Compounds with antitumor activity against KRAS-mutated tumors

Abstract

The present invention relates to compounds having the structure of formula (I) that can be used as KRAS inhibitors, pharmaceutical compositions containing these compounds, methods for making these compounds, and the use of these compounds in the treatment of cancer. [Formula 1] TIFF2025534419000549.tif47170

Description

[Technical Field]

[0001] This application: Chinese Patent Application No. 202211208795.6 (filed September 30, 2022); Chinese Patent Application No. 202211583282.3 (filed December 9, 2022); Chinese Patent Application No. 2023100802872 (filed January 17, 2023); Chinese Patent Application No. 2023102587885 (filed March 16, 2023); Chinese Patent Application No. 2023107213489 (filed June 16, 2023), and Chinese Patent Application No. 2023112477769 (filed September 26, 2023) Priority is claimed based on

[0002] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a group of compounds having novel structures that can be used as KRAS inhibitors, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and uses of the compounds in the treatment of cancer or tumors. [Background technology]

[0003] Ras (rat sarcoma oncogene homolog) refers to a group of closely related globular monomeric proteins that belong to the GTPase protein family. Specifically, under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals and plays a role in regulating cell proliferation, survival, migration, and differentiation. These regulatory functions of Ras are mediated by a transition between a GDP-bound and a GTP-bound state, commonly known as a "molecular switch" (Alamgeer et al., Current Opin Pharmacol., 2013, 13:394-401). GDP-bound Ras is inactive, dormant, or off, and its signaling pathways are turned off. Upon exposure to specific growth-promoting stimuli, activation, for example, by guanosine nucleotide exchange factors (GEFs), induces the release of GDP and the binding of GTP. As a result, Ras is "on," converting to its active form, which recruits and activates various downstream effectors and transduces signals. This process enables signaling from the cell surface to the cytoplasm, regulating many important cellular processes, including differentiation, survival, and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

[0004] Ras possesses GTPase activity. This activity allows Ras to hydrolyze the terminal phosphate of GTP, converting it to GDP, thereby transitioning it to an inactive state. However, the intrinsic GTPase activity of Ras is very low, and the conversion of GTP-bound Ras to GDP-bound Ras requires the involvement of an exogenous protein called a GTPase-activating protein (GAP). GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, if the Ras gene contains a mutation that affects its interaction with GAP or inhibits the conversion of GTP to GDP, Ras remains persistently activated. This results in the continuous transmission of growth and division signals to cells, stimulating uncontrolled cell proliferation and ultimately leading to tumor formation and progression.

[0005] Among the genes associated with human tumors, there are three ubiquitously expressed Ras genes: H-RAS, K-RAS, and N-RAS. These encode highly homologous proteins of approximately 21 kDa: HRas, NRas, and KRas, 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). Subsequently, large-scale genome sequencing studies of various cancer types revealed that Ras proteins are mutated in more than 30% of cancers, with particularly high mutation rates in pancreatic cancer (more than 90%), colorectal cancer (45%), and lung cancer (35%). Furthermore, transgenic and genetically engineered mouse models demonstrated that mutant Ras proteins promote the development and progression of various cancer types. Furthermore, Ras oncogenes play an important role in tumor maintenance and progression in multiple cancer types. For example, RNA interference has been shown to suppress tumor growth in Ras-mutated cancer cell lines and animal models. These studies have established Ras oncoproteins as widely accepted and highly attractive targets for anticancer drug development in the field of pharmacology.

[0006] Research has shown that KRas mutations are the most common Ras mutation, accounting for approximately 85% of cancers caused by Ras mutations. The majority of Ras mutations occur at codons G12, G13, and Q61, with approximately 80% of KRas mutations occurring at codon 12 glycine, including G12C, G12D, G12V, G12A, G12R, and G12S, as well as the G13D mutation. KRas mutations are frequently observed in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer, and have also been observed in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21(8), 1797-1801, 2015). As a result, KRas mutant proteins have become the most important focus in research on Ras drug targets, and the development of inhibitors targeting KRas is considered a very promising direction in the development of anticancer and antitumor drugs.

[0007] However, over the past few decades, drug discovery research targeting Ras has revealed that the Ras protein has a smooth surface without obvious grooves or pockets for small molecule inhibitor binding and has extremely high (picomolar) affinity for guanine nucleotides, making the development of small molecule inhibitors extremely challenging. As a result, Ras has long been considered an "undruggable" target in this field. At the same time, there remains a strong need for compounds with more diverse structural types and mechanisms of action as KRas inhibitors to expand treatment options, improve inhibitory activity compared to existing KRas inhibitors, and ultimately develop more potent clinical therapeutics.

[0008] The present invention addresses these and other needs. It provides novel, structurally innovative inhibitory compounds that exhibit inhibitory activity against KRas mutant proteins. Compared with existing KRas mutant protein inhibitors in the prior art, the compounds of the present invention have enhanced inhibitory activity against KRas mutant proteins and suppression of associated tumors due to their improved structural patterns. Furthermore, the compounds of the present invention have favorable pharmacokinetic properties and excellent drug properties, including convenient administration, easy bioabsorption, and minimal toxicity and side effects. Furthermore, they have an improved resistance profile, enhanced safety, and a low risk of drug interactions. Summary of the Invention

[0009] The present invention provides compounds having structural formula (I) as defined in this disclosure, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates. [ka] Here, the definitions of each group are as defined in the detailed description of the invention.

[0010] The present invention further provides pharmaceutical compositions comprising a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0011] The present invention further provides a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

[0012] The present invention further provides a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, for use as an inhibitor of Ras mutant proteins, in particular KRas mutant proteins (e.g., G12C mutant, G12D mutant, G12V mutant, G12A mutant, G12R mutant, G12S mutant and G13D mutant proteins), preferably KRas G12D.

[0013] The present invention further provides a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of a disease mediated by a Ras mutant protein, in particular a disease mediated by a KRas mutant protein (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant protein), preferably a KRas G12D mutant protein.

[0014] The present invention further provides the use of the compounds of the present invention, or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases mediated by Ras mutant proteins, in particular diseases mediated by KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S and G13D mutant proteins), preferably KRas G12D mutant proteins.

[0015] The present invention further provides the use of a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease mediated by a Ras mutant protein, in particular a disease mediated by a KRas mutant protein (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant protein), preferably a KRas G12D mutant protein.

[0016] The present invention further provides methods for treating and / or preventing diseases mediated by mutant Ras proteins, particularly KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), preferably KRas G12D mutant proteins, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof, or a pharmaceutical composition comprising the same.

[0017] The present invention further provides a method of treating tumors or cancer, comprising administering to a patient in need thereof a compound of the present invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same.

[0018] The present invention further provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as a research tool compound for inhibiting KRas, particularly KRas G12D.

[0019] The present invention further provides pharmaceutical combinations comprising a compound of the present invention, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, and one or more other pharmaceutically active agents.

[0020] The present invention further provides methods for preparing the compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition Unless otherwise specified, each term used in the specification and claims has the following meaning: If a particular term or expression is not specifically defined, it should be understood in accordance with its ordinary meaning in the field. In the case of conflict, the present specification (including definitions) will control.

[0022] In the event of a discrepancy between the chemical structure and the name of a compound disclosed in this disclosure, the chemical structure shall prevail.

[0023] The terms "Ras mutation" or "Ras mutant protein" as used in the present disclosure refer to a protein encoded and expressed by a Ras gene in which one or more codons have been mutated. Typical examples include, but are not limited to, Ras proteins with mutations at codon 12 glycine, codon 13 glycine, or codon 61 glutamine of Ras, such as mutant HRas, NRas, or KRas. Because these residues are located in the active site of Ras, these mutations impair the intrinsic GTPase activity of Ras or the GAP-catalyzed GTPase activity, resulting in the persistent presence of GTP-bound Ras.

