RAS mutant protein, specifically KRAS mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification, which will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease. Compounds, wherein the disease, such as a tumor or cancer, includes but is not limited to: lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma.

[0224] The present invention particularly provides a compound of formula (I) or its isomers, pharmaceutically acceptable salts or solvates thereof, which can be used to treat patients suffering from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, bile duct cancer.

[0225] Pharmaceutical compositions and their administration

[0226] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, preferably a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by RAS, particularly KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, G12A, G12R, G12S or KRAS G13D mutations, or KRAS Q61H mutations, and KRAS amplification-mediated diseases, such as tumors or cancers.

[0227] The pharmaceutical compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th edition. For example, they can be formulated as tablets, powders, capsules, lozenges, granules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The compositions can contain conventional components in pharmaceutical preparations, such as diluents (e.g., glucose, lactose, or mannitol), carriers, pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavorings, flavorings, other known additives, and other active agents. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004.

[0228] The administration and use of the pharmaceutical compositions of the present invention are in accordance with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the location of the agent delivery, the method of administration, the administration schedule, and other factors well known to physician practitioners. The optimal dosage level and frequency of administration of the compounds of the present invention or pharmaceutical compositions can be determined by those skilled in the art through standard tests in the field of pharmaceutical research.

[0229] The compositions of the present invention can be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation, epidural, and intranasal, and for local treatment, intralesional administration can also be employed. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical compositions of the present invention are administered orally.

[0230] For a 70 kg human subject, a suitable dosage range of the compound of the present invention can be routinely determined by those skilled in the art, and may be, for example, 1-1000 mg / day.

[0231] When dosages of a drug or a pharmaceutically acceptable salt thereof are described herein, it is understood that the dosage is based on the weight of the free base and does not include any hydrate or solvate thereof unless the specification indicates that the dosage is based on the weight of the salt, hydrate or solvate.

[0232] Treatment methods and uses

[0233] As described above, the compounds of the present invention and the compounds of various specific embodiments thereof, especially the compounds specifically prepared and characterized in the Examples, show inhibitory effects on RAS, especially KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, G12A, G12R, G12S or KRAS G13D mutations, or KRAS Q61H, and KRAS amplified cells.

[0234] Therefore, on the other hand, the present invention provides a method for inhibiting RAS, especially KRAS mutation, preferably KRAS G12D mutation, in a cell, comprising contacting the cell with a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to inhibit the activity of RAS mutation, especially KRAS mutation (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification in the cell.

[0235] Based on the same properties, the present invention also provides a method for inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof.

[0236] On the other hand, the present invention provides a method for treating and / or preventing diseases mediated by RAS, especially KRAS mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof.

[0237] On the other hand, the present invention provides the use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for inhibiting RAS, especially KRAS mutations, preferably KRAS G12C, KRAS G12D, KRAS G12V, KRASG12A, KRASG12R, KRASG12S or KRAS G13D, or KRAS Q61H mutations, and KRAS amplification-mediated diseases in cells.

[0238] On the other hand, the present invention provides the use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating and / or preventing diseases mediated by RAS, especially KRAS mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification.

[0239] For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or the disease mediated by RAS, especially KRAS mutation, preferably KRAS G12C, KRAS G12D, KRAS G12V, KRASG12A, KRASG12R, KRASG12S or KRAS G13D, or KRAS Q61H mutation, and KRAS amplification, especially refers to cancer or tumor. Exemplary such cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma, or pituitary adenoma.

[0240] For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or the disease mediated by RAS, especially KRAS mutation (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification is preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, bile duct cancer.

[0241] Therefore, in a preferred embodiment of this aspect, the present invention provides the above-mentioned methods and use technical solutions for treating or preventing cancer or tumors by inhibiting RAS mutation or amplification. In a further preferred embodiment, the present invention provides the above-mentioned methods and use technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and bile duct cancer by inhibiting RAS mutation or amplification.

[0242] The present invention also provides the use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a research tool compound for RAS inhibitors, especially KRAS inhibitors (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification inhibitors). Therefore, the present invention relates to the in vitro use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a RAS inhibitor, and in particular to the in vitro use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a research tool compound for the onset of RAS inhibitors. The present invention also relates to a method of inhibiting RAS, especially KRAS (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification), in particular an in vitro method comprising applying a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to a sample (e.g., a biological sample). It will be understood that the term "in vitro" in this particular context is used in the sense of "outside a living human or animal body", which specifically includes experiments performed with cells, cellular or subcellular extracts and / or biomolecules in an artificial environment, such as aqueous solutions or culture media that can be provided in flasks, test tubes, petri dishes, microtiter plates, etc.

[0243] Drug combinations

[0244] The compounds of the present invention may be administered as the sole active ingredient or in combination with another drug or therapy.

[0245] Therefore, on the other hand, the present invention provides a drug combination comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, and another active agent, or consisting of the two. The drug combination is used to inhibit abnormal cell growth in mammals, or to treat and / or prevent diseases mediated by RAS, preferably KRAS mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification.

[0246] The other active agent may be one or more additional compounds of the present invention, or may be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activities. For example, these active agents may be compounds that are known to regulate other biological activity pathways, or may be compounds that regulate different components in the biological activity pathways involved in the compounds of the present invention, or even compounds that overlap with the biological targets of the compounds of the present invention.

[0247] In a specific embodiment, other active agents that can be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiotherapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, and cytotoxic agents.

[0248] Other active agents used in combination with the present invention can be administered simultaneously, separately or sequentially with the compounds of the present invention by the same or different routes of administration. The other active agents can be co-administered with the compounds of the present invention in a single pharmaceutical composition, or administered separately in different discrete units from the compounds of the present invention, such as a combination product, preferably in the form of a kit, which can be administered simultaneously or sequentially when administered separately, and the sequential administration can be close or distant in time. They can be prepared and / or formulated by the same or different manufacturers. Moreover, the compounds of the present invention and the other active agents can be (i) administered before the combination product is sent to the physician (e.g., in the case of a kit comprising the compounds of the present invention and another drug); (ii) administered by the physician himself (or under the guidance of a physician) before administration; (iii) administered by the patient himself, e.g., during the sequential administration of the compounds of the present invention and the other active agents, in a combination therapy.

[0249] The compounds of the present invention may also be combined with anti-tumor therapies including, but not limited to, surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.

[0250] Therefore, in another aspect, the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a device for separately containing the compositions, such as a container, a sub-bottle, or a separate foil package, such as a blister pack for packaging tablets, capsules, etc., and instructions for use. The kit of the present invention is particularly suitable for administering different dosage forms, such as an oral dosage form and a parenteral dosage form, or for administering different compositions at different dosage intervals.

[0251] For the technical solutions of the above-mentioned pharmaceutical composition, drug combination or drug kit of the present invention, the abnormal cell growth involved or the disease mediated by RAS, especially KRAS mutation, preferably KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S or KRAS G13D, or KRAS Q61H mutation, and KRAS amplification are as defined above for the methods and uses of the present invention.

[0252] For the above-mentioned compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits of the present invention, the compounds of the Examples herein are preferred.

[0253] Preparation method of the compound of the present invention

[0254] In another aspect, the present invention also provides a method for preparing the compound defined in the present invention.

[0255] The compounds of the present invention can be prepared by a variety of methods, including the general methods given below, the methods disclosed in the Examples, or methods analogous thereto.

[0256] Standard synthetic methods and operations for preparing organic compounds and functional group conversions and operations are known in the art and can be found in standard textbooks, such as Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 7th edition, Wiley, 2013). For each reaction step of each general synthetic scheme, appropriate reaction conditions are known to those skilled in the art or can be routinely determined. The method steps for synthesizing the compounds of the present invention can be under reaction conditions known per se (including those conditions specifically mentioned), in the absence or conventional presence of a solvent or diluent (including, for example, a solvent or diluent that is inert and soluble to the reagents used), in the absence or presence of a catalyst, a condensing agent or a neutralizing agent (such as an ion exchanger, such as a cation exchanger, such as H +The reaction is carried out at reduced, normal or elevated temperature (e.g., from about -100°C to about 190°C, including, for example, from about -78°C to about 150°C, such as from about 0°C to about 125°C, room temperature, -20 to 40°C or reflux temperature), under atmospheric pressure or in a closed vessel, under pressure when appropriate, and / or under an inert atmosphere, such as an argon or nitrogen atmosphere, depending on the nature of the reaction and / or the reactants.

[0257] Unless otherwise specified, the raw materials and reagents used in the preparation of the compounds are commercially available or known in the literature, or can be prepared by a person skilled in the art by the following methods, methods analogous to those given below, or standard methods known in the art. Unless otherwise specified in the process description, suitable solvents are those conventional solvents well known to a person skilled in the art for the specific type of reaction involved, such as water, esters, ethers, liquid aromatic hydrocarbons, alcohols, nitriles, halogenated hydrocarbons, amides, bases, carboxylic anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for post-processing, for example, post-processing by chromatography or partitioning.

[0258] If desired, the raw materials and intermediates in the synthetic reaction scheme can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging. The materials can be characterized using conventional methods including physical constants and spectral data. The reaction mixture is post-processed in a conventional manner, for example by mixing with water, separating the phases, and, if appropriate, purifying the crude product by chromatography.

[0259] Those skilled in the art will recognize the presence or absence of stereocenters in the compounds of the present invention. At all stages of the reaction, the mixture of isomers formed can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as racemates or mixtures of diastereomers, see, for example, E.L. Eliel, S.H. Wilen and L.N. Mander, "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

[0260] Where a mixture of stereoisomers is produced during the preparation of the compounds of the present invention, the individual stereoisomers of the compounds of the present invention can be obtained by resolution, for example, by starting from the compounds of the present invention obtained as a mixture of stereoisomers using well-known methods, such as formation of diastereomeric pairs, by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography; alternatively, starting materials or intermediates with defined stereochemistry can be used, or any known chiral resolution method can be used to obtain optically pure or enantiomerically enriched synthetic intermediates, which can then be used as such in subsequent steps at various stages of the above-mentioned synthetic processes.

[0261] In certain specific cases, it may be necessary to protect a particular reactive group with an appropriate protecting group to avoid interference with the reaction of other reactive groups. Suitable protecting groups and methods of protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples thereof can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).

[0262] The following is only an example of a general synthetic scheme for synthesizing the compounds of the present invention. Other routes and other reactants and intermediates known to those of ordinary skill in the art can also be used to obtain the compounds of the present invention.

[0263] For the sake of clarity, in the exemplary synthetic schemes described below, unless otherwise specified, R1, R2, R3, R4, R5, R6, R7, X, Y, M, W, and t appearing in the structural formulas of the intermediate compounds are as defined above for the compounds of the present invention, wherein PG represents a suitable protecting group that can be determined by those skilled in the art based on knowledge of organic chemistry.

[0264] Synthesis Scheme A

[0265] The syntheses of the compounds of the present invention can be prepared according to the following exemplary schemes or appropriate variations thereof.

[0266] Compound 1 is commercially available or can be obtained by the methods used in the Examples herein or methods analogous thereto. In step A, compound 1 is subjected to an aromatic nucleophilic substitution reaction to obtain compound 2. Typical aromatic nucleophilic substitution conditions are well known in the art, such as DIEA / THF. In step B, compound 2 is fluorinated by a halogen exchange reaction under conditions such as KF / DMSO to obtain compound 3. The latter is introduced into a naphthalene compound in step C through a metal-catalyzed coupling reaction to obtain compound 4. In step D, compound 4 is subjected to an aromatic nucleophilic substitution reaction to obtain compound 5. In step E, any protecting groups that may be present in compound 5 are removed to obtain a compound of formula I.

