Compound with anti-KRAS mutation tumor activity

Abstract

The present invention provides compounds having the structure of formula (I) useful as KRAS inhibitors, pharmaceutical compositions comprising such compounds, methods of preparing such compounds, and uses of such compounds in the treatment of cancer. (I)

Description

Compounds with activity against KRAS-mutant tumors

[0001] Cross-references

[0002] This application claims priority to Chinese patent application 202310883342.1 filed on July 18, 2023 and Chinese patent application 202410948939.4 filed on July 16, 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 KRAS 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, also known as the rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins that belong to the GTPase family of proteins. 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 achieved through the conversion between GDP-bound and GTP-bound states, 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. It will be activated when exposed to some pro-growth stimuli. 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 on 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, i.e., converting 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 the conversion of GTP to GDP will cause Ras to remain 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, etc. 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 revealed that the smooth surface of the Ras protein, lacking a distinct groove or pocket structure for binding small molecule inhibitors, and its very high affinity for guanine substrates (picomolar), have made the development of small molecule inhibitors difficult to resolve. Consequently, Ras has long been considered an "undruggable" target in the industry. At the same time, there is a significant need for compounds with more structural types or patterns as KRas inhibitors to provide more therapeutic options or to offer 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. The present invention provides novel structural inhibitor compounds with KRas mutant protein inhibitory activity. Due to their improved structural patterns, these compounds have enhanced KRas mutant protein inhibitory activity and tumor-related inhibitory activity compared to existing KRas mutant protein inhibitors in the prior art. They also possess favorable pharmacokinetic properties and, therefore, good 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 (I) as defined herein below, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0012] The definitions of the various groups are as defined in the detailed description of the invention.

[0013] 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.

[0014] 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.

[0015] 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 mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), preferably KRas G12D.

[0016] 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 mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), preferably KRas G12D mutant protein.

[0017] The present invention also provides the use of a compound of the present invention or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), preferably KRas G12D mutant protein.

[0018] 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 mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), preferably KRas G12D mutant protein.

[0019] The present invention also provides a method for treating and / or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), preferably KRas G12D mutant protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising the same.

[0020] 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.

[0021] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, particularly as a research tool compound for inhibiting KRas G12D.

[0022] 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.

[0023] The present invention also provides methods for preparing the compounds of the present invention.

[0024] Detailed Description of the Invention

[0025] definition

[0026] 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.

[0027] In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0028] As used herein, the term "Ras mutant" 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 a Ras protein in which a glycine residue at codon 12, a glycine residue at codon 13, or a glutamine residue at codon 61 of Ras is mutated, such as a 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.

[0029] 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 ( Glycine to valine mutation at codon G12), KRas-G13D (glycine to aspartic acid mutation at codon G13); particularly refers to KRas mutant protein, more particularly 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, most particularly refers to KRas-G12D mutant protein.

[0030] 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.

[0031] 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 mutation-mediated disease as defined herein, particularly a 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.

[0032] 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.

[0033] As used herein, the term "selective inhibition" refers to the ability of a bioactive agent to preferentially reduce the signaling activity of a target of interest over off-target signaling activity by interacting directly or indirectly with the target. With respect to the compounds of the present invention, the compounds have the ability to selectively inhibit G12 or G13 mutations of KRas, HRas, or NRas proteins, such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, and G13D mutations, with the preferred ability to selectively inhibit the G12D mutation of KRas protein, relative to various mutations occurring at one or more codons of the Ras protein. For example, the present invention has at least 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, inhibition of better activity against a specific Ras mutation as compared to another specific Ras mutation, or at least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better activity against a specific Ras mutation (e.g., KRas-G12D) as compared to another specific Ras mutation.

[0034] As used herein, the term "Ras mutation-mediated disease" refers to a disease in which Ras mutations contribute to the onset and progression of the disease, or in which inhibition of Ras mutations reduces the incidence, ameliorate, or eliminates disease symptoms. For purposes of the present invention, "Ras mutation-mediated disease" preferably refers to a KRas mutation-mediated disease, most preferably a KRas-G12D-mediated disease, and even more preferably a KRas-G12D-mediated cancer or tumor.

[0035] 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.

[0036] For various aspects of the present invention, preferably, the cancer or tumor is associated with a Ras mutation, in particular a KRas mutation, preferably a KRas G12D mutation, 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.

[0037] 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.

[0038] 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 mutation-mediated disease," such as a cancer or tumor, requiring treatment. Those skilled in the art can determine the effective amount or dosage of the active ingredient of the present invention by conventional methods and in combination with conventional influencing factors.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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).

[0043] 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.

[0044] 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 names of the compounds or intermediates provided by the present invention to indicate the absolute configuration of the chiral center.

[0045] 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 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.

[0046] The structural fragments used in this article The bonds indicated to be cross-linked are the bonds connecting this structural fragment to the rest of the molecule.

[0047] The ring structures used in this paper indicates that the ring is aromatic, e.g. Among them The ring where it is located is indicated to be an aromatic ring fused to a benzene ring.

[0048] The substituents shown as crossing chemical bonds in the cyclic structure fragments referred to herein are, for example, -(R1) m , means that the one or more R1 substituents can substitute at any chemically feasible one or more substitution sites in the ring.

[0049] 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 can be used, 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 an unlabeled form, while in other embodiments, the compounds of the present invention are provided in an isotopically labeled form, such as a form labeled with a hydrogen isotope D.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "substituted with halogen" as used herein when defining a group is intended to include mono- or poly-halogenated groups in which one or more identical or different halogens replace one or more hydrogens in the corresponding group.

[0054] 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.

[0055] The term "deuterated alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, wherein one or more hydrogen atoms are replaced by deuterium (D). Specifically, the deuterated 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 "deuterated C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, wherein one or more hydrogen atoms are replaced by deuterium (D), examples of which include -CDH2, -CD2H, -CD3, -CH2CDH2, -CH2CD2H, -CH2CD3, etc., preferably -CD3.

[0056] The term "deuterated cycloalkyl" as used herein refers to a cyclic monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, comprising 3 to 8 carbon atoms, wherein one or more hydrogen atoms are replaced by deuterium (D). Specifically, the deuterated cycloalkyl group has 3-8, for example 3-6, carbon atoms, wherein one or more hydrogen atoms are replaced by deuterium (D).

[0057] As used herein, the term "-O-alkyl" or "alkoxy" refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. Specifically, the -O-alkyl 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 "-OC 1-6 The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom, and examples thereof include -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, 2-methylpentyl-O-, and the like.

[0058] 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 alkenyl group having 2 to 6 carbon atoms, such as ethenyl, propenyl, allyl, butenyl, pentenyl, etc. The carbon atom in the alkenyl group that is connected to the rest of the molecule may be saturated or an olefinic carbon atom.

[0059] 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, such as ethynyl, propynyl, propargyl, butynyl, etc. The carbon atom in the alkynyl group that is connected to the rest of the molecule may be saturated or may be an acetylenic bond carbon atom.

[0060] As used herein, the term "C optionally substituted by halogen or CN" 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 "Alkynyl" refers to the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally replaced by halogen or CN. It will be understood by those skilled in the art that when there is more than one halogen or CN substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples include, but are not limited to, -CH2F, -CH2CN, -CHF2, -CF3, -CH2CF3, -CH2Cl, -CCl3, -C2F5, -CH2CH2CN, -CH2CH2CF3, -CF(CF3)2, -CH=CHF, -CH=CF2, -CH=CHCN, -C≡CF, and the like.

[0061] 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, 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. For example, as used herein to define compounds, the term "C 3- "6-cycloalkyl" refers to a monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0062] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic non-aromatic saturated ring structure comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S and the specified number of ring atoms, or an N-oxide thereof, or an S-oxide or S-dioxide thereof. A heterocycloalkyl group may have 3 to 12 ring members (which may 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, or 5 to 6 ring members. A heterocycloalkyl group typically contains up to 4 (e.g., 1, 2, 3, or 4) heteroatoms, for example, a 4-7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S. 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 can be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0063] Preferred heterocycloalkyl groups are, for example It is understood that structures having asymmetric centers encompass racemic and / or single enantiomeric forms thereof, e.g. Can represent and / or

[0064] As used herein, the term "hydroxy" refers to an -OH group.

[0065] As used herein, the term "cyano" refers to a -CN group.

[0066] 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 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.

[0067] 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.

[0068] Unless otherwise specified, C in the definition of compounds of the present invention is n-n+m or C n -C m Including various cases from n to n+m carbons, such as C 1-6 Including C1, C2, C3, C4, C5 and C6, and also including any range from n to n+m, such as C 0-6 Including C1, C2, C3, C4, C5, C6, C 0-1 、C 0-2 、C 0-3 、C 0-4 、C 0-5 、C 1-2 、C 1-3 、C 1-4 、C 2-3 etc., C. 1-6 Including C 1-2 、C 1-3 、C 1-4 、C 2-6 、C 3-6 wait.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] Problems to be solved by the present invention

[0073] As described above, compounds that can inhibit Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), more especially KRas-G12D mutant proteins, can be used to treat or prevent diseases mediated by the mutant proteins (such as cancer or tumors). Therefore, in this field, various structural types of Ras inhibitors have been developed. However, 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 undesirable drug interactions due to inhibition of the cytochrome P450 enzyme system, 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.

[0074] Solutions to the Problem

[0075] Through extensive and in-depth research, the inventors have developed a group of compounds with significant inhibitory activity against Ras mutants, particularly KRas mutants (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutants), and more particularly, the KRas-G12D mutant. Through structural modification and activity verification, the inventors discovered that structural modifications at specific sites on the benzopyrimidine ring and quinazoline ring of the KRas inhibitor structure, along with the resulting polycyclic structures and specific substituent combinations at specific positions, resulted in further enhanced inhibitory activity against the KRas-G12D mutant compared to prior art inhibitors. Furthermore, the resulting compounds exhibited a favorable safety profile, reduced risk of drug interactions, and favorable, and even improved, pharmacokinetic properties, enabling convenient administration.

[0076] Thus, the present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation inhibitors), more specifically KRas-G12D inhibitor compounds; pharmaceutical compositions containing such compounds as active ingredients; and pharmaceutical compositions for treating or preventing diseases caused by Ras, specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation inhibitors). 12A mutation, G12R mutation, G12S mutation and G13D mutation), more specifically KRas-G12D mediated or benefited from Ras, specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), more specifically KRas-G12D inhibition of tumors or cancers; use of the compounds 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 and G13D mutation), more specifically KRas-G12D inhibition of tumors or cancers; and use of the compounds 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 and G13D mutation), more specifically KRas-G12D mediated or benefited from Ras, specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), more specifically KRas-G12D inhibition of diseases such as tumors or cancer; and the use of the compound in the preparation of a method for treating or preventing a disease caused by Ras , specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), more specifically KRas-G12D mediated or benefited from Ras, specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), more specifically KRas-G12D inhibition of diseases such as tumors or cancers.

[0077] The present invention therefore provides the following technical solutions.

[0078] Compounds of the present invention

[0079] The terms "inventive compound" and "compound of the present invention" and the like as used throughout this application, unless otherwise limited, encompass the compounds defined in each embodiment herein and preferred embodiments thereof, or various specific embodiments thereof, including isomers, including atropisomers, enantiomeric mixtures, in particular racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopic variants and salts (e.g., pharmaceutically acceptable salts) thereof.

[0080] 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.

[0081] 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.

[0082] The present invention provides the following compound embodiments:

[0083] Embodiment 1: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

[0084] in:

[0085] X is selected from -CH2-, -CH2CH2- and -CH2OCH2-;

[0086] Y is selected from O, S and NR d ;

[0087] Z is selected from O, S and Se;

[0088] M is selected from N or C-R4;

[0089] B is selected from

[0090] G1 is selected from CH, S and NH, G2 is selected from C-R5 and N, G3 is selected from C-R6 and N; and G4 is selected from C-R9 and N;

[0091] W is selected from H, OH, NH2, halogen, CN and -C 1-6 alkyl;

[0092] U is selected from OH or NH2;

[0093] R1 is selected from H, D, halogen, -CN, -OH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) 0-3-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 with halogen, CN or -OC 1-6 Alkyl substitution,

[0094] Or two R1s connected to the same carbon atom form =C(R e )2, or two R1 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 e 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,

[0095] Or two R1 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 Cycloalkyl,

[0096] or two R1 attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;

[0097] R2 is selected from H, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) 0-3 -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 halogen or CN;

[0098] R3 is selected from halogen, CN, -OH, -OC 1-6 Alkyl and -C 1-6 Alkyl groups, where -C 1-6 Alkyl is optionally substituted with halogen or CN;

[0099] R4 is selected from H, halogen, CN and -C optionally substituted by halogen or CN 1-6 alkyl;

[0100] R5 is selected from H, halogen, CN and NH2;

[0101] R6 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl and -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 or CN;

[0102] R7 and R8 are each independently selected from H, halogen, -NO2, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl and -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 or CN;

[0103] R9 is selected from halogen, CN and -C optionally substituted by halogen or CN 1-6 alkyl;

[0104] R 10 、R 11 and R 12 Each independently selected from H, halogen, CN, -C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, wherein -C 1-6 Alkyl and -C 3-6 The cycloalkyl groups are each independently optionally substituted with halogen or CN;

[0105] R 13 Selected from H, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, wherein -C 1-6 Alkyl and -C 3-6 The cycloalkyl groups are each independently optionally substituted with halogen, CN or -OC 1-6 Alkyl substitution;

[0106] Or when R1 and R 13 When attached to adjacent ring carbon atoms, together with the carbon atoms to which they are attached, they form a C 3-4 Cycloalkyl;

[0107] R 14 Selected from H, D, -C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, where C 1-6 Alkyl and C 3-6The cycloalkyl groups are each independently optionally substituted with halogen or -OC 1-6 Alkyl substituted, or two R 14 Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl;

[0108] R a selected from H and -C optionally substituted by halogen or D 1-6 alkyl;

[0109] R b selected from H and -C optionally substituted by halogen 1-6 Alkyl, or two R attached to the same ring carbon atom b Together they form C 3-6 Spirocyclic rings, or two R b , or R b and R c , or R b and R d Together with the ring atoms to which they are attached, they form a fused 3-6 membered carbocyclic or heterocyclic ring, wherein the C 3-6 The spiro ring and the 3-6 membered fused carbocyclic or heterocyclic ring are each independently optionally substituted with halogen, CN and -C 1-6 Alkyl substitution;

[0110] R c and R d are each independently selected from H and -C optionally substituted by halogen or CN 1-6 alkyl;

[0111] m is an integer from 1 to 8;

[0112] n, p and q are each independently an integer from 0 to 3;

[0113] t is an integer from 1 to 3;

[0114] g is 2; and

[0115] f is selected from 0 and 1, provided that when f is 1, G1 is CH, G2 is C-R5 and G3 is C-R6.

