Ras inhibitor

Abstract

The present invention provides a compound having a structure as represented by formula (I) which can be used as a RAS inhibitor, a pharmaceutical composition comprising the compound, a method for preparing the compound, and a use of the compound in the treatment of cancer.

Description

RAS inhibitors

[0001] Cross-references

[0002] This application claims priority to Chinese patent application 2023111641130 filed on September 8, 2023, Chinese patent application 2024102175790 filed on February 27, 2024, Chinese patent application 2024106366320 filed on May 21, 2024, Chinese patent application 2024111178533 filed on August 14, 2024, and Chinese patent application 2024112398386 filed on September 5, 2024. Technical Field

[0003] 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

[0004] 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).

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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.

[0010] Summary of the Invention

[0011] The present invention provides a compound having structural formula (X), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof as defined herein below:

[0012] wherein A is selected from substituted C 6-10Aryl or substituted 6-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, S, Se, specifically A is selected from the following fragments:

[0013] More specifically

[0014] The definitions of the remaining groups are as defined in the detailed description of the invention.

[0015] In a first aspect, the present invention provides a compound of formula (I) as defined herein, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0016] The definitions of the various groups are as defined in the detailed description of the invention.

[0017] The second aspect of the present invention provides a compound of the following formula (II), its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0018] The definitions of the various groups are as defined in the detailed description of the invention.

[0019] The present invention also provides a compound of the following formula (III), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates:

[0020] The definitions of the various groups are as defined in the detailed description of the invention.

[0021] The present invention also provides a compound of the following formula (IV), its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0022] The definitions of the various groups are as defined in the detailed description of the invention.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] The present invention also provides the use of a compound of the present invention or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] The present invention also provides methods for preparing the compounds of the present invention.

[0034] Detailed Description of the Invention

[0035] definition

[0036] 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.

[0037] In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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).

[0052] 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.

[0053] The compound structural formula or structural fragments used herein Indicates the absolute configuration of a stereocenter, i.e., a chiral center. Accordingly, R or S is used in the naming of the compounds or intermediates provided by the present invention to indicate the absolute configuration of the chiral center; Indicates the relative configuration of a stereocenter, e.g. OH and CN are in cis configuration. OH and CN are in trans configuration; in some definitions of the compounds of the present invention, axial chirality can also be used to represent the configuration of the compound, where a solid bond indicates that the corresponding structural fragment faces outward, and a dotted bond indicates that the corresponding structural fragment faces inward, for example, Indicates that the benzoheterocyclic side faces outward, indicates that the benzoheterocyclic side faces inward; these configurations are named using the Cahn-Ingold-Prelog rules well known to those skilled in the art.

[0054] In the general formula or examples of the compounds of the present invention, an asterisk "*" is also used to indicate a single axial chiral compound whose absolute configuration has not yet been determined, for example, The asterisked points may have axial chirality as appropriate (e.g. depending on the values ​​of R8 and R9), including or

[0055] 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.

[0056] 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.

[0057] Unless otherwise defined, substituents shown as spanning chemical bonds in cyclic structure fragments as referred to herein, for example -(R4) 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.

[0058] 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.

[0059] 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, as R B of In the formula (a), the two R2 can each independently be D, or can be each defined group substituted by D; R5 can be each defined group substituted by D.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the 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 The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include 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, 2-methylpentyl and the like.

[0065] 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 1 to 3" refers to a straight-chain or branched divalent saturated hydrocarbon group having 1 to 3 carbon atoms.

[0066] 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 The term "alkyl" is exemplified by -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 and -O-neopentyl), -O-n-hexyl and 2-methylpentyl-O-.

[0067] As used herein, the term "C optionally substituted by halogen" 1-6 "Alkyl" refers to the C 1-6 Alkyl, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally replaced by halogen. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. 1-6 Examples of "alkyl" are -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CF(CF3)2, etc.

[0068] 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.

[0069] 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.

[0070] As used herein, the term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having a specified number of ring carbon atoms. 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, etc. For example, as used herein, the term "C 3-6 Cycloalkyl" or "C 3-4 "Cycloalkyl" refers to a monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0071] As used herein, the term "heterocycloalkyl" refers to 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, S-oxide, or S-dioxide thereof. In the case of a polycyclic heterocycloalkyl, it suffices that the ring structure attached to the rest of the molecule is a non-aromatic ring, even if the ring further fused, spiro, or bridged to the non-aromatic ring is an aromatic ring, the heterocyclic ring system is still defined herein as a heterocycloalkyl. The heterocycloalkyl group can have 3 to 12 ring members (which can be referred to as a 3-12 membered heterocycloalkyl group), 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 5- to 7-membered monocyclic heterocycloalkyl group such as a 5- to 7-membered monocyclic saturated heterocycloalkyl group, a 4- to 7-membered monocyclic heterocycloalkyl group; or a 6- to 12-membered polycyclic heterocycloalkyl group, such as an 8- to 10-membered spiroheterocycloalkyl group, an 8- to 10-membered fused heterocycloalkyl group, a 9- to 10-membered fused heterocycloalkyl group, a 9- to 11-membered fused heterocycloalkyl group, a 9- to 12-membered fused heterocycloalkyl group, 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 typically contains at least 1 and up to 4 (e.g., 1, 2, 3, or 4) heteroatoms, for example, a 5-7 membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, and S, such as a 5-7 membered monocyclic saturated heterocycloalkyl group, a 4-7 membered monocyclic heterocycloalkyl group, such as a 4-7 membered monocyclic saturated heterocycloalkyl group, for example, a 5-7 membered monocyclic saturated heterocycloalkyl group, a 4-7 membered monocyclic saturated heterocycloalkyl group containing 1 or 2 N atoms, a 5-7 membered monocyclic saturated heterocycloalkyl group, a 4-7 membered monocyclic saturated heterocycloalkyl group containing 1 or 2 heteroatoms selected from N and O atoms, or a 6-12 membered polycyclic heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O, P, Se, and S, for example, an 8-10 membered spiroheterocycloalkyl group or a fused heterocycloalkyl group or a bridged heterocycloalkyl group containing 1-3 N atoms and 0-1 O atoms. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), piperidinyl (e.g., 1-piperidinyl), , 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl (e.g. morpholino), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepanyl such as 1,4-diazacycloheptyl, 3,6-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl, The atom in the heterocycloalkyl group that is attached to the rest of the compound may be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0072] The term "heteroaryl" 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, such as 5-14 membered heteroaryl, 6-10 membered heteroaryl, and the ring connected to the rest of the molecule is an aromatic ring. Specifically, examples of heteroaryl groups suitable for use in the compounds of the present invention include, but are not limited to: 6-10 membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from O, N, Se and S; 5-7 membered monocyclic heteroaryl groups containing 1 or 3 heteroatoms independently selected from O, N and S, for example, 5-7 membered monocyclic heteroaryl groups containing 1 or 2 heteroatoms independently selected from O, N and S (for example, 6 membered monocyclic heteroaryl groups); 9-10 membered fused bicyclic heteroaryl groups containing 1 to 4 heteroatoms independently selected from O, N, Se and S, for example, 9 membered fused bicyclic heteroaryl groups containing 1 to 4 heteroatoms independently selected from O, N, Se and S.

[0073] The term "aryl" as used herein refers to a monocyclic or fused polycyclic aromatic ring structure comprising the specified number of ring carbon atoms, e.g., C 6-14 Aryl, C 6-10 Aryl group. Specific examples of the aryl group are phenyl group or naphthyl group.

[0074] As used herein, the term "hydroxy" refers to an -OH group.

[0075] As used herein, the term "cyano" refers to a -CN group.

[0076] The term "amino" as used herein refers to -NH2.

[0077] 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 The alkyl group may be further optionally substituted as shown below the definitions of the respective groups. In some embodiments, the substituted amino group is in the -CON(R b )2 in -N(R b )2, where R b is -C optionally substituted by halogen or deuterium 1-6Alkyl. 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(CD3)2, -N(CH3)(CH2CH3), -N(CH3)(CF3), -N(CH3)(CH2CF3), -N(CH3)(CH2CH2CN), -NHCH2-OCH3, N(CH3)(CH2CH2-OCH3.

[0078] 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 of the substituents 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.

[0079] 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.

[0080] In the compound definitions herein, the H carried by the 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 atom, such as the structural fragment In the figure, when m is 1 and R4 is not H, there is an H not shown in the ring carbon atom to which it is connected; when m is 2 and R4 is not H, the ring carbon atom to which it is connected does not carry an H atom, and the two R4 it carries can be respectively connected to the shown ring carbon atom with a single bond, or together form a double bond to the shown ring carbon atom, or together form a spiro ring with the shown carbon atom.

[0081] 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 、C0-2 、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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] Problems to be solved by the present invention

[0086] 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.

[0087] Solutions to the Problem

[0088] 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.

[0089] 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.

[0090] It should be understood that each type of KRAS mutation mentioned herein also includes combinations of two or more of the listed KRAS mutations.

[0091] The present invention therefore provides the following technical solutions.

[0092] Compounds of the present invention

[0093] 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 and preferred embodiment thereof herein or various specific embodiments thereof, including isomers, including atropisomers, enantiomeric mixtures, in particular racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, isotopic variants and salts (e.g., pharmaceutically acceptable salts) thereof.

[0094] 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.

[0095] 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.

[0096] In a first aspect, the present invention provides the following compound embodiments:

[0097] Embodiment 1: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0098] in:

[0099] M is selected from N and C-R8;

[0100] W is selected from N and C-R9;

[0101] Z is selected from N and CR 10 ;

[0102] Y is selected from O, S, Se and NR a ;

[0103] B is selected from 5-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, S and Se, and 6-12 membered polycyclic heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, P, S and Se, provided that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom;

[0104] R1 is selected from H, halogen, -CN, -OH, -B(OH)2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)N(R b )2, where C appears1-6 The alkyl group is optionally substituted with halogen;

[0105] R2 are each independently selected from H, D, -C 1-6 Alkyl and -(CH2) n -C 3-6 Cycloalkyl, or two R2 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-4 Cycloalkyl is each independently optionally substituted with halogen, D, C optionally substituted with halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution;

[0106] R3 is selected from -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution;

[0107] R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -(CH2) n -C 3-6 Cycloalkyl, where each occurrence of C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN or -OC 1-6 Alkyl substituted, or

[0108] Two R4 attached to the same carbon atom form =C(R c )2, or two R4 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, wherein R c are each independently selected from H, halogen and -C 1-6 Alkyl, and the spiro C 3-6Cycloalkyl or spiro 4-7 membered heterocycloalkyl optionally substituted with halogen and -C 1-6 Alkyl substitution;

[0109] R5 is selected from H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 Cycloalkyl, where C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 replaced;

[0110] R6 and R7 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 each alkynyl group is independently optionally substituted with halogen;

[0111] R8 is selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b , where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, CN or -OC 1-6 Alkyl substituted; or R8 is -(CH2) n -C 3-6 Cycloalkyl, wherein C 3-6 Cycloalkyl is optionally substituted with halogen or CN;

[0112] R 10 Selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6Each alkynyl group is independently optionally substituted with halogen or CN;

[0113] R9 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OR b and-O-CON(R b )2, where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen or CN;

[0114] R a and R b are each independently selected from H and -C 1-6 Alkyl, or two R b Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocycloalkyl group;

[0115] n and p are each independently an integer from 0 to 3; and

[0116] m and t are each independently an integer from 0 to 8;

[0117] In one embodiment, R8 and R 10 Each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b , where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted by halogen or CN; R a and R b are each independently selected from H and -C 1-6 and the remaining groups are as defined above in formula (I).

[0118] Embodiment 1.1: A compound of Formula (I) according to Embodiment 1, wherein Z is N, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0119] 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 Z is CR 10 .

[0120] Embodiment 1.2.1: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 H; or R 10 It is D.

[0121] Embodiment 1.2.2: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 is a halogen, such as F, Cl, Br, I.

[0122] Embodiment 1.2.3: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 For CN.

[0123] Embodiment 1.2.4: A compound of Formula (I) according to Embodiment 1.2, 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 with halogen or CN; for example, but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CN, -CH2CH2F, -CH2CH2CN, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -C2F5, -C2Cl5.

[0124] Embodiment 1.2.5: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 -C 2-6 Alkenyl, preferably -C 2-4Alkenyl, optionally substituted with halogen or CN; for example, but 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, -C(CH3)=CHCF3, -CH2CH=CHCF3.

[0125] Embodiment 1.2.6: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 -C 2-6 Alkynyl, preferably -C 2-4 Alkynyl, optionally substituted with halogen or CN; for example, but not limited to -C≡C(CF3), -CH2C≡C(CF3),

[0126] Embodiment 1.2.7: A compound of Formula (I) according to Embodiment 1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 10 For-OR b , where R b is H or -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl; for example, but not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)(CH3), -OCH2Cl, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3.

[0127] Embodiment 1.3: 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 Z is CR 10 , preferably Z is C-CN.

[0128] Embodiment 2.1: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 1.3, wherein p is 0.

[0129] Embodiment 2.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 1.3, wherein p is 1; or p is 2; or p is 3.

[0130] Embodiment 2.2.1: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 1.3, wherein R6 is H; or R6 is D.

[0131] 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 R6 is halogen, such as F, Cl, Br, I, preferably F;

[0132] Preferably, there is one R6 which is a halogen and is located in the para, ortho or meta position, more preferably the para position, to the point of attachment of the benzo-fused ring to the rest of the molecule, such as shown; or

[0133] Preferably, there are two R6 which are halogens, the two R6 being located in the para and ortho positions, or para and meta positions, or ortho and meta positions, more preferably para and ortho positions, respectively, with respect to the point of attachment of the benzo-fused ring to the rest of the molecule, such as shown.

[0134] 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 one R6 is present and is selected from CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl is preferably -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 alkynyl, each independently optionally substituted by halogen, wherein R6 is located in the para, ortho or meta position to the point of attachment of the benzo-fused ring to the rest of the molecule; wherein each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Examples of alkynyl groups include, but are not limited to, those shown in Embodiments 1.2.4 to 1.2.6, respectively.

[0135] 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 there are two R6, one of which is selected from halogen (preferably F) or CN, and the other is selected from CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl is preferably -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, each independently optionally substituted by halogen, the two R6 are located in the para and ortho positions, or para and meta positions, or ortho and meta positions, more preferably para and ortho positions, of the point of attachment of the benzo-fused ring to the rest of the molecule; wherein each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Examples of alkynyl groups include, but are not limited to, those shown in Embodiments 1.2.4 to 1.2.6, respectively.

[0136] 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 there are two R6, each independently selected from -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2- 6-alkenyl and -C 2-6 Alkynyl is preferably -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, each independently optionally substituted by halogen, the two R6 are located in the para and ortho positions, or para and meta positions, or ortho and meta positions, more preferably para and ortho positions, of the point of attachment of the benzo-fused ring to the rest of the molecule; wherein each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Examples of alkynyl groups include, but are not limited to, those shown in Embodiments 1.2.4 to 1.2.6, respectively.

[0137] Embodiment 2.2.6: The compound of formula (I) of embodiment 2.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the benzo-fused ring fragment comprising Z is, for example but not limited to

[0138] Embodiment 2.3: The compound of formula (I) according to any one of Embodiments 1 to 1.3, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the benzo-fused ring fragment comprising Z is More specifically Wherein R6 are each independently selected from H and halogen, preferably F; for example

[0139] Embodiment 3.1: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 2.3, wherein M is N.

[0140] Embodiment 3.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 2.3, wherein M is C-R8.

[0141] Embodiment 3.2.1: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is H; or R8 is D.

[0142] Embodiment 3.2.2: A compound of Formula (I) according to Embodiment 3.2, wherein R8 is halogen, eg, F, Cl, Br, I, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0143] Embodiment 3.2.3: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is CN.

[0144] Embodiment 3.2.4: A compound of formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen or CN, or optionally substituted by -OC 1-6Alkyl substitution; for example but not limited to that shown in Embodiment 1.2.4; preferably R8 is -CF3, or R8 is -CH2-CH3, or R8 is -CH2-O-CH3.

[0145] Embodiment 3.2.5: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is -C 2-6 Alkenyl, preferably -C 2-4 Alkenyl, optionally substituted with halogen or CN; for example but not limited to those shown in Embodiment 1.2.5.

[0146] Embodiment 3.2.6: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is -C 2-6 Alkynyl, preferably -C 2-4 Alkynyl, optionally substituted with halogen or CN; for example but not limited to those shown in Embodiment 1.2.6.

[0147] Embodiment 3.2.7: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is -OR b , where R b is H or -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl; for example but not limited to those shown in Embodiment 1.2.7.

[0148] Embodiment 3.2.8: A compound of Formula (I) according to Embodiment 3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R8 is -(CH2) n -C 3-6 Cycloalkyl, wherein n is an integer from 0 to 3, preferably -C 3-6 Alkyl, such as but not limited to embodiment 8.4; in this case, the fused parent ring containing M and W can be, for example

[0149] Embodiment 3.3: A compound of formula (I) according to any one of Embodiments 1 to 2.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-substituted with halogen. 1-6 Alkyl, preferably C-C substituted by halogen 1-3 Alkyl, more preferably C-CF3; or M is CC 1-6 Alkyl, preferably CC 1-3Alkyl, such as C-CH2-CH3; or M is CC 1-6 Alkyl-OC 1-6 Alkyl, preferably CC 1-3 Alkyl-OC 1-3 Alkyl, such as C-CH2-O-CH3.

[0150] Embodiment 4.1: A compound of Formula (I) according to any one of Embodiments 1 to 3.3, wherein W is N, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0151] 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 3.3, wherein W is C-R9.

[0152] Embodiment 4.2.1: A compound of Formula (I) according to Embodiment 4.2, wherein R9 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0153] Embodiment 4.2.2: A compound of formula (I) according to Embodiment 4.2, wherein R9 is halogen, such as F, Cl, Br, I, preferably F, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof.

[0154] Embodiment 4.2.3: A compound of Formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is CN.

[0155] Embodiment 4.2.4: A compound of Formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, preferably -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl groups are each independently optionally substituted with halogen or CN, as shown but not limited to in Embodiments 1.2.4 to 1.2.6, respectively.

[0156] Embodiment 4.2.5: A compound of Formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is -OR b , where R b is H or -C optionally substituted by halogen1-6 Alkyl, preferably -C 1-3 Alkyl; for example but not limited to those shown in Embodiment 1.2.7.

[0157] Embodiment 4.2.6: A compound of Formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is -O-CON(R b )2, where R b is H or -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl; for example, but not limited to -OCONH2, -O-CONHCH3, -O-CONHCF3, -OCON(CH3)2, -OCONHCH2CH3.

[0158] Embodiment 4.3: A compound of formula (I) according to any one of Embodiments 1 to 3.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is selected from N, C-halogen or CO-C optionally substituted with halogen 1-3 Alkyl, preferably N, CF, C-Cl, C-OCH3.

[0159] Embodiment 5.1: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is H; or is D.

[0160] Embodiment 5.2: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is halogen, preferably F or Cl;

[0161] 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 4.3, wherein R7 is CN.

[0162] Embodiment 5.4: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as but not limited to those shown in Embodiment 1.2.4.

[0163] Embodiment 5.5: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -C 2-6 Alkenyl, preferably -C 2-4 Alkenyl, such as but not limited to those shown in Embodiment 1.2.5.

[0164] Embodiment 5.6: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is -C 2-6 Alkynyl, preferably -C optionally substituted by halogen 2-4 Alkynyl groups, such as but not limited to those shown in Embodiment 1.2.6.

[0165] Embodiment 5.7: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is selected from -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted with halogen; for example but not limited to those shown in Embodiment 1.2.7.

[0166] Embodiment 5.8: A compound of formula (I) according to any one of Embodiments 1 to 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-substituted with halogen. 1-6 Alkyl, preferably C-C substituted by halogen 1-3 Alkyl, more preferably C-CF3; W is selected from N, C-halogen or CO-C optionally substituted by halogen 1-3 Alkyl, preferably N, CF, C-Cl, C-OCH3, more preferably CF; R7 is H; a fused parent ring containing M and W, such as but not limited to

[0167] Embodiment 6.1: A compound of formula (I) according to any one of Embodiments 1 to 5.8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 5-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, Se and S, connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom, such as but not limited to wherein each G in each ring may be C, or at most three, preferably at most two, of which are heteroatoms selected from N, O, P, Se and S, such as 5-7 membered monocyclic heterocycloalkyl containing 1-3 nitrogen atoms, 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1-2 heteroatoms selected from O, P, Se and S, 5-7 membered monocyclic heterocycloalkyl containing 2 nitrogen atoms and 1 heteroatom selected from O, P, Se and S, 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1 heteroatom selected from O, P, Se and S (e.g., 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1 O atom), for example but not limited to Each is substituted by 1-8, preferably 1-4 R1, more preferably substituted by 1-2 R1, more preferably R1 is substituted on a ring carbon atom.

[0168] Embodiment 6.1.1: A compound of Formula (I) according to Embodiment 6.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Substituted by 1-2 R1, preferably substituted by R1 at the meta position of N, for example but not limited to

[0169] Embodiment 6.1.1.1: A compound of formula (I) according to Embodiment 6.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R1 on B is in a stereoisomeric form, such as R or S configuration, as appropriate, as long as it is chemically feasible.

[0170] Embodiment 6.1.1.2: Compounds of formula (I) according to Embodiments 6.1 to 6.1.1.1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein the substituents R1 carried on B are each independently selected from halogen, CN, -OH, -B(OH)2, -C 1-6 Alkyl and -OC 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably R1 is selected from -OH and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 More preferably, two R1 are attached to the same ring carbon atom, one of which is -OH and the other is -C 1-6 Alkyl, preferably -C 1-3Alkyl, more preferably methyl; further preferably, two R1 are attached to the ring carbon atom meta to the N atom attached to the rest of the molecule (e.g., pyrimidine ring), one of which is -OH and the other is -C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl, for example, B is Preferred

[0171] Embodiment 6.1.1.3: Compounds of formula (I) according to Embodiments 6.1 to 6.1.1.1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein the substituent R1 carried on B is selected from -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)2, wherein -C 1-6 The alkyl group is preferably C 1-3 Alkyl, optionally substituted by halogen; preferably -CON(C 1-6 alkyl)2, more preferably -CON(C 1-3 alkyl) 2, such as -CON(CH3) 2; further preferably, one R1 is attached to a ring carbon atom in the meta position of the N atom attached to the rest of the molecule (such as a pyrimidine ring), such as B is

[0172] Embodiment 6.1.2: A compound of Formula (I) according to Embodiment 6.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Substituted by 1-2 R1, preferably substituted by R1 at the meta position of N, for example but not limited to

[0173] Embodiment 6.1.2.1: A compound of formula (I) according to Embodiment 6.1.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R1 on B is in a stereoisomeric form, such as R or S configuration, as appropriate, as long as it is chemically feasible.