[0267] Typical metal-catalyzed coupling reactions include, but are not limited to, the Suzuki reaction. Typical reaction conditions are well known to those skilled in the art, and those skilled in the art understand a variety of conditions for promoting such cross-coupling reactions, such as Pd(dtbpf)Cl2 / K3PO4 / dioxane / water, or Pd(OAc)2 / rac-BIDIME / K2CO3 / toluene, or Ruphos Pd G4 / K3PO4 / dioxane / water; Suitable palladium catalysts also include XantPhos Pd G2, APd G3, bis(triphenylphosphine)palladium(II) chloride, Pd(dppf)Cl2, Pd2(dba)3, tetrakis(triphenyl)phosphine palladium and palladium(II) acetate, etc.; if necessary, suitable ligands may include tricyclohexylphosphine and tri-tert-butylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide and potassium phosphate monohydrate, DIPEA, etc.

[0268] It should be noted that the removal of the protecting group in step E can be adjusted according to the protecting group carried by the molecule, and can be a one-step reaction or a multi-step reaction. For example, when the protecting group PG carried by the compound is TIPS, it can be removed by reagents such as CsF.

[0269] Synthesis Scheme B

[0270] The synthesis of the compounds of the present invention can also be prepared according to the following exemplary schemes or appropriate variations thereof.

[0271] Compound 6 is commercially available or can be obtained according to the methods used in the Examples herein or methods analogous thereto. In step A, compound 7 can be obtained according to the method described in Synthesis Scheme A. Compound 7 is then subjected to a metal-catalyzed coupling reaction in step B, oxidation of dimethyl sulfide to sulfoxide (t=1) or sulfone (t=2) in step C, aromatic nucleophilic substitution reaction in step D, and removal reaction, which may include a protecting group, in step E, to obtain a compound of formula I. Typical conditions for the metal-catalyzed coupling reaction, nucleophilic substitution reaction, and protecting group removal reaction involved in this scheme are well known in the art and can be carried out similarly to the relevant reaction conditions described in Synthesis Scheme A.

[0272] Synthesis Example

[0273] The present invention will be further described below with reference to the following examples. It should be noted that the following examples are for illustrative purposes only and should not be considered as limiting the scope of protection of the present invention.

[0274] In describing the embodiments and the specific examples that follow, the following abbreviations are used herein:

[0275] ACN (acetonitrile); Boc (tert-butoxycarbonyl); CDCl3 (deuterated chloroform); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (hexadeuterated dimethyl sulfoxide); EA (ethyl acetate); EDTA-K2 (ethylenediaminetetraacetic acid dipotassium salt); EtOH (ethanol); FCC (flash column chromatography); g (gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl / MeOH (methanolic hydrogen chloride solution); HLM (human liver microsomes); H2O (water); H2SO4 (sulfuric acid); IV (intravenous administration); K2CO3 (potassium carbonate); LCMS (liquid chromatography-mass spectrometry); LC-MS / MS (liquid spectroscopy-mass spectrometry-mass spectrometry); MeOH (methanol); Methanol-d4 (tetradeuterated methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters); mmol (millimoles); MOM (methoxymethyl ether); MTBE (methyl tert-butyl ether); m / z ( mass-to-charge ratio); N2 (nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); Na2SO3 (sodium sulfite); Na2SO4 (sodium sulfate); NCS (chlorosuccinimide); NH4Cl (ammonium chloride); NMR (nuclear magnetic resonance); PdCl2(dtbpf) or Pd(dtbpf)Cl2 (1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride); PdCl2(dppf) or Pd(dppf)Cl2 (1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride) palladium); Pd(OAc) (palladium acetate); Pd(PPh3)4 (tetrakistriphenylphosphine palladium); PE (petroleum ether); PO (oral administration); POCl3 (phosphorus oxychloride); rt (room temperature); SiO2 (silica gel); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIPS (triisopropylsilyl); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); TsOH·H2O (p-toluenesulfonic acid monohydrate); μL (microliter); μM (micromolar); μmol (micromolar).

[0276] In the following examples, the names and structures of the synthesized target compounds are given. Any discrepancies between the names and structures are unintentional; in this case, the structure is decisive.

[0277] In the following examples, experimental procedures, where specific conditions are not specified, generally follow conventional conditions for such reactions or those recommended by the manufacturer. Unless otherwise noted, percentages and parts are by weight. Liquid ratios are by volume unless otherwise noted.

[0278] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels, prepared according to existing methods, or prepared according to methods similar to those disclosed in this application.

[0279] In the following examples, 1 H-NMR spectra were recorded using a Bruker (400 MHz), with chemical shifts expressed as δ (ppm) relative to the deuterated solvent peak (CDCl3: δ = 7.26 ppm; CD3OD: δ = 3.31 ppm; DMSO-d6: δ = 2.50 ppm). Liquid chromatography / mass spectrometry (LC / MS / MS) was performed using an Aglient 1260 liquid chromatograph coupled with an Aglient G6125B mass spectrometer. Gas chromatography / mass spectrometry was performed using a Shimadzu GCMS-QP2010SE.

[0280] Intermediate A

[0281] 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0282] Step A: 4,6-dichloro-5-fluoronicotinoyl chloride

[0283] With stirring at room temperature, thionyl chloride (2.25 mL, 31 mmol) was slowly added to a solution of 4,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.4 mmol) in DCM (100 mL), followed by DMF (175 mg, 2.4 mmol). The resulting reaction solution was stirred at 50°C for 2 h. After completion of the reaction as monitored by TLC, the mixture was concentrated and a small amount of toluene was added to obtain a yellow solid, 4,6-dichloro-5-fluoronicotinyl chloride (4.5 g, 83% yield), which was used directly in the subsequent reaction.

[0284] Step B: (4,6-Dichloro-5-fluoronicotinoyl)carbamidethiomethyl ester

[0285] A mixture of 4,6-dichloro-5-fluoronicotinoyl chloride (4.5 g, 19.8 mmol) and ethylene glycol dimethyl ether (20 ml) was slowly added dropwise to a mixture of 2-methylisothiourea sulfuric acid (15 g, 49.5 mmol) and 1M aqueous NaOH (70 ml) at 0°C with stirring. The mixture was stirred for 1 hour. The precipitated solid was filtered and dried to obtain (4,6-dichloro-5-fluoronicotinoyl)carbamide thiomethyl ester (5.0 g, 90% yield). LCMS (m / z): 282.1 (M+H).

[0286] Step C: 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0287] Dissolve (4,6-dichloro-5-fluoronicotinoyl)carbamoylthiomethyl ester (5.0 g, 17.8 mmol) in DMF (40 mL) and heat to 120°C with stirring for 3 h. After completion of the reaction as monitored by LCMS, cool to room temperature and add water (200 mL). The precipitated solid was filtered and dried to obtain (4,6-dichloro-5-fluoronicotinoyl)carbamoylthiomethyl ester (3.6 g, 82% yield). LCMS (m / z): 245.6 (M+H).

[0288] Intermediate B

[0289] 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0290] Step A: 2,6-Dichloro-3-fluoropyridin-4-amine

[0291] Selectfluor (68 g, 180 mmol) was added to a solution of 2,6-dichloropyridin-4-amine (25 g, 154 mmol) in methanol / water (V / V = 5:1, 300 mL) at room temperature. The resulting mixture was stirred at 50°C for 48 h, concentrated under reduced pressure, diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated, and the crude product was purified by FCC (SiO2, EA / PE = 0-10%) to afford 2,6-dichloro-3-fluoropyridin-4-amine (10 g) as a white solid. LCMS (m / z): 180.9 (M+H).

[0292] Step B: tert-Butyl (tert-Butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate

[0293] 4-Dimethylaminopyridine (307 mg, 2.75 mmol) and di-tert-butyl dicarbonate (30 g, 138 mmol) were added to a solution of 2,6-dichloro-3-fluoropyridin-4-amine (10 g, 55 mmol) in tetrahydrofuran (100 mL) with stirring at room temperature. The resulting mixture was heated to 60°C and stirred for 16 h. The reaction was monitored for completion by TLC and concentrated to afford the crude product. This was then slurried in methanol to afford tert-butyl (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate (16 g) as a white solid. LCMS (m / z): 381.2 (M+H).

[0294] Step C: tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0295] Under a dry ice-ethanol bath, LDA (2.0 M, 63 mL, 126 mmol) was slowly added to a solution of tert-butyl (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate (16 g, 42 mmol) in THF (200 mL). The resulting mixture was stirred at this temperature for 1 h. TLC monitored the reaction completion. Acetic acid was added to quench the reaction, and the mixture was diluted with EA, washed with water, and dried over anhydrous sodium sulfate. Filtration and concentration yielded the crude product, which was purified by FCC (SiO2, EA / PE = 0-20%) to afford tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13 g).

[0296] Step D: 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride

[0297] Concentrated hydrochloric acid (30 ml) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13 g, 34 mmol) in dioxane (90 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, as monitored by LCMS, the reaction was concentrated to yield 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride (8 g). LCMS (m / z): 224.9 (M+H).

[0298] Step E: 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one

[0299] A mixture of 4-amino-2,6-dichloro-5-fluoronicotinic acid (8 g, 30.8 mmol) and thionyl chloride (200 mL) was stirred at 50°C for 3 h. The mixture was then concentrated, and the residue was dissolved in acetone (50 mL) to obtain Solution 1. A mixture of ammonium thiocyanate (7 g, 92 mmol) and acetone (160 mL) was added dropwise to Solution 1 at room temperature, and the resulting reaction mixture was stirred for an additional 1 h at room temperature. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into water, filtered, and the filter cake dried to yield 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (5 g). LCMS (m / z): 265.9 (M+H).

[0300] Step F: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0301] A mixture of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (5 g, 18.8 mmol), methanol (380 mL), aqueous sodium hydroxide (0.1 M, 380 mL, 380 mmol), and iodomethane (5.3 g, 380 mmol) was stirred at room temperature for 2 h. After completion of the reaction, as monitored by LCMS, the reaction solution was poured into 1000 mL of water and acidified with concentrated hydrochloric acid to pH ~6. The solution was filtered, and the filter cake was dried to yield the product, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4 g). LCMS (m / z): 279.9 (M+H).

[0302] Step G: 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0303] A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (400 mg, 1.4 mmol), sodium methoxide (0.38 g, 7.5 mmol), DMA (10 mL), and methanol (2 mL) was stirred at 50°C for 16 hours. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and adjusted to pH ~3 with concentrated hydrochloric acid. The filter cake was filtered and dried to obtain 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (250 mg). LCMS (m / z): 276.0 (M+H).

[0304] Intermediate C

[0305] 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

[0306] Step A: Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate

[0307] To a round-bottom flask equipped with a stirrer at room temperature, add methyl 2-amino-4-bromo-3,5-difluorobenzoate (10 g, 37.6 mmol) and THF (100 mL). Add 2,2,2-trichloroacetyl isocyanate (8.5 g, 45.1 mmol) dropwise while stirring at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to afford methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (crude) as a brown solid, which was used directly in the next step. LCMS (ESI, m / z): 452.8 (M+H).

[0308] Step B: 7-Bromo-6,8-difluoroquinazoline-2,4-diol

[0309] At room temperature, methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate, obtained in the previous step, was added to a round-bottom flask equipped with a stirrer, followed by the addition of 100 mL of 7 M MeOH solution. The resulting mixture was stirred at room temperature for 2 hours, and the reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure, and the resulting solid was slurried with methyl tert-butyl ether and filtered to afford 7-bromo-6,8-difluoroquinazoline-2,4-diol (14 g, crude) as a pale yellow solid, which was used directly in the next step without further purification. LCMS (ESI, m / z): 277.0 (M+H).