[0116] Embodiment 1-1: The compound of formula (I) of embodiment 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein R a selected from H and -C optionally substituted by halogen 1-6 alkyl.

[0117] Embodiment 1.1: A compound of formula (I) according to Embodiment 1 or 1-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Wherein f is 1, G1 is CH, G2 is C-R5, G3 is C-R6, that is, the fused bicyclic portion is

[0118] Embodiment 1.1.1: A compound of formula (I) according to Embodiment 1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is H; or R5 is CN; or R5 is a halogen selected from F, Cl, Br, I; preferably R5 is a halogen, most preferably F.

[0119] Embodiment 1.1.2: A compound of formula (I) according to Embodiment 1.1 or 1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is H; or R6 is a halogen selected from F, Cl, Br, I.

[0120] Embodiment 1.1.3: A compound of Formula (I) according to Embodiment 1.1 or 1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C 1-6 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; preferably -CH2CH3.

[0121] Embodiment 1.1.4: A compound of Formula (I) according to Embodiment 1.1 or 1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C 2-6 Alkenyl, optionally substituted with halogen or CN, such as 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.

[0122] Embodiment 1.1.5: A compound of Formula (I) according to Embodiment 1.1 or 1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C 2-6 Alkynyl, optionally substituted by halogen or CN, such as but not limited to -C≡C(CF3), -CH2C≡C(CF3), Preferred

[0123] Embodiment 1.1.6: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.5, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each H; or R7 and R8 are each halogen, preferably F.

[0124] Embodiment 1.1.7: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of R7 and R8 is H and the other is selected from halogen, CN and NO2, wherein the halogen is preferably F; for example, R7 is H and R8 is selected from halogen (preferably F), CN and NO2; for example, R8 is H and R7 is selected from halogen (preferably F), CN and NO2.

[0125] Embodiment 1.1.8: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of R7 and R8 is H and the other is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, each optionally substituted with halogen or CN; non-hydrogen R7 or R8 such as, but not limited to, those exemplified in Embodiments 1.1.3, 1.1.4, and 1.1.5, respectively.

[0126] Embodiment 1.1.9: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of R7 and R8 is selected from halogen, -NO2 and CN, and the other is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, each optionally substituted with halogen or CN, such as but not limited to those exemplified in Embodiments 1.1.3, 1.1.4, and 1.1.5, respectively.

[0127] Embodiment 1.1.10: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1.1 to 1.1.9, wherein W is -OH.

[0128] Embodiment 1.1.11: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1.1 to 1.1.9, wherein W is -NH2.

[0129] Embodiment 1.1.12: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1.1 to 1.1.9, wherein W is CN.

[0130] Embodiment 1.1.13: A compound of formula (I) according to any one of Embodiments 1.1 to 1.1.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein W is -C 1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3.

[0131] Embodiment 1.1.14: A compound of Formula (I) according to Embodiment 1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Wherein R5 is H or halogen, preferably halogen, R6 is selected from halogen, -C 2-6 Alkynyl and -C 1-6 Alkyl, preferably selected from -C 2-6 Alkynyl and -C 1-6 Alkyl groups, such as but not limited to Preferred

[0132] Embodiment 1.2: A compound of formula (I) according to Embodiment 1 or 1-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is wherein f is 0, G1 is S, G2 is C-R5, and G3 is selected from C-R6 and N, i.e., the fused bicyclic moiety is

[0133] 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 R5 is H; or R5 is a halogen selected from F, Cl, Br, I; or R5 is CN.

[0134] 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 R5 is NH2.

[0135] Embodiment 1.2.3: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is H; or R6 is a halogen selected from F, Cl, Br, I.

[0136] Embodiment 1.2.4: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1.2 to 1.2.2, wherein R6 is CN.

[0137] Embodiment 1.2.5: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is -C 1-6 Alkyl, -C 2-6 Alkenyl or -C 2-6 Alkynyl groups are each independently optionally substituted with halogen or CN, such as but not limited to those exemplified in Embodiments 1.1.3, 1.1.4, and 1.1.5, respectively.

[0138] Embodiment 1.2.6: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 and R8 are each H; or R7 and R8 are each halogen, preferably F; or one of R7 and R8 is H and the other is halogen (preferably F), CN or NO2.

[0139] Embodiment 1.2.7: A compound of formula (I) according to any one of Embodiments 1.2 to 1.2.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of R7 and R8 is H and the other is selected from -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, each independently optionally substituted by halogen or CN; or one of R7 and R8 is halogen, CN or NO2, the other selected from -C1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, each independently optionally substituted by halogen or CN; wherein the other -C 1-6 Alkyl, -C 2-6 Alkenyl or -C 2-6 Alkynyl groups are exemplified by, but not limited to, those exemplified in Embodiments 1.1.3, 1.1.4, and 1.1.5, respectively; preferably, the other is -C optionally substituted by halogen. 1-6 Alkyl, such as but not limited to -CH3, -CF3, such as R7 is H and R8 is -CH3 or -CF3, such as R7 is F and R8 is -CH3 or -CF3.

[0140] Embodiment 1.2.8: A compound of Formula (I) according to any one of Embodiments 1.2 to 1.2.7, wherein W is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0141] Embodiment 1.2.9: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1.2 to 1.2.7, wherein W is halogen, preferably F or Cl; or W is CN.

[0142] Embodiment 1.2.10: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof according to any one of Embodiments 1.2 to 1.2.7, wherein W is -C 1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3; preferably -CH3.

[0143] Embodiment 1.2.11: 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 B is wherein W is selected from H, halogen and -C 1-6 alkyl, R5 is NH2, R6 is CN, R7 is selected from H or halogen, R8 is selected from H, halogen and -C 1-6 Alkyl, B is for example but not limited to

[0144] Embodiment 1.3: A compound of formula (I) according to Embodiment 1 or 1-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Wherein G4 is C-R9, i.e. the aromatic ring portion is Or wherein G4 is N, that is, the aromatic ring portion is

[0145] Embodiment 1.3.1: A compound of Formula (I) according to Embodiment 1.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein U is -NH2; or U is -OH.

[0146] Embodiment 1.3.2: A compound of formula (I) according to any one of Embodiments 1.3 to 1.3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is halogen, preferably F; or R9 is CN; or R9 is -C optionally substituted with halogen or CN 1-6 Alkyl groups, such as but not limited to those exemplified in Embodiment 1.1.3, are preferably -CF3.

[0147] Embodiment 1.3.3: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof according to any one of Embodiments 1.3 to 1.3.2, wherein R 10 H; or R 10 is halogen, preferably F; or R 10 CN; or R 10 is -C optionally substituted by halogen or CN 1-6 Alkyl, such as but not limited to those exemplified in Embodiment 1.1.3, preferably -CF3; or R 10 is -(CH2) optionally substituted by halogen or CN 0-3 -C 3-6 Cycloalkyl, such as but not limited to

[0148] Embodiment 1.3.4: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof according to any one of Embodiments 1.3 to 1.3.3, wherein R 11 H; or R 11 is halogen, preferably F or Cl; or R 11 CN; or R 11 is -C optionally substituted by halogen or CN 1-6 Alkyl, preferably -C 1-3 Alkyl, such as but not limited to the groups exemplified in Embodiment 1.1.3, preferably -CH3 or -CF3; or R11 is -(CH2) optionally substituted by halogen or CN 0-3 -C 3-6 Cycloalkyl groups, such as, but not limited to, those generally exemplified in Embodiment 1.3.3.

[0149] Embodiment 1.3.5: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof according to any one of Embodiments 1.3 to 1.3.4, wherein R 12 H; or R 12 is halogen, preferably F or Cl; or R 12 CN; or R 12 is -C optionally substituted by halogen or CN 1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as but not limited to those exemplified in Embodiment 1.1.3, are preferably -C 1-6 Alkyl, most preferably -CF3; or R 12 is -(CH2) optionally substituted by halogen or CN 0-3 -C 3-6 Cycloalkyl groups, such as but not limited to those exemplified in Embodiment 1.3.3.

[0150] Embodiment 1.3.6: A compound of Formula (I) according to Embodiment 1.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is wherein U is NH2, R9 is selected from halogen (preferably F) or CN, R 10 is selected from H or halogen (preferably F), R 11 Selected from halogen (preferably F or Cl) or -C 1-6 Alkyl (preferably -C 1-3 alkyl), R 12 -C substituted with halogen 1-6 Alkyl, preferably halogen-substituted -C 1-3 Alkyl, most preferably -CF3; B is for example but not limited to

[0151] 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 1.3.6, wherein M is N.

[0152] Embodiment 2.2: A compound of formula (I) according to any one of Embodiments 1 to 1.3.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-R4; wherein R4 is H; or R4 is CN; or R4 is halogen, preferably F or Cl; or R4 is -C optionally substituted with halogen or CN 1-6 Alkyl, preferably -C optionally substituted by halogen or CN 1-3 Alkyl groups, such as but not limited to those exemplified in Embodiment 1.1.3, such as -C 1-6 Alkyl, such as -CF3; In a preferred embodiment, R4 is selected from halogen, CN or C substituted by halogen 1-6 Alkyl (preferably C 1-3 Alkyl groups such as CF3).

[0153] Embodiment 2.3: A compound of formula (I) according to any one of Embodiments 1 to 2.2, wherein R3 is halogen, preferably F, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof.

[0154] Embodiment 2.4: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 2.2, wherein R3 is CN.

[0155] Embodiment 2.5: A compound of formula (I) according to any one of Embodiments 1 to 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is -OH; or R3 is -OC 1-6 Alkyl, preferably -OC 1-3 Alkyl, wherein the alkyl group is optionally substituted with halogen or CN, such as, but not limited to, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -OC(CH3)3, -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -O-CH2Cl, -O-CH2F, -O-CH2CN, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2CN, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF3, -O-C2F5, -O-C2Cl5; or R3 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, wherein the alkyl group is optionally substituted by halogen or CN, such as but not limited to the groups exemplified in Embodiment 1.1.3.

[0156] Embodiment 2.6: A compound of formula (I) according to any one of Embodiments 1 to 1.3.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is N or C-R4, wherein R4 is selected from halogen, CN and -C- substituted by halogen 1-6 Alkyl, preferably F, Cl, CN and -CF3, and R3 is halogen, preferably F.

[0157] Embodiment 3.1: A compound of Formula (I) according to any one of Embodiments 1 to 2.6, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0158] Embodiment 3.2: A compound of formula (I) according to any one of Embodiments 1 to 2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Y is NR d ; where R d H, or R d is -C optionally substituted by halogen or CN 1-6 Alkyl, preferably -C optionally substituted by halogen or CN 1-3 Alkyl groups, such as but not limited to those generally exemplified in Embodiment 1.1.3.

[0159] Embodiment 3.3: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 3.2, wherein X is -CH2-.

[0160] Embodiment 3.4: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 3.2, wherein X is -CH2CH2-.

[0161] Embodiment 3.5: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 3.2, wherein X is -CH2OCH2-.

[0162] Embodiment 3.6: A compound of formula (I) according to any one of Embodiments 1 to 3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein n is an integer from 0 to 3, preferably an integer from 0 to 2, more preferably an integer from 0 to 1, and most preferably 0.

[0163] Embodiment 3.7: A compound of formula (I) according to any one of Embodiments 1 to 3.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R c H, or R c is -C optionally substituted by halogen or CN 1-6 Alkyl, preferably -C optionally substituted by halogen or CN 1-3 Alkyl groups, such as but not limited to those generally exemplified in Embodiment 1.1.3.

[0164] Embodiment 3.8: A compound of formula (I) according to any one of Embodiments 1 to 3.7, wherein t is an integer from 1 to 2, preferably 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0165] Embodiment 3.9: 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 3.8, wherein R a H; or R a is -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl groups, such as but not limited to those generally exemplified in Embodiment 1.1.3, are preferably -CH3.

[0166] Embodiment 3.9.1: A compound of formula (I) according to any one of Embodiments 1 to 3.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein p is an integer from 0 to 3, preferably an integer from 0 to 2, more preferably an integer from 0 to 1.