[0024] For purposes of the present invention, the terms "Ras mutation" or "Ras mutant protein" and "Ras" are used interchangeably when describing inhibitory activity and generally refer to mutant HRas, NRas, or KRas. Examples include, but are not limited to, KRas-G12C (mutation of codon G12 from glycine to cysteine), KRas-G12D (mutation of codon G12 from glycine to aspartic acid), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12 from glycine to valine), and KRas-G13D (mutation of codon G13 from glycine to aspartic acid). Specifically, these terms refer to KRas mutant proteins, more specifically KRas-G12C, KRas-G12D, KRas-G12V, G12A, G12R, G12S, and KRas-G13D mutant proteins, most specifically KRas-G12D mutant protein.

[0025] The term "treatment" as used in this disclosure refers to the administration of one or more compounds of the present invention, a pharmaceutically acceptable salt thereof, or a solvent thereof to a subject, such as a mammal, including a human, suffering from or having symptoms of a described disease, to cure, alleviate, relieve the disease, or affect the symptoms thereof. Preferably, the treatment is curative or ameliorative.

[0026] The term "prevention" as used in the present disclosure is well known in the art and refers to the administration of one or more compounds of the present invention, pharmaceutically acceptable salts thereof, or solvents thereof to a subject suspected of developing or predisposed to a Ras mutation-mediated disease, particularly cancer or tumor, as defined in the present disclosure, to reduce the risk of developing the disease or prevent its onset. The term "prevention" includes the use of a compound of the present invention prior to the diagnosis or identification of clinical and / or pathological symptoms.

[0027] As used in this disclosure, the terms "inhibit" and "reduce," or variations of these terms, refer to the ability of a bioactive agent to decrease the signaling activity of a target by interacting directly or indirectly with the target, and refer to a measurable decrease or complete inhibition of target activity. For example, a maximum or minimum decrease in activity (e.g., KRas activity) compared to normal conditions can be 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.

[0028] The term "selective inhibition," as used herein, refers to the ability of a biologically active substance to preferentially reduce signaling activity of a target of interest relative to signaling activity of a non-target by directly or indirectly interacting with the target. The compounds of the present invention have the ability to selectively inhibit the G12 or G13 mutation of KRas, HRas, or NRas proteins, among various types of mutations occurring at one or more codons in the Ras protein. Examples include the G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations of the KRas protein. These are preferred because of their ability to selectively inhibit the G12D mutation of the KRas protein. For example, the present invention has inhibitory activity against a particular Ras mutation of 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. Alternatively, the present invention has at least 1, 2, 3, 4, 5, 10, 25, 50, 100, 250, or 500 times greater activity against a particular Ras mutation (e.g., KRas-G12D) compared to another particular Ras mutation.

[0029] As used in this disclosure, "Ras mutation-mediated disease" refers to a disease in which a Ras mutation drives the onset and development of the disease, or a disease in which inhibiting the Ras mutation reduces the incidence of the disease and alleviates or eliminates the symptoms of the disease. For purposes of the present invention, "Ras mutation-mediated disease" preferably refers to a disease mediated by a KRas mutation, most preferably a disease mediated by KRas-G12D, and even more preferably a cancer or tumor mediated by KRas-G12D.

[0030] As used in this disclosure, the term "cancer" or "tumor" refers to abnormal cell growth and proliferation, whether malignant or benign, and all pre-cancerous, cancerous cells and cancerous tissues. In all aspects of the invention, cancers or tumors referred to include, but are not limited to, lung adenocarcinoma, lung cancer, osteosarcoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma, adrenal carcinoma, 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 cord tumor, brain stem glioma, or pituitary adenoma.

[0031] In all aspects of the present invention, the cancer or tumor referred to is preferably one associated with a Ras mutation, particularly a KRas mutation, preferably a KRas G12D mutation. Such cancer or tumor includes, but is not limited to, the various tumors listed above and their preferred ranges. Particularly preferred tumors include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, leukemia, and ovarian cancer.

[0032] As used in this disclosure, the terms "subject," "individual," or "patient" refer to a vertebrate. In some embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (e.g., cows, etc.), sport animals, pets (e.g., guinea pigs, cats, dogs, rabbits, horses, etc.), primates, mice, rats, etc. In some embodiments, the mammal is a human.

[0033] The term "therapeutically effective amount" as used in the present disclosure refers to an amount or dosage sufficient to elicit a beneficial therapeutic response in a patient suffering from a "Ras mutation-mediated disease," such as cancer or tumor. Those skilled in the art can determine the effective amount or dosage of the active ingredient of the present invention by using conventional methods and taking into account conventional influencing factors.

[0034] The term "pharmaceutical combination," as used herein, refers to a combination of a compound of the present invention with another active ingredient to achieve the objectives of the present invention. The other active ingredient may be one or more additional compounds of the present invention, or a second or additional (e.g., third) compound that does not adversely affect the compound of the present invention or that exhibits complementary activities. For example, such active agents may be compounds known to modulate other biological pathways, different components of biological pathways in which the compounds of the present invention participate, or even overlapping biological targets of the compounds of the present invention. These active agents may be combined in effective amounts appropriate to achieve the intended purpose. The other active agents may be administered together with the compounds of the present invention in a single pharmaceutical composition, or separately as separate units. If administered separately, administration may be simultaneous or sequential. If administered sequentially, the interval between administrations may be short or long.

[0035] The term "pharmaceutically acceptable" as used in this disclosure refers to molecular entities and compositions that do not produce an adverse, allergic, or other undesirable reaction when administered in suitable amounts to an animal, such as a human.

[0036] As used in this disclosure, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the parent compound and is not biologically or otherwise undesirable. Examples include acid addition salts and base addition salts. A "pharmaceutically acceptable acid addition salt" can be formed from an inorganic acid or an organic acid and a compound having a basic group. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc. The organic acid can be selected from aliphatic, aliphatic, aromatic, heterocyclic, carboxylic, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvate, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic 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 bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, as well as salts derived from pharmaceutically acceptable organic non-toxic bases. Examples include, but are not limited to, primary, secondary, and tertiary amines, substituted ammoniums such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-bismethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hybamine, betaine, ethylenediamine, glucosamine, methylglucosamine, triethanolamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0037] The term "isomer" as used in this disclosure refers to any stereoisomer, enantiomeric mixture, such as a racemate, diastereomeric mixture, geometric isomer, atroisomer, and / or tautomer, that may exist in the structure of a compound. Methods for determining the stereochemistry and separating such isomers are well known to those skilled in the art (SP Parker, Ed., McGraw-Hill Dictionary of Chemical Chemistry Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereotics of Organic Compounds", John Wiley & Sons, Inc., New York, 1994).

[0038] Some of the compounds of the present invention contain at least one asymmetric center, thus giving rise to stereoisomers. The present invention includes all possible isomers of the compounds defined in this disclosure, as well as pharmaceutically acceptable salts or solvates thereof, unless otherwise specified.

[0039] In this disclosure, the formulas used in the structural or partial structural formulas of compounds are [ka] represents the absolute configuration of a stereogenic center, i.e., a chiral center. Correspondingly, in naming compounds or intermediates provided herein, R or S is used to represent the absolute configuration of the associated chiral center. [ka] indicates that both configurations about such a chiral center exist as a racemate. For example, [ka] teeth, [ka] and, [ka] It represents a mixture of

[0040] For some compounds of the present invention, axial chirality may be used to define their configuration. The determination of such configuration follows the Cahn-Ingold-Prelog rules, which are well known to those skilled in the art. The absolute configuration of axial chirality in the following two example structures is described as follows: [ka]

[0041] When an axial chiral bond is marked with an "*", it means that the compound has a single chiral configuration and can be obtained by SFC resolution, but the absolute configuration has not been determined. For example, [ka] teeth, [ka] Represents.

[0042] In the definitions, structural formulas, or structural fragments of the compounds of the present disclosure, the number of groups bonded to each atom is determined according to the valence number, and therefore does not need to be clearly indicated one by one. In the group definitions, structural formulas, or structural fragments, only non-hydrogen atom groups are usually shown, and other groups usually represent H. Those skilled in the art can easily determine the presence and number of groups not clearly indicated.