[0310] Step C: 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

[0311] To a round-bottom flask equipped with a stirrer, add 7-bromo-6,8-difluoroquinazoline-2,4-diol (14 g, crude) and POCl3 (112 mL). DIEA (28 mL) was added dropwise while stirring at room temperature. After the addition was complete, the system was heated to 110°C and stirred overnight. The reaction solution was concentrated under reduced pressure to approximately 30 mL and poured into water (600 mL). The precipitate was collected by filtration and dried to yield 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (11 g, crude) as a yellow solid, which was used directly in subsequent reactions. LCMS (ESI, m / z): 312.9 (M+H).

[0312] The following intermediates were prepared by referring to the above methods and appropriate modifications known in the art:

[0313] Intermediate A-1

[0314] 6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0315] Step A: 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0316] Under N₂, DIEA (1.0 mL, 6.1 mmol) was added to a solution of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 g, 4.1 mmol) in phosphorus oxychloride (10 mL). The reaction mixture was stirred at 90°C for 1 h. After completion of the reaction, the mixture was concentrated to dryness, and the crude product was purified by FCC (SiO₂, EA / PE = 0-10%) to afford 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (810 mg, 75% yield) as a yellow solid. LCMS (m / z): 263.9 (M+H).

[0317] Step B: 6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0318] To a solution of 1-oxa-6-azaspiro[3.5]nonane oxalate (660 mg, 3.1 mmol) in DMF (10 mL) was added DIEA (792 mg, 6.2 mmol) and 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (810 mg, 3.1 mmol) in an ice bath. The reaction mixture was stirred at 0°C for 0.5 h. After completion of the reaction, monitored by LCMS, ethyl acetate (80 mL) was added. The reaction mixture was washed with water, dried, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-20%) to afford 6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (980 mg, 90% yield) as a yellow solid. LCMS (m / z): 355.0 (M+H).

[0319] Intermediate AIA and intermediate AIB

[0320] (R)-6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane and (S)-6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0321] Step A: (S)-1-Oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester and (R)-1-Oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester

[0322] To a solution of trimethylsulfoxide iodide (94 g, 428 mmol) in tert-butanol (200 mL) at 50°C under nitrogen was added sodium tert-butoxide solution (428 mL, 428 mmol, 1N in THF). The resulting reaction mixture was stirred at 50°C for 1.5 h, followed by the addition of benzyl 3-oxopiperidine-1-carboxylate (25 g, 107 mmol). The reaction mixture was allowed to react for another 16 h at 50°C under nitrogen. After completion of the reaction, the mixture was cooled to room temperature and saturated NH4Cl solution (200 mL) was added. The mixture was extracted with EtOAc, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-20%) to afford benzyl 1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (10 g, 36% yield), a colorless, transparent liquid. LCMS (m / z): 262.1 (M+H). 1 H NMR(400MHz,Chloroform-d)δ7.41–7.27(m,5H),5.14(s,2H),4.63–4.42(m,2H),3.82(d,J =13.0Hz,1H),3.65–3.11(m,3H),2.49–2.25(m,2H),1.96–1.64(m,3H),1.57–1.38(m,1H).

[0323] The colorless, transparent liquid product was separated by SFC (Waters SFC 150, REGIS (S,S) WHELK-O1 (250*40mm 10μm), Supercritical CO2 / MeOH (0.1% DEA in MeOH) = 80 / 20) to obtain the first eluting isomer, (R)-1-oxa-6-azaspiro[3.5]nonane-6-carboxylic acid benzyl ester (4.1 g, 15% yield, relatively short retention time). 1 H NMR (400 MHz, Chloroform-d) δ 7.43–7.26 (m, 5H), 5.14 (s, 2H), 4.65–4.43 (m, 2H), 3.82 (d, J = 13.0 Hz, 1H), 3.63–3.13 (m, 3H), 2.49–2.22 (m, 2H), 1.96–1.63 (m, 4H), 1.56–1.33 (m, 1H). LCMS (m / z): 262.1 (M+H). SFC analysis method A-1-2, Rt = 2.584 min. The subsequently eluted isomer was (S)-benzyl 1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (4.5 g, 16% yield, relatively long retention time). 1H NMR (400 MHz, Chloroform-d) δ 7.43–7.27 (m, 5H), 5.14 (s, 2H), 4.64–4.40 (m, 2H), 3.82 (d, J = 13.0 Hz, 1H), 3.62–3.05 (m, 3H), 2.50–2.18 (m, 2H), 2.01–1.65 (m, 3H), 1.54–1.37 (m, 1H). LCMS (m / z): 262.1 (M+H). SFC analysis method A-1-2, Rt = 4.563 min.

[0324] SFC analysis method A-1-2: Waters UPCC (CA-352), analytical column: Daicel IG, 100*3mm*3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% DEA); flow rate: 1.5mL / min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A / B=80 / 20.

[0325] Step B: (R)-1-oxa-6-azaspiro[3.5]nonyl oxalate oxalate and (S)-1-oxa-6-azaspiro[3.5]nonyl oxalate oxalate

[0326] Dissolve (R)-benzyl 1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (4.1 g, 15.6 mmol) in methanol (50 mL). Under N₂ conditions, add Pd / C (1.6 g, 1.56 mmol, 10% w / w), replace the atmosphere with H₂ (15 psi) three times, and stir at room temperature for 8 h. LCMS monitoring indicates the disappearance of the starting material. The reaction mixture is filtered through celite, oxalic acid (1 g) is added to form a salt, and the mixture is concentrated to yield (R)-1-oxa-6-azaspiro[3.5]nonane oxalate oxalate (3.0 g) as a white solid. 1 H NMR(400MHz,D2O)δ4.71–4.51(m,2H),3.65–3.57(m,1H),3.29–3.19(m,2H), 3.08–2.95(m,1H),2.65–2.41(m,2H),2.26–2.11(m,1H),1.96–1.71(m,3H).

[0327] Dissolve (S)-benzyl 1-oxa-6-azaspiro[3.5]nonane-6-carboxylate (4.5 g, 17.2 mmol) in methanol (50 mL). Under N₂ conditions, add Pd / C (1.8 g, 1.7 mmol, 10%), replace the atmosphere with H₂ (15 psi) three times, and stir at room temperature for 8 h. LCMS monitoring indicates the disappearance of the starting material. The reaction mixture is filtered through celite, oxalic acid (1 g) is added to form a salt, and the mixture is concentrated to yield (S)-1-oxa-6-azaspiro[3.5]nonane oxalate oxalate (3.5 g) as a white solid. 1 H NMR(400MHz,D2O)δ4.72–4.52(m,2H),3.67–3.55(m,1H),3.30–3.18(m,2H), 3.08–2.95(m,1H),2.64–2.44(m,2H),2.25–2.12(m,1H),1.95–1.74(m,3H).

[0328] Step C: (R)-6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane and (S)-6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0329] The experimental process was carried out according to the protocol described for Intermediate AI, using (R)-1-oxa-6-azaspiro[3.5]nonyl oxalate oxalate and (S)-1-oxa-6-azaspiro[3.5]nonyl oxalate oxalate.

[0330] Intermediate A-II

[0331] 7-Chloro-8-fluoro-2-(methylthio)-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-1,3,6-triazine

[0332] Step A: 2-Oxa-6-azabicyclo[5.1.0]octane p-toluenesulfonate

[0333] At room temperature, benzyl 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylate (750 mg, 3.03 mmol) and Pd / C (718 mg, 10% w / w, 0.61 mmol) were dissolved in methanol (15 mL). The mixture was purged with H2 (15 psi) twice and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was filtered through celite, and the organic phase was concentrated to afford 2-oxa-6-azabicyclo[5.1.0]octane p-toluenesulfonate (750 mg, 86% yield) as a white solid. LCMS (m / z): 114.1 (M+H).

[0334] Step B: 7-chloro-8-fluoro-2-(methylthio)-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-1,3,6-triazine

[0335] At room temperature, DIEA (1.25 mL, 7.57 mmol) was added to a solution of 2-oxa-6-azabicyclo[5.1.0]octane p-toluenesulfonate (750 mg, 2.63 mmol) and 4,7-dichloro-8-fluoro-2-(methylthio)-1,3,6-triazine (500 mg, 1.89 mmol) in THF (15 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, monitored by LCMS, the reaction solution was concentrated, and 5 mL of acetonitrile was added to dissolve the oil. The mixture was then poured into H₂O (100 mL), whereupon a brown solid precipitated. The filter cake was filtered, washed with H₂O (100 mL), and dried to afford 7-chloro-8-fluoro-2-(methylthio)-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-1,3,6-triazine (640 mg, 99% yield) as a brown solid. LCMS (m / z): 341.0 (M+H).

[0336] Intermediates A-II-A and A-II-B

[0337] 4-((1S,7R)-2-Oxo-6-azabicyclo[5.1.0]oct-6-yl)-7-chloro-8-fluoro-2-(methylthio)-1,3,6-triazanaphthyridine and 4-((1R,7S)-2-Oxo-6-azabicyclo[5.1.0]oct-6-yl)-7-chloro-8-fluoro-2-(methylthio)-1,3,6-triazanaphthyridine

[0338] Step A: (1R,7S)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester and (1S,7R)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester

[0339] At 0°C, ZnEt2 (62.27 mL, 62.3 mmol) was added to a solution of benzyl 4,5,6,7-tetrahydro-1,4-oxolane-4-carboxylate (5.8 g, 24.9 mmol) in DCM (80 mL). The resulting reaction mixture was warmed to room temperature and stirred for 0.5 h. A solution of diiodomethane (8.03 mL, 174 mmol) in DCM (30 mL) was added to the reaction mixture, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into a semi-saturated aqueous solution of NH4Cl (200 mL) and extracted with DCM (50 mL x 3). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by FCC (SiO2, PE / EA = 0-40%) to give a light yellow oily product, 2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester (5 g, yield 81.3%), LCMS (m / z): 248.0 (M+H).

[0340] The pale yellow oily product was separated by SFC (Waters SFC 150, REGIS (S,S) WHELK-O1 (250*40mm 10μm), CO2 / MeOH (0.1% DEA-MeOH) = 90 / 10). The first eluting isomer was (1R,7S)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester (2.2 g, 44% yield, relatively short retention time). SFC analysis method A-1I-2, Rt = 1.505 min. The second eluting isomer was (1S,7R)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester (2.1 g, 42% yield, relatively long retention time). SFC analysis method A-1I-2, Rt = 2.261 min.

[0341] SFC analysis method A-1I-2: Waters UPCC (CA-415), analytical column: Daicel AD, 100*3mm*3μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% DEA); flow rate: 1.5mL / min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-4.0min A / B=90 / 10.

[0342] Step B: (1R,7S)-2-Oxo-6-azabicyclo[5.1.0]octane p-toluenesulfonate and (1S,7R)-2-Oxo-6-azabicyclo[5.1.0]octane p-toluenesulfonate

[0343] The experimental process was carried out according to the protocol described for Intermediate A-II, using (1R,7S)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester and (1S,7R)-2-oxa-6-azabicyclo[5.1.0]octane-6-carboxylic acid benzyl ester.

[0344] Step C: 4-((1R,7S)-2-Oxo-6-azabicyclo[5.1.0]octan-6-yl)-7-chloro-8-fluoro-2-(methylthio)-1,3,6-triazine and 4-((1S,7R)-2-Oxo-6-azabicyclo[5.1.0]octan-6-yl)-7-chloro-8-fluoro-2-(methylthio)-1,3,6-triazine

[0345] The experimental process was carried out according to the protocol described for Intermediate A-II, using (1R,7S)-2-oxo-6-azabicyclo[5.1.0]octane p-toluenesulfonate and (1S,7R)-2-oxo-6-azabicyclo[5.1.0]octane p-toluenesulfonate.