[0167] Embodiment 3.10: A compound of Formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof, according to any one of Embodiments 1 to 3.9.1, wherein R b H; or R b is -C optionally substituted by halogen 1-6 Alkyl, preferably -C 1-3 Alkyl groups; for example, but not limited to, those generally exemplified in Embodiment 1.1.3.

[0168] Embodiment 3.11: A compound of formula (I) according to any one of Embodiments 1 to 3.9.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two R b Together they form C 3-6 Spirocyclic ring, the C 3-6The spiro ring is optionally substituted with halogen, CN and -C optionally substituted with halogen or CN. 1-6 Alkyl substituted; for example, but not limited to, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, optionally substituted with halogen (preferably F), CN and / or C optionally substituted with halogen or CN 1-6 Alkyl (preferably -CF3) substitution.

[0169] Embodiment 3.12: A compound of Formula (I) according to any one of Embodiments 1 to 3.9.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two R b , or R b and R c Together with the ring atoms to which they are attached, they form a fused 3-6 membered carbocyclic or heterocyclic ring, wherein each of the 3-6 membered fused carbocyclic or heterocyclic rings is independently optionally substituted with halogen (preferably F), CN and / or -C 1-6 Alkyl (preferably -CF3) substitution.

[0170] Embodiment 3.13: A compound of Formula (I) according to any one of Embodiments 1 to 3.12, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein q is an integer from 0 to 3, preferably an integer from 0 to 2, more preferably an integer from 0 to 1, and most preferably 0.

[0171] Embodiment 3.14: A compound of formula (I) according to any one of Embodiments 1 to 2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment In which Y is O, X is selected from -CH2- and -CH2CH2-, R a is H or -C optionally substituted by halogen 1-6 Alkyl, R b is selected from H or -C optionally substituted by halogen 1-6 Alkyl, R c is selected from H or -C optionally substituted by halogen 1-6 Alkyl, n is 0 or 1, t is 1-2, p is an integer from 0 to 2, and q is an integer from 0 to 2;

[0172] Preferably, Y is O, X is -CH2CH2-, R a is H or -C optionally substituted by halogen 1-3 Alkyl, R b Selected from H, R c is selected from H, n is 0, t is 1, p is an integer from 0 to 1, and q is 0, i.e., the structural fragment is Further

[0173] Embodiment 4: A compound of formula (I) according to any one of Embodiments 1 to 3.14, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is O; or Z is S; or Z is Se; preferably Z is O.

[0174] Embodiment 5.1: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein g is 2, R 14 Each is H.

[0175] Embodiment 5.2: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein g is 2, one R 14 is deuterium (D), the other is H, or both R14 are deuterium (D).

[0176] Embodiment 5.3: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 14 -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted with halogen or -OC 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; optionally, R 14 -C 1- One or more H of the 6-alkyl group is replaced by deuterium (D).

[0177] Embodiment 5.4: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 14 -(CH2) 0-3 -C 3-6 Cycloalkyl, where C 3-6 Cycloalkyl is optionally substituted with halogen or C1-6 Alkoxy substitution; for example but not limited to

[0178] Embodiment 5.5: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two R 14 Together with the carbon atoms to which they are attached, they form a spiro C 3-4 Cycloalkyl, such as spirocyclopropyl, spirocyclobutyl, etc.

[0179] Embodiment 5.6: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 14 Select from H or D.

[0180] Embodiment 5.7: A compound of formula (I) according to any one of Embodiments 1 to 5.6, 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.

[0181] Embodiment 6.1: 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 5.7, wherein R 13 For H.

[0182] Embodiment 6.2: A compound of formula (I) according to any one of Embodiments 1 to 5.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R 13 -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, CN or C 1-6Alkoxy substitutions, such as but not limited to -CH3, -CH2CN, -CH2CH3, -CH2CH2CN, -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.

[0183] Embodiment 6.3: 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 5.7, wherein R 13 Deuterated C 1-6 Alkyl, preferably deuterated C 1-3 Alkyl groups, such as but not limited to -CH2D, -CHD2, -CD3.

[0184] Embodiment 6.4: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof according to any one of Embodiments 1 to 5.7, wherein R 13 -(CH2) 0-3 -C 3-6 Cycloalkyl, where C 3- 6 cycloalkyl is optionally substituted with halogen, CN or C 1-6 Alkoxy substitution; for example but not limited to

[0185] Embodiment 6.5: A compound of formula (I) according to any one of Embodiments 1 to 5.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein when R1 and R 13 When attached to adjacent ring carbon atoms, together with the carbon atoms to which they are attached, they form a C 3-4 Cycloalkyl; preferably cyclopropyl; for example

[0186] Embodiment 6.6: 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 5.7, wherein R 13 Selected from -C 1-6Alkyl or -deuterated C 1-6 Alkyl groups, such as -CH3 and -CD3.

[0187] Embodiment 6.7: A compound of formula (I) according to any one of Embodiments 1 to 5.7, 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.

[0188] Embodiment 7.1: A compound of formula (I) according to any one of Embodiments 1 to 6.7, wherein R1 is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0189] Embodiment 7.2: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 6.7, wherein R1 is 1 to m Ds.

[0190] Embodiment 7.3: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is a halogen, such as F, Cl, Br, I, preferably F; or R1 is CN.

[0191] Embodiment 7.4: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 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, CN or -OC 1-6 Alkyl substitutions; 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).

[0192] Embodiment 7.5: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 6.7, wherein R1 is -OH.

[0193] Embodiment 7.6: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -OC 1-6 Alkyl, preferably -OC 1-3 Alkyl, wherein the alkyl group is optionally substituted by halogen, CN or C 1-6 Alkoxy substitution; 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-CH2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF 3. -O-C2F5, -O-C2Cl5, -O-CH2-OCH3, -O-CH2-O-CH2CH3, -O-CH2CH2-O-CH3, -O-CH2CH2-O-CH2CH3.

[0194] Embodiment 7.7: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -C 1-6 Alkyl, preferably -C 1-3 Alkyl, optionally substituted by halogen, CN or C 1-6 Alkoxy 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, -CH2CN, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CH2CN, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2.

[0195] Embodiment 7.7.1: A compound of formula (I) according to Embodiment 7.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -deuterated C1-6 Alkyl, preferably deuterated C 1-3 Alkyl, optionally substituted by halogen, CN or C 1-6 Alkoxy substitutions, such as, but not limited to, those exemplified in Embodiment 7.7, wherein one or more H is replaced by D.

[0196] Embodiment 7.8: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -OC 3-6 Cycloalkyl, wherein C 3-6 Cycloalkyl is optionally substituted with halogen, CN or C 1-6 Alkoxy substitution; for example but not limited to

[0197] Embodiment 7.9: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -(CH2) 0-3 -C 3-6 Cycloalkyl, optionally substituted by halogen, CN or C 1-6 Alkoxy substitutions, such as but not limited to those exemplified in Embodiment 6.4.

[0198] Embodiment 7.10: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is -C 2-6 Alkenyl or -C 2-6 Alkynyl, optionally substituted by halogen, CN or -C 1-6 Alkoxy substituted; for example but not limited to each optionally substituted with halogen, CN or -C 1-6 Alkoxy-substituted vinyl, propenyl, ethynyl.

[0199] Embodiment 7.11: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two R1 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form C 3-4 Cycloalkyl, preferably cyclopropyl; for example but not limited to

[0200] Embodiment 7.12: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 6.7 wherein two R1 attached to non-adjacent ring carbon atoms are taken together to form a bridged methylene or ethylene group.

[0201] Embodiment 7.13: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two R1 attached to the same carbon atom form =C(R e )2, where R e 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.

[0202] Embodiment 7.14: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two R1 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, optionally halogen (preferably F) or C optionally substituted by halogen 1-6 Alkyl (preferably -CF3) substitution, such as but not limited to where * indicates an atom attached to the rest of the molecule.

[0203] Embodiment 7.15: A compound of Formula (I) according to any one of Embodiments 1 to 7.14, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein R1 is substituted in the para position relative to the ring atom N-(R2), and wherein R1 is selected from each substituent other than H in the aforementioned R1 embodiments.

[0204] Embodiment 7.16: A compound of formula (I) according to any one of Embodiments 1 to 6.7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 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,

[0205] Or two R1s connected to the same carbon atom form =C(R e )2, where R e Each independently selected from H, F, Cl, Br, I, -C 1-6 alkyl,

[0206] Or two R1 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 substitution; preferably, R1 is substituted in the para position relative to the ring N atom.

[0207] Embodiment 7.17: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 7.16, wherein m is an integer from 1 to 8; preferably an integer from 1 to 4; more preferably an integer from 1 to 2.

[0208] Embodiment 8.1: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 7.17, wherein R2 is H.

[0209] Embodiment 8.2: A compound of formula (I) according to any one of Embodiments 1 to 7.17, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is -C 1-6 Alkyl, optionally substituted by halogen or CN, preferably optionally substituted by halogen; for example but not limited to the groups generally exemplified in Embodiment 1.1.3, preferably -CH2CH3.

[0210] Embodiment 8.2.1: A compound of formula (I) according to any one of Embodiments 1 to 8.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 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.

[0211] Embodiment 8.3: A compound of formula (I) according to any one of Embodiments 1 to 7.17, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is -C 2-6 Alkenyl or -C 2-6 Alkynyl, optionally substituted with halogen or CN; for example, but not limited to, the groups exemplified in Embodiments 1.1.4 and 1.1.5, respectively.

[0212] Embodiment 8.4: A compound of formula (I) according to any one of Embodiments 1 to 7.17, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is -(CH2) 0-3 -C 3-6 Cycloalkyl, the -C3- 6-cycloalkyl is optionally substituted by halogen or CN; for example, but not limited to, the groups exemplified in Embodiment 1.3.3, preferably R2 is cyclopropyl.

[0213] Embodiment 8.5: A compound of formula (I) according to any one of Embodiments 1 to 7.17, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl, preferably -CH3, -CH2CH3 and cyclopropyl.

[0214] Embodiment 9.1: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Specifically In which R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl; R 14 Selected from H and D; R 13 Selected from -C 1-6 Alkyl and deuterated C 1-6 Alkyl; preferably, R1 is substituted in the para position relative to the ring N atom.

[0215] Embodiment 9.2: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Specifically, specifically Examples include, but are not limited to

[0216] Preferred

[0217] Embodiment 9.3: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for where R 14 Each is independently H or D; R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; m is selected from 1 or 2; R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Specific examples of cycloalkyl groups include monofluoro, difluoro, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluoromethylene, difluoromethylene, methylene, spirocyclopropyl, and one or two F-substituted spirocyclopropyl groups.

[0218] Embodiment 9.4: A compound of formula (I) according to any one of Embodiments 1 to 4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for Wherein R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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 3-6Cycloalkyl optionally substituted with halogen and optionally substituted with halogen -C 1-6 Alkyl substituted; m is selected from 1 or 2; R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Specific examples of cycloalkyl include, but are not limited to, fluorine, difluorine, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluorinated methylene, difluoromethylene, methylene, spirocyclopropyl, and one or two F-substituted spirocyclopropyls.

[0219] Embodiment 10.1: A compound of Formula (I) according to Embodiment 1 or 1-1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having the following sub-formula:

[0220] wherein each substituent has the general or preferred meaning as defined above for each corresponding embodiment.

[0221] Embodiment 10.1.1: A compound of Formula (I) according to Embodiment 10.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0222] Z is O;

[0223] Y is O;

[0224] X is -CH2- or -CH2CH2-;

[0225] M is N or C-R4;

[0226] R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; specific examples of R1 include, but are not limited to, fluorine, difluorine, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluorinated methylene, difluoromethylene, methylene, spirocyclopropyl, one or two F-substituted spirocyclopropyls;

[0227] R2 is selected from -C1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl;

[0228] R3 is halogen;

[0229] R4 is selected from halogen, CN and -C substituted by halogen 1-6 Alkyl; preferably halogen, CN or C substituted by halogen 1-3 alkyl;

[0230] R a is H or -C optionally substituted by halogen 1-6 alkyl;

[0231] R b is selected from H or -C optionally substituted by halogen 1-6 alkyl;

[0232] R c is selected from H or -C optionally substituted by halogen 1-6 alkyl;

[0233] R 13 Selected from -C 1-6 Alkyl and deuterated C 1-6 alkyl;

[0234] R 14 are each independently selected from H and D;

[0235] n is 0 or 1, m is 1 or 2, g is 2, t is 1-2, p is an integer of 0-2, and q is an integer of 0-2.

[0236] Embodiment 10.1.1.1: A compound of Formula (I) according to Embodiment 10.1 or 10.1.1, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein n is 0, m is 1 or 2, g is 2, t is 1, p is an integer from 0 to 1, and q is 0.

[0237] Embodiment 10.1.2: A compound of formula (I) according to Embodiment 10.1 or 10.1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein in formula (IA-1), W is -OH, R5 is H or halogen, preferably halogen, and R6 is selected from halogen, -C 2-6 Alkynyl and -C 1-6 Alkyl, preferably selected from -C 2-6 Alkynyl and -C 1-6 Alkyl, R7 and R8 are H.

[0238] Embodiment 10.1.3: A compound of Formula (I) according to Embodiment 10.1 or 10.1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein in Formula (IA-2), (IA-3) and (IA-4), W is selected from H, halogen and -C 1-6 alkyl, R5 is NH2, R6 is CN, R7 is selected from H or halogen, R8 is selected from H, halogen and -C 1-6 alkyl.