[0043] Of course, where one of ordinary skill in the art would recognize, based on the structure of a compound presented in this disclosure, that a pair of chiral isomers of the compound exists, and these can be readily resolved by methods conventional in the art, disclosure of a racemic form of such compound (whether in the form of a structural formula or a chemical name) should be considered to also individually disclose each isomer of such compound.

[0044] In the structural fragments described in this disclosure, the symbol for breaking a bond [ka] means that the bond fragment is connected to the rest of the molecule at the bond cleaved by this symbol.

[0045] In the cyclic structural fragments described herein, substituents that overlap a chemical bond, e.g. [ka] The substituent -(R 12 ) m is a group in which one or more chemically substitutable sites (including z) of the ring are substituted with one or more substituents R 12 It means that it may be substituted with.

[0046] The compounds of the present invention include both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled forms of the compounds are compounds in which one or more atoms in the molecule have been replaced with the corresponding isotopically enriched atoms. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, e.g., 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 and the like. Such isotopically labeled compounds can be used, for example, as probes in biological assays, analytical tools, or therapeutic agents. In one embodiment, the compounds of the present invention are provided in unlabeled form. In another embodiment, such compounds are provided in isotopically labeled form, for example, labeled with deuterium (D). Specifically, in general formula (I) and its subformulas, R 11 and R14 One or more hydrogen atoms (H) in the group may be replaced with deuterium (D). For example, R 14 may be independently substituted with H or D, and R 11 may be substituted with one or more D, particularly -C substituted with one or more D 1-6 It may be an alkyl group.

[0047] The term "solvate" as used herein refers to a solvent addition form of a compound, which contains a stoichiometric or non-stoichiometric amount of solvent. Examples include solvate forms of the compounds of the present invention, such as solvates with water (e.g., hydrates) or solvates with organic solvents (e.g., methanol, ethanol, or acetonitrile) (referred to as methanolates, ethanolates, or acetonitrileates, respectively). Also included are solvates of any polymorphic forms. Of course, solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds.

[0048] The term "metabolite," as used in this disclosure, refers to a product produced by metabolism of a compound in vivo. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Identification and analysis of metabolites were performed by methods well known to those skilled in the art.

[0049] As used herein, the term "pharmaceutically acceptable vehicle" or "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use, are of sufficient purity, and have low toxicity. Examples include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween), humectants (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, etc.

[0050] The term "halogen" or "halogenated" as used in the present disclosure refers to F, Cl, Br, or I. Additionally, the term "halogen-substituted" as used in the definitions of groups in the present disclosure refers to mono- or poly-halogenated groups, i.e., groups in which one or more hydrogens of the corresponding group are replaced with one or more identical or different halogen groups.

[0051] The term "alkyl," as used in this disclosure, refers to a monovalent saturated hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms. Specifically, an alkyl group has 1 to 10 carbon atoms, 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 "Ci_6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neo-pentyl), n-hexyl, 2-methylpentyl, and the like.

[0052] The term "-O-alkyl" or "alkoxy" as used herein refers to an alkyl group, as defined herein, linked to the rest of the molecule via an oxygen atom. Specifically, the -O-alkyl group has 1 to 10 carbon atoms, 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, the term "-O-Ci_6 alkyl," as used herein, refers to a saturated hydrocarbon group having a straight or branched chain of 1 to 6 carbon atoms linked to the rest of the molecule via an oxygen atom. Examples include -O-methyl, -O-ethyl, -O-propyl (e.g., -O-propyl and -O-isopropyl), -O-butyl (e.g., -O-butyl, -O-isobutyl, -O-sec-butyl, or -O-tert-butyl), -O-pentyl (e.g., -O-pentyl, -O-isoamyl, -O-neo-pentyl), -O-hexyl, 2-methylpentyl-O-, and the like.

[0053] The term "-S-alkyl" as used herein refers to an alkyl group, as defined herein, linked to the rest of the molecule via a sulfur atom. Specifically, the -O-alkyl group has 1 to 10 carbon atoms, 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, the term "-S-Ci_6 alkyl," as used herein, refers to a saturated hydrocarbon group having a straight or branched chain of 1 to 6 carbon atoms linked to the rest of the molecule via a sulfur atom. Examples include -S-methyl, -S-ethyl, -S-propyl (e.g., -Sn-propyl and -S-isopropyl), -S-butyl (e.g., -Sn-butyl, -S-isobutyl, -S-sec-butyl, or -S-tert-butyl), -S-pentyl (e.g., -Sn-pentyl, -S-isoamyl, -S-neo-pentyl), -Sn-hexyl, 2-methylpentyl-S-, and the like.

[0054] As used herein, "optionally halogen-substituted C 1-6 The term "C alkyl optionally substituted with halogens" refers to the above-described C alkyl groups in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally substituted with halogens. As will be understood by those skilled in the art, when two or more halogen substituents are present, these halogens may be the same or different and may be bonded to the same or different C atoms. Examples of halogen-substituted C alkyl groups include -CHF, -CHF, -CF, -CCl, -CF, -CCl, -CHCF, -CHCl, -CHCHCF or -CF(CF).

[0055] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group composed of carbon and hydrogen atoms and containing at least one double bond. It may be straight-chain or branched. Specifically, an alkenyl group has 2 to 8 carbon atoms, e.g., 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-6 alkenyl" refers to an alkenyl group having a straight or branched chain of 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, pentenyl, etc. The carbon atom of the alkenyl group that is connected to the rest of the molecule may be a saturated carbon atom or the carbon atom of the alkenyl bond.

[0056] As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon group composed of carbon and hydrogen atoms and containing at least one double or triple bond. It may be straight-chain or branched. Specifically, an alkynyl has 2 to 8 carbon atoms, e.g., 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-6 alkynyl" refers to an alkenyl group having a straight or branched chain of 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The carbon atom of the alkynyl that is connected to the rest of the molecule may be a saturated carbon atom or the carbon atom of the alkynyl bond.

[0057] As used herein, the term "cycloalkyl" (alkenyl) refers to a non-aromatic, fully saturated, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic hydrocarbon group having the specified number of ring carbon atoms. Such cycloalkyl groups include, for example, groups having 3 to 12 carbon atoms (i.e., C 3-12Cycloalkyl) groups can have, for example, 3 to 10, 3 to 8, 3 to 7, 3 to 6, or 5 to 6 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or polycyclic (e.g., bicyclic) structures such as spiro, fused, or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[3.2.1]octyl. For example, as used herein to define certain compounds, "C 3-6 The term "cycloalkyl" means monocyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0058] The term "heterocycloalkyl," as used herein, refers to a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic non-aromatic saturated ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and a specified number of ring atoms, or an N-oxide, or an S-oxide or S-dioxide thereof. Such heterocycloalkyl groups can have, for example, 3 to 12 ring members (sometimes referred to as 3-12-membered heterocycloalkyls), such as 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. Such heterocycloalkyl groups typically contain up to four (e.g., 1, 2, 3, or 4) heteroatoms. For example, such heterocycloalkyl groups can be 4 to 7-membered heterocycloalkyl groups 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), tetrahydrofuryl (e.g., 1-tetrahydrofuryl, 2-tetrahydrofuryl, and 3-tetrahydrofuryl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl), and the like. Examples of heterocyclic alkyl groups include 1,4-diazacycloheptyl, 3,6-diaza-bicyclo[3.1.1]heptyl, and 3-aza-bicyclo[3.2.1]octyl. The atom in the heterocyclic alkyl group that is bonded to the remainder of the compound can be a carbon atom or a heteroatom, provided that this is chemically feasible.

[0059] Examples of preferred heterocycloalkyl groups include: [ka] Examples include:

[0060] Of course, structures having asymmetric centers include their racemic and / or single enantiomeric forms. [ka] teeth, [ka] Represents.