[0346] Intermediate B-1

[0347] 6-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0348] The synthesis of intermediate BI was as described for the synthesis of intermediate AI, using 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol in step A. LCMS (m / z): 385.1 (M+H).

[0349] Intermediate C-1

[0350] 4-((S)-1-Oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2,6,8-trifluoroquinazoline

[0351] Step A: 4-((S)-1-Oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2-chloro-6,8-difluoroquinazoline

[0352] To a solution of (S)-1-oxa-6-azaspiro[3.5]nonyl oxalate oxalate (380 mg, 1.7 mmol) in DMF (10 mL) was added DIEA (617 mg, 4.8 mmol) and 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (500 mg, 1.6 mmol) in an ice bath. The reaction mixture was stirred at 0°C for 1 h. After completion of the reaction, monitored by LCMS, ethyl acetate (80 mL) was added. The reaction mixture was washed with water, dried, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-25%) to afford 4-((S)-1-oxa-6-aza-6-spiro[3.5]nonyl)-7-bromo-2-chloro-6,8-difluoroquinazoline (550 mg, 85% yield) as a yellow solid. LCMS (m / z): 403.9 (M+H).

[0353] Step B: 4-((S)-1-Oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2,6,8-trifluoroquinazoline

[0354] To a solution of 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2-chloro-6,8-difluoroquinazoline (550 mg, 1.3 mmol) in DMSO (10 mL) was added KF (789 mg, 13 mmol) at room temperature. The reaction mixture was stirred at 110°C for 12 h. After completion of the reaction, ethyl acetate (50 mL) was added, as monitored by LCMS. The reaction mixture was washed with water, dried, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-20%) to afford 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2-chloro-6,8-difluoroquinazoline (430 mg, 81% yield) as a yellow solid. LCMS (m / z): 390.0 (M+H).

[0355] Intermediate a

[0356] (R)-3-Methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester

[0357] The compound 3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (120 g) was separated by SFC (SFC150, Waters) (separation column: DAICEL IG, 250*50mm, 10μm; mobile phase: CO2 / MeOH = 90 / 10; flow rate: 120mL / min), the first eluting isomer 1 was obtained, compound a (52.8g, relatively short retention time). Chiral analysis method-a, Rt = 0.682min. 1 H NMR (400 MHz, Chloroform-d) δ 4.59–4.42 (m, 1H), 4.26–3.98 (m, 1H), 3.73 (s, 3H), 3.42–3.24 (m, 1H), 3.16–3.01 (m, 1H), 2.93–2.63 (m, 1H), 2.58–2.40 (m, 1H), 1.49 (s, 9H), 1.31 (s, 3H). LCMS (m / z): 216.1 (M-56+H). The subsequently eluted isomer 2 was compound a-1 (52.4 g, relatively long retention time). Chiral analysis method-a, Rt = 1.035 min. 1 H NMR(400MHz,Chloroform-d)δ4.60–4.41(m,1H),4.24–3.94(m,1H),3.73(s,3H),3.42–3.24 (m,1H),3.17–3.00(m,1H),2.93–2.64(m,1H),2.56–2.40(m,1H),1.49(s,9H),1.31(s,3H).

[0358] Chiral analysis method-a: (Waters UPCC, analytical column: Daicel IG, 100*3mm 3μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 1.5mL / min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min (A / B=90 / 10).

[0359] Intermediate b

[0360] (S,E)–(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0361] Step A: (S,E)-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester and (S,Z)-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester

[0362] Dissolve (fluoromethylene)triphenylphosphine tetrafluoroborate (10.56 g, 27.64 mmol) in anhydrous THF (50 mL) and replace the atmosphere with nitrogen three times. Under dry ice and ethanol, cool the reaction mixture to -70°C and add a solution of potassium tert-butoxide in tetrahydrofuran (27.64 mL, 1 M, 27.64 mmol) dropwise to the reaction system. Maintain the temperature and continue stirring for 1 hour. Then, add a solution of (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.0 g, 18.43 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise to the reaction system. After the addition is complete, slowly warm the mixture to room temperature and stir overnight. After completion of the reaction, monitor the reaction by TLC. Pour the reaction mixture slowly into water (100 mL) and extract three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by FCC (SiO2, EA / PE = 0-15%) to give (S,E)-1-tert-butyl-3-methyl-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate as a colorless oil (1.98 g, 37% yield). LCMS (m / z): 232.1 (M-56+H). 1 H NMR (400 MHz, Chloroform-d) δ 6.55 (d, J = 84.7, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.10–3.82 (m, 1H), 3.69 (s, 3H), 3.00–2.85 (m, 1H), 2.76 (d, J = 13.1 Hz, 1H), 2.71–2.60 (m, 1H), 2.31–2.08 (m, 1H), 1.46 (s, 9H), 1.29 (s, 3H); and the product, (S,Z)-3-methyl-1-tert-butyl-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate, was obtained as a colorless oil (600 mg, 11% yield). LCMS (m / z): 232.1 (M-56+H). 1 H NMR(400MHz,Chloroform-d)δ6.43(d,J=83.7,1H),3.86–3.75(m,1H),3.71(s,3H),3. 62–3.47(m,1H),3.42–3.29(m,2H),2.24–2.06(m,2H),1.46(s,9H),1.43–1.39(m,3H).

[0363] Step B: (S,E)-4-(Fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0364] At room temperature, add 4M HCl-dioxane (10 mL) to 1-tert-butyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate-3-methyl ester (600 mg, 2.09 mmol) and stir at room temperature for 1 hour. Concentrate to remove the acid solution to obtain (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (572 mg, 100% yield) as a white solid. LCMS (m / z): 188.1 (M+H).

[0365] Step C: Methyl (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate

[0366] At room temperature, (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (370 mg, 1.98 mmol) was dissolved in methanol (5 mL). Triethylamine was added dropwise until the reaction solution had a pH of ~10 and stirred for 10 minutes. Glacial acetic acid was then added dropwise until the reaction solution had a pH of ~4. Aqueous formaldehyde solution (481.15 mg, 5.93 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (136.62 mg, 2.17 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure and the solution was evaporated twice from anhydrous tetrahydrofuran to obtain (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (380 mg, 96% yield) as a white solid. LCMS (m / z): 202.1 (M+H).

[0367] Step D: (S,E)-(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0368] Under ice-cooling conditions, a 1 M solution of LiAlH₄-THF (2.83 mL, 107.5 mg, 2.83 mmol) was added dropwise to a solution of (E)-methyl 4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (380 mg, 1.89 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion of the reaction, monitored by LCMS, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles formed. Approximately 5 g of anhydrous sodium sulfate was added to remove water. The reaction solution was filtered through celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to afford (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (300 mg, 92% yield) as a colorless oil. LCMS (m / z): 174.1 (M+H).

[0369] Intermediate c

[0370] ((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0371] Step A: (S)-1-(tert-butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate

[0372] Dissolve (R)-3-methyl-1-(tert-butyl)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (10.0 g, 36.86 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (10.68 g, 55.29 mmol) in anhydrous DMF (100 mL) and replace the atmosphere with nitrogen three times. Cool the mixture in a dry ice-ethanol bath and add a 1 M solution of potassium tert-butoxide in tetrahydrofuran (66.34 mL, 66.34 mmol) dropwise. The resulting mixture is stirred at room temperature for 2 h, then slowly warmed to room temperature and stirred for another 3 h. After completion of the reaction, as monitored by LCMS, the reaction is quenched with saturated aqueous ammonium chloride (50 mL) and extracted five times with water (200 mL) and DCM / MeOH (100 mL, v / v = 10 / 1). The product was washed three times with aqueous LiCl solution (100 mL, 4% w / w), then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-20%) to afford a pale yellow oil (5.2 g, 46% yield). LCMS (m / z): 250.1 (M-56+H).

[0373] Step B: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester

[0374] At room temperature, (S)-1-(tert-butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (6.20 g, 20.31 mmol) was dissolved in methanol (150 mL) and the atmosphere was replaced with nitrogen three times. Palladium on carbon (2.16 g, 10% w / w) was added and the atmosphere was replaced with hydrogen three times. The mixture was stirred at 30°C under a 15 psi hydrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was filtered through celite, and the filter cake was washed three times with methanol. The filtrate was collected and concentrated to dryness to afford the product, (3S,4S)-1-(tert-butyl)-3-methyl-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (5.53 g, 89% yield), as a colorless oil. LCMS (m / z): 252.1 (M-56+H).

[0375] Step C: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0376] At room temperature, (3S,4S)-1-(tert-butyl)-3-methyl-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (5.53 g, 17.99 mmol) was dissolved in 4M HCl / dioxane (60 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated to remove the acid solution, affording (3S,4S)-methyl-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (4.38 g, 100% yield) as a white solid. LCMS (m / z): 208.1 (M+H).

[0377] Step D: Methyl (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate

[0378] Methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (3.58 g, 14.69 mmol) was dissolved in methanol (40 mL) at room temperature, and aqueous formaldehyde (3.58 g, 37% w / w, 44.07 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (1.11 g, 17.63 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 h. After completion of the reaction, monitored by LCMS, the system was concentrated to dryness, the crude product was dissolved in ethyl acetate, and filtered through Celite. The filtrate was purified by FCC (SiO2, MeOH / DCM (containing 0.3% DIEA) = 0-4%) to afford methyl (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (3.0 g, 92% yield) as a colorless oil. LCMS (m / z): 222.1 (M+H).

[0379] Step E: (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0380] Under ice-cooling conditions, 1 M LiAlH₄-THF (17.63 mL, 17.63 mmol) was added dropwise to a solution of (3S,4S)-methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (3.0 g, 13.56 mmol) in anhydrous THF (30 mL). The resulting mixture was stirred at 0°C for 15 min. After completion of the reaction, sodium sulfate decahydrate was added to quench the reaction until no bubbles formed, as monitored by LCMS. Approximately 8 g of anhydrous sodium sulfate was added. The mixture was filtered through celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to afford (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (2.6 g, 99% yield) as a colorless solid. LCMS (m / z): 194.1 (M+H).

[0381] Intermediate b-d3

[0382] (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0383] Step A: Methyl (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0384] Potassium carbonate (5.55 g, 40.2 mmol) was added to a mixture of (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.00 g, 13.4 mmol), deuterated iodomethane (2.33 g, 16.1 mmol), and ACN (100 mL) at room temperature. After complete addition, the mixture was heated to 90°C and stirred overnight. After completion of the reaction, the mixture was filtered and the filter cake was rinsed with EA (50 mL). The filtrate was concentrated and further purified by FCC (SiO2, EA / PE = 0-20%) to afford (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylic acid methyl ester (1.9 g, 69% yield) as a colorless liquid. LC-MS (m / z): 205.1 (M+H).

[0385] Step B: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0386] Under ice-cooling, LiAlH₄ (1M-THF, 9.3 mmol, 9.3 mL) was added dropwise to a mixture of (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d₃)piperidine-3-carboxylic acid methyl ester (1.9 g, 9.3 mmol) and THF (50 mL). After complete addition, the mixture was stirred in an ice-cooling bath at 0°C for 0.5 h. After completion of the reaction, as monitored by LCMS, the reaction was quenched with Na₂SO₄·10H₂O until gas evolution ceased. The reaction solution was filtered through celite, and the filtrate was concentrated at low temperature (35°C) to afford 4-fluoromethylene-3-methyl-1-methyl-d₃-piperidine-3-methanol (1.3 g, 79% yield) as a colorless liquid. LC-MS (m / z): 177.1 (M+H).