[0174] Embodiment 6.1.2.2: A compound of formula (I) according to Embodiment 6.1.2 or 6.1.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein each R1 on B is independently selected from -OH, halogen, CN, -B(OH)2, -C 1-6 Alkyl and -OC 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably R1 is selected from -OH and -C 1-6Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 More preferably, two R1 are attached to the same ring carbon atom, one of which is -OH and the other is -C optionally substituted by halogen. 1-6 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl; further preferably, two R1 are attached to the ring carbon atom meta to the N atom attached to the rest of the molecule (e.g., pyrimidine ring), one of which is -OH and the other is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl, for example, B is Preferred

[0175] Embodiment 6.1.2.3: A compound of formula (I) according to Embodiment 6.1.2 or 6.1.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R1 carried on B is selected from -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)2, wherein -C 1-6 The alkyl group is preferably C 1-3 Alkyl, optionally substituted by halogen; preferably -CON(C 1-6 alkyl)2, more preferably -CON(C 1-3 alkyl) 2, such as -CON(CH3) 2; further preferably, one R1 is attached to a ring carbon atom in the meta position of the N atom attached to the rest of the molecule (such as a pyrimidine ring), such as B is

[0176] Embodiment 6.2: A compound of formula (I) according to any one of Embodiments 1 to 5.8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 6-12 membered polycyclic heterocycloalkyl group comprising 1 to 4 heteroatoms independently selected from N, O, P, Se and S, such as a 6-12 membered spiroheterocycloalkyl group, such as a 6-12 membered fused heterocycloalkyl group, such as a 6-10 membered, 6-9 membered, 6-8 membered, 6-7 membered, 7-10 membered, 7-9 membered, 7-8 membered, 8-10 membered spiroheterocycloalkyl group or a fused heterocycloalkyl group, The heteroatom may be, for example, 1 to 4 nitrogen atoms (e.g., 1, 2, 3, or 4 nitrogen atoms), 1 nitrogen atom and 1 to 3 heteroatoms selected from O, S, P, and Se (e.g., 1 nitrogen atom and 1 heteroatom selected from O, S, P, or Se), 2 nitrogen atoms and 1 to 2 heteroatoms selected from O, S, P, and Se, 3 nitrogen atoms and 1 heteroatom selected from O, S, P, and Se, 1 to 3 nitrogen atoms and 0 to 1 heteroatom selected from O, S, P, or Se (e.g., 1 to 3 nitrogen atoms and 0 to 1 O atom), for example, but not limited to Each is substituted by 0-8, preferably 0-4, R1, more preferably substituted by 0-2 R1, more preferably R1 is substituted on a ring carbon atom.

[0177] Embodiment 6.2.1: A compound of Formula (I) according to Embodiment 6.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Substituted by 0 to 8, preferably 0 to 2 R1, such as but not limited to or substituted by 1 to 3, preferably 1 to 2 R1, such as but not limited to

[0178] Embodiment 6.2.2: The compound of formula (I) of embodiment 6.2 or 6.2.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the substituents R1 carried on B are each independently selected from H, halogen, -CN, -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 Alkyl)2, wherein -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably R1 in the ortho position of the nitrogen atom of the five-membered ring is -CON(C 1-6 alkyl)2, more preferably -CON(C 1-3 alkyl)2, such as -CON(CH3)2, for example, B is or

[0179] B is The substituents R1 carried thereon are independently selected from H, halogen, -CN, -C 1-6 Alkyl, -CONH2, -CONHR b 、-CON(R b )2, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen, wherein R b Yes-C 1-6 Alkyl, or two R b It can form a 4-7 membered heterocycloalkyl group together with the nitrogen atom to which it is attached, for example a 4-7 membered heterocycloalkyl group further comprising 1 or 2 heteroatoms selected from N and O; preferably, R1 in the ortho position of the nitrogen atom of the five-membered ring is selected from -CON(R b )2, for example -CON(C 1-3 alkyl)2, -CO-nitrogen-linked 4-7 membered monocyclic heterocycloalkyl, such as -CON(CH3)2, The remaining R1 are each independently selected from H, halogen and C 1-6 Alkyl groups, e.g.

[0180] Embodiment 6.3: A compound of formula (I) according to any one of Embodiments 1 to 5.8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom or 1 nitrogen atom and 1 heteroatom selected from O, P, Se and S (preferably a 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom or one nitrogen atom and 1 O atom), or an 8-10 membered spiroheterocycloalkyl or fused heterocycloalkyl containing 1-3 nitrogen atoms and 0-1 heteroatoms selected from O, S, P or Se (preferably 1-3 nitrogen atoms and 0-1 O atoms), each optionally substituted by 0-2 -OH, -C 1-6 Alkyl and -CON(C 1-6 alkyl)2, wherein -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted with halogen;

[0181] Preferably, B is selected from wherein R1 is independently selected from -OH and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably one of them is -OH and the other is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl, most preferably or B is selected from Where R1 is -CON(C 1-6 Alkyl) 2, preferably -CON (C 1-3 alkyl)2, more preferably -CON(CH3)2.

[0182] Embodiment 7.1: A compound of Formula (I) according to Embodiments 1 to 6.3, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0183] Embodiment 7.2: A compound of Formula (I) according to Embodiments 1 to 6.3, wherein Y is S, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0184] Embodiment 7.3: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to Embodiments 1 to 6.3, wherein Y is Se.

[0185] Embodiment 7.4: A compound of formula (I) according to Embodiments 1 to 6.3, 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 groups include, but are not limited to, -CH3 and -CH2CH3.

[0186] Embodiment 8.1: A compound of Formula (I) according to Embodiments 1 to 7.4, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein each R2 is H.

[0187] Embodiment 8.2: A compound of formula (I) according to Embodiments 1 to 7.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one R2 is deuterium (D) and the other is H, or both R2 are deuterium (D).

[0188] Embodiment 8.3: A compound of formula (I) according to Embodiments 1 to 7.4, 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, C optionally substituted by halogen or D1-6 alkyl, -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, C optionally substituted by halogen or D 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl substituted; R2-C 1-6 Alkyl groups include, but are not limited to, -CH3, -CH2D, -CD3, -CH2CH3, -CH2CD3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-OCF3, -CH2-OCD3, -CH2-O-CH2CH3. , -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2.

[0189] Embodiment 8.4: A compound of formula (I) according to any one of Embodiments 1 to 7.4, 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 -(CH2) 0- 3-C 3-6 Cycloalkyl, preferably -(CH2) 0-3 -C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 alkyl, -OC optionally substituted by halogen or D 1-6 Alkyl substitution; for example but not limited to

[0190] Embodiment 8.5: A compound of formula (I) according to any one of Embodiments 1 to 7.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two R2 together with the carbon atoms to which they are attached form a spiro C 3-4 Cycloalkyl, where C 3-4 Cycloalkyl optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 alkyl, -OC optionally substituted by halogen or D 1-6Alkyl substitution; for example but not limited to where * indicates an atom attached to the rest of the molecule.

[0191] Embodiment 9.1: A compound of formula (I) according to any one of Embodiments 1 to 8.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitutions, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2; preferably -CH3 or -CH2CH3.

[0192] Embodiment 9.1.1: A compound of formula (I) according to Embodiment 9.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is -deuterated C 1-6 Alkyl, preferably deuterated C 1-3 Alkyl groups, such as but not limited to -CH2D, -CHD2, -CD3.

[0193] Embodiment 9.1.2: A compound of formula (I) according to Embodiment 9.1 or 9.1.1, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein R3 is in a stereoisomeric form, such as the R or S configuration, preferably the S configuration.

[0194] Embodiment 9.2: A compound of formula (I) according to any one of Embodiments 1 to 8.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is -(CH2) 0-3 -C 3-6 Cycloalkyl, preferably -(CH2) 0- 3-C 3-4Cycloalkyl, wherein the cycloalkyl is optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution; for example but not limited to that shown in Embodiment 8.4.

[0195] Embodiment 9.3: A compound of formula (I) according to any one of Embodiments 1 to 9.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment The stereo configuration of shown.

[0196] Embodiment 10.1: A compound of formula (I) according to any one of Embodiments 1 to 9.3, wherein R4 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0197] Embodiment 10.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 9.3, wherein R4 is 1 to 8 Ds.

[0198] Embodiment 10.3: 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 R4 is a halogen, such as F, Cl, Br, I, preferably F; or R1 is CN.

[0199] 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 R4 is -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, wherein -C 1-6 The alkyl group is optionally substituted with halogen, D, CN or -OC 1-6 Alkyl substitution; for example, but 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, and groups formed by replacing one or more H of the alkyl group in the above-mentioned example groups by D.

[0200] Embodiment 10.5: 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 R4 is -OH.

[0201] Embodiment 10.6: 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 R4 is -OC 1-6 Alkyl, preferably -OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by halogen, D, CN or C 1-6 Alkoxy substitutions; for example, but not limited to -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -OC(CH3)3, -O-CH2Cl, -O-CH2CN, -O-CH2F, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH2CH2CN, -O-CH 2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF3, -O-C2F5, -O-C2Cl5, -O-CH2-OCH3, -O-CH2-O-CH2CH3, -O-CH2CH2-O-CH3, -O-CH2CH2-O-CH2CH3, and groups formed by replacing one or more H of the alkyl group in the above-mentioned example groups by D.

[0202] Embodiment 10.7: 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 R4 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, D, CN or -OC 1-6Alkyl is substituted, preferably optionally substituted with halogen; for example, but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -CH2CN, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CH2CN, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2, and groups formed by replacing one or more H of the alkyl group in the above groups by D; preferably -CH3 or -CHF2.

[0203] Embodiment 10.8: 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 R4 is -OC 3-6 Cycloalkyl, wherein C 3-6 Cycloalkyl is optionally substituted with halogen, D, CN or -OC 1-6 Alkyl substitution; for example but not limited to

[0204] Embodiment 10.9: 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 R4 is -(CH2) 0-3 -C 3-6 Cycloalkyl, preferably -(CH2) 0-3 -C 3-4 Cycloalkyl, more preferably -C 3-4 Cycloalkyl, optionally substituted by halogen, D, CN or -OC 1-6 Alkyl substituted, preferably optionally substituted with halogen; for example but not limited to:

[0205] Embodiment 10.10: 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 1 to 9.3, wherein R4 is -C 2-6 Alkenyl or -C 2-6 Alkynyl, optionally substituted by halogen, D, CN or -C 1-6 Alkoxy substituted; for example but not limited to each optionally substituted with halogen, D, CN or -C 1-6Alkoxy-substituted vinyl, propenyl, ethynyl.

[0206] Embodiment 10.11: 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 two R4 attached to the same carbon atom form =C(R c )2, where R c Each independently selected from H, F, Cl, Br, I, -C 1-6 Alkyl; for example, but not limited to, =CH2, =CHF, =CF2, =CCl2, =C(CH3)2, =C(CF3)2.

[0207] Embodiment 10.11: 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 two R4 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, and the spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl 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 where * indicates an atom attached to the rest of the molecule.

[0208] Embodiment 10.12: A compound of formula (I) according to any one of Embodiments 1 to 10.11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R4 is substituted in the para position relative to the ring N atom, i.e. and wherein m is 1 or 2, and R4 is selected from each substituent other than H in the aforementioned R4 embodiments.

[0209] Embodiment 10.13: 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 R4 is selected from halogen, -OC 1-6 Alkyl and -C 1-6 Alkyl, where each occurrence of C 1-6 The alkyl group is preferably C 1-3 alkyl, each independently optionally substituted by halogen, or

[0210] Two R4 attached to the same carbon atom form =C(Rc )2, where R c Each independently selected from H, F, Cl, Br, I, -C 1-6 Alkyl, preferably -C 1-3 alkyl,

[0211] Or two R4 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, and the spiro C 3-6 Cycloalkyl is preferably C 3-4 Cycloalkyl, optionally substituted by halogen and optionally substituted by halogen -C 1-6 Alkyl (preferably -C 1-3 alkyl) substituted;

[0212] Preferably, R4 is substituted in the para position relative to the ring N atom.

[0213] Embodiment 10.14: 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 m is an integer from 1 to 8; preferably an integer from 1 to 4; more preferably an integer from 1 to 2.

[0214] Embodiment 11.1: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 10.14 wherein R5 is H.

[0215] Embodiment 11.2: A compound of formula (I) according to any one of Embodiments 1 to 10.14, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b)2 is substituted, preferably optionally substituted with halogen or D; for example, but not limited to -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, - CH2CN, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CH2CN, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH 2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2, -CH2-OCONH2, -CH2-OCONH(CH3), -CH2-OCON(CH3)2; preferably -CH3 or -CD3.

[0216] Embodiment 11.2.1: A compound of formula (I) according to Embodiment 11.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is -deuterated C 1-6 Alkyl, that is, one in which the hydrogen atoms are replaced by one or more isotopes D, such as -CD3.

[0217] Embodiment 11.3: 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 1 to 10.14, wherein R5 is -C 2-6 Alkenyl or -C 2-6 Alkynyl, optionally substituted by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 substituted; for example, but not limited to, each optionally by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2-substituted vinyl, propenyl, allyl, ethynyl.

[0218] Embodiment 11.4: A compound of formula (I) according to any one of Embodiments 1 to 10.14, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is -(CH2) 0-3 -C 3-6 Cycloalkyl, the -C 3- 6 cycloalkyl is optionally replaced by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 replaced; for example but not limited to

[0219] Embodiment 11.5: 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 1 to 10.14, wherein R5 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl, preferably selected from -C 1-3 Alkyl and deuterated C 1-3 Alkyl groups such as, but not limited to, -CH3, -CD3, -CH2CH3 and cyclopropyl.

[0220] Embodiment 12.1: A compound of formula (I) according to any one of Embodiments 1 to 7.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Specifically In, more specifically In which R2 are independently selected from H and D; R3 is selected from -C 1-6 Alkyl and deuterated C 1-6 Alkyl; m is 1 or 2; R4 is selected from halogen, -OC 1-6 Alkyl and -C 1-6 Alkyl, where each occurrence of C 1-6 The alkyl groups are each independently optionally substituted with halogen, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen, -C 1-6 Alkyl, or two R4 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, and the spiro C 3-6 Cycloalkyl optionally substituted with halogen and optionally substituted with halogen -C 1-6 Alkyl substituted, preferably, R4 is substituted in the para position of the ring N atom, specific examples of R4 include but are not limited to fluorine, difluorine, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluoromethylene, difluoromethylene, methylene, spirocyclopropyl, one or two F-substituted spirocyclopropyl; R5 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3- 6-cycloalkyl;

[0221] Preferably, R2 is independently selected from H and D; R3 is selected from -C 1-3 Alkyl; m is 1 or 2; R4 is halogen, optionally substituted by halogen -C 1-3Alkyl, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen and -C 1-3 Alkyl, or two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro C optionally substituted by halogen 3-4 Cycloalkyl, such as but not limited to F, =CH2, =CHF, =CF2, =CCl2, -CH3, -CHF2, spirocyclopropyl, spirocyclopropyl substituted by fluorine; R5 is -C 1-3 Alkyl or -C substituted by one or more deuterium 1-3 Alkyl groups, such as -CH3, -CH2CH3, -CD3.

[0222] Embodiment 12.2: A compound of formula (I) according to any one of Embodiments 1 to 7.4 and 12.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Specifically More specifically Examples include but are not limited to

[0223] Preferred

[0224] More preferred

[0225] Embodiment 13.1: 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 C-R8 and W is C-R9, wherein R8, R9 and the remaining substituents in the general formula (I) are generally and preferably defined as above for the corresponding embodiment.

[0226] Embodiment 13.2: 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-R8 and W is N, wherein R8 and the remaining substituents in the general formula (I) are generally and preferably defined as above for the corresponding embodiment.

[0227] Embodiment 13.3: 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 N and W is C-R9, wherein R9 and the remaining substituents in the general formula (I) are generally and preferably defined as above for the corresponding embodiment.

[0228] Embodiment 13.4: 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 N and W is N, wherein the remaining substituents in the general formula (I) are generally and preferably defined as above for the corresponding embodiment.

[0229] Embodiment 13.5: A compound of Formula (I) according to any one of Embodiments 13.1 to 13.4, wherein: Z is C-CN, and Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof.

[0230] Embodiment 14.1: 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, having the following sub-formula:

[0231] wherein each substituent has the general or preferred meaning as defined above for each corresponding embodiment.

[0232] Embodiment 14.2: A compound of Formula (I) according to Embodiment 14.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0233] Y is O;

[0234] The benzo-fused ring fragment containing Z is wherein R6 are each independently selected from H and halogen, preferably H and F;

[0235] R7 is H;

[0236] R8 is halogen, preferably Cl; or

[0237] R8 is C substituted by halogen 1-6 Alkyl, preferably C-C substituted by halogen 1-3 Alkyl, more preferably C-CF3; or

[0238] R8 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl; or -C 1-6 Alkyl-OC1-6 Alkyl, preferably -C 1-3 Alkyl-OC 1-3 alkyl;

[0239] R9 is selected from halogen and -O-C optionally substituted by halogen 1-6 Alkyl, preferably selected from F, Cl and -O- optionally substituted by halogen C 1-3 alkyl;

[0240] For Formulas IA-1, IA-2, IB-1 and IB-2 and their respective subformulas, R1 is selected from -OH and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably one of them is -OH and the other is -C 1-3 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl;

[0241] For formulas IA-3 and IB-3 and their respective sub-formulas, R1 adjacent to the nitrogen atom of the five-membered ring is -CON(C 1-6 Alkyl) 2, preferably -CON (C 1-3 alkyl) 2, more preferably -CON(CH3) 2, the remaining R1 are each independently selected from H, halogen and -C 1-6 alkyl;

[0242] R2 are each independently selected from H and D;

[0243] R3 is -C 1-6 Alkyl, preferably -C 1-3 alkyl;

[0244] R4 is selected from halogen, -OC 1-6 Alkyl and -C 1-6 Alkyl, where each occurrence of C 1-6 The alkyl group is preferably C 1-3 alkyl, each independently optionally substituted by halogen, or

[0245] Two R4 attached to the same carbon atom form =C(R c )2, where R c Each independently selected from H, F, Cl, Br, I, -C 1-6 Alkyl (preferably -C 1-3 alkyl),

[0246] Or two R4 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, and the spiro C 3-6 Cycloalkyl is preferably C 3-4Cycloalkyl, optionally substituted by halogen and optionally substituted by halogen -C 1-6 Alkyl (preferably -C 1-3 alkyl) substituted;

[0247] R5 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl, preferably selected from -C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0248] m and p are each independently an integer from 0 to 2.

[0249] Embodiment 14.3: A compound of formula (I) according to Embodiment 14.1 or 14.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Specifically In, more specifically In which R2 are independently selected from H and D; R3 is selected from -C 1-3 Alkyl; m is 1 or 2; R4 is halogen, optionally substituted by halogen -C 1-3 Alkyl, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen and -C 1-3 Alkyl, or two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro C optionally substituted by halogen 3-4 Cycloalkyl, such as but not limited to F, =CH2, =CHF, =CF2, =CCl2, -CH3, -CHF2, spirocyclopropyl, spirocyclopropyl substituted by fluorine; R5 is -C 1-3 Alkyl or -C substituted by one or more deuterium 1-3 Alkyl groups, such as -CH3, -CH2CH3, -CD3.

[0250] Embodiment 15: A compound selected from the group consisting of the compounds of the following Examples or pharmaceutically acceptable salts or solvates thereof.

[0251] In a second aspect, the present invention provides the following compound embodiments:

[0252] Embodiment II-1: A compound of formula (II), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0253] in:

[0254] M is selected from N and C-R8;

[0255] W is selected from N and C-R9;

[0256] Z is selected from N and CR 10 ;

[0257] X is selected from S or Se;

[0258] Q is independently selected from C-R6 or N;

[0259] Y is selected from O, S, Se and NR a ;

[0260] B is selected from 4-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, S and Se, and 6-12 membered polycyclic heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, P, S and Se, with the proviso that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom;

[0261] R1 is selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen, deuterium, -OH or -OC 1-6 Alkyl substitution;

[0262] R2 are each independently selected from H, D, -C 1-6 Alkyl and -(CH2) n -C 3-6 Cycloalkyl, or two R2 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-4 Cycloalkyl is each independently optionally substituted with halogen, D, C optionally substituted with halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution;

[0263] R3 is selected from -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6Alkyl substitution;

[0264] R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -(CH2) n -C 3-6 Cycloalkyl, where each occurrence of C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN or -OC 1-6 Alkyl substituted, or

[0265] Two R4 attached to the same carbon atom form =C(R c )2, or two R4 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, wherein R c are each independently selected from H, halogen and -C 1-6 Alkyl, and the spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl optionally substituted with halogen and -C 1-6 Alkyl substitution;

[0266] R5 is selected from H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 Cycloalkyl, where C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 replaced;

[0267] R6 and R7 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, -OC 1-6 Alkyl or D substituted;

[0268] R8 is selected from H, D, halogen, CN, NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, CN or -OC 1-6 Alkyl substituted; or R8 is -(CH2) n -C 3-6 Cycloalkyl, wherein C 3-6 Cycloalkyl is optionally substituted with halogen or CN;

[0269] R 10 Selected from H, D, halogen, CN, NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen or CN;

[0270] R9 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OR b and-O-CON(R b )2, where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen or CN;

[0271] R a selected from H, -C optionally substituted by halogen 1-6 alkyl;

[0272] R b Selected from H, optionally halogen, -OH, -OC 1-6 Alkyl or deuterium-substituted -C 1-6 Alkyl, and -C 3-6 Cycloalkyl, or two Rb Together with the N atom to which they are attached, they form an optionally halogenated or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl;

[0273] n and p are each independently an integer from 0 to 3; and

[0274] m and t are each independently an integer from 0 to 8;

[0275] In one embodiment, R1 is selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen, R8 and R 10 Each independently selected from H, D, halogen, CN, NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted by halogen or CN, R a and R b are each independently selected from H and -C 1-6 Alkyl, and the remaining groups are as defined above under formula II;

[0276] In one embodiment, R1 is selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen, R a and R b are each independently selected from H and -C 1-6 Alkyl, or two R b Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocycloalkyl group, and the remaining groups are as defined above under formula II;

[0277] In one embodiment, R1 is selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -C2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen, deuterium or -OC 1-6 Alkyl substitution; R a and R b are each independently selected from H and -C optionally substituted by halogen or deuterium 1-6 Alkyl, or two R b Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocycloalkyl group; and the remaining groups are as defined above under formula II;

[0278] Embodiment II-2: The compound of formula (II) of Embodiment II-1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, which is the compound of formula (I) of any one of Embodiments 1 to 15 provided in the first aspect of the present invention, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0279] Embodiment II-3: A compound of formula (II) according to embodiment II-1 or II-2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is selected from N and CR 10 , where R 10 As defined in any one of Embodiments 1.2.1 to 1.3 of the first aspect of the present invention; preferably, Z is C-CN.