[0061] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and a specified number of ring atoms, or an N-oxide, S-oxide, or S-dioxide thereof. Specifically, such aromatic ring structures may have 5 to 12 ring members. Such heteroaryl groups may be, for example, 5- or 6-membered monocyclic structures, or fused bicyclic structures formed from two fused 6-membered rings, two fused 5-membered rings, a fused 6-membered ring and a 5-membered ring, or a fused 5-membered ring and a 4-membered ring. Such heteroaryl rings typically contain up to four heteroatoms, more typically up to three heteroatoms. The heteroatoms are independently selected from O, N, and S, where N and S may be oxidized, e.g., N-oxide, S=O, or S(O)2. According to one embodiment, such heteroaryl groups contain at least one ring nitrogen atom, at least one ring sulfur atom, or at least one ring oxygen atom. For example, such heteroaryl groups may be 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O, or S. For example, heteroaryl may be 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O, or S. Examples of suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl, imidazolyl, furazolyl, oxazolyl, oxadiazolyl, oxotriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. Examples of suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidine, and triazine groups. For example, heteroaryl groups also include fused rings containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S.Examples include benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine. pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,3-c]4-b]pyridine, isoindole, purine, indene, imidazolo[1,2-a]pyridine, imidazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b]pyrimidine, imidazolo[1,2-c]pyrimidine, 5H-pyrrolo [3,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, misoprostol, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-nalidixin, 1,5-nalidixin, 2,6-nalidixin and pyrimidino[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine, and pyrimido[4,5-d]pyrimidine. The atom in the heterocycloalkyl group that is attached to the rest of the compound can be a carbon atom or a heteroatom, wherever chemically feasible.

[0062] As used in this disclosure, the term "hydroxyl" refers to an --OH group.

[0063] As used in this disclosure, the term "cyano" refers to a -CN group.

[0064] As used herein, unless otherwise stated, the term "optionally substituted" means that a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, 5, or more, or any derivable range) substituents as indicated for such group, where such substituents may be the same or different. According to one aspect, an optionally substituted group has one substituent. According to another aspect, an optionally substituted group has two identical or different substituents. According to another aspect, an optionally substituted group has three identical or different substituents. According to another aspect, an optionally substituted group has four identical or different substituents. According to another aspect, an optionally substituted group has five identical or different substituents.

[0065] Many of the groups defined in this disclosure may be optionally substituted, and the list of substituents provided in this definition section is exemplary only and does not limit in any way the substituents defined elsewhere in the specification and in the claims.

[0066] Unless otherwise stated, C in the definition of the compounds of the present invention n-n+m or C n -C m The notation includes the various cases of n to n+m carbons, e.g., C 1-6 C includes C1, C2, C3, C4, C5, and C6, and also includes the range from n to n+m. 0-6 are 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 Including etc. C 1-6 is C 1-2 , C 1-3 , C 1-4 , C 2-6 , C 3-6 etc.

[0067] As will be understood by those skilled in the art of organic synthesis, all substituents in the structures of the compounds described in this disclosure, whether unsubstituted or substituted with defined groups, are designed to ensure the chemical feasibility and stability of the molecule, and the type and number of substituents are determined by the number of atoms and valence of the parent group.

[0068] In this specification and the appended claims, the word "comprising" and its variants, such as "including" and "containing," mean "including, but not limited to," and do not exclude other additives, components, integers, or steps. When an element is described as comprising multiple components, steps, or conditions, it should be understood that the element may also be described as including any combination of multiple components, steps, or conditions, or as "consisting of multiple components, steps, or conditions, or a combination thereof," or as "consisting essentially of multiple components, steps, or conditions, or a combination thereof."

[0069] When this disclosure describes dosage amounts of the compounds of the invention, pharmaceutical compositions, pharmaceutical combinations, kits containing them, and related uses and methods, the dosage amounts should be understood to be based on the weight of the free form, excluding salts, hydrates, or solvates, unless it is stated that the dosage is based on the weight of the salt, hydrate, or solvate.

[0070] Problems to be solved by the present invention As described above, compounds capable of inhibiting Ras mutant proteins, particularly KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), especially KRas-G12D mutant proteins, can be used to treat or prevent mutant protein-mediated diseases (e.g., cancer or tumors). To this end, several structural types of Ras inhibitors have been developed in the art. However, existing KRas inhibitors still have issues to be resolved, such as insufficient antitumor activity, toxic side effects that lead to drug resistance, poor pharmacokinetic properties that hinder convenient administration (i.e., lack of "drug efficacy"), or undesirable drug interactions due to inhibition of the cytochrome P450 enzyme system. Furthermore, even for inhibitors with excellent antitumor activity, further enhancement of the selective inhibitory activity against target proteins in vivo, improvement of drug tolerability (reduced toxicity, improved safety), and optimization of pharmacokinetic properties through structural optimization are desired to provide more and better therapeutic options for clinical use.

[0071] Means to solve the problem Through extensive and detailed research, the present inventors have developed a series of compounds that exhibit significant inhibitory activity against Ras mutant proteins, particularly KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), especially KRas-G12D mutant proteins. Through structural modifications and activity verification, the present inventors have discovered compounds that exhibit significantly enhanced inhibitory activity against KRas-G12D mutant proteins compared to existing inhibitors by introducing specific types of substituents at specific positions on the benzopyrimidine ring of the KRas inhibitor structure and combining specific combinations of substitution sites and types of substituents. Furthermore, these modified compounds are expected to exhibit excellent safety profiles, reduced risk of drug interactions, and favorable or improved pharmacokinetic properties, thereby enhancing the convenience of administration methods.

[0072] Thus, the present invention primarily provides effective Ras inhibitors, in particular KRas inhibitors (e.g., inhibitors targeting G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), more particularly KRas-G12D inhibitor compounds and pharmaceutical compositions comprising these compounds as active ingredients; as pharmaceuticals, these compounds are useful in the treatment or prevention of tumors or cancers that are mediated by or have a beneficial effect through the inhibition of Ras, in particular KRas (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations). and the use of the compounds in the manufacture of a medicament for the treatment or prevention of diseases, such as tumors and cancers, that mediate or are beneficial in the inhibition of Ras, particularly KRas (such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), more particularly KRas-G12D.

[0073] That is, the present invention provides the following technical solutions:

[0074] Compounds of the Invention In this application, unless otherwise defined, the terms "compounds of the invention" and "compounds of the present invention" include the compounds defined in the present disclosure in various aspects, preferred aspects thereof, or each specific aspect thereof, such as atropisomers, mixtures of enantiomers (especially racemates), mixtures of diastereomers, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopic variants, and salts (e.g., pharmaceutically acceptable salts).

[0075] Therefore, all of the various isomers and derivatives of the compounds of the present invention described above are encompassed within the scope of the present invention. Their respective meanings, preparation methods, and specific examples are as defined in the "Definitions" section above or known to those skilled in the art. However, they are preferably the compounds of the present invention and / or their pharmaceutically acceptable salts or solvates.

[0076] To the extent that the compounds of the present invention contain basic nitrogen atoms, such as those present in nitrogen-containing heterocyclic compounds, and are chemically and biologically useful, the compounds of the present invention also include their N-oxides. Certain compounds of the present invention may exist in polymorphic or amorphous forms, and thus are included within the scope of the present invention.

[0077] The present invention provides the following compound embodiments.