[0387] Intermediate b-d5

[0388] (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol

[0389] Step A: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol

[0390] LiAlD4 powder (271.28 mg, 6.46 mmol) was added to a solution of (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-carboxylic acid methyl ester (1.10 g, 5.39 mmol) in anhydrous tetrahydrofuran (15 mL) under ice-cooling conditions. The resulting mixture was stirred at room temperature for 15 min. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles formed, as monitored by LCMS. Approximately 5 g of anhydrous sodium sulfate was then added to the reaction solution to remove water. The reaction solution was filtered through celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to obtain (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol (951 mg, 99% yield) as a colorless oil. This product was used directly in the next reaction without further purification. LCMS (m / z): 179.1 (M+H).

[0391] Intermediate c-d3

[0392] ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0393] The synthesis of intermediate c-d3 was described with reference to the synthesis of intermediate b-d3, using intermediate c-1-3 in step A. LCMS (m / z): 197.1 (M+H).

[0394] Intermediate c-d5

[0395] ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0396] The synthesis of intermediate c-d5 was described as for the synthesis of intermediate b-d5, using intermediate c-1-3-d3 in step A. LCMS (m / z): 199.1 (M+H).

[0397] The following intermediates were synthesized according to the above method.

[0398] Intermediate L

[0399] (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid

[0400] Step A: 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol

[0401] With stirring in an ice bath, TIPSCl (177 g, 920 mmol) was added dropwise to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (CAS: 2621932-34-9, 300 g, 837 mmol) and imidazole (119 g, 1.76 mol) in DCM (3 L). After the addition was complete, the system was slowly warmed to room temperature and stirred for 6 h. TLC monitored the reaction for completion. Water (900 mL) was added, stirred for 30 min, and the layers separated. The aqueous phase was extracted with DCM (900 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness, and purified on a silica gel plug (PE / EA = 50:1) to yield 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-ol (397 g, 92% yield).

[0402] Step B: 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate

[0403] Trifluoromethanesulfonic anhydride (326 g, 1.16 mol) was added dropwise to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol (397 g, 0.77 mol) and DIPEA (298 g, 2.31 mol) in DCM (4 L) at -45 to -35°C. After the addition was complete, stirring was continued at the same temperature for 0.5 h. The reaction was monitored for completion by TLC. The system was added to water (800 mL), the layers were separated, and the aqueous phase was extracted with DCM (1.2 L). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The reaction mixture was purified by silica gel plug (PE / EA=50:1) to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (469 g, yield 94%).

[0404] Step C: (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid

[0405] Under nitrogen, Pd(dppf)Cl2 (13.2 g, 18.2 mmol) was added to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (235 g, 0.36 mol), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborolane) (164 g, 0.73 mol), and potassium acetate (107 g, 1.1 mol) in dioxane (2.4 L). The temperature was raised to 85°C and stirred for 20 h. The reaction was monitored by TLC for completion. The mixture was cooled to room temperature, filtered through celite, rinsed with EA, concentrated, and purified on a silica gel column (EA / PE = 0-5%) to yield the crude compound.

[0406] The crude compound was dissolved in methanol (1.2 L), and 1N HCl (2.4 L) was added. The resulting mixture was stirred at room temperature for 30 minutes. EA (2.4 L) was added and stirring continued for 2 hours. The mixture was allowed to stand and separate. The organic phase was washed sequentially with water (2.4 L) and saturated brine (2.4 L x 2) and concentrated to yield (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (183 g, 92% yield). 1 H NMR(400MHz,Chloroform-d)δ7.66–7.60(m,1H),7.34(d,J=2.5Hz,1H),7.24–7.19(m,1H),7.18(d,J=2.5Hz,1H),4.5 2(s,2H),1.35–1.29(m,3H),1.24–1.21(m,3H),1.20–1.17(m,18H),1.12(d,J=7.3Hz,18H).LCMS(m / z):543.3(M+H).

[0407] Example 1

[0408] 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0409] Step A: 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0410] Under N2, to a solution of 6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (400 mg, 1.1 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS: 262193248-5, 406 mg, 1.1 mmol), potassium phosphate (700 mg, 3.3 mmol), and cata CXium A Pd-G3 (240 mg, 0.33 mmol). The reaction mixture was stirred at 100°C for 2 h. After completion of the reaction, as monitored by LCMS, the reaction solution was filtered through celite, the filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO2, EA / PE = 0-35%) to give 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (420 mg, 67% yield) as a yellow solid. LCMS (m / z): 553.1 (M+H).

[0411] Step B: 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0412] To a solution of 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (420 mg, 0.76 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (154 mg, 0.76 mmol) at room temperature. The reaction was stirred and maintained at this temperature for 1 hour. After completion of the reaction, as monitored by LCMS, 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, which was then extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (380 mg). LCMS (m / z): 569.1 (M+H).

[0413] Step C: 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0414] To a solution of 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (300 mg) and ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (132 mg, 0.69 mol) in anhydrous tetrahydrofuran (6 mL) was added a 1N sodium bis(trimethylsilyl)amide solution (0.22 mL, 0.22 mmol) at -40°C. The reaction mixture was allowed to react at -40°C for 2 h. After the reaction was completed as monitored by LCMS, the reaction solution was poured into 30 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a crude yellow solid product, 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (400 mg). LCMS (m / z): 698.3 (M+H).

[0415] Step D: 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0416] At room temperature, TFA (2 mL) was added to compound 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (300 mg), and the reaction was stirred at the maintained temperature for 0.5 h. After the reaction was completed, the reaction solution was purified by pre-HPLC (C18, CAN / (10 mmol)). The reaction mixture was stirred for 2 hours and then purified by stirring at 4 ℃ for 10 minutes (NH4HCO3 / H2O)=55-75%) to give a white solid product 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (45 mg, yield 14%). 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.23(s,1H),7.77(dd,J=9.1,6.0Hz,1H), 7.40–7.30(m,2H),7.05(dd,J=4.3,2.7Hz,1H),6.31(t,J=55.7Hz,1H),4.53–4 .12(m,6H),4.08–3.85(m,1H),3.61–3.41(m,1H),2.89–2.74(m,2H),2.46–2.3 1(m,3H),2.19–2.04(m,5H),1.93–1.58(m,8H),1.12(s,3H),0.79–0.69(m,3H). 19 F NMR (376MHz, DMSO-d6) δ -119.52~-119.65, -139.08~-139.27. LCMS (m / z): 654.3 (M+H).

[0417] Examples 2 and 3

[0418] 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-((R)-1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol and 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-((S)-1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0419] Step A: 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 1, 45 mg) was separated by SFC (Waters SFC 150, REGIS(S,S)WHELK-O1 (250*40mm 10μm), Supercritical CO2 / EtOH (+0.1% 7.0mol / l Ammonia in MeOH)=80 / 20). The first eluting isomer was Example 2 (5 mg, relatively short retention time). Chiral analysis method SFC-1, Rt=4.409 min. 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.23(s,1H),7.77(dd,J=9.1,6.0Hz,1H),7.41–7.29(m,2H),7.12–6.99(m,1H),6.31(t,J=56.0Hz,1H),4. 49–3.88(m,7H),3.60–3.46(m,1H),2.91–2.75(m,2H),2.44–2.30(m,3H ),2.15–2.03(m,5H),1.89–1.61(m,8H),1.12(s,3H),0.78–0.70(m,3H). 19 F NMR (376 MHz, DMSO-d6) δ -115.43 to -119.39, -119.58, -139.08 to -139.25. LCMS (m / z): 654.3 (M+H). The subsequent eluting isomer was Example 3 (16 mg, relatively long retention time). Chiral analysis method SFC-1, Rt = 5.262 min. 1 H NMR(400MHz, DMSO-d6)δ9.95(s,1H),9.22(s,1H),7.77(dd,J=9.1,6.0Hz,1H),7.42–7.28(m,2H),7.13–6.98(m,1H),6.31(t,J=55.6Hz,1H),4. 56–3.85(m,7H),3.65–3.45(m,1H),2.88–2.78(m,2H),2.45–2.32(m,3H ),2.16–2.05(m,5H),1.88–1.59(m,8H),1.12(s,3H),0.79–0.66(m,3H). 19F NMR (376MHz, DMSO-d6) δ -115.55~-119.41, -119.56~-119.60, -139.07~-139.28. LCMS (m / z): 654.3 (M+H).

[0420] Chiral analysis method SFC-1: Waters UPCC (CA-352), analytical column: REGIS (S,S) WHELK-O1 (100*3 mm*3 μm); mobile phase A: CO2, mobile phase B: EtOH (+0.1% 7.0 mol / l Ammonia in MeOH); flow rate: 1.5 mL / min; column temperature: 35°C; back pressure: 1800 psi; gradient: 0-8.0 min A / B = 80 / 20.

[0421] The following compounds were prepared and characterized according to the above synthetic scheme and appropriate variations:

[0422] Example 17

[0423] 4-(2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza-6-spiro[3.5]nonyl)-6,8-difluoro-7-quinazolinyl)-5-ethyl-6-fluoro-2-naphthol

[0424] Step A: 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-2,6,8-trifluoroquinazoline

[0425] Under N2, to a solution of 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-bromo-2,6,8-trifluoroquinazoline (200 mg, 0.5 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (278 mg, 0.7 mmol), potassium phosphate (218 mg, 1.0 mmol), and cata CXium A Pd-G3 (111 mg, 0.15 mmol). The resulting reaction solution was stirred at 100°C for 5 h. After completion of the reaction, as monitored by LCMS, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-45%) to give 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-2,6,8-trifluoroquinazoline (190 mg, 68% yield) as a yellow solid. LCMS (m / z): 542.2 (M+H).

[0426] Step B: 2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-6,8-difluoroquinazoline

[0427] To a solution of 4-((S)-1-oxo-6-aza-6-spiro[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-2,6,8-trifluoroquinazoline (80 mg, 0.15 mol) and ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (43 mg, 0.22 mol) in anhydrous tetrahydrofuran (5 mL) was added NaH (12 mg, 0.30 mmol) at 0°C. The reaction mixture was allowed to react at 0°C for 1 h. After completion of the reaction, as monitored by LCMS, the reaction solution was poured into 30 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by FCC (SiO2, EA / PE = 30-60%) to give 2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-6,8-difluoroquinazoline (70 mg, 66% yield) as a yellow solid. LCMS (m / z): 715.2 (M+H).

[0428] Step C: 4-(2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza-6-spiro[3.5]nonyl)-6,8-difluoro-7-quinazolinyl)-5-ethyl-6-fluoro-2-naphthol

[0429] At room temperature, TFA (1 mL) was added to the compound 2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza[3.5]nonyl)-7-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-6,8-difluoroquinazoline (70 mg, 0.1 mol), and the reaction was stirred at the maintained temperature for 0.5 h. After completion of the reaction, as monitored by LCMS, the reaction solution was purified by pre-HPLC (C18, ACN / (10 mmol NH4HCO3 / H2O) = 55-75%) to give 4-(2-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-4-((S)-1-oxa-6-aza-6-spiro[3.5]nonyl)-6,8-difluoro-7-quinazolinyl)-5-ethyl-6-fluoro-2-naphthol (2 mg, 3% yield) as a white solid. LCMS (m / z): 671.3 (M+H).

[0430] Example 27

[0431] 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0432] Step A: 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0433] Under N2, to a solution of 6-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (500 mg, 1.4 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (1.15 g, 2.1 mmol), potassium phosphate (897 mg, 4.2 mmol), and cata CXium A Pd-G3 (103 mg, 0.14 mmol). The reaction mixture was stirred at 100°C for 5 h. After completion of the reaction, as monitored by LCMS, the reaction solution was filtered through celite, and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-15%) to give 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (370 mg, 32% yield) as a yellow solid. LCMS (m / z): 718.3 (M+H).

[0434] Step B: 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0435] To a solution of 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (370 mg, 0.45 mmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (92 mg, 0.45 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LCMS, 20 mL of saturated sodium bicarbonate solution was added to the reaction solution, which was then extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude product 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (380 mg). LCMS (m / z): 833.2 (M+H).