[0280] Embodiment II-4: A compound of formula (II) according to any one of Embodiments II-1 to II-3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein p is 0, or p is 1, or p is 2, or p is 3, preferably p is selected from an integer from 0 to 2.

[0281] Embodiment II-5: A compound of formula (II) according to any one of Embodiments II-1 to II-4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the fused ring fragment comprising X, Z and Q is selected from

[0282] In one embodiment, the fused ring fragment comprising X, Z and Q is For example

[0283] Preferred More preferred

[0284] Embodiment II-6: A compound of formula (II) according to any one of Embodiments II-1 to II-5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is as defined in any one of Embodiments 2.2.1 to 2.2.5 of the first aspect of the invention;

[0285] Preferably, R6 is selected from H, halogen, CN and -C 1-6 alkyl, and p is selected from an integer from 0 to 2;

[0286] More preferably, there is one R6 selected from halogen, CN and -C 1-6 Alkyl, preferably selected from halogen, CN and -C 1-6 Alkyl, more preferably halogen, most preferably F, and the R6 is located in the para, ortho or meta position relative to the point of attachment of the fused ring to the rest of the molecule, preferably in the para or ortho position, i.e. For example More specific For example More specific or

[0287] There are two R6, each independently selected from halogen, CN and -C optionally substituted by halogen 1-6 Alkyl, preferably selected from halogen, CN and -C 1-6 Alkyl, more preferably halogen, most preferably F, and the two R6 are respectively located in the para and ortho positions, or para and meta positions, or ortho and meta positions, more preferably para and ortho positions, with respect to the point of connection between the fused ring and the rest of the molecule, i.e. Preferred More preferred

[0288] Embodiment II-7: A compound of formula (II) according to any one of Embodiments II-1 to II-5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein examples of fused ring fragments containing X, Z and Q include, but are not limited to:

[0289] Embodiment II-8: A compound of formula (II) according to any one of Embodiments II-1 to II-7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is as defined in any one of Embodiments 3.1 to 3.3 of the first aspect of the invention.

[0290] Embodiment II-8-1: A compound of formula (II), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments II-1 to II-7, wherein M is NO2.

[0291] Embodiment II-8-2: A compound of formula (II) according to any one of Embodiments II-1 to II-7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is selected from N, CH, C-halogen, C-CN, C-NO2, C-substituted-C 1-6 Alkyl and C-substituted by halogen 2-6 Alkenyl; preferably M is selected from N, C-halogen, C-CN, C-NO2, C- substituted by halogen -C 1-3 Alkyl and C-substituted by halogen 2-4 Alkenyl; more preferably M is selected from N, C-Cl, CF, C-CN, C-NO2, C-CF3, C-CHF2, C-CH=CHF; most preferably M is selected from C-Cl and C-CF3; or

[0292] M is selected from CC 1-6 Alkyl, preferably CC 1-3 Alkyl, such as C-CH2-CH3; or

[0293] M is selected from CC 3-6 Cycloalkyl, such as C-cyclopropyl; or

[0294] M is selected from CC 1-6 Alkyl-OC 1-6 Alkyl, preferably CC 1-3 Alkyl-OC 1-3 Alkyl groups, such as C-CH2-O-CH3;

[0295] In one embodiment, M is selected from C-halogen and C-substituted-C 1-6 Alkyl, preferably C-halogen and C-halogen-substituted-C 1-3 Alkyl groups, such as C-Cl and C-CF3.

[0296] Embodiment II-9: A compound of formula (II) according to any one of Embodiments II-1 to II-8-2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is as defined in any one of Embodiments 4.1 to 4.3 of the first aspect of the invention; preferably W is C-R9, wherein R9 is halogen, preferably F;

[0297] In one embodiment, W is C-R9, wherein R9 is selected from halogen, -C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, preferably selected from halogen, optionally halogen-substituted -C 1-3 Alkyl, -OH, -OC 1-3 Alkyl, specifically F, Cl, -CH3, -CHF2, -OH and -OCH3, more preferably selected from halogen and -C 1-3 Alkyl, such as F or -CH3.

[0298] Embodiment II-10: A compound of formula (II) according to any one of Embodiments II-1 to II-9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is as defined in any one of Embodiments 5.1 to 5.7 of the first aspect of the invention.

[0299] Embodiment II-10-1: A compound of formula (II) according to any one of Embodiments II-1 to II-9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OC 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with -OC 1-6 Alkyl or D substitution, for example but not limited to -CD3, -O-CD3, -CH2-O-CH3, -CH2-O-CD3.

[0300] Embodiment II-10-2: A compound of formula (II) according to any one of Embodiments II-1 to II-9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is H; or R7 is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OC 1-6 Alkyl, where each occurrence of -C1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl is preferably -C 1-3 Alkyl, -C 2-4 Alkenyl and -C 2-4 alkynyl, and each independently optionally substituted by halogen, or each independently substituted by -OC 1-3 Alkyl or D substituted.

[0301] Embodiment II-11: A compound of formula (II) according to any one of Embodiments II-1 to II-7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0302] M is selected from N, CH, C-halogen, C-CN, C-NO2, C-substituted-C 1-6 Alkyl and C-substituted by halogen 2-6 Alkenyl; preferably M is selected from N, C-halogen, C-CN, C-NO2, C- substituted by halogen -C 1-3 Alkyl and C-substituted by halogen 2-4 Alkenyl; more preferably M is selected from N, C-Cl, CF, C-CN, C-NO2, C-CF3, C-CHF2, C-CH=CHF;

[0303] or M is selected from CC 1-6 Alkyl, preferably CC 1-3 Alkyl, such as C-CH2-CH3; or M is selected from CC 3-6 Cycloalkyl, such as C-cyclopropyl; or M is selected from CC 1-6 Alkyl-OC 1-6 Alkyl, preferably CC 1-3 Alkyl-OC 1-3 Alkyl groups, such as C-CH2-O-CH3;

[0304] or M is selected from C-halogen and C-substituted-C 1-6 Alkyl, preferably C-halogen and C-halogen-substituted-C 1-3 Alkyl, more preferably C-Cl and C-CF3;

[0305] W is C-R9, wherein R9 is halogen, preferably F; or R9 is C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen; or R9 is -OC 1-6 Alkyl, preferably -OC 1-3 Alkyl; or R9 is -OH;

[0306] R7 is H; or R7 is selected from -C 1-6Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OC 1-6 Alkyl, where each occurrence of -C 1- 6-alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl is preferably -C 1-3 Alkyl, -C 2-4 Alkenyl and -C 2-4 alkynyl, and each independently optionally substituted by halogen, or each independently substituted by -OC 1-3 Alkyl or D substituted;

[0307] In the compounds of any one of embodiments II-1 to II-7, the fused core comprising M and W is, for example but not limited to Preferred

[0308] In some specific embodiments, the fused core comprising M and W is

[0309] In some specific embodiments, the fused core comprising M and W is

[0310] In some specific embodiments, the fused core comprising M and W is

[0311] In some specific embodiments, the fused core comprising M and W is

[0312] In some specific embodiments, the fused core comprising M and W is

[0313] In some specific embodiments, the fused core comprising M and W is

[0314] In some specific embodiments, the fused core comprising M and W is

[0315] In some specific embodiments, the fused core comprising M and W is

[0316] In some specific embodiments, the fused core comprising M and W is

[0317] In some specific embodiments, the fused core comprising M and W is

[0318] In some specific embodiments, the fused core comprising M and W is

[0319] In some specific embodiments, the fused core comprising M and W is

[0320] In some specific embodiments, the fused core comprising M and W is

[0321] In some specific embodiments, the fused core comprising M and W is

[0322] In some specific embodiments, the fused core comprising M and W is

[0323] In some specific embodiments, the fused core comprising M and W is

[0324] Embodiment II-12: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is as defined in any one of Embodiments 6.1 to 6.3 of the first aspect of the invention;

[0325] In a further embodiment, B is a 4-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom or 1 nitrogen atom and 1 heteroatom selected from O, P, Se and S (preferably a 4-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom or 1 nitrogen atom and 1 O atom), or an 8-10 membered spiroheterocycloalkyl or fused heterocycloalkyl containing 1-3 nitrogen atoms and 0-1 heteroatom selected from O, S, P or Se (preferably 1-3 nitrogen atoms and 0-1 O atoms), each optionally substituted by 0-3 independently selected from -OH, NH2, CN, halogen, -C 1-6 Alkyl, -COC 1-6 Alkyl, -CON(R b )2 group substitution;

[0326] In a specific embodiment, B is a 4-7 membered monocyclic heterocycloalkyl group containing 1 to 2 (preferably 1) heteroatoms independently selected from N, O, P, Se and S (preferably N), such as a 4-membered heterocycloalkyl group, which is attached to the pyrimidine ring portion of the molecule via a nitrogen heteroatom, such as wherein each G in the ring may be C, or at most one of them may be a heteroatom selected from N, O, P, Se and S, such as a 4-membered monocyclic heterocycloalkyl containing 1 nitrogen atom, a 4-membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1 heteroatom selected from O, P, Se and S (e.g., a 4-membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1 O atom), a 5-7-membered monocyclic heterocycloalkyl containing 2 nitrogen atoms; for example, B is For example wherein R1 is as defined in Embodiment II, in one embodiment, R1 is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, for example, R1 is selected from -C(O)-C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2.

[0327] Embodiment II-12-1: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Substituted with 1-2 R1, such as but not limited to wherein R1 is independently selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen; preferably selected from halogen, CN, -OH, -C 1-6 Alkyl and -OC 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted with halogen;

[0328] In one embodiment, B is wherein R1 is selected from halogen, CN, -C substituted by halogen 1-6 alkyl;

[0329] In one embodiment, B is It can also be expressed as One of R1 is selected from halogen, CN, -C substituted by halogen 1-6 Alkyl, preferably located in the para position of the ring nitrogen atom, the other is selected from H, -OH, -C optionally substituted by halogen 1-6 Alkyl or -OC1-6 Alkyl; for example but not limited to

[0330] In one embodiment, B is One of R1 is -OH and the other is -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl; further preferably Wherein one of R1 is -OH and the other is -C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl, for example, B is Preferred

[0331] Embodiment II-12-2: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 7-membered monocyclic saturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S;

[0332] In one embodiment, B is Substituted with 1-2 R1, such as but not limited to Preferred As defined in any one of embodiments 6.1.2 to 6.1.2.3 of the first aspect of the invention.

[0333] Embodiment II-12-3: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 6-12 membered polycyclic heterocycloalkyl group comprising 1 to 4 heteroatoms independently selected from N, O, P, Se and S, such as a 6-12 membered spiroheterocycloalkyl group, such as a 6-12 membered fused heterocycloalkyl group, as specifically defined and / or exemplified in Embodiment 6.2 of the first aspect of the invention;

[0334] In one embodiment, B is a piperidine spiro 4-5 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O, such as but not limited to Preferred Each is substituted with 0 to 8, preferably 0 to 2, R1;

[0335] In one embodiment, B is an oxazepane or diazepane cyclopropane, such as but not limited to Preferred

[0336] Embodiment II-12-3-1: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is, in a specific embodiment, a 9-10 membered fused bicyclic heterocycloalkyl group connected via a nitrogen atom, further comprising 1 to 3 heteroatoms selected from N and O, such as a six-membered and five-membered fused heterocycloalkyl group, a seven-membered and five-membered fused heterocycloalkyl group, and can be specifically represented as in Indicates that the ring may be saturated, partially unsaturated or aromatic, U1 is selected from C or N, U2 is selected from N, C or O, for example but not limited to substituted by 0 to 8, preferably 1 to 3, more preferably 1 to 2 R1, wherein each R1 is independently selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C appears 1-6 The alkyl group is optionally substituted with halogen, preferably selected from H, halogen, -CN, -NH2, oxo, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen, R b Preferably H or -C 1-3 Alkyl, or two R b Together with the nitrogen atom to which it is attached, it may form a 4-7 membered heterocycloalkyl group, for example a 4-7 membered heterocycloalkyl group further comprising 1 or 2 heteroatoms selected from N and O;

[0337] Preferably, B is selected from For example Wherein R1 is selected from H, halogen, -CN, -NH2, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, or two R b It can form a 4-7 membered heterocycloalkyl group together with the nitrogen atom to which it is attached, for example, a 4-7 membered heterocycloalkyl group further comprising 1 or 2 heteroatoms selected from N and O; more preferably, R1 in the ortho position of the nitrogen heteroatom of the five-membered ring is selected from -C(O)-C1-6 Alkyl and -C(O)N(R b )2, for example -CON(C 1-3 alkyl)2, -CO-4-7 membered monocyclic heterocycloalkyl, for example -CON(CH3)2, The remaining R1 are each independently selected from H, halogen, -CN, -NH2 and -C 1-6 Alkyl, preferably selected from H, halogen and -C 1-6 alkyl;

[0338] Embodiment II-12-3-2: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 9-10 membered fused bicyclic heterocycloalkyl group connected via a nitrogen atom, further comprising 1 to 2 heteroatoms selected from N and O, specifically in Indicates that the ring may be saturated, partially unsaturated or aromatic, U1 is selected from C or N, and U2 is selected from N, C or O, for example but not limited to is substituted by 1 to 3, for example 1, 2 or 3 R1, wherein each R1 is independently selected from H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C(O)N(R b )2, preferably selected from H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1- 6-alkyl, -C(O)N(R b )2, where R b are each independently H or -C optionally substituted with one or more deuteriums 1-6 Alkyl, wherein -C 1-6 The alkyl group is preferably -C 1-3 alkyl, optionally substituted with one or more halogens or deuterium; or, wherein R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl or -C 3-6 Cycloalkyl, or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6Alkyl-substituted 4-7 membered heterocycloalkyl;

[0339] Preferably, B is selected from For example in

[0340] R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H or -C optionally substituted with one or more deuteriums 1-6 Alkyl, preferably each independently H or -C 1-3 Alkyl, such as -C(O)N(CH3)2, -C(O)N(CD3)2,

[0341] R1 at the position of the nitrogen heteroatom on the five-membered ring is selected from H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, -NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by one or more halogens or deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -CN, -OH, -NH2, -CH3, -C≡CH, -O-CH3, -O-CD3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3,

[0342] B is connected to the rest of the molecule and the adjacent nitrogen R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H, -CH3 or -CH2CH3;

[0343] or

[0344] R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R bare each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, or -C 3-6 Cycloalkyl, preferably each independently H or -C 1-3 alkyl, most preferably each independently -C 1-3 Alkyl, for example -C(O)CH3, -C(O)N(CH3)(CH2CH2F), -C(O)N(CH3)2, -C(O)N(CH3)(cyclopropyl), -C(O)NH(CH3), -C(O)N(CD3)2, -C(O)N(CH3)(CH2CH2OCH3); or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl, for example azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,

[0345] R1 at the position of the nitrogen heteroatom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, more preferably selected from -C 1-3 Alkyl-OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by one or more halogens, OH or deuterium, preferably by one or more deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -OH, -NH2, -CN, -O-CH3, -CH3, -ethynyl, -CH2F, -CHF2, -O-CD3, -CH2OH, -CH2-CH3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3, -CH2-O-CD3, -CH2-O-CH2CH3,

[0346] B is connected to the rest of the molecule and the adjacent nitrogen R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3Alkyl, such as H, -CH3 or -CH2CH3;

[0347] As a specific embodiment of this preferred solution, B can be wherein each R1 is as defined in the scheme, with the proviso that each is not H;

[0348] In some embodiments, B is a 9-11 membered fused bicyclic heterocycloalkyl group attached via a nitrogen atom, specifically in Indicates that the ring may be saturated, partially unsaturated or aromatic, U1 is selected from C or N, U2 is selected from N, C or O, for example but not limited to is substituted by 1 to 3, for example 1, 2 or 3 R1, wherein each R1 is independently selected from H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, preferably selected from H, halogen, -CN, -OH, -NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -C(O)N(R b )2, where R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl (preferably -OC 1-3 Alkyl-substituted-C 1-3 alkyl) or -C 3-6 Cycloalkyl, or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl (preferably -C 1-3 alkyl) substituted 4-7 membered heterocycloalkyl;

[0349] Preferably, B is For example in

[0350] R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, or -C 3-6 Cycloalkyl, preferably each independently H or -C 1-3 alkyl, most preferably each independently -C 1-3 Alkyl, for example -C(O)CH3, -C(O)N(CH3)(CH2CH2F), -C(O)N(CH3)2, -C(O)N(CH3)(cyclopropyl), -C(O)NH(CH3), -C(O)N(CD3)2, -C(O)N(CH3)(CH2CH2OCH3); or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl, for example azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,

[0351] R1 at the position of the nitrogen heteroatom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, more preferably selected from -C 1-3 Alkyl-OC 1-3Alkyl, wherein the alkyl group is optionally substituted by one or more halogens, OH or deuterium, preferably by one or more deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -OH, -NH2, -CN, -O-CH3, -CH3, -ethynyl, -CH2F, -CHF2, -O-CD3, -CH2OH, -CH2-CH3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3, -CH2-O-CD3, -CH2-O-CH2CH3,

[0352] B is connected to the rest of the molecule and the adjacent nitrogen R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H, -CH3 or -CH2CH3;

[0353] As a specific embodiment of this preferred solution, B can be wherein each R1 is as defined in that embodiment, with the proviso that each is not H.

[0354] Embodiment II-12-3-3: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein specific examples of B include but are not limited to

[0355] In some embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is In other embodiments, B is

[0356] Embodiment II-12-3-4: A compound of formula (II) according to any one of Embodiments II-12-3-1 to II-12-3-3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein in each embodiment of the above B, R1 located in the ortho position of the ring nitrogen atom attached to the rest of the molecule may be in stereoisomeric form, such as R or S configuration, for example

[0357] Embodiment II-12-4: A compound of formula (II) according to any one of Embodiments II-1 to II-11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is selected from the structural fragments generally or specifically defined in Embodiments II-12-1, II-12-2 and II-12-3; preferably, B is selected from wherein R1 is independently selected from -OH and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, optionally substituted by halogen; preferably one of them is -OH and the other is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, more preferably methyl, most preferably or B is selected from One of the R1 (preferably the R1 adjacent to the nitrogen heteroatom) is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, the remaining R1 is selected from H, halogen, -CN, -NH2 and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl; for example, one R1 (preferably R1 adjacent to a nitrogen heteroatom) is selected from -CON(C 1- 6-alkyl)2,-CONHC 1-6 Alkyl, -CONH2, -COC 1-6 Alkyl, preferably -CON(C 1-3 Alkyl)2, -CONHC 1-3 Alkyl, -COC 1-3 Alkyl, more preferably -CON(CH3)2, -CONHCH3, -COCH3, the remaining R1 is selected from H, F, Cl, -CN, -NH2 and -C 1-3 Alkyl (eg, methyl); or B is One of R1 is selected from halogen, CN, -C substituted by halogen 1- 6 alkyl, preferably located in the para position of the ring nitrogen atom, and the other is selected from H, -OH, -C optionally substituted by halogen1-6 Alkyl or -OC 1-6 alkyl.

[0358] Embodiment II-12-5: A compound of formula (II) according to any one of Embodiments II-1 to II-12-4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R1 on B is in a stereoisomeric form, such as the R or S configuration, as appropriate.

[0359] Embodiment II-13: A compound of formula (II) according to any one of Embodiments II-1 to II-12-5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Y is as specifically defined and / or exemplified in any one of Embodiments 7.1 to 7.4 of the first aspect of the invention; preferably, Y is O.

[0360] Embodiment II-14: A compound of formula (II) according to any one of Embodiments II-1 to II-13, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is as specifically defined and / or exemplified in any one of Embodiments 8.1 to 8.4 of the first aspect of the invention; preferably, R2 is each independently selected from H and D; for example, both are H, one is H and the other is D, or both are D.

[0361] Embodiment II-15: A compound of formula (II) according to any one of Embodiments II-1 to II-14, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is as specifically defined and / or exemplified in any one of Embodiments 9.1 to 9.4 of the first aspect of the present invention; preferably R3 is -C 1-6 Alkyl, more preferably -C 1-3 Alkyl, most preferably methyl, optionally substituted with one or more D; structural fragment The stereo configuration is preferably shown.

[0362] Embodiment II-16: A compound of formula (II) according to any one of Embodiments II-1 to II-15, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R4 is as specifically defined and / or exemplified in any one of Embodiments 10.1 to 10.13 of the first aspect of the invention; more preferably,

[0363] R4 is selected from halogen and -C 1-6 Alkyl, where -C 1-6 The alkyl group is preferably -C 1-3Alkyl, substituted by halogen (preferably F), such as -CHF2; or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen (preferably F), -C 1-6 Alkyl (preferably -C optionally substituted by halogen, preferably F 1-3 alkyl), such as =CH2, =CHF, =CHCF3;

[0364] Preferably, R4 is substituted in the para position relative to the ring N atom, i.e. and wherein m is 1 or 2;

[0365] wherein R4 is in a stereoisomeric form as appropriate, for example, R or S configuration.