[0239] Embodiment 10.1.4: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 10.1 to 10.1.3, having the following sub-formula:

[0240] wherein each substituent has the general or preferred meaning defined in accordance with the aforementioned embodiments 1-9.4, and further has the meaning defined in any one of embodiments 10.1.1 to 10.1.3.

[0241] Embodiment 10.1.5: A compound of formula (I) according to embodiment 10.1.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for

[0242] Embodiment 10.1.6: A compound of Formula (I) according to Embodiments 10.1 to 10.1.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, which is of the following formula:

[0243] Specifically

[0244] wherein each substituent has the general or preferred meaning defined in accordance with the aforementioned embodiments 1-9.4, and further has the meaning defined in any one of embodiments 10.1.1 to 10.1.3; wherein R 14 are each independently H or D.

[0245] Embodiment 10.2: 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, having the following sub-formula:

[0246] wherein each substituent has the general and preferred meanings as defined above for each corresponding embodiment.

[0247] Embodiment 10.2.1: A compound of Formula (I) according to Embodiment 10.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0248] Z is O;

[0249] Y is O;

[0250] X is -CH2- or -CH2CH2-;

[0251] M is N or C-R4;

[0252] R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; specific examples of R1 include, but are not limited to, fluorine, difluorine, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluorinated methylene, difluoromethylene, methylene, spirocyclopropyl, one or two F-substituted spirocyclopropyls;

[0253] R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl;

[0254] R3 is halogen;

[0255] R4 is selected from halogen, CN and -C substituted by halogen 1-6 Alkyl; preferably halogen, CN or C substituted by halogen 1-3 alkyl;

[0256] R a is H or -C optionally substituted by halogen 1-6 alkyl;

[0257] R b is selected from H or -C optionally substituted by halogen 1-6 alkyl;

[0258] R c Selected from H or halogen;

[0259] R 13 Selected from -C 1-6 Alkyl and deuterated C 1-6 alkyl;

[0260] R 14 Selected from H and D;

[0261] n is 0 or 1, m is 1 or 2, g is 2, t is 1-2, p is an integer of 0-2, and q is an integer of 0-2.

[0262] Embodiment 10.2.1.1: A compound of Formula (I) according to Embodiment 10.2 or 10.2.1, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein n is 0, m is 1 or 2, g is 2, t is 1, p is an integer from 0 to 1, and q is 0.

[0263] Embodiment 10.2.2: A compound of formula (I) according to Embodiment 10.2 or 10.2.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein in formula (IB-1) and (IB-2), U is -NH2, R9 is selected from halogen (preferably F) or CN, R 10 is selected from H or halogen (preferably F), R 11 Selected from halogen (preferably F or Cl) or -C 1-6 Alkyl (preferably -C 1-3 alkyl), R 12 -C substituted with halogen 1-6 Alkyl, preferably halogen-substituted -C 1-3 Alkyl, most preferably -CF3.

[0264] Embodiment 10.2.3: A compound of formula (I) according to any one of Embodiments 10.2 to 10.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, having the following sub-formula:

[0265] wherein each substituent has the general or preferred meaning defined in accordance with the aforementioned embodiments 1-9.4, and further has the meaning defined in any one of embodiments 10.2.1 to 10.2.2.

[0266] Embodiment 10.2.4: A compound of formula (I) according to embodiment 10.2.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for

[0267] Embodiment 10.2.5: A compound of Formula (I) according to Embodiments 10.2 to 10.2.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, which is of the following formula:

[0268] Specifically:

[0269] wherein each substituent has the general or preferred meaning defined in accordance with the aforementioned embodiments 1-9.4, and further has the meaning defined in any one of embodiments 10.2.1 to 10.2.2; wherein R 14 are each independently H or D.

[0270] Embodiment 11: A compound selected from the group consisting of the compounds of the following Examples or pharmaceutically acceptable salts or solvates thereof.

[0271] 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.

[0272] Advantageous Effects of the Invention

[0273] As mentioned above, Ras mutant proteins, especially KRas mutant proteins, are known to play a role in tumorigenesis and various 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 and G13D mutant proteins), especially KRas-G12D mutant proteins, and thus have 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 that are inhibited by Ras mutants (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), especially KRas-G12D mutants, such as cancer or tumors as defined herein.

[0274] Specifically, it has been found through research that the compounds of the present invention can achieve one or more of the following technical effects:

[0275] ● High mutant protein inhibitory activity: The compounds of the present invention, especially the compounds specifically exemplified herein, show proliferation inhibitory activity against KRas G12D mutant cells in a KRASG12D mutant cell AGS cell proliferation inhibition assay, with an IC50 value of 10 pM to 10 μM, for example, 10 pM to 5 μM, 100 pM to 5 μM, 100 pM to 1 μM, 100 pM to 0.5 μM, 500 pM to 1 μM, 0.001 to 10 μM, 0.001 to 5 μM, 0.01 to 1 μM, preferably 100 pM to 1 μM, more preferably 100 pM to 0.5 μM, and most preferably 0.1 to 100 nM, as shown in Activity Example 1;

[0276] ●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, with better drugability and higher bioavailability, as shown in Active Example 2; and

[0277] ● It has a significantly satisfactory safety profile, reduced risk of drug interactions, and no significant inhibitory effect on key CYP isoforms of drug metabolism, as shown in Active Example 3.

[0278] 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.

[0279] Compounds of the invention for use in therapy or as medicine

[0280] 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.

[0281] In another aspect, the present invention provides a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as an inhibitor of KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), more specifically a RAS G12D inhibitor.

[0282] 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 or inhibited by Ras mutations, particularly KRas mutants (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), more particularly KRAS G12D mutant proteins.

[0283] In a specific embodiment, the present invention provides a method for treating and / or preventing Ras mutant proteins, specifically KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), more specifically KRAS G12D mutant proteins, which promote the occurrence and development of the disease or inhibit Ras mutant proteins, specifically KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutant proteins), more specifically KRAS The G12D mutant protein will reduce the incidence of, reduce or eliminate the symptoms of a disease, such as a tumor or cancer, including but 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.

[0284] 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.

[0285] Pharmaceutical compositions and their administration

[0286] 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 mutations, particularly KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, G12A, G12R, G12S or KRas G13D mutations, particularly KRas G12D mutations, such as tumors or cancer.

[0287] The pharmaceutical composition 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, it can be formulated into tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The composition 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] Treatment methods and uses

[0293] 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 an inhibitory effect on Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, G12A, G12R, G12S or KRas G13D mutations, especially KRas G12D.

[0294] Therefore, on the other hand, the present invention provides a method for inhibiting Ras mutations, especially KRas mutations, preferably KRas G12D mutations in cells, comprising contacting the cells with a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to inhibit the activity of Ras mutations, especially KRas mutations (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations and G13D mutations), preferably KRas G12D mutations in the cells.

[0295] 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.

[0296] On the other hand, the present invention provides a method for treating and / or preventing diseases mediated by Ras mutations, especially KRas mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), preferably KRas G12D mutation, 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.

[0297] 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 mutations in cells, especially KRas mutations, preferably KRas G12D mutations, or for inhibiting abnormal cell growth in mammals, or for treating and / or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V, KRasG12A, KRasG12R, KRasG12S or KRas G13D, most preferably KRas G12D mutations.

[0298] 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 mutations, especially KRas mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), preferably KRas G12D mutation.

[0299] For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or the disease mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRasG12A, KRasG12R, KRasG12S or KRas G13D, most preferably KRas G12D mutation, 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.

[0300] For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or the disease mediated by Ras mutation, especially KRas mutation (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), preferably KRas G12D, is preferably 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.

[0301] Therefore, in preferred embodiments of this aspect, the present invention provides the above-mentioned methods and uses for treating or preventing cancer or tumors by inhibiting KRas G12V and / or KRas-G12D mutations. In further preferred embodiments, the present invention provides the above-mentioned methods and uses for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer by inhibiting KRas-G12D mutations.

[0302] The present invention also provides the use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a KRas inhibitor (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation inhibitor) in research, in particular as a research tool compound for inhibiting KRas G12D. 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 KRas inhibitor, in particular a KRas G12D 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 effectiveness of a KRas inhibitor, in particular a KRas G12D inhibitor. The present invention also relates to methods of inhibiting KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation), in particular KRas G12D, in particular in vitro methods, which comprise administering a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to a sample (e.g., a biological sample). It should 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 conducted 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, culture dishes, microtiter plates, etc.

[0303] Drug combinations

[0304] The compounds of the present invention may be administered as the sole active ingredient or in combination with another drug or therapy.

[0305] Therefore, in another aspect, 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 both. The drug combination is used to inhibit abnormal cell growth in mammals, or to treat and / or prevent diseases mediated by Ras mutations, preferably KRas mutations (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, and G13D mutations), most preferably KRas-G12D mutations.

[0306] 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.

[0307] 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.

[0308] Other active agents used in combination with the present invention can be administered simultaneously, separately or sequentially with the compounds of the present invention by the same or different routes of administration. The other active agents can be co-administered with the compounds of the present invention in a single pharmaceutical composition, or administered separately in different discrete units from the compounds of the present invention, such as a combination product, preferably in the form of a kit, which can be administered simultaneously or sequentially when administered separately, and the sequential administration can be close or distant in time. They can be prepared and / or formulated by the same or different manufacturers. Moreover, the compounds of the present invention and the other active agents can be (i) administered before the combination product is sent to the physician (e.g., in the case of a kit comprising the compounds of the present invention and another drug); (ii) administered by the physician himself (or under the guidance of a physician) before administration; (iii) administered by the patient himself, e.g., during the sequential administration of the compounds of the present invention and the other active agents, in a combination therapy.

[0309] 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.

[0310] 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.

[0311] 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 mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, most preferably KRas G12D mutation is as defined above for the method and use of the present invention.

[0312] 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.

[0313] Preparation method of the compound of the present invention

[0314] In another aspect, the present invention also provides a method for preparing the compound defined in the present invention.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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).

[0320] 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.

[0321] 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).

[0322] 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.

[0323] Synthesis Scheme Ia

[0324] The synthesis of compounds of the general formula Part I of the present invention can be prepared according to the following illustrative schemes, wherein the variables are as defined above unless otherwise stated.

[0325] Starting material I-1 is commercially available, or prepared by known methods reported in the literature, or prepared according to the exemplary intermediate synthesis method of the present invention and its appropriate variants. In step A, compound I-1 reacts with trichloroacetyl isocyanate to produce compound I-2, which is cyclized in step B under conditions such as ammonia methanol to produce compound I-3. In step C, compound I-3 undergoes chlorination under conditions such as POCl3 to produce compound I-4. In step D, compound I-4 is selectively hydrolyzed under conditions such as NaHCO3 / THF to produce compound I-5. In step E, compound I-5 undergoes an aromatic nucleophilic substitution reaction with I-6 to produce compound I-7. In step F, compound I-7 undergoes intramolecular condensation and cyclization to produce compound I-8. In step G, compound I-8 undergoes a halogen exchange reaction under conditions such as KF / DMSO to produce compound I-9. In step H, compound I-9 is introduced into group B through a metal-catalyzed coupling reaction to produce compound I-10. In step I, compound I-10 undergoes an aromatic nucleophilic substitution reaction and removes any protecting groups to obtain a compound of formula I. It should be noted that the removal of the protecting groups in step I may be a one-step reaction (when any protecting groups can be removed simultaneously under the same conditions) or a multi-step reaction (when multiple protecting groups cannot be removed simultaneously under the same conditions).

[0326] Synthesis Scheme Ib

[0327] The synthesis of compounds of the general formula Part I of the present invention can be prepared according to the following schemes, wherein the variables are as defined above unless otherwise stated.

[0328] The synthesis of compound I-8 was carried out according to Synthesis Scheme Ia. In Step A, compound I-8 undergoes an aromatic nucleophilic substitution reaction to provide compound I-11, which is then subjected to a metal-catalyzed coupling reaction in Step B to introduce a B group, followed by removal of any protecting groups to provide a compound of Formula I.

[0329] Synthesis Scheme IIa

[0330] The synthesis of compounds of the general formula Part I of the present invention can be prepared according to the following illustrative schemes, wherein the variables are as defined above unless otherwise stated.

[0331] The synthesis of starting material I-12 is carried out by referring to the intermediate synthesis scheme or appropriate variations in the examples, or by referring to methods reported in the literature. In step A, compound I-12 undergoes an aromatic nucleophilic substitution reaction with I-6 to produce compound I-13, which then undergoes a condensation reaction in step B in the presence of a condensing agent such as T3P, BOP, or the like to produce compound I-14. In step C, compound I-14 is subjected to a metal-catalyzed coupling reaction to introduce group B to produce compound I-15. In step D, compound I-15 is oxidized to produce sulfoxide compound I-16a, or sulfone compound I-16b, or a mixture of I-16a and I-16b. In step E, compound I-16a, or I-16b, or a mixture of I-16a and I-16b undergoes an aromatic nucleophilic substitution reaction, followed by removal of any protecting groups to produce a compound of formula I.

[0332] Synthesis Scheme IIb

[0333] The synthesis of compound I-14 is carried out as described in Synthesis Scheme IIa. In step A, compound I-14 is oxidized to produce sulfoxide compound I-17a, or sulfone compound I-17b, or a mixture of I-17a and I-17b. In step B, compound I-17a, or I-17b, or a mixture of I-17a and I-17b undergoes an aromatic nucleophilic substitution reaction to produce compound I-18. In step C, compound I-18 is subjected to a metal-catalyzed coupling reaction to introduce group B, and any protective groups are subsequently removed to produce compound I.