[0436] Step C: 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane

[0437] To a solution of 6-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (180 mg, 0.22 mol) and ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (50 mg, 0.26 mol) in anhydrous tetrahydrofuran (5 mL) was added 1N sodium bis(trimethylsilyl)amide solution (0.44 mL, 0.44 mmol) at -40°C. The reaction mixture was allowed to react at -40°C for 1 hour. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a crude yellow solid product, 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (130 mg). LCMS (m / z): 962.3 (M+H).

[0438] Step D: 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0439] To a solution of compound 6-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (130 mg, 0.13 mol) in DMF (2 mL) was added CsF (205 mg, 1.3 mmol) at room temperature, and the reaction was stirred at 50°C for 1 h. After the reaction was completed as monitored by LCMS, the reaction solution was purified by pre-HPLC (C18, CAN / (10 mmol NH4HCO3 / H2O) = 45-75%) to give a white solid product 4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (32 mg, yield 36%). 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.29–9.06(m,1H),7.98(dd,J=9.3,5.8Hz,1H) ,7.51–7.43(m,1H),7.40(d,J=2.5Hz,1H),7.21(dd,J=5.0,2.5Hz,1H),6.32(t,J=55 .4Hz,1H),4.52–4.10(m,6H),4.04–3.80(m,2H),3.58–3.41(m,1H),3.30(s,1H),2.9 1–2.76(m,2H),2.44–2.31(m,1H),2.21–2.00(m,4H),1.97–1.55(m,8H),1.13(s,3H). 19 FNMR (376MHz, DMSO-d6) δ-110.71,-140.03. LCMS (m / z): 650.3 (M+H).

[0440] Example 57

[0441] 7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-8-ethyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol

[0442] Step A: (2-(1',7-difluoro-7'-(methylthio)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphthyl-8-{ethynyl)tri(isopropyl)silane

[0443] At room temperature, a mixture of 7-chloro-8-fluoro-2-(methylthio)-4-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-1,3,6-triazine (1.83 g, 3.38 mmol), cataCXium A Pd G3 (274 mg, 376 μmol), K3PO4 (980 mg, 5.66 mmol), and 1,4-dioxane / H2O = 4 / 1 (15 mL) was replaced with nitrogen three times, then heated to 110°C and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into H2O (100 mL) and extracted with EA (60 mL × 3). The collected organic phase was washed with saturated NaCl (20 mL) and concentrated. The crude product was purified by FCC (EtOH / EA = 1 / 3) / PE = 0-20%) to give 2-{1',7-difluoro-7'-(methylthio)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphthyl-8-{ethynyl)tri(isopropyl)silane as a yellow solid (900 mg, 59%). LCMS (m / z): 804.2 (M+H).

[0444] Step B: (2-(1',7-difluoro-7'-(methylsulfinyl)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6'-,8'-triaza-1,2'-binaphthyl-8'-ethynyl)tri(isopropyl)silane

[0445] At room temperature, m-chloroperbenzoic acid (273 mg, 1.34 mmol, 85% content) was added to a solution of 2-(1',7-difluoro-7'-(methylthio)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphthyl-8-(ethynyl)tri(isopropanol)silane (900 mg, 1.34 mmol) and DCM (15 mL) and stirred at room temperature for 2 h. After the reaction was completed as monitored by TLC and LCMS, the reaction solution was diluted with DCM (50 mL) and half-saturated aq The mixture was washed with NaHCO₃ (20 mL) and extracted with DCM (60 mL x 3). The organic phase was collected, washed with saturated NaCl (30 mL), dried over anhydrous Na₂SO₄, filtered, and the organic solution was concentrated to obtain (2-{1',7-difluoro-7'-(methylsulfinyl)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6'-,8'-triaza-1,2'-binaphthyl-8'-ethynyl)tri(isopropyl)silane (900 mg, 98% yield) as a yellow solid. LCMS (m / z): 819.2 (M+H).

[0446] Step C: [2-(7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphth-8-yl)ethynyl]tri(isopropyl)silane

[0447] At -78 ° C, t-BuONa (0.73 mL, 2.0 M THF solution, 1.46 mmol) was added dropwise to a solution of [(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl] methanol (85 mg, 440 umol) in THF (3 mL) and stirred for 0.5 h. Then, (2-{1',7-difluoro-7'-(methylsulfinyl)-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6'-,8'-triaza-1,2'-binaphthyl-8'-ethynyl)tri(isopropyl)silane (300 mg, 366 umol) was added to the reaction solution and stirred at -78 ° C for 1 h. After the reaction was completed, the reaction solution was poured into half-saturated NH4Cl (50 mL) and extracted with EA (50 mL×3). The organic phase was collected, washed with saturated NaCl (20 mL) solution, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by FCC (SiO2, (EtOH / EA=1 / 3) / PE=0-40%) to give a yellow solid [2-(7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphth-8-yl)ethynyl]tri(isopropyl)silane (110 mg, yield 32%). LCMS (m / z): 474.8 (M / 2+H).

[0448] Step D: 7'-{[(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy}-8-ethynyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol

[0449] CsF (100 mg, 0.66 mmol) was added to a solution of [2-(7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3-[tri(isopropyl)methoxy]-3',6',8'-triaza-1,2'-binaphth-8-yl)ethynyl]tri(isopropyl)silane (110 mg, 116 umol) in DMF (3 mL) at room temperature. The reaction mixture was heated to 45°C for 1 h. After completion of the reaction, the reaction mixture was purified by Pre-HPLC (C18, ACN / 10 mM NH4HCO3 = 50-80%) to give 7'-{[(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy}-8-ethynyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol (60 mg, 81% yield) as a pale yellow solid. LCMS (m / z): 636.3 (M+H). 1 H NMR(400MHz, Methanol-d4)δ9.43–9.30(m,1H),7.91–7.80(m,1H),7.38–7.26(m,2H),7.22(d,J=2.5Hz,1H), 6.20(t,J=55.6Hz,1H),4.80–4.50(m,3H),4.06–3.95(m,1H),3.90–3.78(m,2H),3.74–3.65(m,1H),3.55–3.4 9(m,0.6H),3.41–3.34(m,1H),3.27–3.25(m,0.4H),3.16–3.05(m,1H),3.01–2.92(m,1H),2.49–2.32(m,1H) ,2.24(s,3H),2.05–1.70(m,6H),1.47–1.38(m,1H),1.32–1.27(m,1H),1.24–1.16(m,3H),0.96–0.75(m,1H). 19 F NMR (376MHz, Methanol-d4) δ-110.94–-113.36, -118.79–-122.50, -139.31–-140.89.

[0450] Step E: 7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-8-ethyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol

[0451] At room temperature, 7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-8-ethynyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol (30 mg, 47.2 μmol) and Pd / C (28 mg, 10% w / w, 23.6 μmol) were dissolved in methanol (10 mL). The air was replaced twice with an H2 balloon, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, which was monitored by LCMS, the reaction mixture was filtered to obtain a clear organic phase, which was then concentrated completely. Acetonitrile (1 mL) and deionized water (2 mL) were added, and the mixture was lyophilized to give 7'-([(3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl]methoxy)-8-ethyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol (20 mg, 66% yield) as a white solid. LCMS (m / z): 640.3 (M+H). 1 H NMR (400MHz, Methanol-d4) δ9.46–9.33(m,1H),7.67(dd,J=9.0,5.9Hz,1H),7.29(d,J=2.7Hz,1H),7. 27–7.19(m,1H),7.11–7.04(m,1H),6.20(t,J=55.6Hz,1H),4.76–4.49(m,3H),4.05–3.94(m,1H),3.89 –3.78(m,2H),3.75–3.63(m,1H),3.43–3.34(m,1H),3.15–3.04(m,1H),3.00–2.90(m,1H),2.53–2.33( m,2H),2.25–2.15(m,4H),1.98–1.72(m,6H),1.45–1.36(m,1H),1.25–1.17(m,3H),0.87–0.68(m,4H). 19 F NMR (376MHz, Methanol-d4) δ-117.86–-123.89,-136.19–-142.09.

[0452] The following compounds were prepared and characterized according to the above synthetic schemes and appropriate variations.

[0453] Example 81

[0454] 7'-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-8-ethynyl-1',7-difluoro-5'-(2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-3',6',8'-triaza-[1,2'-binaphthyl]-3-ol

[0455] The synthesis of Example 81 was carried out according to the relevant steps described in Example 57. LCMS (m / z): 636.3 (M+H). 1 H NMR(400MHz, Methanol-d4)δ9.43–9.30(m,1H),7.91–7.80(m,1H),7.38–7.26(m,2H),7.22(d,J=2.5Hz,1H), 6.20(t,J=55.6Hz,1H),4.80–4.50(m,3H),4.06–3.95(m,1H),3.90–3.78(m,2H),3.74–3.65(m,1H),3.55–3.4 9(m,0.6H),3.41–3.34(m,1H),3.27–3.25(m,0.4H),3.16–3.05(m,1H),3.01–2.92(m,1H),2.49–2.32(m,1H) ,2.24(s,3H),2.05–1.70(m,6H),1.47–1.38(m,1H),1.32–1.27(m,1H),1.24–1.16(m,3H),0.96–0.75(m,1H). 19 F NMR (376MHz, Methanol-d4) δ-110.94–-113.36, -118.79–-122.50, -139.31–-140.89.

[0456] Example 82

[0457] 7'-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-5'-((1S,7S)-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-8-ethynyl-1',7-difluoro-3',6',8'-triaza-(1,2'-binaphthyl)-3-ol

[0458] The synthesis of Example 82 was carried out according to the synthesis of Example 57, using intermediate A-II-A in step A. LCMS (m / z): 636.3 (M+H). 1 H NMR(400MHz, Methanol-d4)δ9.47–9.30(m,1H),7.96–7.73(m,1H),7.43–7.29(m,2H),7.26–7.16(m,1H),6.47–5.97( m,1H),4.59–4.49(m,3H),4.08–3.95(m,1H),3.90–3.78(m,2H),3.76–3.65(m,1H),3.54–3.47(m,0.5H),3.20–3.06(m ,1H),3.03–2.92(m,1H),2.60–2.41(m,1H),2.24(s,3H),2.21–2.15(m,0.5H),2.07–1.96(m,2H),1.95–1.86(m,1H),1 .83–1.73(m,3H),1.66–1.52(m,0.5H),1.48–1.39(m,1H),1.25–1.17(m,3H),0.96–0.87(m,1H),0.84–0.75(m,0.5H). 19 F NMR (376MHz, Methanol-d4)δ-111.71,-119.23,-121.69,-140.14.

[0459] Example 83

[0460] 7'-(((3S,4S)-4-(difluoromethyl)-1-methyl-3-methyl-3-piperidinyl)methoxy)-5'-((1S,7S)-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-8-ethynyl-1',7-difluoro-3',6',8'-triaza-(1,2'-binaphthyl)-3-ol

[0461] The synthesis of Example 83 was carried out according to the synthesis of Example 57, using intermediate A-II-B in step A. LCMS (m / z): 636.3 (M+H). 1H NMR(400MHz, Methanol-d4)δ9.46–9.30(m,1H),7.94–7.75(m,1H),7.44–7.27(m,2H),7.21(d,J=2.6Hz,1H),6.43 –6.00(m,1H),4.78–4.70(m,1H),4.63–4.50(m,2H),4.08–3.94(m,1H),3.90–3.79(m,2H),3.76–3.65(m,1H),3.57 –3.50(m,0.5H),3.43–3.35(m,1H),3.27–3.23(m,0.5H),3.17–3.08(m,1H),3.01–2.91(m,1H),2.50–2.31(m,1H), 2.29–2.16(m,3H),2.05–1.89(m,2H),1.87–1.70(m,4H),1.47–1.38(m,1H),1.24–1.17(m,3H),0.94–0.76(m,1H). 19 F NMR (376MHz, Methanol-d4)δ-111.77,-119.41,-121.48,-140.13.