[0366] Embodiment II-17: A compound of formula (II) according to any one of Embodiments II-1 to II-16, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is as specifically defined and / or exemplified in any one of Embodiments 11.1 to 11.5 of the first aspect of the present invention; more preferably, R5 is selected from -C 1-6 Alkyl and deuterated C 1-6 Alkyl, preferably selected from -C 1-3 Alkyl and deuterated C 1-3 Alkyl groups, such as but not limited to -CH3, -CD3 and -CH2CH3.

[0367] Embodiment II-18: A compound of formula (II) according to any one of Embodiments II-1 to II-12-5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment As specifically defined and / or exemplified in embodiment 12.1 or 12.2 of the first aspect of the present invention; more preferably, for R2 is each independently selected from H and deuterium; R3 is selected from -C optionally substituted with one or more deuterium 1-3 Alkyl; m is 1 or 2; R4 is selected from halogen and halogen (preferably F) substituted-C 1-3 Alkyl, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen, -C 1-3 Alkyl, preferably, R4 is substituted in the para position of the ring N atom, specific examples of R4 include but are not limited to fluorine, difluorine, fluoromethyl, difluoromethyl, fluoromethylene, difluoromethylene, preferably fluorine, difluoromethyl, fluoromethylene; R5 is selected from -C optionally substituted with one or more deuterium1-3 Alkyl groups, such as -CH3, -CH2CH3, -CD3;

[0368] Preferred fragments are exemplified by

[0369] Embodiment II-19: A compound of formula (II) of Embodiment II-1 or II-2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having a sub-formula as defined in any one of Embodiments 14.1 to 14.3 of the first aspect of the invention.

[0370] Embodiment II-19-1: The compound of formula (II) of Embodiment II-1 or II-2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which may have the following sub-formula:

[0371] wherein each group or each structural fragment has the general, specific or preferred definitions given above in accordance with embodiments II-1 to II-18 of the second aspect of the present invention;

[0372] In some specific embodiments of the above sub-formula and its examples,

[0373] X is selected from S and Se;

[0374] Q is independently selected from C-R6 and N;

[0375] R6 are each independently selected from H and halogen;

[0376] The fused ring fragment containing X is preferably wherein R6 are each independently selected from H and halogen, wherein halogen is preferably F;

[0377] M is selected from N and C-R8;

[0378] W is selected from N and C-R9;

[0379] R7 is H;

[0380] R8 is C optionally substituted by halogen (preferably F) 1-3 Alkyl, optionally substituted by halogen (preferably F) C 2-4 alkenyl, CN, NO2, halogen (preferably Cl); or R8 is -C 1-6 Alkyl-OC1-6 Alkyl, preferably -C 1-3 Alkyl-OC 1-3 Alkyl groups, such as -CH2-O-CH3;

[0381] R9 is selected from F, Cl and -O- optionally substituted by halogen C 1-3 alkyl;

[0382] For formula II-1 and its sub-formulas, one of R1 is selected from halogen, CN, -C substituted by halogen 1-6 Alkyl, preferably located in the para position of the ring nitrogen atom, the other is selected from H, -OH, -C optionally substituted by halogen 1-6 Alkyl or -OC 1-6 alkyl;

[0383] For formula II-2 and its various subformulas, one of R1 is -OH and the other is -C 1-3 alkyl;

[0384] For formula II-3 and its respective sub-formulas, R1 at the adjacent position of the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl and -CON(C 1-6 alkyl)2, or a 4-7 membered monocyclic heterocycloalkyl group connected to a -C(O)- nitrogen atom and further containing 1 or 2 heteroatoms selected from N and O, the remaining R1 being independently selected from H, NH2, CN, halogen and -C 1-6 alkyl;

[0385] Y is O;

[0386] R2 are each independently selected from H and D;

[0387] R3 is -C 1-3 alkyl;

[0388] R4 is selected from halogen, -OC 1-3 Alkyl and -C 1-3 Alkyl, where each occurrence of C 1-3 The alkyl groups are each independently optionally substituted with halogen, or

[0389] Two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen, -C 1-3 Alkyl, or

[0390] Two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro C 3-4 Cycloalkyl, and the spiro C 3-4Cycloalkyl optionally substituted with halogen and optionally substituted with halogen -C 1-3 Alkyl substitution;

[0391] R5 is selected from -C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0392] m is an integer from 1 to 2, and p is an integer from 0 to 2;

[0393] Preferably, R4 is located in the para position relative to the ring nitrogen atom of the ring to which it is attached;

[0394] Preferably, the structural fragment for

[0395] Embodiment II-19-2: Compounds of formula (II) of embodiment II-19-1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein, for formula II-3 and each of its sub-formulas, fragment B is Wherein R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H or -C optionally substituted with one or more deuteriums 1-6 Alkyl, preferably each independently H or -C 1-3 Alkyl, such as -C(O)N(CH3)2, -C(O)N(CD3)2;

[0396] R1 at the position of the nitrogen heteroatom on the five-membered ring is selected from H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, -NH2, -C 1- 3 alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3Alkyl, wherein the alkyl group is optionally substituted by one or more halogens or deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -CN, -OH, -NH2, -CH3, -C≡CH, -O-CH3, -O-CD3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3,

[0397] B is connected to the rest of the molecule and the adjacent nitrogen R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H or -CH3;

[0398] For example, B is selected from wherein each R1 is as defined above, but is not H;

[0399] The remaining groups in formula II-3 and its subformulae are generally or specifically defined as in embodiment II-19-1.

[0400] Embodiment II-19-3: Compounds of formula (II) of Embodiment II-19-1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein, for Formula II-3 and each of its sub-formulas (including sub-formula examples),

[0401] B fragment is in

[0402] R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, or -C 3-6 Cycloalkyl, preferably each independently H or -C 1-3 alkyl, most preferably each independently -C 1-3 Alkyl, for example -C(O)CH3, -C(O)N(CH3)(CH2CH2F), -C(O)N(CH3)2, -C(O)N(CH3)(cyclopropyl), -C(O)NH(CH3), -C(O)N(CD3)2, -C(O)N(CH3)(CH2CH2OCH3); or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6Alkyl-substituted 4-7 membered heterocycloalkyl, for example azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,

[0403] R1 at the position of the nitrogen heteroatom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, more preferably selected from -C 1-3 Alkyl-OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by one or more halogens, OH or deuterium, preferably by one or more deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -OH, -NH2, -CN, -O-CH3, -CH3, -ethynyl, -CH2F, -CHF2, -O-CD3, -CH2OH, -CH2-CH3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3, -CH2-O-CD3, -CH2-O-CH2CH3,

[0404] B is connected to the rest of the molecule and the adjacent nitrogen R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H, -CH3 or -CH2CH3;

[0405] Specifically, B can be wherein each R1 is as defined in this embodiment, with the proviso that each is not H;

[0406] The fused ring fragment containing X is Wherein R6 are each independently selected from H and halogen (preferably F); preferably

[0407] M is C-R8;

[0408] W is C-R9;

[0409] R7 is H;

[0410] R8 is halogen (preferably Cl), C optionally substituted by halogen (preferably F) 1-3Alkyl (eg CF3), C optionally substituted by halogen (preferably F) 2-4 Alkenyl, CN, NO2, -C 1-6 Alkyl-OC 1-6 Alkyl (preferably -C 1-3 Alkyl-OC 1-3 Alkyl, such as -CH2-O-CH3); preferably halogen or halogen-substituted C 1-3 Alkyl groups, such as Cl and CF3;

[0411] R9 is selected from halogen, -C 1-3 Alkyl, -OH and -O- are optionally substituted with halogen. 1-3 Alkyl; preferably halogen and -C 1-3 Alkyl groups; for example, F, Cl, CH3 and -O-CH3;

[0412] Y is O;

[0413] R2 are each independently selected from H and D;

[0414] R3 is -C 1-3 alkyl;

[0415] R4 is -C 1-3 Alkyl, substituted by halogen, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H and halogen;

[0416] R5 is selected from -C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0417] m is an integer from 1 to 2;

[0418] Preferably, R4 is located in the para position relative to the ring nitrogen atom of the ring to which it is attached;

[0419] Preferably, the structural fragment for

[0420] Embodiment II-20: Compounds of formula (II) according to Embodiment II, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein the compounds are specifically synthesized and characterized in the Examples.

[0421] In a third aspect, the present invention provides the following compound embodiments:

[0422] Embodiment III-1: A compound of formula (III), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0423] wherein B, Y, R1, R2, R3, R4, R5, R6, R7, M, W, t, m, and p each or in combination have the meanings generally or specifically defined for the compounds of formula (II) in embodiments II-1 to II-20 of the second aspect of the present invention.

[0424] Embodiment III-2: A compound of formula (III) of Embodiment III-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein p is 1, or p is 2, or p is 3, preferably p is selected from an integer of 1 to 2.

[0425] Embodiment III-3: A compound of formula (III) of embodiment III-1 or III-2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment In the example, p is 1 or 2. R6 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, -OC 1-6 Alkyl or D substituted; preferably selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 each alkynyl group is independently optionally substituted with halogen;

[0426] In one embodiment, R6 in the fragment are each independently selected from halogen, -CN, -C optionally substituted by halogen, 1-6 Alkyl; preferably the R6 adjacent to the point of attachment of the fragment to the rest of the molecule is -C 1-6 Alkyl (preferably -C 1-3 alkyl), when R6 at the meta position exists, it is selected from halogen and CN (preferably F or Cl); examples include but are not limited to

[0427] Embodiment III-4: A compound of formula (III) according to any one of Embodiments III-1 to III-3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is generally or specifically defined as in any one of Embodiments II-8 to II-8-2.

[0428] Embodiment III-5: A compound of formula (III) according to any one of Embodiments III-1 to III-4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is as generally or specifically defined in Embodiment II-9.

[0429] Embodiment III-6: A compound of formula (III), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments III-1 to III-5, wherein R7 is generally or specifically defined as in any one of Embodiments II-10 to II-10-2.

[0430] Embodiment III-7: A compound of formula (III) according to any one of Embodiments III-1 to III-6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the fused core comprising M and W is generally or specifically defined as in Embodiment II-11.

[0431] Embodiment III-8: A compound of formula (III) according to any one of Embodiments III-1 to III-7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment t is selected from an integer of 0 to 6, an integer of 0-4, an integer of 0-3, for example, t is 0, or t is 1, or t is 2, or t is 3;

[0432] In a specific embodiment, the structural fragment As generally or specifically defined in any one of Embodiments II-12 to II-12-5;

[0433] Preferably, the structural fragment B is selected from For example Wherein R1 is selected from H, halogen, -CN, -NH2, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, where -C 1-6 The alkyl group is preferably -C 1-3 Alkyl, or two R bIt can form a 4-7 membered heterocycloalkyl group together with the nitrogen atom to which it is attached, for example, a 4-7 membered heterocycloalkyl group further comprising 1 or 2 heteroatoms selected from N and O; more preferably, R1 in the ortho position of the nitrogen heteroatom of the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, for example -CON(C 1-3 alkyl)2, -CO-4-7 membered monocyclic heterocycloalkyl, for example -CON(CH3)2, The remaining R1 are each independently selected from H, halogen, -CN, -NH2 and -C 1-6 Alkyl, preferably selected from H, halogen and -C 1-6 alkyl;

[0434] Wherein, R1 located in the ortho position to the ring nitrogen atom attached to the rest of the molecule may exist in stereoisomeric forms, such as R or S configuration, for example

[0435] Embodiment III-9: A compound of formula (III) according to any one of Embodiments III-1 to III-8-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment As generally or specifically defined in any one of embodiments II-13 to II-18.

[0436] Embodiment III-10: The compound of formula (III) of Embodiment III-1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, which may have the definitions of the various sub-formulas and various groups as shown in Embodiment II-19-1, wherein the difference is that the left fragment is defined in any one of Embodiments III-1 to III-3

[0437] In a fourth aspect, the present invention provides the following compound embodiments:

[0438] Embodiment IV-1: A compound of formula (IV), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0439] Wherein B, Y, Q, R1, R2, R3, R4, R5, R6, R7, M, W, t, m, and p each or in combination have the meaning generally or specifically defined for the compound of formula (II) in embodiments II-1 to II-20 of the second aspect of the present invention.

[0440] Embodiment IV-2: A compound of formula (IV) of Embodiment IV-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein p is 1, or p is 2, or p is 3, preferably p is selected from an integer from 1 to 2.

[0441] Embodiment IV-3: A compound of formula (IV) of embodiment IV-1 or IV-2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for For example wherein R6 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, -OC 1-6 Alkyl or D substituted; preferably each independently selected from halogen, CN, optionally substituted by halogen -C 1-6 alkyl;

[0442] In one embodiment, the R6 carried by the Q position in the fragment is selected from halogen and CN, and the R6 located at the para position of -NH2 is -C optionally substituted by halogen. 1-6 Alkyl, preferably substituted by halogen -C 1-3 Alkyl, such as -CF3, the meta-position R6 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, such as -CH3.

[0443] Embodiment IV-4: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is generally or specifically defined as in any one of Embodiments II-8 to II-8-2.

[0444] Embodiment IV-5: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is as generally or specifically defined in Embodiment II-9.

[0445] Embodiment IV-6: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is generally or specifically defined as in any one of Embodiments II-10 to II-10-2.

[0446] Embodiment IV-7: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the fused core comprising M and W is generally or specifically defined as in Embodiment II-11.

[0447] Embodiment IV-8: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment As generally or specifically defined in Embodiment III-8.

[0448] Embodiment IV-9: A compound of formula (IV) according to any one of Embodiments IV-1 to IV-8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment As generally or specifically defined in any one of embodiments II-13 to II-18.

[0449] Embodiment IV-10: The compound of formula (IV) of Embodiment IV-1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, which may have the definitions of each sub-formula and each group as shown in Embodiment II-19-1, wherein the difference is that the left fragment is defined in any one of Embodiments IV-1 to IV-3

[0450] 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.

[0451] Advantageous Effects of the Invention

[0452] 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.

[0453] Specifically, it has been found through research that the compounds of the present invention can achieve one or more of the following technical effects:

[0454] 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, especially 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 ​​ranging from 0.001 nM to 10 μM, for example, 0.001 nM to 1 μM, 0.01 nM to 0.5 μM, 0.01 nM to 0.1 μM, and 0.01 nM to 0.05 μM, as shown in Activity Examples 1, 2, 5, 6, and 8;

[0455] · 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

[0456] 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.

[0457] Oral administration has a good tumor inhibitory effect, as demonstrated in Active Examples 7 or 9.

[0458] 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.

[0459] Compounds of the invention for use in therapy or as medicine

[0460] 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.

[0461] 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, G12C-Q99L, G12C-R68M, G12C-Y96S, G12C-95H, G12C-A59S and Q61H mutations or combinations thereof) and KRAS wild-type amplified cell inhibitors.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] Pharmaceutical compositions and their administration

[0466] 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.

[0467] 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.

[0468] 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.

[0469] 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.

[0470] 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.

[0471] 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.

[0472] Treatment methods and uses

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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.

[0483] Drug combinations

[0484] The compounds of the present invention may be administered as the sole active ingredient or in combination with another drug or therapy.

[0485] 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.

[0486] 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.

[0487] 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.

[0488] 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, When administered separately, they can be administered simultaneously or sequentially, 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 other drugs); (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.

[0489] 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.

[0490] 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.

[0491] 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.

[0492] 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.

[0493] Preparation method of the compound of the present invention

[0494] In another aspect, the present invention also provides a method for preparing the compound defined in the present invention.

[0495] 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.

[0496] 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.

[0497] 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.

[0498] 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.

[0499] 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).

[0500] 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.

[0501] 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).

[0502] 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.

[0503] For the sake of clarity, in the exemplary synthesis schemes described below, unless otherwise specified, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R 10 , X, Y, Z, n, m and t are as defined above for the compounds of the present invention, wherein PG represents a suitable protecting group which can be determined by those skilled in the art based on the knowledge of organic chemistry.

[0504] Synthesis Scheme A

[0505] The synthesis of the compounds of the present invention can be prepared according to the following scheme or its appropriate variants. Unless otherwise specified, the definitions of the various groups are as described above.

[0506] Compound 1 is commercially available, can be obtained according to known methods reported in the literature, or can be obtained according to the methods used in the examples herein or methods analogous thereto, wherein Hal represents a halogen atom, such as Cl, Br, or I. In step A, compound 1 is introduced into fragment B-(R1) by an aromatic nucleophilic substitution reaction. t , 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 via a halogen exchange reaction under conditions such as KF / DMSO to obtain compound 3. In step C, compound 3 is introduced into a benzothiophene or benzothiazole fragment via a metal-catalyzed coupling reaction to obtain compound 4. Typical metal-catalyzed coupling reactions include Suzuki-Miyaura coupling reactions, with typical conditions such as Ruphos Pd G4 / K3PO4 / dioxane / water. In step D, compound 4 is introduced into a piperidine derivative fragment via an aromatic nucleophilic substitution reaction to obtain compound 5. The latter is then freed from any protecting groups in step E to obtain a compound of formula I.

[0507] Synthesis Scheme B

[0508] The synthesis of some (Z=C-CN) compounds of the present invention can also be prepared according to the following scheme or its appropriate variations. Unless otherwise specified, the definitions of the various groups are as described above.

[0509] In Step A, compound 3 is reverse-introduced into a benzothiophene fragment via metal-catalyzed coupling to yield compound 4-1. In Step B, compound 4-1 undergoes iodination with NIS to yield compound 4-2. In Step C, compound 4-2 undergoes metal-catalyzed cyanation to yield compound 4-3. Typical cyanation conditions include Zn(CN)2 / Pd(PPh3)4. In Step D, compound 4-3 is subjected to aromatic nucleophilic substitution to introduce a piperidine derivative fragment to yield compound 5-1. In Step E, any protecting groups present in the latter are removed to yield a compound of the general formula I (Z=C-CN).

[0510] Synthesis Scheme C

[0511] The synthesis of the compound of formula II of the present invention can be prepared according to the following scheme or its appropriate variants. Unless otherwise specified, the definitions of the various groups are as described above.

[0512] Intermediate 6 can be prepared by referring to the synthesis of some intermediates in the examples of the present invention. In step A, intermediate 6 is subjected to chlorination reaction under conditions such as oxalyl chloride / DMF / DCM to obtain intermediate 7. In step B, intermediate 7 is subjected to substitution reaction under conditions such as DIPEA / DMF by aromatic nucleophilic substitution reaction to obtain compound 8. In step C, compound 8 is subjected to oxidation reaction under conditions such as magnesium monoperoxyphthalate hexahydrate / DCM / water to obtain compound 9. Compound 9 can be a sulfone or sulfoxide, or a mixture of the two, depending on the reaction conditions. In step D, compound 9 is subjected to aromatic nucleophilic substitution reaction under conditions such as tBuONa / THF to obtain compound 10. Compound 10 in step E is deprotected using appropriate reaction conditions to obtain a compound of formula II. It should be noted that the final compound of formula II can be separated into diastereoisomers by Pre-HPLC or SFC to obtain a chiral single compound of formula II; intermediate 6 can also be subjected to SFC chiral separation to obtain an axial chiral single intermediate 6A, which can be used to obtain a chiral single compound of formula II according to the above scheme.

[0513] It should be noted that the typical metal-catalyzed coupling reactions involved in the present invention are well known in the art, such as but not limited to Suzuki-Miyaura coupling, Negishi coupling, Stille coupling, etc. Suitable catalysts include XantPhos Pd G2, A Pd G3, bis(triphenylphosphine)palladium(II) chloride, Pd(dppf)Cl2, Pd2dba3, tetraphenylphosphine palladium and palladium(II) acetate, etc.; if necessary, suitable ligands may include tricyclohexylphosphine and triphenylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide and potassium phosphate monohydrate, etc.

[0514] 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.

[0515] Synthesis Example

[0516] The present invention will be further described below with reference to the following examples. It should be noted that the following examples are illustrative only and should not be considered as limiting the scope of protection of the present invention.

[0517] In describing the embodiments and the specific examples that follow, the following abbreviations are used herein:

[0518] ACN (acetonitrile); Boc (tert-butoxycarbonyl); CDCl3 (deuterated chloroform); CSI (chlorosulfonyl isocyanate); DCM (dichloromethane); DephosPdCl2 or DPEphosPdCl2 (bis(diphenylphosphinophenyl ether)palladium(II) dichloride); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (hexadeuterated dimethyl sulfoxide); EA or EtOAc (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 (hydrogen chloride methanol 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 chromatography-mass spectrometry-mass spectrometry); MeOH (methanol); Methanol-d4 (tetradeuterated methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters); mmol (millimoles); MMPP (magnesium monoperoxyphthalate hexahydrate); 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); nM (sodium molar concentration); 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(diphenylphosphino)ferrocenepalladium dichloride); Pd(OAc) (palladium acetate); Pd(PPh3)4(tetrakis) triphenylphosphine palladium); PE (petroleum ether); PO (oral administration); POCl3 (phosphorus oxychloride); rt (room temperature); Selectfluor (1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate)); SiO2 (silica gel); TCDI (N,N'-thiocarbonyldiimidazole); 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 (micromole).

[0519] 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.

[0520] 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.

[0521] 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.

[0522] 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.

[0523] Intermediate A

[0524] 7-Bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline

[0525] Step A: Methyl 2-amino-4-bromo-3-fluorobenzoate

[0526] SOCl2 (156 mL, 210 mmol) was added to a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (50 g, 214 mmol) and methanol (300 mL) at 0°C. The reaction system was heated to 100°C and stirred for 16 h. The reaction was monitored by TLC. The reaction solution was returned to room temperature, concentrated under reduced pressure, diluted with EA (1 L), and washed with saturated aqueous NaHCO3 (500 mL). The collected organic phase was dried over anhydrous Na2SO4 and filtered. The organic solution was concentrated and purified by FCC (SiO2, EA / PE = 0-20%) to yield methyl 2-amino-4-bromo-3-fluorobenzoate (40 g) as a white solid. LCMS (m / z): 249.9 (M+H).

[0527] Step B: Methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate

[0528] At room temperature, 1-(Trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (19 g, 60 mmol) was added to a mixture of methyl 2-amino-4-bromo-3-fluorobenzoate (5 g, 20 mmol) and ACN (20 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 72 h. Following completion of the reaction, the reaction mixture was returned to room temperature, concentrated, diluted with EA (100 mL), and washed with water (50 mL x 2). The collected organic phase was dried over anhydrous NaSO, filtered, and concentrated. The organic solution was purified by FCC (SiO, EA / PE = 0-10%) to afford methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (1.2 g) as a pale yellow solid. LCMS (m / z): 317.1 (M+H).