[0334] It should be noted that the typical reaction conditions and reagents used for the metal-catalyzed coupling reaction, aromatic nucleophilic substitution reaction, and protecting agent removal reaction involved in the above synthesis scheme are well known in the art and fall within the routine experience of those skilled in the art, or can be determined by those skilled in the art by making appropriate changes based on the typical conditions of such reactions in the art, the characteristics of the raw materials used, and the target product.

[0335] Synthesis Example

[0336] 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.

[0337] In describing the embodiments and the specific examples that follow, the following abbreviations are used herein:

[0338] ACN (acetonitrile); BAST (bis(2-methoxyethyl)aminosulfur trifluoride); Boc (tert-butoxycarbonyl); BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate); CDCl3 (deuterated chloroform); DAST (diethylaminosulfur trifluoride); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (hexadeuterated dimethyl sulfoxide); EA (ethyl acetate); EDTA-K2 (ethylenediaminetetraacetic acid dipotassium salt); EtOH (ethanol) ; FCC (flash column chromatography); g (gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl / MeOH (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 (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimolar); MOM (methoxymethyleneimine) ether); MTBE (methyl tert-butyl ether); m / z (mass-to-charge ratio); N2 (nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); Na2SO3 (sodium sulfite); Na2SO4 (sodium sulfate); NCS (chlorosuccinimide); NH4Cl (ammonium chloride); NMR (nuclear magnetic resonance); PdCl2(dtbpf) or Pd(dtbpf)Cl2 (1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride); PdCl2(dppf) or Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride) ; Pd(OAc)2 (palladium acetate); Pd(PPh3)4 (tetrakistriphenylphosphine palladium); PE (petroleum ether); PO (oral administration); POCl3 (phosphorus oxychloride); rt (room temperature); SFC (supercritical fluid chromatography); SiO2 (silica gel); TBAF (tetrabutylammonium fluoride); 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 concentration); μmol (micromole).

[0339] In the following examples, the names and structures of the synthesized target compounds are given. Any discrepancies between the names and structures are not intentional; in such cases, the structures shall prevail.

[0340] 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.

[0341] 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.

[0342] 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). Mass spectra were recorded using an Aglient 1100 liquid chromatograph coupled with an Aglient G6100 LCMS / MS instrument.

[0343] Intermediate I-12a

[0344] 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0345] Step A: 2,6-Dichloro-3-fluoropyridin-4-amine

[0346] 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 EA, 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).

[0347] Step B: tert-Butyl (tert-Butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate

[0348] 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. The crude product was concentrated to afford the crude product, which 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).

[0349] Step C: tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0350] 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 hour. 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 yield tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13 g).

[0351] Step D: 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride

[0352] 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).

[0353] Step E: 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one

[0354] A mixed solution 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 mixed solution of ammonium thiocyanate (7 g, 92 mmol) and acetone (160 mL) was added dropwise to Solution 1 at room temperature, and the resulting reaction solution was stirred for an additional 1 h at room temperature. After completion of the reaction, as monitored by LCMS, the reaction solution 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).

[0355] Step F: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0356] A mixture of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (5 g, 18.8 mmol), methanol (380 mL), aqueous sodium hydroxide (0.1 M, 380 mL, 380 mmol), and iodomethane (5.3 g, 380 mmol) was stirred at room temperature for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture 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).

[0357] Intermediate I-1a

[0358] 2-Amino-4-bromo-3,6-difluorobenzoic acid methyl ester

[0359] Step A: 2,4-Dibromo-3,6-difluorobenzoic acid

[0360] Dissolve 1,3-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in THF (30 mL) at room temperature. Under nitrogen, cool the system to -78°C. Add LDA (2 M in THF, 12 mL, 23.9 mmol) slowly dropwise to the reaction mixture while stirring. Stir at -78°C for 40 min. Add an appropriate amount of dry ice dried over NaH / THF to the reaction mixture. After stirring for 1 h, quench the reaction by adding water (20 mL). After warming to room temperature, adjust the pH to 10 by adding 1 M NaOH. Remove impurities by washing with EA (15 mL x 2). Adjust the pH of the aqueous phase to 3 with 3 M HCl and extract with EA (25 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 2,4-dibromo-3,6-difluorobenzoic acid (1.5 g, yield 26%) as a white solid. LCMS (m / z): 316.8 (M+H).

[0361] Step B: 2-Amino-4-bromo-3,6-difluorobenzoic acid

[0362] Under N2 protection at room temperature, a solution of 2,4-dibromo-3,6-difluorobenzoic acid (2.7 g, 8.55 mmol) in aqueous ammonia (5 mL) and EA (5 mL) was slowly added dropwise to a mixture of Cu2O (122 mg, 0.85 mmol) and aqueous ammonia (5 mL). The system was heated to 35°C and stirred for 24 h. After completion of the reaction, EDTA (497 mg, 1.7 mmol) was added, and the pH was adjusted to 5 with 1 M HCl. The resulting mixture was extracted with EA (25 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered and concentrated under reduced pressure to afford the crude product, which was then purified by FCC (SiO2, EA / PE = 0-50%) to afford 2-amino-4-bromo-3,6-difluorobenzoic acid (0.9 g, 42% yield) as a white solid. LCMS (m / z): 251.9 (M+H).

[0363] Step C: Methyl 2-amino-4-bromo-3,6-difluorobenzoate

[0364] 2-Amino-4-bromo-3,6-difluorobenzoic acid (3.7 g, 14.7 mmol) was dissolved in MeOH (50 mL) with stirring at room temperature, and concentrated sulfuric acid (1 mL) was slowly added. The resulting reaction solution was heated at reflux for 24 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (C18, MeOH / H2O = 5-95%) to afford methyl 2-amino-4-bromo-3,6-difluorobenzoate (1 g, 26% yield) as a white solid. LCMS (m / z): 267.9 (M+H).

[0365] Intermediate I-1b

[0366] 2-Amino-4-bromo-3,5,6-trifluorobenzoic acid methyl ester

[0367] Step A: 4-Bromo-2,3,5,6-tetrafluorobenzoic acid

[0368] Under nitrogen, dissolve 1,4-dibromo-2,3,5,6-tetrafluorobenzene (10.0 g, 32.5 mmol) in THF (500 mL). Cool the reaction system to -70°C in a dry ice-acetone bath. Then, slowly add n-butyllithium (13.0 mL, 2.5 M, 32.5 mmol) dropwise to the mixture, maintaining the temperature at -70°C with stirring for 30 min. Slowly add dry ice chips (approximately 40 g) to the reaction flask. After addition, continue stirring and allow the mixture to warm naturally to room temperature. (Note that during this warming period, a large amount of CO₂ gas will escape; prevent it from saturating the reaction mixture.) Post-treatment: Cool the reaction mixture in an ice bath and slowly adjust the pH to 3-5 with 2N hydrochloric acid. Then, extract with EA (400 mL x 3). Combine the organic phases, wash with brine, and dry over anhydrous Na₂SO₄. The residue was filtered and concentrated under reduced pressure to give 4-bromo-2,3,5,6-tetrafluorobenzoic acid (8.0 g, yield 90%) as a gray solid.

[0369] Step B: Methyl 4-bromo-2,3,5,6-tetrafluorobenzoate

[0370] With stirring at room temperature, concentrated sulfuric acid (8.0 mL, 147 mmol) was added dropwise to a solution of 4-bromo-2,3,5,6-tetrafluorobenzoic acid (8.0 g, 29.3 mmol) in methanol (100 mL). The resulting mixture was heated under reflux and stirred overnight. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate was slowly added until the pH reached ≈ 7. The mixture was then extracted with EA (300 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na2SO4. Filtered and concentrated under reduced pressure to afford methyl 4-bromo-2,3,5,6-tetrafluorobenzoate (8.0 g, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ3.94 (s, 3H).

[0371] Step C: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-3,5,6-trifluorobenzoate

[0372] DIPEA (11.8 g, 55.7 mmol) and 2,4-dimethoxybenzylamine (4.7 g, 27.9 mmol) were added dropwise to a solution of methyl 4-bromo-2,3,5,6-tetrafluorobenzoate (8.0 g, 27.9 mmol) in toluene (500 mL) with stirring at room temperature. The resulting system was heated to 100°C and stirred overnight. After completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure to afford the crude product, which was then purified by FCC (SiO2, EA / PE = 0-50%) to afford methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-3,5,6-trifluorobenzoate (7.0 g, 58% yield) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ.07(d,J=8.3Hz,1H),6.52(d,J=2.4Hz,1H),6.44(dd, J=8.3,2.4Hz,1H),4.29(d,J=2.7Hz,2H),3.83(s,3H),3.73(d,J=2.0Hz,6H). 19 F NMR(376MHz, DMSO-d6)δ-108.04,-123.05(dd,J=11.4,5.9Hz),-137.79–-137.88(m),-144.38(dd,J=25.0,6.4Hz).

[0373] Step D: Methyl 2-amino-4-bromo-3,5,6-trifluorobenzoate

[0374] Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-3,5,6-trifluorobenzoate (7.0 g, 16.1 mmol) was dissolved in trifluoroacetic acid (50 mL) at room temperature and stirred at room temperature for 2 hours. Following completion of the reaction, as monitored by LCMS, the solution was concentrated under reduced pressure to remove the excess trifluoroacetic acid. The resulting residue was neutralized with an appropriate amount of saturated sodium bicarbonate aqueous solution and extracted with EA (300 × 3). The combined organic phases were washed with saturated brine and dried over anhydrous NaSO. The mixture was filtered and concentrated under reduced pressure to afford methyl 2-amino-4-bromo-3,5,6-trifluorobenzoate (4.0 g, 84% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ6.59(brs,2H),3.87(s,3H). 19 F NMR (376MHz, DMSO-d6) δ-130.20–-130.37 (m), -138.01 (dd, J = 24.3, 11.7Hz), -150.11–-150.32 (m). LCMS (m / z): 283.8 (M+H).

[0375] According to the method described in Synthesis Scheme 1 or appropriate literature methods, the present invention prepared the following intermediates using the above intermediates or commercially available starting materials.

[0376] Intermediate I-14a

[0377] tert-Butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-naphtho[1,8-ab]heptalene-14-carboxylate

[0378] Step A: (1R,2S,5S)-tert-butyl 2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0379] At room temperature, tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (447 mg, 1.85 mmol) was dissolved in THF (10 mL). NaH (201 mg, 5.03 mmol) was added and stirred at room temperature for 10 min. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (470 mg, 1.68 mmol) was added. The resulting mixture was stirred at 60°C for 1 h, then cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The reaction mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous NaSO, filtered, and concentrated to afford crude tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 98% yield), which was used directly in the next step. LCMS: m / z: 486.1 (M+H).

[0380] Step B: tert-Butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbazo[1,8-ab]heptalene-14-carboxylate

[0381] At room temperature, tert-butyl (1R,2S,5S)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.65 mmol) was dissolved in DMF (10 mL). BOP (803 mg, 1.82 mmol) and DIPEA (327 mg, 3.24 mmol) were added. The resulting mixture was heated to 50°C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into water (50 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by FCC (SiO2, EA / PE = 0-45%) to afford tert-butyl (8aS,9S,12R)-5-chloro-4-fluoro-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbazo[1,8-ab]heptalene-14-carboxylate (470 mg, 61% yield). LCMS: m / z: 468.1 (M+H).

[0382] Intermediate k0

[0383] (R)-tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate-3-carboxylate methyl

[0384] Step A: 3-Methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester

[0385] At room temperature, CH₃I (13.79 g, 97.17 mmol) was added dropwise to a stirred mixture of 1-(tert-butyl)-3-methyl 4-oxopiperidine-1,3-dicarboxylate (5.0 g, 19.43 mmol), K₂CO₃ (8.06 g, 58.30 mmol), and anhydrous acetonitrile (50 mL). The reaction was allowed to react overnight at room temperature. After TLC monitoring, the reaction solution was poured into NH₄Cl (100 mL) and extracted with EA (100 mL × 3). The collected organic phase was washed with saturated brine (50 mL). The organic phase was concentrated to obtain a crude product, which was purified by FCC (SiO₂, EA / PE = 0-20%) to afford 1-(tert-butyl)-3-methyl 4-oxopiperidine-1,3-dicarboxylate (4.85 g, 92% yield) as a colorless oil. LCMS (m / z): 216.0 (M+H-56). 1H NMR (400MHz, Methanol-d4) δ4.51 (d, J = 13.7Hz, 1H), 4.23–4.05 (m, 1H), 3.73 (s, 3H), 3.47–3. 27(m,1H),3.17(d,J=13.7Hz,1H),2.75(s,1H),2.57–2.41(m,1H),1.50(s,9H),1.28(s,3H).

[0386] Step B: (R)-tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate-3-carboxylate methyl ester

[0387] The compound 3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (120 g) was separated by SFC (SFC150, Waters) (separation column: DAICEL IG, 250*50mm, 10μm; mobile phase: CO2 / MeOH = 90 / 10; flow rate: 120mL / min), the first eluting isomer 1 was obtained, compound k0 (52.8g, relatively short retention time). Chiral analysis method SFC-1, Rt = 0.682min. 1 H NMR (400 MHz, Chloroform-d) δ 4.59–4.42 (m, 1H), 4.26–3.98 (m, 1H), 3.73 (s, 3H), 3.42–3.24 (m, 1H), 3.16–3.01 (m, 1H), 2.93–2.63 (m, 1H), 2.58–2.40 (m, 1H), 1.49 (s, 9H), 1.31 (s, 3H). LCMS (m / z): 216.1 (M-56+H). The subsequently eluted isomer 2 was compound k0-b (52.4 g, relatively long retention time). Chiral analysis by SFC-1: 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).