[0078] Aspect 1: Compounds of formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof [ka] (In the formula, R1 and R1 ’ together with the intracyclic bridge -(CH2) t - or -CH2=CH2-; R2 and R3 are each independently H, halogen, or —C optionally substituted with halogen. 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl; G is selected from CH and N; Y is selected from O, S and Se; M is selected from N or C-R4; Z is selected from N, C, O, S and Se; B is [ka] Selected from; X is selected from C and S, and p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C; W is H, halogen, -C 1-6 selected from alkyl, OH, or NH; R4 is H, halogen, CN, -C 1-6 Alkyl or -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl and the -C 3-6 Each cycloalkyl is independently optionally substituted with halogen or CN; R5 is selected from H, halogen and NH2; R6 is H, halogen, CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -Se-C 1-6 Alkyl or -C 2-6 alkynyl, wherein said -C 1-6 Alkyl and the -C 2-6 Each alkynyl is independently optionally substituted with halogen; R7 and R8 each independently represent H, halogen, -NO2, CN, or -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2 or -C(O)OR a wherein -C 1-6 The alkyl may optionally be a halogen or -N(R a ) optionally substituted with 2; R9 is -Si(R b )3, CN, NO2, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -(CH2) n -C 3-6 Cycloalkyl, -(CH2) n-5-6 membered heteroaryl or -(CH2) n -phenyl, wherein said -C 1-6 Alkyl, said -C 2-6 alkenyl, said -C 3-6 cycloalkyl, said 5-6 membered heteroaryl, and said phenyl each independently optionally include halogen, -Se-C 1-6 alkyl and optionally halogen-substituted -C 1-6 optionally substituted with a group selected from alkyl; R a is H and —C optionally substituted with halogen 1-6 alkyl; R b each optionally substituted with halogen, -C 1-6 Alkyl and -C 2-6 alkenyl; R 10 is H, halogen, CN, -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl and the -C 3-6 Each cycloalkyl is independently optionally substituted with halogen or CN; R 11 -H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl, said -C 2-6 alkenyl, said -C 2-6 alkynyl or the C 3-6 Each cycloalkyl is independently optionally selected from halogen, -CN, -OC 1-6 Alkyl or -O-CON(R a ) optionally substituted with 2; R 12 is H, halogen, -CN, -OH, -N(R a )2, -OC1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl or C 3-6 Cycloalkyl at each occurrence is independently optionally selected from halogen, -CN, or -OC. 1-6 may be substituted with alkyl, Alternatively, two R bonded to the same carbon atom 12 But together =C(R c )2, Spiro C 3-6 forms a cycloalkyl or spiro 4-7 membered heterocycloalkyl, where R c are each independently H, halogen, or —C optionally substituted with halogen. 1-6 alkyl, wherein said spiro C 3-6 The cycloalkyl or spiro 4-7 membered heterocycloalkyl is optionally halogen or -C optionally substituted with halogen. 1-6 may be substituted with alkyl, Alternatively, two R's bonded to adjacent ring carbon atoms 12 together with the ring carbon atom C 3-4 forming a cycloalkyl, Alternatively, two R's attached to non-adjacent ring carbon atoms 12 together with the ring carbon atoms form a bridging methylene or ethylene; R 13 -H, -C 1-6 Alkyl, and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl or -C 3-6 Each cycloalkyl is independently optionally selected from halogen and -OC 1-6 optionally substituted with alkyl; Or, R 12 and R 13 are attached to adjacent ring carbon atoms, they together with the ring carbon atoms form -C 3-4 Forming a cycloalkyl; R 14 -H, -C 1-6 Alkyl, and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl or the -C 3-6 Each cycloalkyl is independently optionally selected from halogen and -OC 1-6 Alternatively, two R 14 together with the ring carbon atom -C 3-4 Forming a cycloalkyl; k is selected from 0 or 1; m and n are each independently selected from integers of 0 to 2; t is selected from 1 to 2.

[0079] Embodiment 1.1: W is selected from OH and NH; R and R are each independently H, halogen, and —OC optionally substituted with halogen. 1-6 alkyl; R5 is selected from H and halogen; R6 is H, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -Se-C 1-6 Alkyl, and -C 2-6 alkynyl, wherein said -C 1-6 Alkyl and -C 2-6 A compound of Formula (I) according to Aspect 1, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein each alkynyl is independently optionally substituted with halogen.

[0080] Aspect 1.2: R2 and R3 are H, halogen, optionally halogen-substituted -C 1-6 alkyl and -OC optionally substituted with halogen;1-6 alkyl, or two R 12 are attached to the same carbon atom, =C(R c )2, Spiro C 3-6 cycloalkyl, or spiro 4-7 membered heterocycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0081] Aspect 1.3: A compound of Formula (I) according to Aspect 1, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof, wherein W is selected from H, halogen, OH, and NH2.

[0082] Aspect 1.4:

[0083] Aspect 2.1: B is [ka] where p is 1 and X is C, i.e., the fused bicyclic moiety in which X is present is [ka] A compound of formula (I) according to any one of embodiments 1 to 1.3, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein

[0084] Embodiment 2.1.1: Compounds of formula (I) according to embodiment 2.1, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R5 is H; or R5 is a halogen selected from F, Cl, Br, I; preferably R5 is a halogen, most preferably R5 is F.

[0085] Embodiment 2.1.2: Compounds of formula (I) according to embodiment 2.1 or 2.1.1, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R6 is H; or R6 is halogen selected from F, Cl, Br, I.

[0086] Embodiment 2.1.3: R6 is -C optionally substituted with halogen 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -Se-C 1-6 Compounds of formula (I) according to embodiment 2.1 or 2.1.1, wherein R is alkyl, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -O-CH3, -O-CH2CH3, -SCH3, -S-CH2CH3, -SeCH3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0087] Embodiment 2.1.4: R6 is -C optionally substituted with halogen 2-6 Alkynyl, for example, but not limited to, [ka] , preferably [ka] A compound of formula (I) according to embodiment 2.1 or 2.1.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0088] Embodiment 2.1.5: A compound of Formula (I) according to any one of Embodiments 2.1 to 2.1.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each H; or R7 and R8 are each halogen, preferably F.

[0089] Embodiment 2.1.6: A compound of Formula (I) according to any one of Embodiments 2.1 to 2.1.4, a stereoisomer, a tautomer, a stable isotope 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 halogen is preferably F.

[0090] Embodiment 2.1.7: One of R7 and R8 is H and the other is -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR a wherein said -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, where R a is optionally substituted with H and optionally halogen; 1-6 alkyl, where R7 or R8 is not hydrogen, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CH A compound of formula (I) according to any one of aspects 2.1 to 2.1.4, wherein the compound is F2, -CH2CH2CF3, -C2F5, -C2Cl5, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0091] Embodiment 2.1.8: One of R7 and R8 is H, halogen, —NO2, CN, and —C 1-6 alkyl, and the other is selected from -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR a wherein said -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, and R a is H and —C optionally substituted with halogen 1-6 A compound of Formula (I) according to any one of Embodiments 2.1 to 2.1.4, wherein R is selected from alkyl, and is specifically as exemplified in Embodiment 2.1.7, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0092] Embodiment 2.1.9: A compound of Formula (I) according to any one of Embodiments 2.1 to 2.1.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein W is -OH.

[0093] Embodiment 2.1.10: A compound of Formula (I) according to any one of Embodiments 2.1 to 2.1.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein W is -NH2.

[0094] Aspect 2.1.11: B is [ka] wherein R5 is H or halogen, preferably halogen, and R6 is halogen, -C 2-6 Alkynyl and -C 1-6 alkyl, B is selected from, for example, [ka] A compound of formula (I) according to embodiment 2.1, any one of its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein:

[0095] Aspect 2.2: B is [ka] where p is 0 and X is S, i.e., the fused bicyclic moiety in which X is present is [ka] A compound of formula (I) according to any one of embodiments 1 to 1.3, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein

[0096] Embodiment 2.2.1: Compounds of formula (I) according to embodiment 2.2, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R5 is H; or R5 is a halogen selected from F, Cl, Br, I; preferably R5 is a halogen, most preferably R5 is F.

[0097] Embodiment 2.2.1.1: Compounds of formula (I) according to embodiment 2.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R5 is NH2.

[0098] Embodiment 2.2.2: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.1.1, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is H; or R6 is a halogen selected from F, Cl, Br, I.

[0099] Embodiment 2.2.2.1: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.1.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R6 is CN.

[0100] Embodiment 2.2.3: R6 is -C optionally substituted with halogen 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -Se-C 1-6and a compound of Formula (I) according to any one of Aspects 2.2 to 2.2.1.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -O-CH3, -O-CH2CH3, -SCH3, -S-CH2CH3, -SeCH3.

[0101] Embodiment 2.2.4: R6 is -C optionally substituted with halogen 2-6 Alkynyl, for example, but not limited to, [ka] , preferably [ka] A compound of Formula (I) according to any one of Aspects 2.2 to 2.2.1.1, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0102] Embodiment 2.2.5: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each H; or R7 and R8 are each halogen, preferably F.