[0529] Step C: Methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)urea)-5-(trifluoromethyl)benzoate

[0530] At room temperature, 2,2,2-trichloroacetyl isocyanate (0.7 mL, 5.7 mmol) was added to a mixture of methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (1.2 g, 3.8 mmol) and THF (10 mL). The reaction system was stirred at room temperature for 0.5 h. Following completion of the reaction, the reaction solution was concentrated to afford methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)urea)-5-(trifluoromethyl)benzoate (1.6 g) as a white solid, which was used directly in the next reaction.

[0531] Step D: 7-Bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol

[0532] At room temperature, a 7M solution of ammonia in methanol (20 mL) was added to methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)urea)-5-(trifluoromethyl)benzoate (1.6 g). The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated to afford 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (1.0 g) as a white solid, which was used directly in the next reaction. LCMS (m / z): 328.8 (M+H).

[0533] Step E: 7-Bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline

[0534] DIEA (1.8 g, 14 mmol) was added to a mixture of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (1.0 g, 3.0 mmol) and POCl3 (10 mL) at 0°C. The reaction system was heated to 110°C and stirred for 2 h. After completion of the reaction, as monitored by LCMS, the reaction solution was returned to room temperature, concentrated, and diluted with acetonitrile (0.5 mL). The resulting mixture was then added dropwise to water (10 mL), resulting in the precipitation of a solid. The filter cake was filtered and dried to afford a brownish-yellow solid, 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (1.5 g). LCMS (m / z): 365.8 (M+H).

[0535] Intermediate B

[0536] 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

[0537] Step A: Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate

[0538] 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).

[0539] Step B: 7-Bromo-6,8-difluoroquinazoline-2,4-diol

[0540] 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).

[0541] Step C: 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

[0542] 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).

[0543] Intermediate C

[0544] 7-Bromo-2,4-dichloro-8-fluoroquinazoline

[0545] Step A: 7-Bromo-8-fluoroquinazoline-2,4(1H,3H)-dione

[0546] 2-Amino-4-bromo-3-fluorobenzoic acid (10.0 g, 42.7 mmol) and urea (25.7 g, 427.3 mmol) were mixed at room temperature, heated to 200°C, and stirred for 2 hours. The reaction gradually transitioned from a solid to a liquid state, and then to a solid state. LCMS monitored the reaction. After completion, the solid was washed with hot water (250 mL) and filtered to obtain 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (12 g, crude product). LCMS (ESI, m / z): 258.9 (M+H).

[0547] Step B: 7-Bromo-2,4-dichloro-8-fluoroquinazoline

[0548] DIPEA (13.5 mL, 77.2 mmol) was added to a mixture of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.0 g, 15.4 mmol) and POCl3 (35.9 mL, 386.0 mmol) at room temperature. The mixture was heated to 100°C and stirred for 5 h. Following completion of the reaction, the solvent and base were removed by concentration, and the mixture was diluted with ACN (10 mL). The resulting solution was slowly added dropwise to water with stirring at room temperature. The precipitated solid was filtered and dried to afford 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.8 g, 83% yield) as a yellow solid. LCMS (ESI, m / z): 296.8 (M+H).

[0549] The following intermediates were prepared according to the above synthesis method:

[0550] Intermediate F

[0551] 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0552] Step A: 4,6-dichloro-5-fluoronicotinoyl chloride

[0553] 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.

[0554] Step B: (4,6-Dichloro-5-fluoronicotinoyl)carbamidethiomethyl ester

[0555] 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).

[0556] Step C: 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0557] 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 yield 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.6 g, 82% yield). LCMS (m / z): 245.6 (M+H).

[0558] Intermediate G

[0559] 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0560] Step A: 2,6-Dichloro-3-fluoropyridin-4-amine

[0561] 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).

[0562] Step B: tert-Butyl (tert-Butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate

[0563] 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).

[0564] Step C: tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0565] 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).

[0566] Step D: 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride

[0567] 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 mixture was concentrated to yield 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride (8 g). LCMS (m / z): 224.9 (M+H).

[0568] Step E: 5,7-Dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol

[0569] 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).

[0570] Step F: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0571] A mixture of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol (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 a pH of ~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-ol (4 g). LCMS (m / z): 279.9 (M+H).

[0572] Step G: 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0573] A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (6.0 g, 22 mmol), sodium methoxide (10.3 g, 330 mmol), DMA (100 mL), and methanol (10 mL) was stirred at 50°C for 16 h. 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 mixture was filtered, and the filter cake was collected and dried to obtain 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.5 g). LCMS (m / z): 276.0 (M+H).

[0574] Intermediate H

[0575] 5-Bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0576] Step A: 2-Chloro-3-fluoro-5-iodopyridin-4-amine

[0577] At room temperature, 2-chloro-3-fluoro-4-aminopyridine (25.0 g, 171 mmol) was dissolved in 250 mL of acetonitrile. NIS (35.4 g, 205 mmol) and p-toluenesulfonic acid monohydrate (3.24 g, 17.1 mmol) were then added separately. The resulting mixture was heated to 70°C and stirred overnight. The reaction was monitored by LCMS. After cooling to room temperature, the reaction mixture was quenched by pouring into water (500 mL) and extracted with ethyl acetate (800 mL x 3). The organic phases were combined, washed with saturated NaHCO₃, saturated Na₂S₂O₃, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO₂, EA / PE = 0-50%) to afford 2-chloro-3-fluoro-5-iodopyridin-4-amine (42 g, 90% yield) as a white solid. LCMS (m / z): 272.9 (M+H). 1 HNMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 6.69 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) δ-138.90. Step B: 4-amino-6-chloro-5-fluoronicotinate

[0578] At room temperature, 2-chloro-3-fluoro-5-iodopyridin-4-amine (40 g, 147 mmol) was dissolved in 400 mL of anhydrous ethanol. The system was purged with CO, repeated three times. Pd(PPh3)2Cl2 (10.3 g, 14.7 mmol) and TEA (95.0 g, 735 mmol) were then added to the reaction flask, and the CO atmosphere was purged three times. The resulting mixture was heated to 80°C under a CO atmosphere and allowed to react overnight. The reaction was monitored by LCMS, cooled to room temperature, and filtered through Celite. The filtrate was concentrated to dryness to obtain the crude product, which was purified by FCC (SiO2, EA / PE = 0-50%) to afford ethyl 4-amino-6-chloro-5-fluoronicotinate (30 g, 93% yield) as a white solid. LCMS (m / z): 219.0 (M+H).

[0579] Step C: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate

[0580] Under stirring at room temperature, Boc2O (65.9 g, 302 mmol) was added dropwise to a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (30.0 g, 137 mmol) and DMAP (3.4 g, 27.5 mmol) in anhydrous dichloromethane (600 mL). After the addition was complete, the mixture was heated to 45°C and allowed to react overnight. Imidazole (9.33 g, 137 mmol) was added to the system and stirred for half an hour. The mixture was then washed with saturated ammonium chloride solution (300 mL x 3). The organic phase was separated and washed with saturated brine (300 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (45.9 g, 80% yield) as a yellow solid. LCMS (m / z): 419.1 (M+H).

[0581] Step D: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate

[0582] A solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (45.0 g, 107 mmol) in anhydrous THF (450 mL) was cooled to -40°C in a dry ice acetonitrile bath. A solution of TMPMgCl-LiCl in THF (161 mL, 161 mmol, 1 M) was added dropwise at this temperature with stirring. After the addition, stirring was continued at this temperature for 4 hours, followed by the dropwise addition of a solution of dibromotetrachloroethane (42.0 g, 129 mmol) in THF (100 mL). Stirring was continued at -40°C for 4 hours. The mixture was quenched by the addition of 500 mL of saturated ammonium chloride solution, followed by extraction with EtOAc (500 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO2, EA / DCM = 0-50%) to afford ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (17.0 g, 32% yield) as a white solid. LCMS (m / z): 497.0 (M+H).

[0583] Step E: 4-amino-2-bromo-6-chloro-5-fluoronicotinate HCl

[0584] At room temperature, dissolve 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (28.0 g, 56.3 mmol) in 4M hydrochloric acid-dioxane (500 mL). Stir at room temperature for 1 hour. LCMS monitored the reaction completion, and the system was concentrated to dryness to give the crude product, 4-amino-2-bromo-6-chloro-5-fluoronicotinate HCl (19.1 g, crude), as a white solid. LCMS (m / z): 296.9 (M+H). Step F: 4-Amino-2-bromo-6-chloro-5-fluoronicotinate

[0585] At room temperature, 1N NaOH (45.0 mL, 45.0 mmol) was added to a solution of ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate·HCl (5.00 g, 15.0 mmol) in MeOH / THF (V:V = 1:1, 100 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction solution was concentrated to remove the organic solvent, and the residue was adjusted to pH 5-6 with 1M HCl and extracted with EA (80 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid (1.90 g, 47% yield) as a white solid. LCMS (m / z): 269.0 (M+H).

[0586] Step G: 5-Bromo-7-chloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol

[0587] At room temperature, 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid (1.90 g, 7.05 mmol) was dissolved in thionyl chloride (40 mL, 551 mmol). A catalytic amount of DMF (2 drops) was added to the reaction system, and the temperature was raised to 80°C with stirring for 4 hours. The reaction solution was directly concentrated to dryness to obtain the intermediate acid chloride. The resulting acid chloride was dissolved in anhydrous acetone (50 mL) at room temperature, and ammonium thiocyanate (2.15 g, 28.2 mmol) was slowly added. The resulting mixture was stirred at room temperature for 3 hours, resulting in the formation of a large amount of solid. After completion of the reaction, the reaction solution was slowly poured into stirred water (400 mL). The solid precipitated and stirred for 15 minutes, then filtered and the filter cake dried to obtain 5-bromo-7-chloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol (1.55 g, 71% yield). LCMS (m / z): 309.8 (M+H).

[0588] Step H: 5-Bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0589] At room temperature, 0.1M NaOH (100mL, 10.0mmol) and iodomethane (1.42g, 9.98mmol) were added sequentially to a solution of 5-bromo-7-chloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol (1.55g, 4.99mmol) in methanol (50mL). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction solution was slowly poured into stirred water (400mL). The pH was then adjusted to neutral with 1M HCl, resulting in the precipitation of a white solid. After stirring for approximately 15 minutes, the solid was filtered and the filter cake was dried to afford 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.5g, 93% yield). LCMS (m / z): 323.8 (M+H).

[0590] Intermediate I

[0591] 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol

[0592] Step A: 7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol

[0593] At room temperature, 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (500 mg, 1.54 mmol), Pd(PPh3)2Cl2 (216 mg, 0.31 mmol), and CuI (147 mg, 0.77 mmol) were dissolved in 10 mL of anhydrous THF. The system was purged with nitrogen three times, and triisopropylsilyl acetylene (562 mg, 3.08 mmol) and TEA (779 mg, 7.70 mmol) were added. The system was purged with nitrogen three times again. The resulting mixture was heated to 50°C for 16 h. The reaction was monitored by LCMS, cooled to room temperature, and filtered through celite. The filtrate was concentrated to dryness to give a crude product, which was purified by FCC (SiO2, EA / PE = 0-50%) to afford 7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol (330 mg, 46% yield) as a white solid. LCMS (m / z): 426.0 (M+H).

[0594] Intermediate J

[0595] 7-Bromo-8-fluoro-2-methylthio-6-(trifluoromethyl)quinazolin-4-ol

[0596] Step A: 2-Amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoic acid

[0597] At room temperature, a solution of LiOH (15.17 g, 630 mmol) in water (100 mL) was added to a mixture of methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (20 g, 63 mmol), THF (100 mL), and MeOH (100 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LCMS. 1M HCl was added to adjust the pH to ~6, and the mixture was extracted with EA (100 mL x 3). The organic phase was collected, washed with saturated brine, and concentrated to afford 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoic acid (19 g, 99% yield) as a yellow solid. LCMS (m / z): 301.9 (M+H).

[0598] Step B: 2-Amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoyl chloride

[0599] 2-Amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoic acid (19 g, 63 mmol) was added to SOCl2 (200 mL) at room temperature and stirred at 50°C for 3 h. LCMS monitored the reaction completion and the reaction mixture returned to room temperature. The reaction mixture was concentrated to afford 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoyl chloride (20 g, 99% yield) as a yellow oil. LCMS (m / z): 315.9 (M-Cl + OMe).

[0600] Step C: 7-Bromo-8-fluoro-2-mercapto-6-(trifluoromethyl)quinazolin-4-ol

[0601] At room temperature, 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoyl chloride (20 g, 62.4 mmol) was added to acetone (200 mL). Ammonium thiocyanate (14.2 g, 187 mmol) was dissolved in acetone (100 mL) and added to the reaction mixture, stirring for 2 h. LCMS monitored the reaction for completion. The reaction mixture was slowly poured into stirred water (1000 mL), resulting in the formation of flocculent insoluble matter. The filter cake was collected by filtration and dried to afford 7-bromo-8-fluoro-2-mercapto-6-(trifluoromethyl)quinazolin-4-ol (20 g, 93% yield) as a yellow solid. LCMS (m / z): 342.9 (M+H).

[0602] Step D: 7-Bromo-8-fluoro-2-methylthio-6-(trifluoromethyl)quinazolin-4-ol

[0603] At room temperature, MeI (20.68 g, 146 mmol) was added to a mixture of 7-bromo-8-fluoro-2-mercapto-6-(trifluoromethyl)quinazolin-4-ol (20 g, 58.3 mmol), MeOH (200 mL), and 0.1 M NaOH (200 mL) and stirred for 2 h. The reaction was monitored by LCMS. The mixture was then slowly poured into stirred water (1000 mL). The pH was adjusted to ~6 with concentrated hydrochloric acid. A flocculent insoluble material formed, which was collected by filtration and dried to afford 7-bromo-8-fluoro-2-methylthio-6-(trifluoromethyl)quinazolin-4-ol (20 g, 96% yield) as a yellow solid. LCMS (m / z): 356.9 (M+H).

[0604] Intermediate K

[0605] 7-Bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline

[0606] Step A: 7-Bromo-8-fluoro-6-nitroquinazoline-2,4-diol

[0607] Dissolve 7-bromo-8-fluoroquinazoline-2,4-diol (11.0 g, 42.5 mmol) in concentrated sulfuric acid (60 mL). Add potassium nitrate (8.6 g, 84.9 mmol) under ice-cooling and stir for 1 hour. Pour the reaction mixture into ice water (200 mL). Collect the precipitated solid by filtration, wash with water (50 mL), and dry in vacuo to obtain 7-bromo-8-fluoro-6-nitroquinazoline-2,4-diol (12.0 g, 93% yield) as a yellow solid. LCMS (m / z): 303.9 (M+H).

[0608] Step B: 7-Bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline

[0609] Disperse 7-bromo-8-fluoro-6-nitroquinazoline-2,4-diol (10.0 g, 32.9 mmol) in toluene (60 mL), add phosphorus oxychloride (30 mL) and DIPEA (10 mL), and stir at 90°C for 2 h. The reaction mixture is concentrated, and an appropriate amount of acetonitrile (15 mL) is added, followed by pouring into ice water (100 mL). The precipitated solid is collected by filtration, washed with water (50 mL), and dried under vacuum to obtain 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (10.0 g, 89% yield) as a yellow solid. LCMS (m / z): 341.9 (M+H).

[0610] Intermediate L

[0611] 7-Bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile

[0612] The synthesis of intermediate L was carried out with reference to document WO2022095960.

[0613] Intermediate O

[0614] 7-Bromo-2,4-dichloro-6-(difluoromethyl)-8-fluoroquinazoline

[0615] Step A: Methyl 2-amino-4-bromo-3-fluoro-5-vinylbenzoate

[0616] At room temperature, methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (20 g, 53.76 mmol), vinylboronic acid pinacol (16.4 g, 107.52 mmol), Pd(dppf)Cl2·DCM (2.2 g, 2.68 mmol), and K2CO3 (22 g, 161.28 mmol) were added sequentially to DMF (300 mL). After nitrogen displacement three times, the mixture was heated to 60°C and stirred for 48 h. LCMS monitored the reaction completion. The reaction mixture was returned to room temperature and filtered through celite to remove the palladium catalyst. The mother liquor was concentrated to obtain a crude product, which was purified by FCC (SiO2, EA / PE = 0-8%) to afford methyl 2-amino-4-bromo-3-fluoro-5-vinylbenzoate (8.5 g, 57% yield) as a yellow solid. LCMS (m / z): 274.0 (M+H).

[0617] Step B: Methyl 2-amino-4-bromo-3-fluoro-5-formylbenzoate

[0618] At room temperature, methyl 2-amino-4-bromo-3-fluoro-5-vinylbenzoate (3 g, 10.99 mmol), K₂OsO₄·2H₂O (1.2 g, 3.3 mmol), and NaIO₄ (9.2 g, 43.92 mmol) were added sequentially to THF / H₂O (V / V = 1:1, 60 mL) and stirred at room temperature for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered and extracted with EA (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried, filtered, and concentrated. The crude product was purified by FCC (SiO₂, EA / PE = 0-10%) to afford methyl 2-amino-4-bromo-3-fluoro-5-formylbenzoate (2.3 g, 76% yield) as a gray solid. LCMS (m / z): 275.9 (M+H).

[0619] Step C: Methyl 2-amino-4-bromo-5-(difluoromethyl)-3-fluorobenzoate

[0620] DAST (1.2 g, 7.25 mmol) was slowly added dropwise to a solution of methyl 2-amino-4-bromo-3-fluoro-5-formylbenzoate (1 g, 3.62 mmol) in DCM (20 mL) at 0°C and stirred at room temperature for 16 h. Upon completion of the reaction, DCM (20 mL) was added and the organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2). The reaction solution was then concentrated to dryness and the crude product was purified by FCC (SiO2, EA / PE = 0-5%) to afford methyl 2-amino-4-bromo-5-(difluoromethyl)-3-fluorobenzoate (500 mg, 46% yield) as a gray solid. LCMS (m / z): 298.0 (M+H).

[0621] Step D: Methyl 4-bromo-5-(difluoromethyl)-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate

[0622] At room temperature, methyl 2-amino-4-bromo-5-(difluoromethyl)-3-fluorobenzoate (450 mg, 1.5 mmol) and 2,2,2-trichloro-1-isocyanatoethane-1-one (432 mg, 2.25 mmol) were added sequentially to THF (10 mL) and stirred at room temperature for 0.5 h. LCMS monitored the reaction completion, and the reaction solution was concentrated to afford methyl 4-bromo-5-(difluoromethyl)-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (600 mg, crude) as a yellow solid. LCMS (m / z): 484.9 (M+H).

[0623] Step E: 7-Bromo-6-(difluoromethyl)-8-fluoroquinazoline-2,4-diol

[0624] At room temperature, methyl 4-bromo-5-(difluoromethyl)-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (600 mg) and NH3 / MeOH (1 mL, 7 M) were added to MeOH (10 mL) in sequence and stirred at room temperature for 0.5 h. LCMS monitored the completion of the reaction, and the reaction solution was concentrated. The residue was slurried with MeOH (5 mL). The filter cake was collected by filtration and dried to obtain 7-bromo-6-(difluoromethyl)-8-fluoroquinazoline-2,4-diol (400 mg) as a white solid.

[0625] Step F: 7-Bromo-2,4-dichloro-6-(difluoromethyl)-8-fluoroquinazoline

[0626] Under an ice bath, DIEA (1.2 ml, 6.45 mmol) was slowly added dropwise to a mixture of 7-bromo-6-(difluoromethyl)-8-fluoroquinazoline-2,4-diol (400 mg, 1.29 mmol) and POCl₃ (3 mL, 30.32 mmol). The mixture was heated to 105°C and stirred for 1 h. LCMS monitored the reaction completion. The reaction solution was concentrated, and the residue was slowly poured into H₂O (20 mL). A flocculent product formed, which was filtered, collected, and dried in a vacuum oven to afford 7-bromo-2,4-dichloro-6-(difluoromethyl)-8-fluoroquinazoline (350 mg, 78% yield) as a yellow solid.

[0627] Intermediate P

[0628] (Z)-7-Bromo-2,4-dichloro-8-fluoro-6-(2-fluorovinyl)quinazoline

[0629] Step A: (Z)-2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoic acid methyl ester (P-1) and (E)-2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoic acid methyl ester (Q-1)

[0630] Dissolve (fluoromethyl)triphenylphosphine tetrafluoroborate (2.49 g, 6.525 mmol) in THF (15 mL), cool to -78°C, and add potassium tert-butoxide (1 M in THF, 6.53 mL, 6.53 mmol). After stirring for 1 hour, add methyl 2-amino-4-bromo-3-fluoro-5-formylbenzoate (1.2 g, 4.35 mmol), slowly warm to room temperature, and continue stirring for 1 hour. TLC and LCMS monitoring indicate completion of the reaction. Extraction with saturated NH4Cl (200 mL) and EA (80 mL x 3) is performed. The organic phase is collected, washed with saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain the crude product, which is then purified by FCC (SiO2, EA / PE = 3%) to afford methyl (Z)-2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoate (390 mg, 31% yield) as a white solid. LCMS (m / z): 294.0 (M+H). 1 H NMR (400 MHz, CDCl3) δ 8.16 (t, J = 1.6 Hz, 1H), 6.70 (dd, J1 = 82.8 Hz, J2 = 5.6 Hz, 1H), 5.88 (dd, J1 = 43.2 Hz, J2 = 5.6 Hz, 1H), 3.90 (s, 3H). The product was a white solid (E)-methyl 2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoate (612 mg, 48% yield). LCMS (m / z): 294.0 (M+H). 1 H NMR (400MHz, CDCl3) δ7.64 (d, J=2.0Hz, 1H), 7.03 (dd, J1=82.8Hz, J2=11.2Hz, 1H), 6.55 (dd, J1=18.0Hz, J2=11.2Hz, 1H), 3.90 (s, 3H).

[0631] Step B: Methyl (Z)-4-bromo-3-fluoro-5-(2-fluorovinyl)-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate

[0632] Methyl (Z)-2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoate (390 mg, 1.335 mmol) was dissolved in THF (6.7 mL) and cooled to 0°C. Trichloroacetyl isocyanate (238 μL, 2 mmol) was added, stirred for 10 minutes, and then slowly warmed to room temperature and stirred for another 30 minutes. LCMS monitored the reaction completion, and the reaction solution was concentrated under reduced pressure to obtain a white solid, which was used directly in the next step. LCMS (m / z): 502.9 (M+Na).