[0462] The following compounds were synthesized and characterized according to the above synthetic scheme and appropriate variations.

[0463] Active Examples

[0464] Example 1: Inhibitory effect of the compounds of the present invention on proliferation of KRAS G12V mutant NCI-H727 cells

[0465] This experiment evaluated and verified the proliferation inhibitory activity of the compounds of the present invention on KRAS G12V mutant NCI-H727 cells.

[0466] NCI-H727 cells (Nanjing Kebai Biotechnology Co., Ltd., product number CBP60182, adherent, culture medium RPMI-1640 + 10% FBS (GIBCO, Cat#10091-148)) were cultured at 37°C, 5% CO2, and 95% humidity.

[0467] 3D cell viability assay: Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Prepare RPMI-1640 medium containing 1% MC (Sigma, Cat#M0512) and 10% FBS to prepare 3D cell culture medium. Adjust the cell concentration to 14815 cells / mL and the MC content to 0.65% using 3D culture medium. Add 135 μL of the cell suspension to each well of a 96-well, clear, flat-bottom, black-walled plate (Greiner, Cat#655096). Incubate the cells in the 96-well plate at 37°C, 5% CO2 overnight.

[0468] IC50 determination drug preparation: Prepare 10x drug solution in culture medium and add 10 μL of drug solution to each well of a 96-well plate seeded with cells to make the working concentration up to 10 μM. 3x dilution, 9 concentrations, and 2 replicates for each drug concentration. The cells in the 96-well plate with drug were cultured at 37°C and 5% CO2 for 7 days before CTG assay ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).

[0469] Equilibrate the cell plate to room temperature for 30 minutes and thaw the CTG reagent ( Luminescent Cell Viability Assay (Promega, Cat# G7573) was used. 75 μL of CTG solution was added to each well and the cells were shaken on an orbital shaker for 5 minutes to lyse the cells. The cell plate was placed at room temperature for 25 minutes to stabilize the luminescence signal and the luminescence value was read ( Multi-function microplate reader, PerkinElmer #2105).

[0470] Data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was used to fit the data to obtain a dose-effect curve, from which the IC50 value was calculated.

[0471] Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0472] The compounds of the present invention exhibit satisfactory antiproliferative activity against KRAS G12V mutated NCI-H727 human lung cancer cells, with IC50 values ​​in the range of <1000 nM, preferably <100 nM. Representative activity data are shown in the following table:

[0473] Example 2: Inhibitory effect of the compounds of the present invention on the proliferation of AGS cells with KRAS G12D mutation

[0474] This experiment evaluated and verified the proliferation inhibitory activity of the compounds of the present invention on KRAS G12D mutant AGS cells.

[0475] AGS cells (Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60476, adherent) were cultured in F12K Nutrient Mixture + 10% FBS (GIBCO, Cat. #10091-148) at 37°C, 5% CO2, and 95% humidity at 1500 cells / well. Cells in the logarithmic growth phase were harvested and counted and viability was determined using a Countstar automated cell counter based on the classic trypan blue staining method to ensure that cell viability was above 90%. The cell concentration was adjusted; 80 μL of the cell suspension was added to each 96-well clear flat-bottom black-walled plate (Greiner, Cat. #655090), and the cells in the 96-well plate were cultured at 37°C, 5% CO2.

[0476] IC 50 Assay drug preparation: Prepare a 5x drug solution in culture medium and add 20 μL of the drug solution to each well of a 96-well plate seeded with cells, achieving a working concentration of up to 10 μM. Perform a 3x dilution across nine concentrations, with two replicates per well. Incubate the cells in the drug-treated 96-well plate at 37°C, 5% CO2 for 3 days before performing the CTG assay.

[0477] Equilibrate the cell plate to room temperature for 30 minutes and thaw the CTG reagent ( Luminescent Cell Viability Assay (Promega, Cat# G7573) was used. 50 μL of CTG solution was added to each well and the cells were shaken on an orbital shaker for 2 minutes to lyse the cells. The cell plate was placed at room temperature for 10 minutes to stabilize the luminescence signal and the luminescence value was read ( Multi-function microplate reader, PerkinElmer #2105).

[0478] Data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was used to fit the data to obtain a dose-effect curve, from which the IC50 value was calculated.

[0479] Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%.

[0480] The compounds of the present invention show satisfactory anti-proliferative activity against AGS human gastric adenocarcinoma cells with KRAS G12D mutation, with IC50 ranging from <1000 nM, preferably <100 nM. Representative activity data are shown in the table below.

[0481] Example 3: Pharmacokinetic properties of the compounds of the present invention in rats by cassette administration

[0482] The pharmacokinetic characteristics of the compounds of the present invention were evaluated by rat Cassette pharmacokinetic experiment (Nagilla R. et al., J. Pharm. Sci. 2011, 100, 3862-3874).

[0483] This study used male SD rats, aged 6-8 weeks and weighing 220-250 g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and used the following reagents: tolbutamide (Aladdin, product number H1401054); sulfobutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biological, product number 20191013); propylene glycol (15) stearate (Solutol, Meilun Biological, product number S0206A); DMSO (Vetec, product number WXBD0293V); acetonitrile (Sigma-Aldrich, product number WXBD1744V); methanol (Sigma-Aldrich, product number WXBD2831V).

[0484] The compound combination was formulated in a solvent of 5% DMSO / 10% Solutol / 85% (20% Captisol) to a final concentration of 1 mg / mL for each compound. The drug formulation was injected into the tail vein of SD rats at an injection volume of 1 mL / kg. Blood was collected by puncture of the external jugular vein at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. The blood was centrifuged at low temperature for 20 minutes, and the plasma was collected and stored at -20°C for testing.

[0485] The LC-MS / MS analysis method for the compounds was established as follows:

[0486] Preparation of standard curve: For each compound, aspirate 20 μL of 1 mg / mL DMSO stock solution and transfer it to 900 μL of 50% methanol working solution. Dilute the solution serially to obtain a standard curve working solution with the concentrations of 20,000, 10,000, 5,000, 1,000, 500, 100, 50, 20, and 10 ng / mL. Then, aspirate 5 μL of the standard curve working solution and mix it with 45 μL of rat blank plasma to obtain a standard curve with the concentrations of 2,000, 1,000, 500, 100, 50, 10, 5, 2, and 1 ng / mL for quantification of unknown samples.

[0487] Sample pretreatment: 50 μL of unknown plasma sample and standard curve sample were added with 250 μL of acetonitrile containing tolbutamide as internal standard as precipitant to precipitate plasma proteins and extract the test compounds in the plasma. The samples were centrifuged at low temperature for 20 minutes, and the supernatant was collected and mixed with 0.1% formic acid in water. 5 μL of the supernatant was injected and the blood drug concentration was analyzed by LC-MS.

[0488] Mass spectrometry software Analyst 1.6.1 was used to draw a standard curve and quantify unknown samples. Pharmacokinetic parameters were calculated using Winnonlin 8.2 based on the drug concentrations at each time point of the unknown samples.

[0489] The experimental results showed that the compounds of the present invention exhibited good pharmacokinetic properties in the cassette administration pharmacokinetic evaluation.

[0490] Example 4: Cytochrome P450 inhibition test of the compounds of the present invention

[0491] This experiment evaluates the inhibitory effect of the inventive compounds on cytochrome P450.

[0492] The following reagents were used in this experiment: human liver microsomes (Corning, Catalog No. 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE, Catalog No. HY-F0003 / CS-4998); phenacetin, diclofenac, α-naphthoflavone, omeprazole, and ketoconazole were all purchased from TCI; S-mephenytoin and testosterone were purchased from CAYMAN; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from Damas-beta; sulfaphenazole was purchased from MCE; and bufuralol was purchased from TRC.

[0493] 100 mM potassium phosphate buffer (K-buffer) was prepared with potassium dihydrogen phosphate and dipotassium hydrogen phosphate, and the pH was adjusted to 7.4 to prepare 0.1 M potassium phosphate buffer (K-buffer).

[0494] Prepare a 400× test compound by dissolving 8 μL of a 10 mM test compound stock solution in 12 μL of acetonitrile. Prepare a mixed solution of CYP1A2, CYP2C9, and CYP2D6 inhibitors by mixing 12 μL of 1 mM α-naphthoflavone, 10 μL of 40 mM sulfaphenazole, 10 μL of 10 mM quinidine, and 8 μL of DMSO. Prepare a CYP3A4 inhibitor solution by dissolving 8 μL of a 2.5 mM ketoconazole DMSO solution in 12 μL of acetonitrile. Prepare a CYP2C19 inhibitor solution by dissolving 8 μL of a 100 mM omeprazole DMSO solution in 12 μL of acetonitrile.

[0495] Prepare a 4× NADPH potassium phosphate solution by adding 66.7 mg of NADPH to 10 mL of 0.1 M K-buffer, pH 7.4. Prepare a 4× substrate potassium phosphate solution by adding 10 mL of 0.1 M K-buffer to a solution 4 times the required concentration for the assay.

[0496] Add 10 μL of 20 mg / mL human liver microsomes to 990 μL of K-buffer to prepare a 0.2 mg / mL human liver microsome (HLM) solution, and store it in an ice bath until use.

[0497] Add 600 μL of 0.2 mg / mL HLM to a 96-well plate, followed by 3 μL of a 400-fold dilution of the test compound solution. Add 200 μL of 0.2 mg / mL HLM to a 96-well plate, followed by 1 μL of the diluted positive control inhibitor solution. Aliquot 30 μL of the compound-human liver microsome mixture into a 96-well plate, then add 15 μL of the substrate solution. Preheat the above solution and the prepared NADPH solution at 37°C for 5 minutes. Add 15 μL of the preheated NADPH solution to the reaction plate, mix well, and initiate the reaction. Incubate the reaction plate at 37°C. Incubate 3A4 for 5 minutes; 1A2, 2C9, and 2D6 for 10 minutes; and 2C19 for 45 minutes. At the end of the reaction, terminate the reaction by adding 120 μL of acetonitrile containing an internal standard. Vortex the sample for 10 minutes, centrifuge at 5594 g for 15 minutes, and prepare the sample for LC-MS / MS analysis.

[0498] The experimental results show that at the tested concentrations, the compounds of the present invention have no significant inhibitory effect on key CYP subtypes of drug metabolism, demonstrating better drug-drug interaction safety.

[0499] Example 5: Inhibitory effect of the compounds of the present invention on proliferation of KRAS G12C mutant NCI-H358 cells

[0500] This experiment evaluated and verified the proliferation inhibitory activity of the compounds of the present invention on KRAS G12C mutant NCI-H358 cells.

[0501] NCI-H358 cells (Nanjing Kebai Biotechnology Co., Ltd., product number CBP60136, adherent, culture medium RPMI-1640 + 10% FBS (GIBCO, Cat#10091-148)) were cultured at 37°C, 5% CO2, and 95% humidity.

[0502] 3D cell viability assay: Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Prepare RPMI-1640 medium containing 1% MC (Sigma, Cat#M0512) and 10% FBS to prepare complete 3D cell culture medium. Adjust the cell concentration to 12,500 cells / mL and the MC content to 0.65% using 3D culture medium. Add 80 μL of the cell suspension to each well of a 96-well, clear, flat-bottom, black-walled plate (Greiner, Cat#655096). Incubate the cells in the 96-well plate at 37°C, 5% CO2 overnight.

[0503] IC50 determination drug preparation: Prepare 5 times drug solution in culture medium, add 20 μL of drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, and 2 replicates for each drug concentration. The cells in the 96-well plate with drug addition were cultured at 37°C and 5% CO2 for 5 days, and then CTG assay was performed ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).