[0103] Embodiment 2.2.6: Compounds of formula (I) according to any one of embodiments 2.2 to 2.2.4, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R8 is H and the other is selected from halogen, CN and NO2, where halogen is preferably F; for example, R7 is H and R8 is halogen, preferably F, or R8 is H and R7 is halogen, preferably F.

[0104] Embodiment 2.2.7: One of R7 and R8 is H and the other is -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR a wherein -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, and R a is optionally H and -C 1-6 Alkyl is optionally substituted with halogen and is selected from the group consisting of, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2 F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0105] Embodiment 2.2.8: One of R7 and R8 is H, halogen, —NO2, CN, and —C 1-6 alkyl, and the other is selected from -C1-6 Alkyl, -N(R a )2, -C(O)N(R a )2 and -C(O)OR a wherein -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, and R a is H and —C optionally substituted with halogen 1-6 A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.4, wherein R is selected from alkyl, and is specifically as exemplified in Embodiment 2.2.7, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0106] Embodiment 2.2.9: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein W is -OH.

[0107] Embodiment 2.2.10: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein W is -NH2.

[0108] Aspect 2.2.11: B is [ka] wherein R5 is H or halogen, and R6 is halogen, -C 2-6 Alkynyl and -C 1-6 alkyl, B is selected from, for example, [ka] A compound of formula (I) according to embodiment 2.2, wherein:

[0109] Embodiment 2.2.12: A compound of Formula (I) according to any one of Embodiments 2.2 to 2.2.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein W is -H.

[0110] Embodiment 2.2.13: W is halogen, preferably F; or W is -C 1-6 A compound of Formula (I) according to any one of embodiments 2.2 to 2.2.8, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, for example, —CH 3 or —CH 2 CH 3 .

[0111] Aspect 2.2.14: B is [ka] where W is H, -C 1-6 alkyl and halogen, and R7 and R8 are each H, or each halogen, or one is H and the other is halogen or halogen-substituted C 1-6 alkyl, or one is halogen and the other is halogen-substituted C 1-6 and R7 and R8 are each H, or one is H and the other is halogen, wherein halogen is preferably F, and the compounds of formula (I) according to embodiment 2.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0112] Examples of embodiment 2.2.15:B include, but are not limited to: [ka] Compounds of Formula (I) according to embodiment 2.2.14, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, including

[0113] Aspect 2.2.16: [ka] The position indicated by an asterisk indicates the axial chirality, [ka] Compounds of Formula (I) according to embodiments 2.2 to 2.2.15, including stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0114] Aspect 2.3: B is [ka] A compound of formula (I) according to any one of embodiments 1 to 1.3, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein

[0115] Embodiment 2.3.1: Compounds of formula (I) according to embodiment 2.3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are each H; or R7 and R8 are each halogen, preferably F.

[0116] Embodiment 2.3.2: Compounds of formula (I) according to embodiment 2.3, wherein one of R7 and R8 is H and the other is selected from halogen, CN and NO2, where halogen is preferably F, for example R7 is H and R8 is selected from halogen, CN and NO2, where halogen is preferably F, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0117] Embodiment 2.3.3: One of R7 and R8 is H and the other is -C 1-6 Alkyl, -N(R a )2, -C(O)N( a )2, and -C(O)OR a wherein said -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, and R a is H and —C optionally substituted with halogen 1-6alkyl, for example, when R7 is H, R8 is selected from the groups described above; non-hydrogen R7 or R8 are, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2 A compound of formula (I) according to embodiment 2.3, wherein the compound is CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0118] Embodiment 2.3.4: One of R7 and R8 is selected from H, halogen, —NO2, CN and —C 1-6 alkyl, and the other is selected from -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2 and -C(O)OR a wherein -C is selected from 1-6 The alkyl is optionally substituted with a halogen or -N(R a )2, and R a is H and —C optionally substituted with halogen 1-6 Compounds of formula (I) according to embodiment 2.3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein the non-hydrogen group is selected from alkyl, as specifically exemplified in embodiment 2.3.3.

[0119] Embodiment 2.3.4.1: Compounds of formula (I) according to embodiment 2.3.4, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R7 is selected from halogen, preferably F; and R8 is CN.

[0120] Aspect 2.3.5:R 10 A compound of Formula (I) according to any one of Aspects 2.3 to 2.3.4, wherein is H, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0121] Aspect 2.3.6:R 10 is halogen or CN, for example F, Cl, Br, I, CN, preferably F or Cl, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof.

[0122] Aspect 2.3.7:R 10 is optionally substituted with halogen or CN; 1-6 Alkyl, preferably -C 1-3 and a compound of Formula (I) according to any one of Aspects 2.3 to 2.3.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN.

[0123] Aspect 2.3.8:R 10 optionally substituted with halogen or CN -(CH2) n -C 3-6 Cycloalkyl, preferably -C 3-6 Cycloalkyl, for example, but not limited to: [ka] A compound of Formula (I) according to any one of Aspects 2.3 to 2.3.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0124] Embodiment 2.3.9: R7 is H and R8 is H, CN, halogen, NO2, -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR a wherein -C is selected from 1-6 The alkyl may optionally be a halogen or -N(R a )2, and R a is H and —C optionally substituted with halogen 1-6 alkyl, and R 10 is halogen and -C 1-6 Compounds of Formula (I) according to Embodiment 2.3, wherein R is selected from alkyl, each of which is specifically as exemplified in Embodiments 2.3.3, 2.3.6, and 2.3.7, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt, or a solvate thereof.

[0125] Embodiment 2.3.10: R9 is -Si(R b )3, where R b -C 1-6 Alkyl and -C 2-6 and alkenyl, each of which is optionally substituted with halogen, such as, but not limited to, —Si(CH3)3, —Si(CH3)2(CH2CH3), —Si(CH3)2(CH=CH2), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof.

[0126] Aspect 2.3.11: R9 is -C 1-6 alkyl, which optionally contains halogen, -Se-C 1-6 , and C 1-6and optionally substituted with alkyl, which may be optionally substituted with halogen, such as, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, A compound of Formula (I) according to any one of Aspects 2.3 to 2.3.9, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein the compound is -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -CH2(Se-CH3), -CH(CH3)(Se-CH3), -C(CH3)2(Se-CH3), -C2F5, -C2Cl5.

[0127] Aspect 2.3.12: R9 is -C 2-6 alkenyl, which optionally contains halogen, -Se-C 1-6 Alkyl, and C 1-6 and optionally substituted with alkyl, which are optionally substituted with halogen, for example, but not limited to, -CH=CH2, -CH2CH=CH2, -CH=CF2, -CF=CF2, -C(CH3)=CH2, -C(CF3)=CH2, -C(CH3)=CF2, -CH=CHCF3, -C(CH3)=CHCF3, -CH2CH=CF2, -CH2CF=CF2, -CH2C(CF3)=CH2, -CH2CH=CHCF3, -CH2C(CH3)=CHCF3, -CH=CH(Se-CH3), -C(Se-CH3)=CH2, -CF=CH(Se-CH3), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof of a compound of Formula (I) according to any one of Aspects 2.3 to 2.3.9.

[0128] Aspect 2.3.13: R9 is -C 2-6 Alkynyl, which optionally contains halogen, -Se-C 1-6 Alkyl, and C 1-6Compounds of Formula (I) according to any one of Aspects 2.3 to 2.3.9, and stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, optionally substituted with alkyl, which may be optionally substituted with halogen, for example, but not limited to, -C≡CH, -CHC≡CH, -C≡CF, -C≡CF, -C≡C(CH), -C≡C(CF), -CHC≡CF, -CHC≡C(CF), -C≡C-Se-CH, -C≡C-Se-CF.