[0633] Step C: (Z)-7-Bromo-8-fluoro-6-(2-fluorovinyl)quinazoline-2,4-diol

[0634] MeOH (6.7 mL) was added to the crude product from step B to obtain a white suspension. NH3 (7N MeOH solution, 1.34 mL, 9.38 mmol) was then added at room temperature. The resulting mixture was stirred for 30 minutes to obtain a pale yellow, clear solution. Stirring was continued for 2 hours. A large amount of white solid precipitated, and the reaction was monitored for completion by LCMS. The filter cake was filtered and dried to obtain (Z)-7-bromo-8-fluoro-6-(2-fluorovinyl)quinazoline-2,4-diol (404 mg, 99% yield) as a white solid. LCMS (m / z): 304.9 (M+H).

[0635] Step D: (Z)-7-Bromo-2,4-dichloro-8-fluoro-6-(2-fluorovinyl)quinazoline

[0636] (Z)-7-Bromo-8-fluoro-6-(2-fluorovinyl)quinazoline-2,4-diol (404 mg, 1.33 mmol) was dissolved in POCl₃ (3 mL, 32.16 mmol) and cooled to 0°C. DIEA (1.9 mL, 10.72 mmol) was added, stirred for 10 minutes, and then refluxed in an oil bath at 110°C for 4 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and extracted with saturated NaHCO₃ (100 mL) and EA (80 mL x 3). The organic phase was collected, washed with saturated brine, dried, and concentrated under reduced pressure to obtain a crude product, which was purified by FCC (SiO₂, EA / PE = 8%) to afford (Z)-7-bromo-2,4-dichloro-8-fluoro-6-(2-fluorovinyl)quinazoline (301 mg, 67% yield) as a white solid. LCMS (m / z): 333.0 (M-2Cl+2MeO+H).

[0637] Intermediate Q

[0638] (Z)-7-Bromo-2,4-dichloro-8-fluoro-6-(2-fluorovinyl)quinazoline

[0639] Synthesis of Intermediate Q Referring to Intermediate P, (E)-methyl 2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoate was used in step B instead of methyl (Z)-2-amino-4-bromo-3-fluoro-5-(2-fluorovinyl)benzoate.

[0640] Intermediate T

[0641] Step A: Compound T-1

[0642] At room temperature, LiOH·H₂O (67.7 g, 1612.9 mmol) was added to a mixture of methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate (O-1, 60 g, 161.3 mmol) in THF (200 mL), MeOH (200 mL), and H₂O (200 mL). The mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and LCMS. The pH was adjusted to 6 by adding 1M HCl, and the mixture was extracted with EA (300 mL x 3). The organic phase was collected, washed with saturated brine, and concentrated to afford the product T-1 (56 g, 97% yield) as a yellow solid. LCMS (m / z): 359.9 (M+H).

[0643] Step B: Compound T-2

[0644] Compound T-1 (56 g, 155.6 mmol) was added to SOCl2 (200 mL) at room temperature and stirred at 70°C for 3 h. LCMS monitored the reaction completion and the reaction temperature returned to room temperature. The reaction solution was concentrated to afford T-2 (57.5 g, 98% yield) as a yellow oil. LCMS (m / z): 374.9 (M-Cl + OMe).

[0645] Step C: Compound T-3

[0646] At room temperature, compound T-2 (57.5 g, 153.2 mmol) was added to acetone (500 mL). Ammonium thiocyanate (34.9 g, 459.7 mmol) was dissolved in acetone (500 mL) and added to the reaction mixture. Stirring was continued for 2 h. LCMS monitoring indicated the reaction was complete. The mixture was slowly poured into stirred water (1000 mL). A flocculent insoluble material formed, which was collected by filtration and dried to afford compound T-3 as a yellow solid (60 g, 98% yield). LCMS (m / z): 400.8 (M+H).

[0647] Step D: Compound T-4

[0648] At room temperature, MeI (63.9 g, 450 mmol) was added to a mixed solution of compound T-3 (60 g, 150 mmol), MeOH (400 mL), and NaOH (24 g, 600 mmol) and stirred for 2 h. LCMS monitored the reaction for completion. The solution was then slowly poured into stirred water (1000 mL). The pH was adjusted to 6 with concentrated hydrochloric acid. A flocculent insoluble material formed, which was collected by filtration and dried to afford compound T-4 as a yellow solid (61 g, 98% yield). LCMS (m / z): 414.8 (M+H).

[0649] Step E: Compound T-5

[0650] DIEA (57.3 g, 442.1 mmol) was slowly added dropwise to a mixed solution of POCl3 (530.3 g, 3462.5 mmol) and compound T-4 (61 g, 147.3 mmol) at 0°C. The mixture was heated to 110°C and stirred for 1 h. LCMS monitored the reaction completion. The reaction solution was concentrated, and the residue was slowly added to ice water. A flocculent insoluble material was formed, which was collected by filtration and dried to afford compound T-5 (60 g, 94% yield) as a yellow solid. LCMS (m / z): 434.8 (M+H).

[0651] Step F: Intermediate T

[0652] t-BuOK (152.7 mL, 1 M THF solution, 152.7 mmol) was added to a mixed solution of compound T-5 (60 g, 138.8 mmol) and THF (1000 mL) at 0°C and stirred at 0°C for 1 hour. The mixture was then allowed to rise to room temperature and stirred for 1 hour. The reaction was monitored by LCMS and TLC. The reaction mixture was poured into a semi-saturated NH4Cl solution (200 mL) and extracted with EA (500 mL x 3). The organic phase was collected, washed with saturated brine (300 mL), dried over anhydrous Na2SO4, and the concentrated organic phase was purified by FCC (SiO2, THF / PE = 0-5%) to afford intermediate T (45 g, 69.2% yield) as a yellow solid. LCMS (m / z): 414.9 (M-56+H).

[0653] Intermediate n-1

[0654] Step A: Compound n-1-2

[0655] At room temperature, (S)-3-aminobutanol (19.9 g, 223 mmol) was added to a solution of ethyl 5-formylpyrazole-3-carboxylate (n-1-1, 25.0 g, 149 mmol) and anhydrous methanol (250 mL) and stirred for 30 min. The reaction mixture was cooled to 0-5°C with ice water. Sodium borohydride (11.3 g, 297 mmol) was slowly added to the reaction system, maintaining the internal temperature above 20°C. After the addition, the mixture was stirred at room temperature for 2 h. LCMS monitored the reaction for completion. An equal volume of water (250 mL) was added, and Boc2O (64.9 g, 297 mmol) was added to the reaction system in one portion at room temperature. The mixture was stirred at room temperature overnight. LCMS monitored the reaction for completion, and the reaction mixture was poured into H2O (500 mL) and extracted with EtOAc (500 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give a crude product which was purified by FCC (SiO2, EA / PE = 0-100%) to give a colorless oily product n-1-2 (26.2 g, yield 52%). LCMS (m / z): 342.4 (M+H).

[0656] Step B: Compound n-1-3

[0657] Under an ice-water bath, DIAD (31.0 g, 153 mmol) was added dropwise to a mixture of compound n-1-2 (26.2 g, 76.4 mmol), triphenylphosphine (38.1 g, 153 mmol), and anhydrous THF (500 mL). The mixture was allowed to warm to room temperature and stirred overnight. Upon completion of the reaction, LCMS was used to monitor the reaction. The reaction mixture was poured into H₂O (400 mL) and extracted with EtOAc (400 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO₂, EA / PE = 0-100%) to afford n-1-3 as a colorless oil (18.0 g, 73% yield). LCMS (m / z): 324.1 (M+H).

[0658] Step C: Compound n-1-4

[0659] Under ice, NaOH (11.3 g, 278 mmol) was added to a solution of compound n-1-3 (18.0 g, 55.7 mmol) and MeOH / THF / H₂O (450 mL, 1:1:1) and stirred at room temperature for 1 h. Upon completion of the reaction, the organic solution was concentrated. The remaining aqueous phase was cooled to 0-10°C in an ice-water bath, adjusted to pH 3-4 with 2N HCl, and extracted with EtOAc (400 mL x 5). The organic phases were combined, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated to dryness to afford crude compound n-1-4 (16 g, 97% yield) as a white solid. LCMS (m / z): 296.1 (M+H).

[0660] Step D: Compound n-1-5

[0661] At room temperature, HATU (34.7 g, 91.4 mmol) was added to a mixture of compound n-1-4 (18.0 g, 60.9 mmol), dimethylamine hydrochloride (9.82 g, 122 mmol), DIPEA (39.4 g, 305 mmol), and DMF (250 mL). The mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was poured into aqueous LiCl solution (5 wt%, 500 mL) and extracted with EtOAc (400 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO2, EA / PE = 0-100%) to afford the white product n-1-5 (12.4 g, 63% yield). LCMS (m / z): 323.2 (M+H). 1 H NMR(400MHz,DMSO-d6)δ6.39(s,1H),4.88–4.53(m,1H),4.51–4.11(m,3H),4.09–3.93(m,1 H), 3.23 (s, 3H), 2.94 (s, 3H), 2.18–1.93 (m, 2H), 1.45–1.24 (m, 9H), 1.20 (d, J = 6.6Hz, 3H).

[0662] Step E: Intermediate n-1

[0663] At room temperature, 4M HCl-ethyl acetate (200 mL, 800 mmol) was added to compound n-1-5 (12.4 g, 60.9 mmol) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The acid solution was concentrated to obtain intermediate n-1 as an oil (10.0 g, 100% yield). LCMS (m / z): 223.1 (M+H).

[0664] Intermediate n-1E

[0665] The synthesis of intermediate n-1E was carried out according to the synthesis scheme of intermediate n-1, except that (S)-3-amino-1-pentanol was used instead of (S)-3-aminobutanol in step A. LCMS (m / z): 237.1 (M+H).

[0666] Intermediate n-1-d6

[0667] The synthesis of intermediate n-1-d6 was prepared by referring to the synthesis of n-1, except that deuterated dimethylamine hydrochloride was used instead of dimethylamine hydrochloride in step D. LCMS (m / z): 229.3 (M+H).

[0668] Intermediate n-2

[0669] Step A: Compound n-2-1

[0670] At room temperature, NCS (311 mg, 2.33 mmol) was added to a solution of compound n-1-5 (500 mg, 1.55 mmol) and anhydrous DMF (5 mL). The mixture was heated to 40-50°C and stirred for 3 h. Upon completion of the reaction, the mixture was poured into 5% aqueous LiCl (50 mL) and extracted with EtOAc (40 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give the crude product, which was then purified by FCC (SiO2, EA / PE = 0-100%) to afford n-2-1 as a colorless oil (370 mg, 67% yield). LCMS (m / z): 357.1 (M+H).

[0671] Step B: Intermediate n-2

[0672] At room temperature, 4M HCl-ethyl acetate (20 mL, 80 mmol) was added to compound n-2-1 (370 mg, 1.04 mmol) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The acid solution was concentrated to obtain intermediate n-2 (300 mg) as a semi-solid oil. LCMS (m / z): 257.3 (M+H).

[0673] Intermediate n-3

[0674] Step A: Compound n-3-1

[0675] To a solution of compound n-1-5 (270 mg, 0.8 mmol) in acetonitrile (15 mL) was added 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (2.26 g, 6.4 mmol) at room temperature. The mixture was heated to 40°C and stirred for 24 hours. After completion of the reaction, the reaction solution was filtered through celite and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO2, THF / PE = 0-50%) to afford n-3-1 as a pale yellow oil (60 mg, 21% yield). LCMS (m / z): 341.2 (M+H).

[0676] Step B: Intermediate n-3

[0677] To compound n-3-1 (60 mg, 0.17 mmol) was added 4N HCl / EA solution (2 mL) at room temperature. The resulting reaction mixture was stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated to dryness to obtain the crude intermediate n-3 (62 mg) as a yellow oil. LCMS (m / z): 241.1 (M+H).

[0678] Intermediate n-4

[0679] Step A: Compound n-4-1

[0680] At room temperature, NIS (1.40 g, 6.20 mmol) was added to a solution of compound n-1-5 (1.00 g, 3.10 mmol) and anhydrous DMF (10 mL). The mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the mixture was poured into a 5% aqueous LiCl solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated sodium thiosulfate (50 mL). Finally, the mixture was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO2, EA / PE = 0-100%) to afford n-4-1 as a colorless oil (750 mg, 54% yield). LCMS (m / z): 449.0 (M+H).

[0681] Step B: Compound n-4-2

[0682] At room temperature, compound n-4-1 (300 mg, 0.669 mmol), methylboronic acid (80.1 mg, 1.34 mmol), cataCXium-A-Pd-G3 (48.7 mg, 0.067 mmol), and K3PO4 (426 mg, 2.01 mmol) were added sequentially to a mixture of 1,4-dioxane and water (5 mL, V / V = 5:1). After nitrogen displacement three times, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-100%) to afford n-4-2 (185 mg, 82% yield), a white solid. LCMS (m / z): 337.2 (M+H).

[0683] Step C: Intermediate n-4

[0684] At room temperature, 4M HCl-ethyl acetate (20 mL, 80 mmol) was added to compound n-4-2 (185 mg, 0.55 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the acid solution was concentrated to obtain intermediate n-4 (150 mg) as a semisolid oil. LCMS (m / z): 237.1 (M+H).

[0685] Intermediate n-5

[0686] Step A: Compound n-5-1

[0687] At room temperature, compound n-4-1 (200 mg, 0.446 mmol), triisopropylsilyl acetylene (162 mg, 0.890 mmol), bistriphenylphosphine palladium dichloride (31 mg, 0.044 mmol), CuI (10 mg, 0.052 mmol), and TEA (225 mg, 2.28 mmol) were added sequentially to tetrahydrofuran (5 mL). After nitrogen substitution three times, the temperature was raised to 50°C and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-100%) to afford n-5-1 (50 mg, 22% yield), a white solid. LCMS (m / z): 503.2 (M+H).

[0688] Step B: Intermediate n-5

[0689] At room temperature, 4M HCl-ethyl acetate (10 mL, 40 mmol) was added to compound n-4-1 (50 mg, 0.099 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the acid solution was concentrated to obtain intermediate n-5 (40 mg) as a semisolid oil. LCMS (m / z): 403.2 (M+H).

[0690] Intermediates n-6A and n-6B

[0691] Step A: Compounds n-6-1A and n-6-1B

[0692] Compound n-6-1 (2.10 g) was separated by SFC (Waters SFC 150, separation column: 250*30mm 10μm; mobile phase: CO2 / MeOH (+0.1% 7.0mol / l NH3-MeOH) = 70 / 30; flow rate: 120mL / min) The first eluting isomer 1 was compound n-6-1A (1.04g, relatively short retention time). Chiral analysis method SFC-n-6, Rt = 1.184, LCMS (m / z): 217.1 (M+H). The second eluting isomer 2 was compound n-6-1B (1.05g, relatively long retention time). Chiral analysis method SFC-n-6, Rt = 2.250, LCMS (m / z): 217.1 (M+H).

[0693] Chiral analysis method SFC-n-6: Waters UPCC, analytical column: Daicel 100 x 3 mm, 3 μm; mobile phase A: CO2, mobile phase B: MeOH (+0.1% DEA); flow rate: 1.5 mL / min; column temperature: 35°C; back pressure: 1800 psi; gradient: 0-5.0 min, A / B = 80 / 20.

[0694] Step B: Intermediate n-6A

[0695] At room temperature, compound n-6-1A (1.04 g, 48.1 mmol) and Pd / C (10 wt%, 1 g, 9.6 mmol) were added sequentially to a MeOH (10 mL) solution. After three H2 balloon replacements, the mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The palladium catalyst was removed by filtration through Celite, and the mother liquor was collected. The organic solution was concentrated to afford intermediate n-6A (2.4 g, 20.7% yield). LCMS (m / z): 127.0 (M+H).

[0696] The intermediate n-6B was prepared from compound n-6-1B using the same method.

[0697] Intermediates n-7A and n-7B

[0698] Step A: Compound n-7-2

[0699] At room temperature, compound n-7-1 (7.0 g, 30.9 mmol), p-nitrobenzoic acid (5.2 g, 30.9 mmol), PPh3 (9.7 g, 37.1 mmol), and DIAD (7.5 g, 37.1 mmol) were added sequentially to a THF (100 mL) solution. After nitrogen displacement three times, the mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS and TLC. The reaction mixture was added to water (200 mL) and extracted with EA (100 mL × 3). The collected organic phases were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic solution was purified by FCC (SiO2, DCM / PE = 0-100%) to afford compound n-7-2 (2.4 g, 20.7% yield) as a white solid. LCMS (m / z): 398.0 (M+Na).

[0700] Step B: Compounds n-7-2A and n-7-2B

[0701] Compound n-7-2 (2.4 g) was separated by SFC (Waters SFC 150, separation column: 250*30mm 10μm; mobile phase: CO2 / MeOH (+0.1% 7.0mol / l NH3-MeOH) = 75 / 25; flow rate: 120mL / min) The first eluted isomer 1 was compound n-7-2A (1.25g, relatively short retention time), chiral analysis method SFC-n-7, Rt = 0.861; the second eluted isomer 2 was compound n-7-2B (1.15g, relatively short retention time), chiral analysis method SFC-n-7, Rt = 1.883.

[0702] Chiral analysis method SFC-n-7: Waters UPCC, analytical column: Daicel 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: 0-5.0min A / B=80 / 20.

[0703] Step C: Compound n-7-3A

[0704] At room temperature, compound n-7-2A (200 mg, 0.53 mmol) and K2CO3 (147 mg, 1.07 mmol) were added to a MeOH (5 mL) solution and stirred for 20 h. The reaction was monitored by LCMS and TLC. The reaction solution was poured into H2O (20 mL) and extracted with EA (20 mL x 3). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic phase was purified by FCC (SiO2, EA / PE = 0-50%) to obtain compound n-7-2A (120 mg, 99.5% yield) as a white solid. LCMS (m / z): 227.3 (M+H).

[0705] Using the same method, n-7-3B was prepared from compound n-7-2B.

[0706] Step D: Intermediate n-7A

[0707] At room temperature, compound n-7-3A (120 mg, 0.53 mmol) was added to a mixture of DCM (3 mL) and TFA (1 mL) and stirred for 1 h. The reaction was monitored by LCMS. The reaction solution was concentrated and poured into saturated NaHCO₃ (10 mL). Extraction was performed with EA (10 mL x 3). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to afford intermediate n-7A (90 mg, 70.6% yield). LCMS (m / z): 127.0 (M+H).

[0708] Intermediate n-7B was prepared from compound n-7-3B using the same method.

[0709] Intermediate n-8

[0710] Step A: Compound n-8-1

[0711] At room temperature, NBS (5.0 g, 27.9 mmol) was added to a mixture of compound n-1-5 (6.0 g, 18.6 mmol) and DMF (60 mL). The mixture was stirred at room temperature for 3 h. Upon completion of the reaction, the mixture was poured into 5% aqueous LiCl (200 mL) and extracted with EtOAc (200 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain the crude product, which was purified by FCC (SiO2, EA / PE = 0-100%) and lyophilized to afford compound n-8-1 (7.0 g, 94% yield) as a white solid. LCMS (m / z): 401.1 / 403.1 (M+H). 1H NMR(400MHz,DMSO-d6)δ4.68-4.58(m,1H),4.45-4.39(m,2H),4.31-4.20(m,1H),4.09-3.9 0(m,1H),2.96(s,3H),2.95(s,3H),2.18-2.05(m,2H),1.33(s,9H),1.19(d,J=6.4Hz,3H).

[0712] Step B: Compound n-8-2

[0713] At room temperature, compound n-8-1 (1 g, 2.5 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled in a dry ice-ethanol bath for 10 min. n-Butyl lithium (1.6 M, 2.4 mL, 3.75 mmol) was slowly added dropwise to the reaction system. Stirring was continued in a dry ice-ethanol bath for 10 min. Bromomethyl methyl ether (468 mg, 3.75 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL) and slowly added dropwise to the reaction system. Stirring was continued for 10 min after the addition was complete, then the mixture was allowed to warm to room temperature and stirred for 20 min. The reaction was monitored by LCMS. The reaction was quenched with aqueous ammonium chloride (5 mL), 20 mL of water was added, and the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain a crude product which was purified by FCC (SiO2, EA / PE = 0-100%) to obtain white solid compound n-8-2 (465 mg, yield 49%). LCMS (m / z): 367.2 (M+H).

[0714] Step C: Intermediate n-8

[0715] At room temperature, 4M HCl-ethyl acetate (10 mL, 40 mmol) was added to compound n-8-2 (465 mg, 1.27 mmol) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The acid solution was concentrated to obtain intermediate n-8 (385 mg, 100%) as a semi-solid oil. LCMS (m / z): 267.1 (M+H).

[0716] Prepare the following intermediates by referring to the above intermediates

[0717] Intermediate n-9

[0718] Step A: Compound n-9-2

[0719] At room temperature, CH3I (1.44 g, 10.2 mmol) was added to a mixture of compound n-1-4 (1.00 g, 3.39 mmol), K2CO3 (1.40 g, 10.2 mmol), and ACN (20 mL). The mixture was stirred at 40°C overnight. LCMS monitored the reaction completion. The reaction mixture was then filtered through Celite and then concentrated to a filter to obtain a clear organic phase. After complete concentration, a yellow solid, compound n-9-2 (1.03 g, 98% yield), was obtained. LCMS (m / z): 310.2 (M+H).

[0720] Step B: Compound n-9-3

[0721] NIS (1.60 g, 7.11 mmol) was added to a mixture of compound n-9-2 (1.10 g, 3.56 mmol) and AcOH (15 mL) at room temperature and stirred at 80°C for 1 h. The reaction was monitored by LCMS. After concentration to remove the acid, the mixture was purified by FCC (SiO2, EA / PE = 0-60%) to afford a dark yellow solid. This was then purified by slurrying with PE:EA = 10:1, 15 mL, and filtered to afford compound n-9-3 (980 mg, 63% yield) as a yellow solid. LCMS (m / z): 436.1 (M+H).