[0388] Chiral analysis method SFC-1: Waters UPCC, analytical column: Daicel IG, 100*3mm 3μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 1.5 mL / min; column temperature: 35°C; back pressure: 1800 psi; gradient: 0-8.0 min A / B = 90 / 10.

[0389] Intermediate k1

[0390] (S,E)–(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0391] 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

[0392] 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 (Intermediate k0, 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 EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to yield the crude product. The crude product was purified by FCC (SiO2, EA / PE = 0-15%) to afford (S,E)-3-methyl-1-tert-butyl-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate as a colorless oil (1.98 g, 37% yield). LCMS (m / z): 232.1 (M-56+H). 1H NMR (400 MHz, Chloroform-d) δ 6.55 (d, J = 84.7, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.10–3.82 (m, 1H), 3.69 (s, 3H), 3.00–2.85 (m, 1H), 2.76 (d, J = 13.1 Hz, 1H), 2.71–2.60 (m, 1H), 2.31–2.08 (m, 1H), 1.46 (s, 9H), 1.29 (s, 3H); and the product, (S,Z)-3-methyl-1-tert-butyl-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate, was obtained as a colorless oil (600 mg, 11% yield). LCMS (m / z): 232.1 (M-56+H). 1 H NMR(400MHz,Chloroform-d)δ6.43(d,J=83.7,1H),3.86–3.75(m,1H),3.71(s,3H),3. 62–3.47(m,1H),3.42–3.29(m,2H),2.24–2.06(m,2H),1.46(s,9H),1.43–1.39(m,3H).

[0393] Step B: (S,E)-4-(Fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0394] 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).

[0395] Step C: Methyl (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate

[0396] 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).

[0397] Step D: (S,E)-(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0398] 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).

[0399] Intermediate K2

[0400] ((3S,4S)-4-(Difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0401] Step A: (S)-1-(tert-butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate

[0402] Dissolve (R)-3-methyl-1-(tert-butyl)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (3.00 g, 11.06 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (3.20 g, 16.59 mmol) in 30 mL of anhydrous DMF and replace the atmosphere with nitrogen three times. Cool the resulting mixture in a dry ice-ethanol bath. Add potassium tert-butoxide-tetrahydrofuran solution (19.90 mL, 1 M, 19.90 mmol) dropwise to the reaction system. Maintain the temperature and stir for 1 hour. Add saturated aqueous ammonium chloride (30 mL) dropwise to the reaction system, then warm to -40°C. Add hydrochloric acid (6 M, 20 mL) dropwise to the reaction system. After the addition is complete, slowly warm the reaction solution to 70°C and stir for two days. After LCMS monitoring, slowly add saturated aqueous potassium carbonate to the reaction solution to adjust the pH to 9. The mixture was extracted three times with a mixture of dichloromethane and methanol (volume ratio = 10 / 1). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was dissolved in 20 mL of dichloromethane, and di-tert-butyl dicarbonate (5 mL) and triethylamine (5 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness and the crude product was purified by FCC (SiO2, EA / PE = 0-7%) to obtain (S)-1-(tert-butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (1.0 g, 30% yield) as a colorless solid. LCMS (m / z): 250.1 (M-56+H).

[0403] Step B: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester

[0404] At room temperature, (S)-1-(tert-butyl)-3-methyl-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (250 mg, 0.82 mmol) was dissolved in methanol (20 mL) and the atmosphere was replaced with nitrogen three times. Palladium on carbon (87 mg, 0.08 mmol) was added and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature overnight under a 15 psi hydrogen atmosphere. 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 obtain the product, (3S,4S)-1-(tert-butyl)-3-methyl-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (200 mg, 79% yield), as a colorless oil. LCMS (m / z): 252.1 (M+H).

[0405] Step C: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

[0406] At room temperature, 4M HCl-dioxane (5 mL) was added to (3S,4S)-1-(tert-butyl)-3-methyl-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (190 mg, 0.62 mmol). The resulting mixture was stirred at room temperature for 30 min and concentrated to remove the acid solution, affording (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (150 mg, 100% yield) as a white solid. LCMS (m / z): 208.1 (M+H).

[0407] Step D: Methyl (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate

[0408] Methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (12.55 g, 51.50 mmol) was dissolved in methanol (130 mL) at room temperature, and aqueous formaldehyde (12.54 g, 154.51 mmol, 37%) was added. The resulting mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (3.88 g, 61.80 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the system was concentrated to dryness, and the crude product was dissolved in EA and filtered through Celite. The filtrate was purified by FCC (SiO2, MeOH / DCM = 0-4%, 0.3% DIEA in DCM), concentrated to dryness, and distilled twice with anhydrous THF to afford (3S,4S)-methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (10.30 g, 90% yield) as a colorless oil. LCMS (m / z): 222.1 (M+H).

[0409] Step E: ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0410] Under ice-cooling conditions, 1 M LiAlH₄-THF (61 mL, 60.52 mmol) was added dropwise to a solution of (3S,4S)-methyl 4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (10.30 g, 46.55 mmol) in anhydrous THF (100 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 10 g of anhydrous sodium sulfate was added. The mixture was filtered through celite, and the filter cake was washed three times with anhydrous THF. The filtrate was collected and concentrated to dryness to afford (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (7.30 g, 81% yield) as a colorless crystalline solid. LCMS (m / z): 194.1 (M+H).

[0411] Intermediate k1-D3

[0412] (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0413] Step A: Methyl (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0414] Potassium carbonate (5.55 g, 40.2 mmol) was added to a mixture of (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.00 g, 13.4 mmol), deuterated iodomethane (2.33 g, 16.1 mmol), and ACN (100 mL) at room temperature. After complete addition, the mixture was heated to 90°C and stirred overnight. After completion of the reaction, the mixture was filtered and the filter cake was rinsed with EA (50 mL). The filtrate was concentrated and further purified by FCC (SiO2, EA / PE = 0-20%) to afford (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylic acid methyl ester (1.9 g, 69% yield) as a colorless liquid. LC-MS (m / z): 205.1 (M+H).

[0415] Step B: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0416] Under ice-cooling, LiAlH₄ (1M-THF, 9.3 mmol, 9.3 mL) was added dropwise to a mixture of (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d₃)piperidine-3-carboxylic acid methyl ester (1.9 g, 9.3 mmol) and THF (50 mL). After complete addition, the mixture was stirred in an ice-cooling bath at 0°C for 0.5 h. After completion of the reaction, as monitored by LCMS, the reaction was quenched with Na₂SO₄·10H₂O until gas evolution ceased. The reaction solution was filtered through celite, and the filtrate was concentrated at low temperature (35°C) to afford 4-fluoromethylene-3-methyl-1-methyl-d₃-piperidine-3-methanol (1.3 g, 79% yield) as a colorless liquid. LC-MS (m / z): 177.1 (M+H).

[0417] Intermediate k1-D5

[0418] (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol

[0419] Step A: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol

[0420] LiAlD4 powder (271.28 mg, 6.46 mmol) was added to a solution of (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-carboxylic acid methyl ester (1.10 g, 5.39 mmol) in anhydrous tetrahydrofuran (15 mL) under ice-cooling conditions. The resulting mixture was stirred at room temperature for 15 min. After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles formed, as monitored by LCMS. Approximately 5 g of anhydrous sodium sulfate was then added to the reaction solution to remove water. The reaction solution was filtered through celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to obtain (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methylene-d2-ol (951 mg, 99% yield) as a colorless oil. This product was used directly in the next reaction without further purification. LCMS (m / z): 179.1 (M+H).

[0421] The following intermediates were prepared according to the above synthesis scheme:

[0422] ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methanol

[0423] ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0424] Intermediate k1-E

[0425] (S,E)-(1-Ethyl-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol

[0426] Step A: (S,E)-1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester

[0427] Potassium carbonate (370.73 mg, 2.68 mmol) and iodoethane (278.92 mg, 1.79 mmol) were added sequentially to a solution of (S,E)-methyl 4-(fluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (200 mg, 0.894 mmol) in acetonitrile (6 mL) at room temperature. The resulting mixture was heated to 90°C and stirred overnight. After completion of the reaction, monitored by LCMS, the reaction mixture was filtered through celite, and the filter cake was washed twice with acetonitrile. The filtrate was collected and concentrated to dryness to obtain the crude product. The crude product was purified by FCC (SiO2, EA / PE = 0-90%) to afford (S,E)-methyl 1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (100 mg, 69% yield) as a colorless oil. LCMS (m / z): 216.1 (M+H).

[0428] Step B: (S,E)-(1-ethyl-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol

[0429] Under ice-cooling conditions, a 1M solution of LiAlH₄-THF (0.7 mL, 0.7 mmol) was added dropwise to a solution of (S,E)-1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester (100 mg, 0.46 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion of the reaction, sodium sulfate decahydrate was added to quench the reaction until no bubbles formed, as monitored by LCMS. The mixture was then dried over approximately 5 g of anhydrous sodium sulfate. The reaction 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 (S,E)-(1-ethyl-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol (80 mg, 92% yield) as a colorless oil. LCMS (m / z): 188.1 (M+H).

[0430] Intermediate k2-E

[0431] ((3S,4S)-4-(Difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methanol

[0432] Step A: Methyl (3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidine-3-carboxylate

[0433] Methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (150 mg, 0.62 mmol) was dissolved in methanol (5 mL) at room temperature. Aqueous acetaldehyde (184 mg, 1.85 mmol, 40%) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (46 mg, 0.74 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the system was concentrated to dryness and stripped twice with anhydrous tetrahydrofuran to afford methyl (3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidine-3-carboxylate (140 mg, 97% yield) as a colorless oil. LCMS (m / z): 236.1 (M+H).

[0434] Step B: ((3S,4S)-(4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methanol

[0435] Under ice-cooling conditions, 1 M LiAlH₄-THF (0.9 mL, 0.89 mmol) was added dropwise to a solution of (3S,4S)-methyl 4-(difluoromethyl)-1-ethyl-3-methylpiperidine-3-carboxylate (140 mg, 0.60 mmol) in anhydrous THF (5 mL). The resulting mixture was stirred at room temperature for 15 min. After completion of the reaction, monitored by LCMS, sodium sulfate decahydrate was added to quench the reaction until no bubbles formed. Approximately 5 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 the product ((3S,4S)-(4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methanol) as a colorless oil (120 mg, 97% yield). LCMS (m / z): 208.1 (M+H).

[0436] Example 1

[0437] 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carboxynaphtho[1,8-ab]heptalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0438] Step A: tert-Butyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylthio))-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-naphtho[1,8-ab]heptalene-14-carboxylate

[0439] Compound (8aS,9S,12R)-5-chloro-4-fluoro-2-(methylthio)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbaquinone[1,8-ab]heptalene-14-carboxylic acid tert-butyl ester (470 mg, 1.0 mmol), compound (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (654 mg, 1.21 mmol), PdCl2(dtbpf) (65 mg, 0.1 mmol) and K3PO4 (640 mg, 3.01 mmol) were dissolved in 10 mL of dioxane and 2 mL of water and stirred at 100°C for 2 h under nitrogen protection. The solvent was concentrated, and the resulting crude product was purified by FCC (SiO2, EA / PE = 0-40%) to afford tert-butyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptalene-14-carboxylate (630 mg, 67% yield). LCMS (m / z): 930.2 (M+H).

[0440] Step B: (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylsulfinyl))-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-naphtho[1,8-ab]heptalene-14-carboxylic acid tert-butyl ester

[0441] At room temperature, tert-butyl (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-carbaphtho[1,8-ab]heptalene-14-carboxylate (600 mg, 0.645 mmol) was dissolved in DCM (5 mL). m-CPBA (131 mg, 0.645 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous NaHSO₃ (15 mL) was added, and the mixture was extracted with DCM (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous NaSO, filtered, and concentrated to yield crude product: (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptalene-14-carboxylic acid tert-butyl ester (600 mg, 97% yield). LCMS (m / z): 946.3 (M+H).

[0442] Step C: tert-Butyl (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-naphtho[1,8-ab]heptalene-14-carboxylate

[0443] Compound (5aS,6R,9S)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-12-(methylsulfinyl))-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-carbazo[1,8-ab]heptalene-14-carboxylic acid tert-butyl ester (350 mg, 0.37 mmol) and compound ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (143 mg, 0.74 mmol) were dissolved in anhydrous THF (5 mL). Under nitrogen protection, LiHMDS (0.74 mL, 0.74 mmol, 1 M The resulting mixture was stirred at room temperature for 1 h. Saturated aqueous NH4Cl solution (5 mL) was added to quench the reaction. The mixture was extracted with EA (10 mL × 3), washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give the crude product (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (330 mg, yield 83%). LCMS (m / z): 538.3 (M / 2+H)

[0444] Step D: (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-naphtho[1,8-ab]heptalene

[0445] A solution of tert-butyl (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-carbazyl[1,8-ab]heptalene-14-carboxylate (330 mg, 0.31 mmol) in hydrochloric acid-dioxane (5 mL, 4 M) was stirred at room temperature for 30 min. After the system was concentrated, saturated aqueous NaHCO₃ solution (20 mL) was added and extracted with EA (15 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered and concentrated to give the crude product (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptalene, which was used directly in the next reaction.