[0129] Embodiment 2.3.14: R9 is -OC 1-6 Alkyl or -SC 1-6 alkyl, which are optionally halogenated, -Se-C 1-6 Alkyl and C 1-6and optionally substituted with alkyl, which may be optionally substituted with halogen, such as, 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-CH2F, -O-CHF2 , -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF 3, -OC(CH3)2CF3, -O-CH2(Se-CH3), -O-CH(CH3)(Se-CH3), -OC(CH3)2(Se-CH3), -O-C2F5, -O-C2Cl5, -S-C H3, -S-CH2CH3, -S-CH2CH2CH3, -S-CH(CH3)(CH3), -S-CH2CH2CH2CH3, -S-CH2CH(CH3)CH3, -SC(CH3)3, -S -CH2Cl, -S-CH2F, -S-CHF2, -S-CF3, -S-CCl3, -S-CH2CH2F, -S-CH2CHF2, -S-CH2CF3, -S-CH2CH2CH2F, -S-C A compound of Formula (I) according to any one of Aspects 2.3 to 2.3.9, wherein the compound is H2CH2CHF2, -S-CH2CH2CF3, -SC(CH3)2CF3, -S-CH2(Se-CH3), -S-CH(CH3)(Se-CH3), -SC(CH3)2(Se-CH3), -S-C2F5, -S-C2Cl5, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0130] Embodiment 2.3.15: R9 is -(CH2) n -C 3-6 Cycloalkyl, preferably -C 3-6 Cycloalkyl, most preferably cyclopropyl, and the aforementioned -(CH) n -C 3-6 Cycloalkyl is optionally halogen, -Se-C 1-6 Alkyl and C 1-6 The —Se—C 1-6 Alkyl and C 1-6Alkyl may be optionally substituted with halogen; for example, but not limited to, [ka] A compound of Formula (I) according to any one of Aspects 2.3 to 2.3.9, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0131] Embodiment 2.3.16: R9 is -(CH2) n - a 5-6 membered heteroaryl group, preferably a 5-6 membered heteroaryl group, which optionally contains halogen, -Se-C 1-6 Alkyl and C 1-6 It may be substituted with alkyl, which may be optionally substituted with halogen; for example, a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O and S, a 5-6 membered heteroaryl group containing 1 to 3 N atoms, a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N and O, a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from N and S; specific examples include, but are not limited to: [ka] and the like, each of which may optionally be substituted with a halogen, -Se-C 1-6 Alkyl and C 1-6and optionally substituted with alkyl, which may be optionally substituted with halogen, such as F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CH A compound of formula (I) according to any one of aspects 2.3 to 2.3.9, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, optionally substituted with F2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -Se-CH3, -Se-CH2-CH3, -C2F5, and / or -C2Cl5.

[0132] Embodiment 2.3.17: R9 is phenyl, optionally halogen, -Se-C 1-6 Alkyl and C 1-6 and optionally substituted with alkyl, which may be optionally substituted with halogen; for example, F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF 2, a compound of formula (I) according to any one of aspects 2.3 to 2.3.9, optionally substituted by -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -Se-CH3, -Se-CH2-CH3, -C2F5, and / or -C2Cl5, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof.

[0133] Embodiment 2.3.18: A compound of Formula (I) according to any one of Embodiments 2.3 to 2.3.9, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 is CN or NO2.

[0134] Embodiment 2.3.19: R9 is -Si(R b )3, -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl and -C 3-6 Each cycloalkyl is independently optionally selected from halogen, -Se-C 1-6 Alkyl and C 1-6 alkyl, which may be optionally substituted with halogen; R b -C 1-6 Alkyl and -C 2-6 alkenyl, each of which is optionally substituted with halogen, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof.

[0135] Embodiment 2.3.20: R7 is H and R8 is H, CN, halogen, NO2, -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR a wherein said -C is selected from 1-6 The alkyl is optionally halogen or -N(R a )2, where R a -H and -C 1-6 alkyl, which may be optionally substituted with halogen; R is selected from -Si(R b )3, NO2, CN, -C 1-6 Alkyl, -(CH2) n -C 3-6 cycloalkyl, wherein said -C 1-6 Alkyl and -C 3-6 Each cycloalkyl is independently optionally selected from halogen, -Se-C 1-6 Alkyl and C 1-6 alkyl, which may be optionally substituted with halogen; R 10 is halogen and -C 1-6A compound of formula (I) according to embodiment 2.3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0136] Embodiment 2.3.20.1: R7 is halogen, preferably F, R8 is selected from CN, and R9 is halogen, optionally substituted with halogen -C 3-6 cycloalkyl and optionally halogen-substituted -C 1-6 alkyl, and R 10 is a halogen and -C optionally substituted with halogen 1-6 A compound of formula (I) according to embodiment 2.3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0137] Embodiment 2.3.21: A compound of Formula (I) according to any one of Embodiments 2.3 to 2.3.20.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof, wherein W is -OH.

[0138] Embodiment 2.3.22: Compounds of Formula (I) according to any one of Embodiments 2.3 to 2.3.20.1, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein W is -NH2.

[0139] Aspect 2.3.23: B is [ka] [ka] A compound of Formula (I) according to embodiment 2.3, wherein:

[0140] Aspect 3.1: A compound of Formula (I) according to any one of Aspects 1 to 2.3.23, wherein G is N, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0141] Aspect 3.2: A compound of Formula (I) according to any one of Aspects 1 to 2.3.23, wherein G is C, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0142] Aspect 3.3: R1 and R1 ' together form -CH-, -CHCH- or -CH=CH-, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0143] Aspect 3.4: R1 and R1 ' Examples of heterocycles having the formula: [ka] Preferably [ka] A compound of Formula (I) according to any one of Aspects 1 to 2.3.23, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, comprising:

[0144] Embodiment 4.1: A compound of Formula (I) according to any one of Embodiments 1 to 3.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein R2 is H; or R2 is CN.

[0145] Embodiment 4.2: R2 is halogen and -OC optionally substituted with halogen 1-6alkyl, for example, but not limited to, F, Cl, Br, I, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -OC(CH3)3, -O-CH2Cl, -O-CH2F, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF3, -O-C2F5, -O-C2Cl5; preferably -O-CH3; R2 is -OC 1-6 A compound of Formula (I) according to any one of Aspects 1 to 3.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from alkyl, wherein said alkyl is optionally substituted with one or more isotopes, such as deuterium (D), e.g., —O—CD3.

[0146] Embodiment 4.2.1: R2 is -C optionally substituted with halogen 1-6 The compounds of formula (I) according to any one of aspects 1 to 3.4, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein alkyl is selected from, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -C2F5, -C2Cl5; preferably -CH3.

[0147] Embodiment 4.2.2: R2 is -C optionally substituted with halogen 2-6A compound of Formula (I) according to any one of Aspects 1 to 3.4, wherein alkynyl is selected from, for example, but not limited to, -C≡CH, -C≡CF, -C≡C-CH3, -CH2-C≡CH, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0148] Embodiment 4.3: R3 is halogen and -OC optionally substituted with halogen 1-6 and alkyl, for example, but not limited to, F, Cl, Br, I, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -OC(CH3)3, -O-CH2Cl, -O-CH2F, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F, -O-CH 2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF3, -O-C2F5, -O-C2Cl5; preferably R3 is selected from halogen, most preferably F, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, of formula (I) according to any one of aspects 1 to 4.2.2.

[0149] Embodiment 4.3.1: R3 is -C optionally substituted with halogen 1-6 and the compounds of Formula (I) according to any one of Aspects 1 to 4.2.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein alkyl is selected from, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -C2F5, -C2Cl5; preferably -CH3.

[0150] Embodiment 4.4: R2 is H and R3 is halogen, preferably F; or R2 is -C 2-6 Alkynyl, preferably -C≡CH, and R3 is halogen, preferably F; or R2 is -OC 1-6 A compound of formula (I) according to any one of aspects 1 to 3.4, wherein R is alkyl, preferably -OCH3, -OCD3, -OCH2CH3, and R3 is halogen, preferably F, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0151] Aspect 5.1: A compound of Formula (I) according to any one of Aspects 1 to 4.4, wherein M is N, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0152] Aspect 5.2: A compound of Formula (I) according to any one of Aspects 1 to 4.4, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is C-R4.

[0153] Embodiment 5.2.1: Compounds of formula (I) according to embodiment 5.2, wherein R4 is H, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0154] Embodiment 5.2.2: Compounds of formula (I) according to embodiment 5.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R4 is halogen, preferably Cl, F.