[0504] Equilibrate the cell plate to room temperature for 30 minutes and thaw the CTG reagent ( Luminescent Cell Viability Assay (Promega, Cat# G7573) was used. 50 μL of CTG solution was added to each well and the cells were shaken on an orbital shaker for 5 minutes to lyse the cells. The cell plate was placed at room temperature for 25 minutes to stabilize the luminescence signal and the luminescence value was read ( Multi-function microplate reader, PerkinElmer #2105).

[0505] Data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was used to fit the data to obtain a dose-effect curve, from which the IC50 value was calculated.

[0506] Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%.

[0507] The compounds of the present invention exhibit satisfactory anti-proliferative activity against KRAS G12C mutated NCI-H358 human lung cancer cells, with IC50 values ​​in the range of <1000 nM, preferably <100 nM. Representative activity data are shown in the table below.

[0508] Example 6: Inhibitory effect of the compounds of the present invention on the proliferation of 6 tumor cell lines

[0509] This experiment evaluated and verified the proliferation inhibitory activity of the compounds of the present invention on the following 6 KRAS-related tumor cell lines.

[0510] The following materials, reagents, and instruments were used in this experiment: six cell lines were obtained from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. (NCI-H441, KC-0510; Capan-2, KC-0185; A549, KC-0284; HCT116, KC-0281; NCI-H460, KC-0512; EBC-1, KC-0195; A375, KC-0158); RPMI-1640 (Hyclone, SH30809.01); fetal bovine serum (FBS) (GIBCO, 10099-141); methylcellulose (SIGMA, 9004-67-5); phosphate-buffered saline (PBS) (Solarbio, P1020-500); and CellCounting-Lite 2.0 Luminescent Cell Viability Assay. Assay (Nanjing Novozymes, DD1101-04); 96-well transparent flat-bottom black wall plate (Thermo, 165305); multifunctional microplate reader (BMG LABTECH, Plus); CO2 incubator (Thermo Scientific, Model 3100 Series).

[0511] Prepare sterile 1% methylcellulose 3D culture medium in advance. Harvest cells in the logarithmic growth phase and count them using a platelet counter. Assess cell viability using trypan blue exclusion to ensure viability is above 90%. Adjust the concentration of NCI-H441, A549, HCT116, NCI-H460, EBC-1, and A375 cells to a final methylcellulose concentration of 0.65%, mix well, and allow to stand. Once no visible gas is present in the cell suspension, add 180 μL of the cell suspension to each 96-well plate for a total of 2500 cells. Adjust the concentration of capan-2 cells using complete culture medium and add 180 μL of the cell suspension to each 96-well plate for a total of 3000 cells. Incubate the cells in the 96-well plate overnight at 37°C, 5% CO2, and 95% humidity.

[0512] IC 50 Assay drug preparation: First, prepare a 10 mM DMSO stock solution of each compound. Prepare nine concentrations of each compound in DMSO using a 3.16-fold dilution. A second 1:100 dilution of each compound was prepared using complete culture medium. Finally, add 20 μL of each compound dilution to each well of a 96-well plate seeded with cells. The final maximum drug concentration was 10 μM. Nine concentrations were measured using a 3.16-fold dilution, with triplicate wells for each concentration.

[0513] Incubate the treated cells in the 96-well plate at 37°C, 5% CO2 for 144 hours before performing CTG analysis. Thaw the CTG reagent and equilibrate the plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well. Shake on an orbital shaker for 5 minutes to lyse the cells. Allow the plate to stand at room temperature for 20 minutes to stabilize the luminescence signal. Read the luminescence value and collect the data.

[0514] Data were analyzed using GraphPad Prism 7.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 value.

[0515] Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 溶剂对照 -Lum 培养液对照 )×100%.

[0516] The compounds of the present invention, such as the compounds in the examples, showed satisfactory anti-proliferative activity against KRAS mutant cells and wild-type amplified cells in this example, with IC50 ranging from <1000 nM, preferably <500 nM. Representative activity data are shown in the table below.

[0517] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Therefore, such changes and modifications are intended to be covered by the appended claims.

[0518] All publications cited in this specification are herein incorporated by reference.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, Wherein: M is selected from N or C-R9; W is selected from N or C-R 10 ; R9 is selected from H, halogen, CN, NO2 and -C 1-6 alkyl optionally substituted by halogen; R 10 selected from H, halogen, CN, OH, -C 1-6 alkyl optionally substituted by halogen and -OC 1-6 alkyl; Z is selected from H, OH and NH2; X is selected from CH2 and O, provided that when k is 0, X is CH2; Y is selected from O, S, Se and N-R a ; R1 is selected from H and optionally substituted -C 1-6 alkyl, wherein the substituent is selected from halogen, D, and -O-C 1-6 alkyl optionally substituted by halogen or D; Each R2 is independently selected from H, D, and optionally substituted -C 1-6 alkyl, wherein the substituent is selected from halogen, D, and -O-C 1-6 alkyl which is optionally substituted by halogen or D; R3 is selected from H, D, halogen, -CN, -OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH2) n -C 3-6 cycloalkyl and =C(R c )2, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl is optionally substituted, and the substituents are selected from halogen, CN, D and -OC 1-6 alkyl optionally substituted by halogen, where the C 3-6 cycloalkyl is optionally substituted, and the substituents are selected from halogen, CN, D, -C 1-6 alkyl optionally substituted by halogen and -OC 1-6 alkyl, or Two R3 groups attached to the same ring carbon atom together with the carbon atom to which they are attached form a spiro C 3-6 cycloalkyl or spiro 4-7-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, S, said cycloalkyl or heterocycloalkyl being optionally substituted by halogen or -C 1-6 alkyl substituted with halogen; R4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH2) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl is optionally substituted, and the substituents are selected from D, halogen, CN, OH, -O-C 1-6 alkyl optionally substituted by halogen or D, and -OCON(R b )2, wherein the C 3-6 cycloalkyl is optionally substituted, and the substituents are selected from D, halogen, CN, OH, -C 1-6 alkyl optionally substituted by halogen or D, -O-C 1-6 alkyl optionally substituted by halogen or D, and -OCON(R b )2; R5 is selected from H, halogen, -CN, -NO2; R6 is selected from halogen, CN, -C 1-6 alkyl and -C 2-6 alkynyl, wherein the -C 1-6 alkyl and -C 2-6 alkynyl are each independently optionally substituted with halogen; R7 is selected from H, halogen, CN, -C 1-6 alkyl optionally substituted by halogen or D, -OC 1- 6alkyl and -C 2-6 alkynyl optionally substituted by halogen or D; R8 and R8' attached to non-adjacent ring carbon atoms together form an internal bridging -(CH2) 1-2 - or -CH2=CH2-, or R8 and R8' attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a 4- to 6-membered spiroalkyl group or a 4- to 6-membered spiroheteroalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S; or R8 and R8' attached to adjacent ring carbon atoms together with the ring carbon atoms to which they are attached form a fused C 3-6 cycloalkyl or a 4-6 membered fused heterocycloalkyl containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the bridged ring, spiro ring or fused ring is each independently optionally substituted, and the substituent is selected from OH, oxo, -OC 1-6 alkyl optionally substituted by halogen and -C 1-6 alkyl; R a and R b each independently selected from H and optionally halogen-substituted -C 1-6 alkyl; R c each independently selected from H, halogen, and -C 1-6 alkyl optionally substituted with halogen; k and n are each independently selected from integers from 0 to 3; and m is selected from integers from 0 to 6.

2. The compound of claim 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M is N.

3. The compound of claim 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M is C-F, C-Cl, C-CN, C-NO2, C-CF3.

4. The compound of any one of claims 1 to 3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein W is C-halogen, preferably C-F.

5. A compound according to any one of claims 1 to 4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R7 is selected from H, -OC optionally substituted by halogen or D 1-6 alkyl and -C optionally substituted by halogen or D 2-6 alkynyl.

6. The compound of any one of claims 1 to 5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R5 is selected from H and halogen, preferably F.

7. A compound according to any one of claims 1 to 6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R6 is selected from halogen, -C 1-3 alkyl and -C 2-4 alkynyl, preferably F, Cl, ethyl and ethynyl.

8. A compound according to any one of claims 1 to 4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is OH, R5 is selected from halogen, and R6 is selected from halogen, -C 1-3 alkyl and -C 2-4 alkynyl.

9. A compound according to any one of claims 1 to 8, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment is selected from 10. The compound of claim 9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment is selected from and a 5- to 7-membered heterocycloalkyl having an in-ring bridging -(CH2) 1-2 - or -CH2=CH2-, preferably -(CH2) 1-2 -, wherein G1 is selected from CH2, NH, O and S, at least one of G2, G3, G4 is selected from CH2, NH, O and S, and the rest are each independently optionally selected from absent, CH2, NH, O and S; wherein the spiro ring or bridged ring is optionally substituted, and the substituents are selected from OH, oxo, -OC 1- 6 alkyl optionally substituted by halogen and -C 1-6 alkyl optionally substituted by halogen.

11. The compound of claim 10, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein is wherein both G1 and G2 are CH2, or one of them is CH2 and the other is selected from NH, O and S, preferably NH and O; or is wherein G1, G2 and G3 are each independently selected from CH2, NH, O and S; wherein the spiro ring is optionally substituted, and the substituents are selected from OH, oxo, -OC optionally substituted by halogen 1-6 alkyl and -C optionally substituted by halogen 1-6 alkyl.

12. A compound according to any one of claims 1 to 11, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein, Wherein Y is O.

13. A compound according to any one of claims 1 to 12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural moiety is preferably 14. The compound of claim 13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R2 is selected from H or D, for example both R2 are H; or both R2 are D; or one of R2 is H and the other is D.

15. The compound of claim 13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R1 is -C 1-3 alkyl or -deuterated C 1-3 alkyl.

16. The compound of claim 13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R3 is selected from halogen, preferably F; -C 1-6 alkyl, preferably C 1-3 alkyl, substituted by halogen, preferably substituted by F; or =C(R c )2, wherein R c are each independently selected from H and halogen, preferably H and F; preferably, R3 is substituted at the para position of the ring N atom, and m is an integer from 1 to 2.

17. The compound of claim 13, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R4 is selected from -C 1-3 alkyl and -deuterated C 1-3 alkyl, preferably -CH3, -CD3, -CH2CH3.

18. A compound according to any one of claims 1 to 11, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural moiety is selected from 19. A compound selected from the compounds of the examples or its pharmaceutically acceptable salts or solvates.

20. A pharmaceutical composition comprising the compound of any one of claims 1-19, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable excipient.

21. The compound of any one of claims 1-19 or its pharmaceutically acceptable salts or solvates or the pharmaceutical composition of claim 20, for use as a medicament for the treatment and / or prevention of diseases mediated by RAS mutations and RAS amplifications.

22. Use of the compound of any one of claims 1-19 or its pharmaceutically acceptable salts or solvates or the pharmaceutical composition according to claim 20 in the manufacture of a medicament for the prevention or treatment of diseases mediated by RAS mutations and RAS amplifications.

23. Use according to claim 22, wherein the diseases mediated by RAS mutation and RAS amplification are selected from: pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, melanoma of the skin or uvea, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvic cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma or pituitary adenoma.

24. Use according to claim 22, wherein the diseases mediated by RAS mutation and RAS amplification are selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, cholangiocarcinoma.

25. A method for treating and / or preventing a disease mediated by an RAS protein, especially a KRAS mutant protein and KRAS amplification, comprising administering to a subject in need a therapeutically effective amount of a compound according to any one of claims 1-19 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 20.

26. The method according to claim 25, wherein the diseases mediated by RAS mutation and RAS amplification are selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, cholangiocarcinoma.

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