[0446] Step E: 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-methylnaphtho[1,8-ab]heptalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0447] Compound (5aS,6R,9S)-12-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-1-fluoro-2-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-carbazo[1,8-ab]heptalene (crude product from Step D) was dissolved in DMF (2 mL) at room temperature, and CsF (233 mg, 1.53 mmol) was added. The mixture was heated to 50° C. and stirred for 1 h. Insoluble material was removed by filtration, and the filtrate was purified by Prep-HPLC to afford 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbazo[1,8-ab]heptalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (85 mg, 42% yield over two steps). LCMS (m / z): 663.3 (M+H). 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.00–7.92(m,1H),7.50–7.41(m,1H),7.37(dd,J=2.6, 1.5Hz,1H),7.14(dd,J=38.2,2.5Hz,1H),6.30(t,J=55.5Hz,1H),4.90–4.77(m,1H),4.59–4.4 7(m,1H),4.45–4.29(m,3H),4.17–4.03(m,1H),4.03–3.97(m,1H),3.63–3.49(m,2H),3.15–3. 04(m,1H),2.88–2.79(m,2H),2.55–2.53(m,1H),2.11(s,3H),1.89–1.52(m,9H),1.11(s,3H).

[0448] Example 2 and Example 2a

[0449] 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carboxynaphtho[1,8-ab]heptalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol and 4 -((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carboxynaphtho[1,8-ab]heptalen-5-yl)-6-fluoro-5-vinylnaphthalen-2-ol

[0450] Step A: 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbazo[1,8-ab]heptalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol and 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carboxynaphtho[1,8-ab]heptalen-5-yl)-6-fluoro-5-vinylnaphthalen-2-ol

[0451] Under nitrogen at room temperature, 4-((8aS,9R,12S)-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-4-fluoro-8a,9,10,12,13-hexahydro-8H-7-oxa-1,3,6,13a,14-pentaaza-9,12-carbazo[1,8-ab]heptalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (60 mg, 0.091 mmol) was dissolved in methanol (5 mL). Pd / C (10 mg) was added, and the system was purged with hydrogen and stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated and purified by Prep-HPLC to afford Example 2 (12 mg, 20% yield). LCMS (m / z): 667.2 (M+H). 1H NMR(400MHz, DMSO-d6)δ9.94(s,1H),7.75(dd,J=9.0,5.9Hz,1H),7.39–7.28(m,2H),7.00(dd,J=43.4,2.6Hz,1 H),6.30(t,J=66.4Hz,1H),4.83(d,J=12.9Hz,1H),4.58–4.49(m,1H),4.49–4.35(m,3H),4.06–3.98(m,1H),3. 63–3.58(m,1H),3.54–3.50(m,1H),3.48–3.41(m,2H),3.15–3.06(m,1H),2.88–2.78(m,2H),2.45–2.38(m,1H) ,2.37–2.27(m,1H),2.12(s,3H),1.89–1.51(m,9H),1.11(s,3H),0.85(t,J=7.3Hz,1H),0.75(t,J=7.3Hz,1H).

[0452] and Example 2a (12 mg, yield 20%). LCMS (m / z): 665.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.43–7.34 (m, 1H), 7.35–7. 30(m,1H),7.11(dd,J=46.3,2.5Hz,1H),6.29(t,J=62.6Hz,1H),6.13–5.92(m,1H),5.09–4.79 (m,3H),4.57–4.47(m,1H),4.48–4.34(m,3H),4.07–3.97(m,1H),3.63–3.57(m,1H),3.54–3. 49(m,1H),3.13–3.05(m,1H),2.89–2.73(m,3H),2.12(s,3H),1.87–1.53(m,9H),1.10(s,3H).

[0453] Following the general synthetic scheme described above or appropriate variations thereof, the following examples were synthesized and characterized:

[0454] Example 79

[0455] Step A: Compound 79-2

[0456] Under an ice-water bath, 60% NaH (116 mg, 2.90 mmol) was added to a solution of tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (73-1, CAS: 2820537-22-0, 247 mg, 0.964 mmol) in anhydrous THF (10 mL). The mixture was then stirred at room temperature for 30 min. Finally, intermediate I-12a (270 mg, 0.964 mmol) was added to the reaction mixture, which was stirred at room temperature overnight. The reaction was monitored by LCMS and quenched with 1 mL of saturated ammonium chloride solution. The reaction mixture was concentrated to dryness, and the crude product was purified by FCC (SiO2, THF / PE = 0-100%) to afford 79-2 as a brown solid (420 mg, 87% yield). LCMS (m / z): 500.3 (M+H).

[0457] Step B: Compound 79-3

[0458] At room temperature, BOP (557 mg, 1.26 mmol) was added to a solution of compound 79-P2 (420 mg, 0.840 mmol), DIPEA (0.543 mg, 4.20 mmol), and anhydrous DMF (10 mL). The mixture was heated at 60°C overnight. Upon completion of the reaction, the mixture was poured into 5% aqueous LiCl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated NaCl, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO2, THF / PE = 0-100%) to afford 79-3 as a white solid (175 mg, 43% yield). LCMS (m / z): 482.1 (M+H).

[0459] Step C: Compound 79-5

[0460] At room temperature, compound 79-3 (175 mg, 0.363 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-4-(trifluoromethyl)aniline (79-4, CAS: 2803281-62-9, 175 mg, 0.545 mmol), Pd(dtbpf)Cl2 (23.4 mg, 0.036 mmol), and K3PO4 (231 mg, 1.09 mmol) were added to a mixed solution of 1,4-dioxane and water (5 mL, V / V = 4:1) in sequence. After N2 replacement three times, the temperature was raised to 85 ° C and stirred for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by FCC (SiO2, THF / PE = 0-100%) to give a white solid product 79-5 (170 mg, 73% yield). LCMS (m / z): 641.4 (M+H).

[0461] Step D: Compound 79-6

[0462] To a solution of compound 79-5 (170 mg, 0.265 mmol) in toluene and water (1:1, 10 mL) at room temperature was added magnesium monoperoxyphthalate hexahydrate (MMPP, CAS: 84665-66-7, 463 mg, 85% purity, 0.796 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LCMS, 10 mL of water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford crude product 79-6 (180 mg) as a white solid. LCMS (m / z): 673.2 (M+H).

[0463] Step E: Compound 79-7

[0464] Under a dry ice-ethanol bath (-70°C), tBuOK (1.34 mL, 1M in THF, 1.34 mmol) was added dropwise to a mixture of compound 79-6 (180 mg, 0.267 mmol), intermediate k1 (69.5 mg, 0.401 mmol), and anhydrous THF (5 mL). The mixture was then allowed to warm to room temperature and stirred for 1 h. LCMS monitored the reaction completion. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with EA (30 mL x 3). The organic phase was collected, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to afford the crude product 79-7 (140 mg) as a white solid. LCMS (m / z): 766.3 (M+H).

[0465] Step F: Example 79

[0466] At room temperature, 4M HCl-ethyl acetate (20 mL, 80 mmol) was added to compound 79-7 (140 mg, crude product) and stirred at room temperature for 1 hour. After completion of the reaction, the acid solution was concentrated to obtain the crude product, which was then purified by pre-HPLC (C18, CA1N / (0.1% FA / H2O) = 35-65%) and lyophilized to afford a white solid (3.1 mg). LCMS (m / z): 666.3 (M+H). 1 H NMR(400MHz,DMSO-d6)δ8.34(s,HCOOH),6.89–6.78(m,1H),6.64–6.24(m,2H),5.15 –4.99(m,1H),4.67–4.47(m,2H),4.35–4.20(m,1H),4.02–3.90(m,1H),3.61–3.53(m ,1H),3.07–2.99(m,1H),2.74–2.65(m,2H),2.57–2.53(m,1H),2.28–2.17(m,1H),2. 15(s,3H),1.96–1.74(m,2H),1.72–1.48(m,3H),1.43(d,J=6.3Hz,3H),1.10(s,3H). 19 F NMR(376MHz, DMSO-d6)δ-53.35,-138.70,-146.59.

[0467] Example 80

[0468] Step A: Compound 80-1

[0469] To a solution of compound 79-3 (277 mg, 0.575 mmol) in toluene and water (1:1, 5 mL) at room temperature was added magnesium monoperoxyphthalate hexahydrate (MMPP, 1.67 mg, 85% purity, 2.87 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by LCMS, 10 mL of water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the crude product, compound 80-1 (270 mg), as a white solid. LCMS (m / z): 514.1 (M+H).

[0470] Step B: Compound 80-2

[0471] Under a dry ice-ethanol bath (-70°C), tBuOK (1.05 mL, 1 M in THF, 1.05 mmol) was added dropwise to a mixture of compound 80-1 (135 mg), intermediate k1-E (98.4 mg, 0.525 mmol), and anhydrous THF (5 mL). The mixture was then allowed to warm to room temperature and stirred for 2 h. Following completion of the reaction, LCMS was used to quench the reaction with saturated NH4Cl (20 mL) and extract with EA (30 mL x 3). The organic phases were collected, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to afford the crude product, compound 80-2 (163 mg), as a white solid. LCMS (m / z): 621.3 (M+H).

[0472] Step C: Compound 80-3

[0473] At room temperature, compound 80-2 (163 mg), compound 79-4 (175 mg, 0.545 mmol), Pd(dtbpf)Cl2 (23.4 mg, 0.036 mmol), and K3PO4 (231 mg, 1.09 mmol) were added sequentially to a mixture of 1,4-dioxane and water (5 mL, 4:1). After nitrogen displacement three times, the temperature was raised to 85°C and stirred for 4 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by FCC (SiO2, THF / PE = 0-100%) to afford compound 80-3 (70 mg) as a white solid. LCMS (m / z): 780.3 (M+H).

[0474] Step D: Example 80

[0475] At room temperature, 4M HCl-ethyl acetate (20 mL, 80 mmol) was added to compound 80-3 (70 mg) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The acid solution was concentrated to obtain the crude product, which was then purified by pre-HPLC (C18, CA1N / (0.1% FA / H2O) = 15-40%) and lyophilized to afford a white solid (4.2 mg). LCMS (m / z): 680.2 (M+H). 1HNMR(400MHz,DMSO-d6)δ8.14(s,0.4H),6.91–6.23(m,5H),5.23(dd,J=14.3,2.8H z,1H),4.78–4.66(m,1H),4.66–4.54(m,1H),4.37–4.26(m,1H),4.26–4.17(m,1H) ,4.17–4.09(m,1H),4.04–3.92(m,1H),2.92–2.73(m,2H),2.64–2.52(m,4H),2.43 –2.16(m,2H),2.09–1.72(m,5H),1.46(d,J=6.3Hz,3H),1.12(s,3H),1.00(s,3H).

[0476] Example 81

[0477] The synthesis of Example 81 was carried out by referring to Example 80, except that Intermediate k1-D3 was used instead of Intermediate k1 in Step B. LCMS (m / z): 669.3 (M+H).

[0478] Example 82

[0479] The synthesis of Example 82 was carried out by referring to Example 80, except that Intermediate k1-D5 was used instead of Intermediate k1 in Step B. LCMS (m / z): 671.3 (M+H).

[0480] Example 83

[0481] The synthesis of Example 83 was carried out by referring to Example 80, except that Intermediate k2-D3 was used instead of Intermediate k1 in Step B. LCMS (m / z): 689.3 (M+H). 1 H NMR(400MHz, DMSO-d6)δ8.14(s,1H),6.86(d,J=2.2Hz,1H),6.58–6.10(m,1H),5.19(d,J=11.1Hz,1H),4.74–4.58(m,1H),4.51–4.37(m,2H),4.19 –4.08(m,1H),3.99–3.88(m,1H),3.86–3.76(m,1H),2.93–2.80(m,2H),2 .57–2.51(m,2H),2.02–1.59(m,7H),1.46(d,J=6.2Hz,3H),1.12(s,3H).

[0482] Example 84

[0483] The synthesis of Example 84 was carried out by referring to Example 80, except that Intermediate k2 was used instead of Intermediate k1 in Step B. LCMS (m / z): 686.3 (M+H).

[0484] Example 85

[0485] The synthesis of Example 85 was carried out by referring to Example 80, except that Intermediate k2-E was used instead of Intermediate k1 in Step B. LCMS (m / z): 700.3 (M+H).

[0486] Example 86

[0487] The synthesis of Example 86 was carried out by referring to Example 80, except that Intermediate k2-D5 was used instead of Intermediate k1 in Step B. LCMS (m / z): 691.3 (M+H).

[0488] The following compounds were prepared by referring to the above-mentioned synthetic scheme or appropriate variations:

[0489] Active Examples

[0490] Example 1: Inhibitory effect of the compounds of the present invention on the proliferation of AGS cells with KRAS G12D mutation

[0491] This experiment evaluated and verified the proliferation inhibitory activity of representative compounds of the present invention on KRAS G12D mutant AGS cells.

[0492] AGS cells (Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60476, adherent) were cultured in F12K Nutrient Mixture + 10% FBS (GIBCO, Cat. #10091-148) at 37°C, 5% CO2, and 95% humidity at 1500 cells / well. Cells in the logarithmic growth phase were harvested and counted and viability was determined using a Countstar automated cell counter based on the classic trypan blue staining method to ensure that cell viability was above 90%. The cell concentration was adjusted; 80 μL of the cell suspension was added to each 96-well clear flat-bottom black-walled plate (Greiner, Cat. #655090), and the cells in the 96-well plate were cultured at 37°C, 5% CO2.