[0722] Step C: Compound n-9-4

[0723] At room temperature, compound n-9-3 (960 mg, 2.21 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.82 g, 22.1 mmol), Pd(PPh3)2Cl2 (155 mg, 0.221 mmol), and TEA (1.12 g, 11.0 mmol) were added to ACN (15 mL) in sequence. After nitrogen was replaced three times, the temperature was raised to 40°C and stirred overnight. The reaction was monitored by LCMS. The reaction solution was returned to room temperature and the palladium catalyst was removed by filtration through celite. The mother liquor was collected, water (50 mL) was added, and the mixture was extracted with EA (50 mL × 3). The collected organic phase was concentrated, and the crude product was purified by FCC (SiO2, EA / PE = 0-60%) to give compound n-9-4 (960 mg, crude) as a brown-yellow solid. Boronic ester LCMS (m / z): 436.3 (M+H) and boronic acid LCMS (m / z): 354.2 (M+H).

[0724] Step D: Compound n-9-5

[0725] At room temperature, H₂O₂ (1.52 g, 30% in H₂O, 13.4 mmol) was added to a mixture of compound n-9-4 (950 mg, 2.69 mmol), NaOH (215 mg, 5.38 mmol), and THF (15 mL). The mixture was stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. Water (50 mL) and EA (100 mL) were added, and the pH was adjusted to ~6 with 1M HCl. Extraction was performed with EA (50 mL x 3). The collected organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the collected organic phase was concentrated to yield compound n-9-5 (800 mg, 91%) as a yellow solid. LCMS (m / z): 326.1 (M+H).

[0726] Step E: Compound n-9-6

[0727] At room temperature, LiOH·H₂O (774 mg, 18.4 mmol) was added to a solution of compound n-9-5 (500 mg, 1.54 mmol) and MeOH:H₂O (V / V = 1:1, 10 mL) and stirred overnight at room temperature. LCMS monitored the reaction. The reaction solution was concentrated to remove the MeOH, diluted with EA (50 mL), and the pH was adjusted to ~6 with 1M HCl. Extraction was performed with EA (50 mL x 5). The collected organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield compound n-9-6 (400 mg, 84%) as a yellow oil. LCMS (m / z): 256 (M+H-56).

[0728] Step F: Compound n-9-7

[0729] At room temperature, TEA (650 mg, 6.42 mmol) was added to a mixture of compound n-9-6 (400 mg, 1.28 mmol), dimethylamine hydrochloride (207 mg, 2.57 mmol), HATU (732 mg, 1.93 mmol), and DCM (10 mL). The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was concentrated and purified by FCC (SiO2, EA / PE = 0-80%) to afford compound n-9-7 (250 mg, crude) as a yellowish yellow oil. LCMS (m / z): 339.2 (M+H).

[0730] Step G: Intermediate n-9

[0731] At room temperature, TFA:DCM (V / V = 3:1, 20 mL) was added to compound n-9-7 (150 mg, 0.443 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the acid was removed by concentration, and the product was lyophilized with a small amount of ACN and water to afford intermediate n-9 (160 mg) as a yellow oil, which was used directly in subsequent reactions. LCMS (m / z): 239.1 (M+H).

[0732] Intermediate n-10

[0733] Step A: Compound n-10-2

[0734] At room temperature, CH3I (1.31 g, 9.22 mmol) was added to a mixture of compound n-9-5 (300 mg, 0.922 mmol), K2CO3 (637 mg, 4.16 mmol), and ACN (15 mL), and stirred at 40°C overnight. LCMS monitored the reaction completion. The reaction solution was concentrated over Celite to yield the crude product, which was then purified by FCC (SiO2, EA / PE = 0-80%) to afford a yellow solid, giving compound n-10-2 (160 mg, 51% yield) as a white solid. LCMS (m / z): 340.2 (M+H).

[0735] Step B: Compound n-10-3

[0736] At room temperature, LiOH·H₂O (238 mg, 5.66 mmol) was added to a solution of compound n-10-2 (160 mg, 0.471 mmol) and MeOH:H₂O (V / V = 1:1, 10 mL) and stirred overnight at room temperature. LCMS monitored the reaction. The reaction solution was concentrated to remove the MeOH, diluted with EA (50 mL), and the pH was adjusted to ~6 with 1M HCl. Extraction was performed with EA (50 mL x 5). The collected organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the collected organic phase was concentrated to yield compound n-10-3 (150 mg, 98%) as a yellow oil. LCMS (m / z): 326.2 (M+H).

[0737] Step C: Compound n-10-4

[0738] DIPEA (298 mg, 2.31 mmol) was added to a mixture of compound n-10-3 (150 mg, 0.461 mmol), dimethylamine hydrochloride (74.3 mg, 0.922 mmol), HATU (263 mg, 0.692 mmol), and DCM (10 mL) at room temperature and stirred for 2 h. The reaction was monitored by LCMS. The mixture was concentrated and purified by FCC (SiO2, EA / PE = 0-80%) to afford compound n-10-4 (140 mg, 86% yield) as a white solid. LCMS (m / z): 353.2 (M+H).

[0739] Step D: Intermediate n-10

[0740] At room temperature, TFA:DCM (V / V = 3:1, 20 mL) was added to compound n-10-4 (140 mg, 0.397 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the acid was removed by concentration, and the product was lyophilized with a small amount of ACN and water to afford intermediate n-10 (160 mg) as a white solid, which was used directly in subsequent reactions. LCMS (m / z): 253.2 (M+H).

[0741] Intermediate n-11

[0742] Intermediate n-11 was prepared according to the method of intermediate n-10. LCMS (m / z): 267.2 (M+H).

[0743] Referring to the above synthesis scheme or appropriate variations, the present invention also prepared and characterized the following intermediates:

[0744] Intermediate n-22

[0745] Step A: Compound n-22-1

[0746] At room temperature, N-methyl-O-methylhydroxylamine hydrochloride (992 mg, 10.17 mmol) was added to a mixed solution of compound n-1-4 (2 g, 6.78 mmol), HATU (3.86 g, 10.17 mmol), DIEA (2.04 g, 20.34 mmol) and THF (40 mL). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and LCMS to be complete. The reaction solution was poured into water (200 mL) and extracted with EA (50 mL × 3). The collected organic phase was washed with saturated NaCl (50 mL) and dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic phase was separated by FCC (SiO2, EA / PE = 10-40%) to obtain compound n-22-1 (3.1 g) as a white solid. LCMS (m / z): 339.1 (M+H)

[0747] Step B: Compound n-22-2

[0748] Methylmagnesium bromide solution (1M, 1.76 mL, 1.76 mmol) was added to a mixed solution of compound n-22-1 (300 mg) and THF (5 mL) at 0°C. The mixture was stirred at 0°C for 0.5 hours. After completion of the reaction as monitored by LCMS, the reaction solution was poured into H2O (20 mL) and extracted with EA (10 mL x 3). The collected organic phase was washed with saturated NaCl (20 mL) and dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic phase was separated by FCC (SiO2, EA / PE = 10-30%) to afford compound n-22-2 (150 mg, 58% yield over two steps) as a colorless oil. LCMS (m / z): 294.1 (M+H).

[0749] Step C: Intermediate n-22

[0750] Compound n-22-2 (150 mg, 0.51 mmol) was added to a 4M HCl-EA solution at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS monitored the reaction completion. The reaction solution was concentrated to afford intermediate n-22 (88 mg, 89% yield) as a white solid. LCMS (m / z): 194.1 (M+H).

[0751] Intermediate n-23

[0752] Step A: Compound n-23-1

[0753] To a solution of compound n-1-5 (1.0 g, 3.1 mmol) in DMF (15 mL) and acetic acid (0.5 mL) at room temperature was added N-iodosuccinimide (768 mg, 3.4 mmol). The temperature was raised to 60°C and the reaction was stirred for 12 h. After completion of the reaction, as monitored by LCMS, the reaction solution was slowly added to ice water 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 = 0-70%) to afford compound n-23-1 (1.3 g, 93% yield) as a pale yellow solid. LCMS (m / z): 449.1 (M+H).

[0754] Step B: Compound n-23-2

[0755] To a solution of compound n-23-1 (1.3 g, 2.9 mmol) in DMF (20 mL) under N₂ was added vinylboronic acid pinacol ester (1.34 g, 8.7 mmol), potassium carbonate (1.4 g, 10.1 mmol), and Pd(dppf)Cl₂ (222 mg, 0.29 mmol). The resulting reaction mixture was stirred at 90°C for 15 h. After completion of the reaction, monitored by LCMS, the reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO₂, EA / PE = 0-75%) to afford compound n-23-2 (820 mg, 81% yield) as a yellow oil. LCMS (m / z): 349.2 (M+H).

[0756] Step C: Compound n-23-3

[0757] To a solution of compound n-23-2 (300 mg, 0.86 mmol) in methanol (10 mL) was added Pd / C (9.2 mg, 0.08 mmol, 10%) and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was filtered through celite and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-75%) to afford compound n-23-3 (260 mg, 86% yield) as a yellow oil. LCMS (m / z): 351.2 (M+H).

[0758] Step D: Intermediate n-23

[0759] To compound n-23-2 (260 mg, 0.74 mmol) was added HCl / EA (5 mL, 4 N) at 0°C and stirred for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness to afford intermediate n-23 (270 mg) as a yellow oil. LCMS (m / z): 251.2 (M+H).

[0760] Intermediate n-24

[0761] Step A: Compound n-24-1

[0762] Potassium osmate (45 mg, 0.29 mmol) was added to a solution of compound n-23-2 (500 mg, 2.9 mmol) in THF (10 mL) and water (5 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 0.5 h. Sodium periodate (1.23 g, 5.75 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for another 12 h. After the reaction was completed, the reaction mixture was slowly added to water and extracted with ethyl acetate, as monitored by LCMS. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-80%) to afford compound n-24-1 (120 mg, 24% yield) as a yellow oil. LCMS (m / z): 351.2 (M+H).

[0763] Step B: Compound n-24-2

[0764] To a solution of compound n-24-1 (120 mg, 0.86 mmol) in dichloromethane (3 mL) at room temperature was added diethylaminosulfur trifluoride (552 mg, 3.4 mmol). The temperature was raised to 40°C and the reaction was stirred for 6 h. After completion of the reaction, as monitored by LCMS, the reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. 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 pre-TLC (EA) to afford compound n-24-2 (42 mg, 33% yield) as a yellow oil. LCMS (m / z): 373.2 (M+H).

[0765] Step C: Intermediate n-24

[0766] To compound n-24-2 (42 mg, 0.11 mmol) was added HCl / EA (2 mL, 4 N) at 0°C and stirred for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness to afford intermediate n-24 (45 mg) as a yellow oil. LCMS (m / z): 273.2 (M+H).

[0767] Intermediate n-25

[0768] Step A: Compound n-25-2

[0769] PMBCl (12.9 g, 82.7 mmol) was slowly added dropwise to a mixture of compound n-25-1 (6.70 g, 75.2 mmol) and KCO (20.0 g, 225 mmol) in MeCN (200 mL) at 0°C. The mixture was stirred at room temperature for 16 h, and the reaction was monitored for completion by LCMS. The crude product was filtered and concentrated, and purified by FCC (SiO, THF / PE = 0-15%) to afford compound n-25-2 (2.3 g, 15% yield) as a colorless oil. LCMS (m / z): 210.1 (M+H).

[0770] Step B: Compound n-25-3

[0771] Compound n-25-2 (2.0 g, 9.56 mmol), 3-chloropropyne (848 mg, 11.4 mmol), and KCO (2.64 g, 19.1 mmol) were added sequentially to a MeCN (40 mL) solution at room temperature. The mixture was heated to 80°C and stirred for 16 h. The reaction was monitored by LCMS for completion. The crude product was filtered and concentrated, and purified by FCC (SiO, THF / PE = 0-10%) to afford compound n-25-3 (1.7 g, 74% yield) as a colorless oil. LCMS (m / z): 247.1 (M+H).

[0772] Step C: Compound n-25-4

[0773] At 0°C, SOCl2 (1.06 mL, 14.5 mmol) was slowly added dropwise to a mixture of pyridine (0.883 mL, 10.9 mmol) and compound n-25-3 (1.7 g, 6.88 mmol) in DCM (30 mL). The mixture was stirred at 0°C for 6 h, and the reaction was monitored for completion by LCMS. The reaction was quenched with NaHCO3, extracted with ethyl acetate (30 mL × 3), and the organic phase was dried and concentrated. To a solution of the crude product from the previous step in DMF (20 mL) was added NaN3 (450 mg, 6.88 mmol), and the mixture was stirred at 80°C for 16 h, and the reaction was monitored for completion by LCMS. Ethyl acetate (50 mL) was added, and the mixture was washed with saturated brine (15 mL × 3). The organic phase was dried and concentrated to give crude compound n-25-4 (1.8 g). LCMS (m / z): 273.1 (M+H).

[0774] Step D: Compound n-25-5

[0775] At room temperature, compound n-25-4 (1.30 g), CuI (89.3 mg, 0.476 mmol), and DIEA (1.85 g, 14.28 mmol) were added sequentially to a DMF (10 mL) solution and stirred at 80°C for 0.5 h. Upon completion of the reaction, ethyl acetate (50 mL) was added and washed with saturated brine (15 mL x 3). The organic phase was dried and concentrated to afford the crude product, which was then purified by FCC (SiO2, THF / PE = 0-20%) to afford compound n-25-4 as a colorless oil (550 mg, 42% yield over two steps). LCMS (m / z): 273.1 (M+H).

[0776] Step E: Compound n-25-6

[0777] At room temperature, compound n-25-5 (550 mg, 2.02 mmol) was added to TFA (8 mL) and stirred at 80°C for 2 h. The reaction was monitored by LCMS. The reaction solution was concentrated to give a brown compound n-25-6 (246 mg, crude product). LCMS (m / z): 153.1 (M+H).

[0778] Step F: Compound n-25-7

[0779] At room temperature, compound n-25-6 (246 mg, 1.61 mmol), TEA (0.801 mg, 8.05 mmol), and Boc2O (702 mg, 3.22 mmol) were added sequentially to DCM (10 mL) and stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction solution was then purified by FCC (SiO2, THF / PE = 0-20%) to afford compound n-25-7 (400 mg, 90% yield over two steps) as a colorless oil. LCMS (m / z): 253.1 (M+H).

[0780] Step G: Compound n-25-8

[0781] At room temperature, compound n-25-7 (93.1 mg, 0.369 mmol) and NCS (73.3 mg, 0.551 mmol) were added sequentially to MeCN (3 mL) and stirred at 60°C for 2 h. The reaction was monitored by LCMS. The reaction solution was purified by C18 (H2O / MeOH = 0-40%) to afford compound n-25-8 (88.7 mg, 79% yield) as a white solid. LCMS (m / z): 287.1 (M+H).

[0782] Step H: Compound n-25

[0783] Compound n-25-8 (88.7 mg, 0.309 mmol) was added to EA / HCl (10 mL) at room temperature and stirred for 2 h. LCMS monitored the reaction completion. The reaction mixture was concentrated to afford compound n-25 (56 mg, 92% yield) as a white solid. LCMS (m / z): 187.1 (M+H).

[0784] Intermediate n-26

[0785] Intermediate n-26 was prepared according to the above protocol. LCMS (m / z): 281.2 (M+H).

[0786] Intermediate n-8-d3

[0787] The synthesis of intermediate n-8-d3 was carried out according to the scheme of intermediate n-26. LCMS (m / z): 270.2 (M+H).

[0788] Intermediate AIF

[0789] (R)-1-(7-Bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0790] Step A: (R)-1-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0791] DIEA (2.45 mL, 13.62 mmol) was added to a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (1.8 g, 3.79 mmol), (R)-3-methyl-3-piperidinol hydrochloride (600 mg, 3.79 mmol), and THF (30 mL) at 0°C and stirred at room temperature for 2 h. The reaction was monitored for completion by TLC. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EA (50 mL x 3). The collected organic phase was washed with saturated NaCl (20 mL). The organic solution was concentrated to obtain a crude product, which was purified by FCC (SiO2, EA / PE = 0-20%) to afford (R)-1-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.38 g, 79.3% yield) as a yellow solid.

[0792] Step B: (R)-1-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0793] (R)-1-(7-Bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.33 g, 3 mmol) was added to a mixture of 1,4-diazabicyclo[2.2.2]octane (34 mg, 301 μmol), KF (1.75 g, 30 mmol), MsOH (29 mg, 301 μmol), and DMSO (15 mL) at room temperature. The mixture was stirred at 65°C for 16 h. The reaction was complete as monitored by LCMS. After cooling, the reaction solution was poured into H2O (100 mL), and a brown solid precipitated. The mixture was filtered, the filter cake was washed with H2O (100 mL), and then dried to obtain (R)-1-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (1 g, yield 78.1%) as a brown solid. LCMS (m / z): 427.9 (M+H).

[0794] Intermediate A-II-F

[0795] (S)-4-(7-Bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol

[0796] Step A: (S)-4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol

[0797] At room temperature, DIPEA (2.70 mL, 15.8 mmol) was added to a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (1.80 g, 3.95 mmol), (S)-6-methyl-1,4-oxacyclohexane-6-ol hydrochloride (660 mg, 3.95 mmol) and THF (20 mL), and the reaction was stirred at room temperature for 1 h. The reaction was monitored by TLC and LCMS. H₂O (100 mL) and EA (100 mL x 3) were added for extraction. The organic phase was collected, washed with saturated brine, and concentrated. The resulting crude product was purified by FCC (SiO₂, EA / PE = 0-30%) to afford (S)-4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol (1.4 g, 78% yield) as a yellow solid. LCMS (m / z): 459.9 (M+H).

[0798] Step B: (S)-4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol

[0799] At room temperature, (S)-4-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol (1.40 g, 3.05 mmol), KF (1.77 g, 30.5 mmol), DABCO (34 mg, 0.31 mmol), and MsOH (29 mg, 0.31 mmol) were added sequentially to DMSO (15 mL). The mixture was heated to 65°C and stirred for 3 h. LCMS monitored the reaction completion, and the reaction solution was allowed to return to room temperature. The mixture was then slowly poured into stirred water (200 mL), resulting in a flocculent insoluble material. The filter cake was collected by filtration and dried to afford (S)-4-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-6-methyl-1,4-oxazol-6-ol (1.1 g, 81% yield) as a yellow solid. LCMS (m / z): 443.9 (M+H).

[0800] Intermediate BIF

[0801] (R)-1-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0802] Step A: (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0803] DIPEA (39.9 mL, 229 mmol) was added to a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (18.0 g, 57 mmol), (R)-3-methylpiperidin-3-ol hydrochloride (8.69 g, 57 mmol), and THF (200 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS. The THF was removed by concentration, and acetonitrile (15 mL) was added. The mixture of acetonitrile and the compound was slowly poured into stirred water (600 mL). A flocculent insoluble material was produced. The filter cake was filtered and dried to afford (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (21.7 g, 96% yield) as a yellow solid. LCMS (m / z): 393.9 (M+H).

[0804] Step B: (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0805] At room temperature, (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (12.0 g, 30.6 mmol), KF (17.8 g, 306 mmol), DABCO (137 mg, 1.22 mmol), and MsOH (117 mg, 1.22 mmol) were added sequentially to DMSO (60 mL). The mixture was heated to 65°C and stirred for 10 h. After completion of the reaction, the reaction solution was returned to room temperature and then slowly poured into stirred water (600 mL). A flocculent insoluble material was produced, which was filtered and the filter cake dried to afford (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (11.3 g, 98% yield) as a yellow solid. LCMS (m / z): 378.0 (M+H).

[0806] Intermediate B-II-F

[0807] (S)-4-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0808] Step A: (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0809] DIPEA (1.55 mL, 8.92 mmol) was added to a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (700 mg, 2.23 mmol), (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (374 mg, 2.23 mmol), and THF (12 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS. The THF was removed by concentration, and acetonitrile (2 mL) was added. The mixture was slowly poured into stirred water (50 mL). A flocculent insoluble material formed. The filter cake was filtered and dried to afford (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (720 mg, 79% yield) as a brown solid. LCMS (m / z): 409.9 (M+H).

[0810] Step B: (S)-4-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0811] At room temperature, (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (700 mg, 1.71 mmol), KF (995 mg, 17.1 mmol), MsOH (16 mg, 171 umol), and DABCO (19 mg, 171 umol) were added to DMSO (10 mL) in sequence. The mixture was heated to 65°C and stirred for 18 h. LCMS monitored the reaction completion, and the reaction solution was allowed to return to room temperature. The mixture was then slowly poured into stirred water (60 mL), resulting in the formation of a yellow, flocculent insoluble material. The filter cake was filtered and dried to afford (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (600 mg, 89% yield) as a yellow solid. LCMS (m / z): 392.0 (M+H).

[0812] Intermediate DIF

[0813] (R)-1-(7-Bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol

[0814] Step A: (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol

[0815] DIEA (4.5 mL, 27.24 mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (3.0 g, 3.03 mmol), (R)-3-methyl-3-piperidinol hydrochloride (1.38 g, 9.08 mmol), and THF (50 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 h. TLC confirmed the completion of the reaction. The reaction solution was concentrated to yield an oil, which was dissolved in acetonitrile (5 mL). This solution was poured into H₂O (300 mL), resulting in the precipitation of a brownish-yellow solid. The solid was filtered, and the filter cake was washed with H₂O (100 mL). The filter cake was dried to yield (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.7 g, 9.04 mmol, 99% yield) as a brown solid.

[0816] Step B: (R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol

[0817] At room temperature, (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.7 g, 9.04 mmol) was added to a mixture of DABCO (102 mg, 904 μmol), KF (5.25 g, 90.45 mmol), MsOH (87 mg, 904 μmol), and DMSO (50 mL). The resulting mixture was heated to 65°C and stirred for 16 h. LCMS confirmed the reaction was complete. After cooling, the reaction solution was poured into H₂O (400 mL), resulting in the precipitation of a brownish-yellow solid. The solid was filtered, and the filter cake was washed with H₂O (100 mL). The filter cake was dried to afford (R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.0 g, 84% yield) as a brown solid. LCMS (m / z): 393.9 (M+H).