[0493] IC 50Assay drug preparation: Prepare a 5x drug solution in culture medium and add 20 μL of the drug solution to each well of a 96-well plate seeded with cells, achieving a working concentration of up to 10 μM. Perform a 3x dilution across nine concentrations, with two replicates per well. Incubate the cells in the drug-treated 96-well plate at 37°C, 5% CO2 for 3 days before performing the CTG assay.

[0494] Equilibrate the cell plate to room temperature for 30 minutes and thaw the CTG reagent ( Luminescent Cell Viability Assay (Promega, Cat# G7573) was used. 50 μl of CTG solution was added to each well and shaken on an orbital shaker for 2 minutes to lyse the cells. The cell plate was placed at room temperature for 10 minutes to stabilize the luminescence signal and the luminescence value was read ( Multi-function microplate reader, PerkinElmer #2105).

[0495] Data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was used to fit the data to obtain a dose-effect curve, from which the IC50 value was calculated.

[0496] Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%.

[0497] Representative compounds of the present invention show satisfactory anti-proliferative activity against AGS human gastric adenocarcinoma cells with KRAS G12D mutation, with IC50 ranging from 0.0001 to 1 μM, preferably 0.0001 to 0.5 μM, and most preferably 0.1 to 100 nM.

[0498] Example 2: Pharmacokinetic properties of the compounds of the present invention in mice

[0499] The pharmacokinetic characteristics of some compounds of the present invention were evaluated by mouse pharmacokinetic experiments.

[0500] [Experimental Materials] Male CD-1 mice, aged 6-8 weeks, were purchased from Zhejiang Weitonglihua Experimental Animal Co., Ltd.

[0501] [Experimental Procedures] For the IV administration group, the compound was formulated into 20% Captisol (sulfobutyl β-cyclodextrin) in sodium acetate buffer (10 mM sodium acetate solution, pH adjusted to 4.0 with acetic acid) to a final concentration of 0.6 mg / mL for each compound. The drug preparation was injected into CD-1 mice via the tail vein at an injection volume of 5 mL / kg. Blood was collected from the submandibular vein or other appropriate means at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were centrifuged at low temperature for 6 minutes, and the plasma was collected and stored at -80°C for testing. For the PO administration group, the compound was formulated in a solvent of 0.5% Tween 80 and 99.5% (0.5% MC (400 cp)) to a final concentration of 1 mg / mL for each compound. The drug preparation was orally administered to CD-1 mice at a dosing volume of 10 mL / kg. Blood was collected from the submandibular vein or other appropriate means 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were centrifuged at low temperature for 6 minutes, and the plasma was collected and stored at -80°C for testing.

[0502] [Sample Analysis] Take 10 μL of plasma sample, add 200 μL of methanol containing internal standard as a precipitant to precipitate plasma proteins, extract the test compound in the plasma, centrifuge at low temperature, take 10 μL of the supernatant for injection, and use LC-MS / MS to analyze the drug blood concentration.

[0503] [Data processing] The pharmacokinetic parameters were calculated using Winnonlin using the blood drug concentration data at different time points.

[0504] [Experimental results] The experimental results showed that the compound of the present invention exhibited good pharmacokinetic properties in the mouse pharmacokinetic evaluation.

[0505] Example 3: Cytochrome P450 inhibition test of the compounds of the present invention

[0506] This experiment evaluates the inhibitory effect of the inventive compounds on cytochrome P450.

[0507] [Experimental Materials] Human liver microsomes (Corning, Catalog No. 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE, Catalog No. HY-F0003 / CS-4998); phenacetin, diclofenac, α-naphthoflavone, omeprazole, and ketoconazole were purchased from TCI; S-mephenytoin and testosterone were purchased from CAYMAN; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from Damas-beta; sulfaphenazole was purchased from MCE; and bufuralol was purchased from TRC.

[0508]

Experimental steps

[0509] Prepare 0.1 M potassium phosphate buffer (K-buffer): Prepare 100 mM potassium phosphate buffer (K-buffer) with potassium dihydrogen phosphate and dipotassium hydrogen phosphate, and adjust the pH to 7.4.

[0510] Prepare 400× the test compound and reference inhibitor: Dissolve 8 μL of 10 mM test compound stock solution in 12 μL of acetonitrile. Prepare a mixed solution of CYP1A2, CYP2C9, and CYP2D6 inhibitors: Combine 12 μL of 1 mM α-naphthoflavone, 10 μL of 40 mM sulfaphenazole, 10 μL of 10 mM quinidine, and 8 μL of DMSO. Prepare a solution of CYP3A4 and CYP2C19 inhibitors: Dissolve 8 μL of DMSO in 12 μL of acetonitrile.

[0511] Prepare 4× NADPH potassium phosphate solution: Add 66.7 mg NADPH to 10 mL 0.1 M K-buffer, pH 7.4. Prepare 4× substrate potassium phosphate solution: Add different substrates to the required concentration in 10 mL 0.1 M K-buffer to make a solution 4 times the required concentration for the assay.

[0512] Prepare 0.2 mg / mL human liver microsome (HLM) solution: add 10 μL of 20 mg / mL human liver microsome to 990 μL K-buffer and store on ice until use.

[0513] Add 600 μL of 0.2 mg / mL HLM to a 96-well plate, followed by 3 μL of a 400-fold dilution of the test compound solution. Add 200 μL of 0.2 mg / mL HLM to a 96-well plate, followed by 1 μL of the diluted positive control inhibitor solution. Aliquot 30 μL of the compound-human liver microsome mixture into a 96-well plate, then add 15 μL of the substrate solution. Preheat the above solution and the prepared NADPH solution at 37°C for 5 minutes. Add 15 μL of the preheated NADPH solution to the reaction plate, mix well, and initiate the reaction. Incubate the reaction plate at 37°C. Incubate 3A4 for 5 minutes; 1A2, 2C9, and 2D6 for 10 minutes; and 2C19 for 45 minutes. At the end of the reaction, terminate the reaction by adding 120 μL of acetonitrile containing an internal standard. Vortex the sample for 10 minutes, centrifuge at 5594 g for 15 minutes, and prepare the sample for LC-MS / MS analysis.

[0514]

Experimental results

[0515] The experimental results show that at the tested concentrations, the compounds of the present invention have no significant inhibitory effect on key CYP subtypes of drug metabolism, demonstrating better drug-drug interaction safety.

[0516] Having fully described the invention, those skilled in the art will understand that the invention can be practiced over a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.

[0517] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

[0518] All patents and publications cited herein are incorporated by reference in their entirety.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, in: X is selected from -CH2-, -CH2CH2- and -CH2OCH2-; Y is selected from O, S and NR d ; Z is selected from O, S and Se; M is selected from N or C-R4; B is selected from G1 is selected from CH, S and NH, G2 is selected from C-R5 and N, G3 is selected from C-R6 and N; and G4 is selected from C-R9 and N; W is selected from H, OH, NH2, halogen, CN and -C 1-6 alkyl; U is selected from OH or NH2; R1 is selected from H, D, halogen, -CN, -OH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) 0-3 -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 with halogen, CN or -OC 1-6 Alkyl substitution, Or two R1s connected to the same carbon atom form =C(R e )2, or two R1 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 e 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 is optional halogen and optionally halogen-substituted -C 1-6 Alkyl substitution, Or two R1 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 Cycloalkyl, or two R1s attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group; R2 is selected from H, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, where C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 The cycloalkyl radicals are each independently optionally substituted with halogen or CN; R3 is selected from halogen, CN, -OH, -OC 1-6 Alkyl and -C 1-6 Alkyl groups, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; R4 is selected from H, halogen, CN and -C optionally substituted by halogen or CN 1-6 alkyl; R5 is selected from H, halogen, CN and NH2; R6 is selected from H, halogen, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, 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; R7 and R8 are each independently selected from H, halogen, -NO2, CN, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Alkynyl, 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; R9 is selected from halogen, CN and -C optionally substituted by halogen or CN 1-6 alkyl; R 10 , R 11 and R 12 are each independently selected from H, halogen, CN, -C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, where -C 1-6 Alkyl and -C 3-6 The cycloalkyl radicals are each independently optionally substituted with halogen or CN; R 13 Selected from H, -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, where -C 1-6 Alkyl and -C 3-6 The cycloalkyl groups are each independently optionally substituted with halogen, CN or -OC 1-6 Alkyl substitution; Or when R1 and R 13 When attached to adjacent ring carbon atoms, together with the carbon atoms to which they are attached, they form a C 3-4 Cycloalkyl; R 14 Selected from H, D, -C 1-6 Alkyl and -(CH2) 0-3 -C 3-6 Cycloalkyl, where C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with halogen or -OC 1-6 Alkyl substituted, or two R 14 Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl; R a is selected from H and -C optionally substituted by halogen 1-6 alkyl; R b is selected from H and -C optionally substituted by halogen 1-6 Alkyl, or two R attached to the same ring carbon atom b Together they form C 3-6 Spirocyclic rings, or two R b , or R b and R c , or R b and R d Together with the ring atoms to which they are attached, they form a fused 3-6 membered carbocyclic or heterocyclic ring, wherein the C 3-6 The spiro ring and the 3-6 membered fused carbocyclic or heterocyclic ring are each independently optionally substituted with halogen, CN and -C 1-6 Alkyl substitution; R c and R d are each independently selected from H and -C optionally substituted by halogen or CN 1-6 alkyl; m is an integer from 1 to 8; n, p, q are each independently an integer from 0 to 3; t is an integer from 1 to 3; g is 2; and f is selected from 0 and 1, provided that when f is 1, G1 is CH, G2 is C-R5 and G3 is C-R6.

2. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein B is Wherein R5 is H or halogen, preferably halogen, and R6 is selected from halogen, -C 2-6 Alkynyl and -C 1-6 Alkyl, preferably selected from -C 2-6 Alkynyl and -C 1-6 alkyl.

3. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is Wherein W is selected from H, halogen and -C 1-6 alkyl, R5 is NH2, R6 is CN, R7 is selected from H or halogen, and R8 is selected from H, halogen and -C 1- 6 alkyl.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein M is N, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

5. A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-R4; wherein R4 is halogen, CN or C-R4 substituted by halogen 1-3 alkyl.

6. A compound of formula (I) according to any one of claims 1 to 5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is halogen, preferably F.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

8. A compound of formula (I) according to any one of claims 1 to 7, wherein X is -CH2CH2-, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

9. A compound of formula (I) according to any one of claims 1 to 8, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein n is an integer of 0-2 and t is an integer of 1-2.

10. A compound of formula (I) according to any one of claims 1 to 9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R c For H.

11. A compound of formula (I) according to any one of claims 1 to 10, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R a is H or -C optionally substituted by halogen 1-3 alkyl, p is an integer from 0 to 2, and R b is H or -C optionally substituted by halogen 1-3 Alkyl, q is an integer of 0-2.

12. A compound of formula (I) according to any one of claims 1 to 11, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment for Where R 14 Each is independently H or D; R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; m is selected from 1 or 2; R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl.

13. A compound of formula (I) according to any one of claims 1 to 12, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the structural fragment Selected from 14. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, which has the following sub-formula: in: W is selected from H, halogen and -C 1-6 alkyl; R1 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 R1 attached to the same carbon atom form =C(R e )2, where R e are each independently selected from H, halogen, -C 1-6 Alkyl, or two R1 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; R1 is preferably fluorine, difluoro, fluoromethyl, methyl, dimethyl, difluoromethyl, methoxy, fluoromethylene, difluoromethylene, methylene, spirocyclopropyl, one or two F-substituted spirocyclopropyl; R2 is selected from -C 1-6 Alkyl, -deuterated C 1-6 Alkyl and -C 3-6 Cycloalkyl; R4 is selected from halogen, CN and -C substituted by halogen 1-3 alkyl; R5 is H or halogen, preferably halogen, R6 is selected from halogen, -C 2-6 Alkynyl and -C 1-6 Alkyl, preferably selected from -C 2-6 Alkynyl and -C 1-6 alkyl; R7 is selected from H or halogen, R8 is selected from H, halogen and -C optionally substituted by halogen 1-6 alkyl, R 14 Selected from H and D; R a is H or -C optionally substituted by halogen 1-6 alkyl; R b is selected from H or -C optionally substituted by halogen 1-6 alkyl; R c is selected from H or -C optionally substituted by halogen 1-6 alkyl; m is 1 or 2, and q is an integer of 0-2.

15. A compound selected from the group consisting of the compounds of Examples 1-86, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable excipient.

17. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 16, for use as a medicament for the treatment and / or prevention of a disease mediated by a KRas mutation, preferably a KRas G12D mutation.

18. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for preventing or treating a disease mediated by a KRas mutation, preferably a KRas G12D mutation.

19. The method of claim 18, wherein the disease mediated by a KRas mutation, preferably a KRas G12D mutation, is selected from the group consisting of pancreatic cancer, lung cancer, lung adenocarcinoma, bone 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 tumors (CNS), primary CNS lymphomas, spinal tumors, brain stem gliomas or pituitary adenomas.

20. The use according to claim 19, wherein the disease mediated by KRas mutation, preferably KRas G12D mutation, is 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.

21. A method for treating and / or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins, preferably KRas G12D mutant proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 16.

22. The method of claim 21, wherein the disease mediated by KRas mutation, preferably KRas G12D mutation, is 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.

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