[0818] Intermediate D-II-F

[0819] (S)-4-(7-Bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxazepan-6-ol

[0820] Step A: (S)-6-Methyl-1,4-oxacyclohexane-6-ol hydrochloride

[0821] At room temperature, HCl-dioxane (4M) (10 mL, 10 V) was added to tert-butyl (S)-6-hydroxy-6-methyl-1,4-oxol-4-carboxylate (1.00 g, 4.32 mmol) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After concentration, the reaction solution afforded (S)-6-methyl-1,4-oxan-6-ol hydrochloride (840 mg, crude) as a white solid. LCMS (m / z): 132.1 (M+H).

[0822] Step B: (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol

[0823] DIPEA (1.56 g, 12.1 mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.00 g, 3.03 mmol), (S)-6-methyl-1,4-oxan-6-ol hydrochloride (655 mg, 12.1 mmol), and THF (20 mL) at room temperature and stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EA (30 mL x 3). The organic phase was collected, washed with saturated aqueous NaCl (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol (1.2 g, 93% yield) as a white solid. LCMS (m / z): 425.9 (M+H).

[0824] Step C: (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol

[0825] At room temperature, MsOH (27.0 mg, 0.282 mmol) was added to a mixed solution of (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol (1.20 g, 2.82 mmol), KF (1.64 g, 28.2 mmol), DABCO (31.7 mg, 0.282 mmol) and DMSO (30 mL). The reaction solution was heated to 100 °C and stirred for 1 h. The reaction was monitored by LCMS. The reaction solution was slowly added dropwise to water (150 mL) to precipitate a solid, which was then filtered. The filter cake was dissolved in EA (100 mL) and dried over anhydrous NaSO. The mixture was filtered and the organic solution was concentrated to afford (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol (1.0 g, 87% yield) as a yellow solid. LCMS (m / z): 409.9 (M+H).

[0826] Intermediate FI

[0827] (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0828] Step A: (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0829] At room temperature, DIPEA (2.37 g, 18.3 mmol) was added to a mixture of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.50 g, 6.11 mmol), (R)-3-methylpiperidin-3-ol hydrochloride (1.06 g, 7.02 mmol), BOP (5.40 g, 12.2 mmol), and DMF (20 mL). The reaction system was heated to 45°C and stirred for 18 h. The reaction was completed by TLC monitoring. After the reaction solution returned to room temperature, it was slowly poured into stirred H2O (200 mL). Solid precipitated and was filtered. The filter cake was washed with H2O (100 mL) and dried to give a brown solid (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2.0 g, yield 98%).

[0830] Intermediate F-II

[0831] (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0832] The synthesis of intermediate F-II was carried out according to the scheme described for intermediate FI, except that (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride was used instead of (R)-3-methylpiperidin-3-ol hydrochloride in step A.

[0833] Intermediate G-II

[0834] (S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0835] Step A: (S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0836] At room temperature, DIEA (1.4 g, 11 mmol) was added to a mixture of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 g, 3.6 mmol), (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (770 mg, 4.64 mmol), BOP (2.4 g, 5.4 mmol), and DMF (15 mL). The reaction system was heated to 50°C and stirred for 2 h. The reaction was monitored by LCMS. After returning to room temperature, the reaction solution was slowly poured into stirred H2O (100 mL). Solid precipitated and was filtered. The filter cake was dried to obtain (S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (900 mg, 64% yield) as a brownish-yellow solid. LCMS (m / z): 389.0 (M+H).

[0837] Intermediate GI

[0838] (R)-1-(7-chloro-8-fluoro-5-methoxy-2-methylthiopyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0839] The synthesis of intermediate GI was carried out according to the scheme described for intermediate G-II, except that (R)-6-methylpiperidin-3-ol hydrochloride was used instead of (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride in step A.

[0840] Intermediate II

[0841] (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0842] Step A: (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0843] At room temperature, 7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.47 mmol) was dissolved in POCl3 (2 mL), and DIPEA (360 mg, 2.35 mmol) was added. The resulting mixture was heated to 100°C for 3 h and then concentrated to dryness under reduced pressure. The mixture was cooled to room temperature, and 5 mL of anhydrous THF was added, followed by (R)-3-methyl-3-hydroxypiperidine hydrochloride (107 mg, 0.704 mmol) and DIPEA (360 mg, 2.35 mmol). The resulting mixture was stirred at room temperature for 2 h, and the reaction was monitored for completion by LCMS. The reaction mixture was concentrated to dryness, and the resulting crude product was purified by FCC (SiO2, EA / PE = 0-50%) to afford (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol as a white solid (200 mg, 81% yield). LCMS (m / z): 523.2 (M+H).

[0844] Intermediate I-II

[0845] The synthesis of (S)-4-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol intermediate I-II was carried out according to the scheme described for intermediate II, except that (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride was used in step A instead of (R)-3-methyl-3-hydroxypiperidine hydrochloride.

[0846] The following intermediates were prepared according to the above synthesis scheme:

[0847] Intermediate X

[0848] The compound 3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (CAS: 193274-53-2, 120 g) was separated by SFC (SFC150, Waters) (separation column: DAICEL 250*50mm, 10μm; mobile phase: CO2 / MeOH = 90 / 10; flow rate: 120mL / min), the first eluting isomer 1 was obtained, compound X (52.8g, relatively short retention time). Chiral analysis method -X, Rt = 0.682min. 1H 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 X-1 (52.4 g, relatively long retention time). Chiral analysis method - X, 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).

[0849] Chiral analysis method-X: Waters UPCC, analytical column: Daicel 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.

[0850] Intermediate a

[0851] ((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0852] Step A: (S)-1-(tert-Butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate

[0853] 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).

[0854] Step B: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester

[0855] 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).

[0856] Step C: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0857] 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).

[0858] Step D: Methyl (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate

[0859] 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).

[0860] Step E: (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0861] 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).

[0862] Intermediate b

[0863] (S,E)–(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0864] 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

[0865] 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). 1H 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).

[0866] Step B: (S,E)-4-(Fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0867] 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).

[0868] Step C: Methyl (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate

[0869] 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).

[0870] Step D: (S,E)-(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0871] 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).

[0872] Intermediate c

[0873] ((3S,4S)-4-(Fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0874] 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

[0875] The synthesis of step A was carried out with reference to the synthesis of intermediate b, step A.

[0876] Step B: (3S,4S)-4-(Fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl)-3-methyl ester

[0877] Under nitrogen at room temperature, wet Pd / C (400 mg, 10% w / w) was added to a mixture of (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl-3-methyl ester and (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl-3-methyl ester (850 mg, 2.96 mmol) in methanol (10 mL). The system was purged with a hydrogen balloon, and the reaction was stirred under a hydrogen atmosphere overnight. After completion of the reaction, monitored by TLC, the mixture was filtered through celite, and the filtrate was concentrated to dryness to obtain the crude product. Purification by FCC (SiO2, EA / PE = 0-10%) afforded the product (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl-3-methyl ester (600 mg, 70% yield) as a colorless oil. LCMS (m / z): 234.1 (M-56+H), 312.1 (M+Na).1 H NMR (400 MHz, methanol-d4) δ 4.76–4.70 (m, 0.5H), 4.64–4.52 (m, 1H), 4.46–4.41 (m, 0.5H), 4.23 (d, J = 13.7 Hz, 1H), 4.08–3.99 (m, 1H), 3.67 (s, 3H), 3.06–2.86 (m, 1H), 2.86–2.70 (m, 1H), 1.95–1.81 (m, 1H), 1.80–1.68 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H). 19 F NMR (376 MHz, met...

Claims

1. A compound of formula (II), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, in: M is selected from N and C-R8; W is selected from N and C-R9; Z is selected from N and CR 10 ; X is selected from S or Se; Q is each independently selected from C-R6 or N; Y is selected from O, S, Se and NR a ; B is selected from 4-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, S and Se, and 6-12 membered polycyclic heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, P, S and Se, provided that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom; R1 is selected from H, halogen, -CN, -OH, -NH2, -B(OH)2, oxo, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)N(R b )2, where C 1-6 The alkyl group is optionally substituted with halogen, deuterium, OH or -OC 1-6 Alkyl substitution; R2 is independently selected from H, D, -C 1-6 Alkyl and -(CH2) n -C 3-6 Cycloalkyl, or two R2 together with the carbon atom to which they are attached form a C 3-4 Cycloalkyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-4 The cycloalkyl groups are each independently optionally substituted with halogen, D, C 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution; R3 is selected from -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution; R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -(CH2) n -C 3-6 Cycloalkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN or -OC 1-6 Alkyl substituted, or Two R4 attached to the same carbon atom form =C(R c )2, or two R4 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, wherein R c are each independently selected from H, halogen and -C 1-6 alkyl, and the spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl optionally substituted with halogen and -C 1-6 Alkyl substitution; R5 is selected from H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 Cycloalkyl, where C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted with D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 replaced; R6 and R7 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, -OC 1-6 Alkyl or D substituted; R8 is selected from H, D, halogen, CN, NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Each alkynyl group is independently optionally substituted with halogen, CN or -OC 1-6 Alkyl substituted; or R8 is -(CH2) n -C 3-6 Cycloalkyl, wherein C 3-6 Cycloalkyl is optionally substituted by halogen or CN; R 10 Selected from H, D, halogen, CN, NO2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 The alkynyl groups are each independently optionally substituted with halogen or CN; R9 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OR b AND-O-CON(R b )2, where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 The alkynyl groups are each independently optionally substituted with halogen or CN; R a is selected from H, -C optionally substituted by halogen 1-6 alkyl; R b Selected from H, optionally halogen, -OH, -OC 1-6 Alkyl or deuterium substituted -C 1-6 Alkyl, and -C 3-6 Cycloalkyl, or two R b Together with the N atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl; n and p are each independently an integer from 0 to 3; and m and t are each independently an integer of 0 to 8.

2. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, in: M is selected from N and C-R8; W is selected from N and C-R9; Z is selected from N and CR 10 ; Y is selected from O, S, Se and NR a ; B is selected from 5-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, S and Se, and 6-12 membered polycyclic heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, P, S and Se, provided that the ring atom attached to the pyrimidine ring portion of the molecule is a nitrogen heteroatom; R1 is selected from H, halogen, -CN, -OH, -B(OH)2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)N(R b )2, where C 1-6 The alkyl group is optionally substituted with halogen; R2 is independently selected from H, D, -C 1-6 Alkyl and -(CH2) n -C 3-6 Cycloalkyl, or two R2 together with the carbon atom to which they are attached form a C 3-4 Cycloalkyl, where C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-4 The cycloalkyl groups are each independently optionally substituted with halogen, D, C 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution; R3 is selected from -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen, D, C optionally substituted by halogen or D 1-6 Alkyl or -OC optionally substituted by halogen or D 1-6 Alkyl substitution; R4 is selected from H, D, halogen, -CN, -OH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -(CH2) n -C 3-6 Cycloalkyl, where each occurrence of C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted by D, halogen, CN or -OC 1-6 Alkyl substituted, or Two R4 attached to the same carbon atom form =C(R c )2, or two R4 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, wherein R c are each independently selected from H, halogen and -C 1-6 alkyl, and the spiro C 3-6 Cycloalkyl or spiro 4-7 membered heterocycloalkyl optionally substituted with halogen and -C 1-6 Alkyl substitution; R5 is selected from H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 Cycloalkyl, where C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl groups are each independently optionally substituted with D, halogen, CN, -OC 1-6 Alkyl or -O-CON(R b )2 replace; R6 and R7 are each independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl and -Se-C 1-6 Alkyl, where each occurrence of -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 The alkynyl groups are each independently optionally substituted with halogen; R8 and R 10 Each is independently selected from H, D, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -OR b， Among them -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 The alkynyl groups are each independently optionally substituted with halogen or CN; R9 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OR b AND-O-CON(R b )2, where -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 The alkynyl groups are each independently optionally substituted with halogen or CN; R a and R b are each independently selected from H and -C optionally substituted by halogen 1-6 alkyl; n and p are each independently an integer from 0 to 3; and m and t are each independently an integer of 0 to 8.

3. The compound of claim 1 or 2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein Z is C-CN.

4. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the benzo-fused ring fragment comprising Z is Wherein R6 is independently selected from H and halogen, wherein halogen is preferably F.

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein M is C-substituted by halogen 1-6 Alkyl, C-substituted by halogen 2-6 alkenyl, C-halogen, C-CN, C-NO2, preferably M is C-substituted by halogen 1-6 Alkyl or C-halogen.

6. The compound according to any one of claims 1 to 5, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein W is selected from N, C-halogen or CO-C optionally substituted by halogen. 1-3 Alkyl; or W is selected from C-halogen or CC 1-3 alkyl.

7. The compound of any one of claims 1 to 6, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is a 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom, a 5-7 membered monocyclic heterocycloalkyl containing 1 nitrogen atom and 1 O atom, an 8-10 membered spiroheterocycloalkyl containing 1-3 nitrogen atoms and 0-1 O atoms, or an 8-10 fused heterocycloalkyl, each optionally substituted by 0-3 independently selected from -OH, NH2, CN, halogen, -C 1-6 Alkyl, -CO-C 1-6 Alkyl and -CON(R b )2 is substituted by a group.

8. The compound of claim 7, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is selected from Wherein R1 is independently selected from -OH and -C 1- 6 alkyl, optionally substituted by halogen; or B is selected from The R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -COC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl and -CON(C 1-6 alkyl)2, the rest are selected from H, NH2, CN, halogen and -C 1-6 Alkyl; or B is wherein one R1 is selected from halogen, CN, -C substituted by halogen 1-6 Alkyl, preferably located in the para position of the ring N atom, the other is selected from H, -OH, -C optionally substituted by halogen 1-6 Alkyl or -OC optionally substituted by halogen 1-6 alkyl.

9. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is For example in The R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, or -C 3-6 Cycloalkyl, preferably each independently H or -C 1-3 alkyl, most preferably each independently a -C 1-3 Alkyl, for example -C(O)CH3, -C(O)N(CH3)(CH2CH2F), -C(O)N(CH3)2, -C(O)N(CH3)(cyclopropyl), -C(O)NH(CH3), -C(O)N(CD3)2, -C(O)N(CH3)(CH2CH2OCH3); or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl, for example azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, R1 at the position between the nitrogen heteroatom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, more preferably selected from -C 1-3 Alkyl-OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by one or more halogens, OH or deuterium, preferably by one or more deuterium, and R1 at this position is, for example but not limited to, H, F, Cl, -OH, -NH2, -CN, -O-CH3, -CH3, -ethynyl, -CH2F, -CHF2, -O-CD3, -CH2OH, -CH2-CH3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3, -CH2-O-CD3, -CH2-O-CH2CH3, B is connected to the rest of the molecule at the position adjacent to the nitrogen and R1 is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H, -CH3 or -CH2CH3; Preferably, B is selected from wherein each R1 is as defined in the claims, with the proviso that each is not H.

10. The compound of any one of claims 1 to 9, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

11. The compound of any one of claims 1 to 10, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein each R2 is independently H or D.

12. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R3 is -C 1-6 alkyl.

13. The compound of any one of claims 1 to 12, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R4 is selected from halogen, -OC 1-6 Alkyl and -C 1-6 Alkyl, where each occurrence of C 1-6 The alkyl groups are each independently optionally substituted with halogen, or Two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen, -C 1-6 Alkyl, or Two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro 3-6 Cycloalkyl, and the spiro C 3-6 Cycloalkyl optionally substituted with halogen and optionally substituted with halogen -C 1-6 Alkyl substitution; Preferably, R4 is substituted in the para position relative to the ring N atom.

14. The compound of any one of claims 1 to 13, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R5 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl, preferably selected from -C 1-3 Alkyl and -deuterated C 1-3 alkyl.

15. The compound of any one of claims 1 to 14, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the structural fragment for Preferably Wherein R2 is independently selected from H and D; R3 is selected from -C 1-3 alkyl; m is 1 or 2; R4 is halogen, optionally substituted by halogen 1-3 Alkyl, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen and -C 1-3 Alkyl, or two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro C optionally substituted by halogen 3-4 Cycloalkyl; R5 is -C 1-3 Alkyl or -C substituted by one or more deuterium 1-3 alkyl.

16. The compound of claim 15, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the structural fragment Selected from 17. The compound of claim 1 or 2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which has the following sub-formula: wherein each group has the meaning defined in any one of claims 1 to 15, preferably X is selected from S and Se; Q is each independently selected from C-R6 and N; R6 are each independently selected from H and halogen; The benzo-fused ring fragment containing Z is preferably wherein R6 are each independently selected from H and halogen, wherein halogen is preferably F; M is selected from N and C-R8; W is selected from N and C-R9; R7 is H; R8 is C substituted by halogen (preferably F) 1-3 Alkyl, C substituted by halogen (preferably F) 2-4 alkenyl, CN, NO2, halogen (preferably Cl); or R8 is -C 1-6 Alkyl-OC 1-6 Alkyl, preferably -C 1-3 Alkyl-OC 1-3 alkyl; R9 is selected from F, Cl and -O-C optionally substituted by halogen 1-3 alkyl; For Formulas IA-1, IA-2 and II-2, one of R1 is -OH and the other is -C 1-3 alkyl; For Formula II-1, one R1 is selected from halogen, CN, -C substituted by halogen 1-6 Alkyl, preferably located in the para position of the ring N atom, the other is selected from H, -OH, -C optionally substituted by halogen 1-6 Alkyl or -OC 1-6 alkyl; For formula IA-3 and II-3', R1 at the ortho position of the nitrogen heteroatom on the five-membered ring is selected from -COC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl and -CON(C 1-6 alkyl)2, the remaining R1 is selected from H, NH2, CN, halogen and -C 1-6 alkyl; Y is O; R2 are each independently selected from H and D; R3 is -C 1-3 alkyl; R4 is selected from halogen, -OC 1-3 Alkyl and -C 1-3 Alkyl, where each occurrence of C 1-3 The alkyl groups are each independently optionally substituted with halogen, or Two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H, halogen, -C 1-3 Alkyl, or Two R4 attached to the same ring carbon atom together with the ring carbon atom to which they are attached form a spiro 3-4 Cycloalkyl, and the spiro C 3-4 Cycloalkyl optionally substituted with halogen and optionally substituted with halogen -C 1-3 Alkyl substitution; R5 is selected from -C 1-3 Alkyl and -deuterated C 1-3 alkyl; m is an integer from 1 to 2, and p is an integer from 0 to 2; Preferably, R4 is located in the para position to the ring nitrogen atom of the attached ring; Preferably, the structural fragment for More preferably, the structural fragment Selected from Selected from 18. A compound of claim 1, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, having the following general formula: in, The fused heterocyclic fragment carrying R1 is in The R1 adjacent to the nitrogen heteroatom on the five-membered ring is selected from -C(O)-C 1-6 Alkyl and -C(O)N(R b )2, preferably -C(O)N(R b )2,R b are each independently H, optionally substituted with one or more halogen, deuterium, -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, or -C 3-6 Cycloalkyl, preferably each independently H or -C 1-3 alkyl, most preferably each independently a -C 1-3 Alkyl, for example -C(O)CH3, -C(O)N(CH3)(CH2CH2F), -C(O)N(CH3)2, -C(O)N(CH3)(cyclopropyl), -C(O)NH(CH3), -C(O)N(CD3)2, -C(O)N(CH3)(CH2CH2OCH3); or two R b Together with the nitrogen atom to which they are attached, they form an optionally substituted halogen or -C 1-6 Alkyl-substituted 4-7 membered heterocycloalkyl, for example azetidinyl, 3-F-azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, R1 at the position between the nitrogen heteroatom on the five-membered ring is selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, preferably selected from H, halogen, -CN, -OH, NH2, -C 1-3 Alkyl, -C 2-4 Alkenyl, -C 2-4 Alkynyl, -OC 1-3 Alkyl and -C 1-3 Alkyl-OC 1-3 Alkyl, more preferably selected from -C 1-3 Alkyl-OC 1-3 alkyl wherein the alkyl group is optionally substituted by one or more halogens, OH or deuterium, preferably by one or more deuterium, and the R1 at this position is, for example but not limited to, H, F, Cl, -OH, -NH2, -CN, -O-CH3, -CH3, -ethynyl, -CH2F, -CHF2, -O-CD3, -CH2OH, -CH2-CH3, -O-CH2-CH3, -CH2-O-CH3, -CD2-O-CD3, -CH2-O-CD3, -CH2-O-CH2CH3, The R1 at the adjacent position of the nitrogen to which the fragment is connected to the rest of the molecule is selected from H or -C 1-6 Alkyl, preferably H or -C 1-3 Alkyl, such as H, -CH3 or -CH2CH3; Specifically, the segment can be wherein R1 is each as defined herein, with the proviso that each is not H; R6 are each independently selected from H and halogen (preferably F); the fragment carrying R6 is preferably M is C-R8; W is C-R9; R7 is H; R8 is halogen (preferably Cl), C optionally substituted by halogen (preferably F) 1-3 Alkyl (e.g. CF3), C optionally substituted by halogen (preferably F) 2-4 Alkenyl, CN, NO2, -C 1-6 Alkyl-OC 1-6 Alkyl (preferably -C 1-3 Alkyl-OC 1-3 alkyl, such as -CH2-O-CH3); preferably halogen or halogen-substituted C 1-3 Alkyl groups, such as Cl and CF3; R9 is selected from halogen, -C 1-3 Alkyl, -OH and -O- are optionally substituted with halogen. 1-3 Alkyl; preferably halogen and -C 1-3 Alkyl; for example, F, Cl, CH3 and -O-CH3; Y is O; R2 are each independently selected from H and D; R3 is -C 1-3 alkyl; R4 is -C 1-3 Alkyl, substituted by halogen, or two R4 attached to the same carbon atom form =C(R c )2, where R c are each independently selected from H and halogen; R5 is selected from -C 1-3 Alkyl and -deuterated C 1-3 alkyl; m is an integer of 1 to 2.

19. A compound selected from the group consisting of the compounds of Examples or pharmaceutically acceptable salts or solvates thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable excipient.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to 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 a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for preventing or treating a disease mediated by RAS mutation and RAS amplification.

23. The method of claim 22, wherein the disease mediated by RAS mutation and RAS amplification is selected from the group consisting of pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, skin 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 tumors (CNS), primary CNS lymphoma, spinal tumors, brain stem gliomas or pituitary adenomas.

24. The use of claim 22, wherein the disease mediated by RAS mutation and RAS amplification is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.

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

26. The method of claim 25, wherein the disease mediated by RAS mutation and RAS amplification is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.

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