[0155] Embodiment 5.2.3: Compounds of formula (I) according to embodiment 5.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R4 is CN.

[0156] Embodiment 5.2.4: R4 is -C optionally substituted with halogen or CN 1-6Compounds of formula (I) according to embodiment 5.2, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein -CF is alkyl; for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(CH3)2CF3, -CH2CN, -CH2CH2CN; preferably -CF3.

[0157] Embodiment 5.2.5: R4 is -(CH2) optionally substituted with halogen or CN n -C 3-6 is cycloalkyl; [ka] A compound of formula (I) according to embodiment 5.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0158] Aspect 5.3: A compound of Formula (I) according to any one of Aspects 1 to 4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein M is selected from N, CF, C—Cl, C—CN and C—CF3.

[0159] Aspect 5.4: Structural Fragment [ka] M in is C-R4, where R4 is halogen (preferably F or Cl), or -C 1-6 alkyl, which may be optionally substituted with halogen (preferably -CF), where R is H and R is halogen, preferably F; or M is N and R is H, -C 2-6 Alkynyl (preferably —C≡CH) and —OC 1-6alkyl (preferably -OCH3, -OCD3, -OCH2CH3), where R3 is halogen, preferably F; specific examples include, but are not limited to: [ka] A compound of formula (I) according to any one of Aspects 1 to 3.4, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof,

[0160] Aspect 6.1: A compound of Formula (I) according to any one of Aspects 1 to 5.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein Y is O.

[0161] Aspect 6.2: A compound of Formula (I) according to any one of Aspects 1 to 5.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt, or solvate thereof, wherein Y is S.

[0162] Aspect 6.3: A compound of Formula (I) according to any one of Aspects 1 to 5.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein Y is Se.

[0163] Aspect 7.1:R 14 is H; or R 14 A compound of Formula (I) according to any one of Aspects 1 to 6.3, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein one or both of

[0164] Aspect 7.2:R 14 optionally halogen or C 1-6 -C optionally substituted with alkoxy 1-6alkyl; for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2 2. A compound of formula (I) according to any one of aspects 1 to 6.3, wherein:

[0165] Aspect 7.3:R 14 But -(CH2) n -C 3-6 cycloalkyl, wherein C 3-6 The cycloalkyl is optionally halogen or C 1-6 and optionally substituted with alkoxy; for example, but not limited to, [ka] A compound of formula (I) according to any one of aspects 1 to 6.3, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0166] Aspect 7.4: Two R attached to the same carbon atom 14 However, together with the carbon atom, C 3-4 Compounds of Formula (I) according to any one of embodiments 1 to 6.3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, which form a cycloalkyl group, for example cyclopropyl, cyclobutyl.

[0167] Aspect 8.1: Structural Fragment [ka] In this case, if k is 0, the structural fragment is [ka] wherein Z is selected from N, C, O, S and Se, preferably C, O and Se, for example, but not limited to: [ka] A compound of formula (I) according to any one of aspects 1 to 7.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0168] Aspect 8.2: Structural Fragment [ka] In the case where k is 1, the structural fragment is [ka] wherein Z is selected from N, C, O, S and Se, preferably C, O and Se, for example, but not limited to: [ka] A compound of formula (I) according to any one of aspects 1 to 7.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0169] Aspect 8.3:R 13 A compound of Formula (I) according to any one of Aspects 1 to 8.2, wherein is H, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0170] Aspect 8.3.1:R 13 A compound of Formula (I) according to any one of Aspects 1 to 8.2, wherein is halogen, preferably F, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0171] Aspect 8.3.2:R 13 optionally halogen or C 1-6 -C optionally substituted with alkoxy 1-6 Alkyl, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2 2. A compound of formula (I) according to any one of aspects 1 to 8.2, wherein:

[0172] Aspect 8.3.3:R 13 But -(CH2) n -C 3-6 cycloalkyl, where C 3-6 The cycloalkyl is optionally halogen or C 1-6 and optionally substituted with alkoxy; for example, but not limited to, [ka] A compound of formula (I) according to any one of aspects 1 to 8.2, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0173] Embodiment 8.3.4: R attached to adjacent ring carbon atoms 12 and R 13 C together with the carbon atoms to which they are attached 3-4 Forms cycloalkyl, preferably cyclopropyl; for example, but not limited to, [ka] A compound of formula (I) according to any one of aspects 1 to 8.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0174] Aspect 8.3.4:R 13 is H, halogen, and —C optionally substituted with halogen 1-6 A compound of formula (I) according to any one of aspects 1 to 8.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0175] Aspect 8.4:R 11 A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, wherein is H, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0176] Aspect 8.4.1:R 11 But -C 1-6 alkyl, which optionally includes halogen, CN, -C 1-6 Alkoxy or -O-CON(R a )2, preferably optionally substituted with halogen or -C 1-6 and optionally substituted with alkoxy; for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OCH3 , -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH(CH3)F, -CH(CH3)CH2F, -CH 2CH(CH3)F, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2, -CH2CN, -CH2CH2CN, [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0177] Aspect 8.4.1.1:R 11 But -C 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, wherein R is alkyl, wherein one or more hydrogen atoms are optionally replaced by an isotope D, e.g., -CD3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0178] Aspect 8.4.2:R 11 Ga-C 2-6 Alkenyl or -C 2-6 alkynyl, which are optionally halogenated, CN, -C 1-6 Alkoxy or -O-CON(R a )2; for example, but not limited to, vinyl, propyl, ethynyl, each of which is optionally substituted with halogen or -C 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, optionally substituted with alkoxy.

[0179] Aspect 8.4.3:R 11 is -(CH2) n -C 3-6 cycloalkyl, wherein the -C 3-6 Cycloalkyl is optionally substituted with halogen, CN, -C 1-6 Alkoxy or -O-CON(R a )2; for example, but not limited to, [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0180] Aspect 8.4.4:R 11 optionally halogen or -C 1-6 -C optionally substituted with alkoxy 1-6 alkyl; for example, -CH3, -CH2CH2-O-CH3, -CH2CH2F; or R 11 But -C 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.3.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein alkyl, wherein one or more hydrogen atoms are replaced by the isotope D, preferably -CD3.

[0181] Aspect 8.5:R 12 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, wherein is H, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0182] Aspect 8.5.1:R 12 is halogen, e.g., F, Cl, Br, I, preferably F, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof;

[0183] Aspect 8.5.2:R 12 -N(R a )2, e.g., —NH2, —NHCH3, —N(CH3)2, N(CH3)(CH2CH3), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0184] Aspect 8.5.3:R 12 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein is -OH.

[0185] Aspect 8.5.4:R 12 Ga-OC 1-6 alkyl,1-6 Alkyl is optionally halogen, CN or C 1-6 and optionally substituted with alkoxy; 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, - A compound of formula (I) according to any one of aspects 1 to 8.4.4, wherein the compound is O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC(CH3)2CF3, -O-C2F5, -O-C2Cl5, -O-CH2-OCH3, -O-CH2-O-CH2CH3, -O-CH2CH2-O-CH3, -O-CH2CH2-O-CH2CH3, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0186] Aspect 8.5.5:R 12 Ga-C 1-6 alkyl, which is optionally halogen, CN or C 1-6 and optionally alkoxy substituted, for example, but not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -C A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, wherein the compound is HCN, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CH2CN, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -C2Cl5, -CF(CF3)2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0187] Aspect 8.5.6:R 12 Ga-OC 3-6 cycloalkyl, where C 3-6 Cycloalkyl is optionally halogen, CN or C 1-6 and optionally substituted with alkoxy; for example, but not limited to, [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0188] Aspect 8.5.7:R 12 Ga-(CH2) n -C 3-6 cycloalkyl, which is optionally halogen, CN or C 1-6 and optionally alkoxy substituted, for example, but not limited to, [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0189] Embodiment 8.5.8: R bonded to two adjacent ring carbon atoms 12 C along with the carbon atom to which they are attached 3-4 Forms cycloalkyl, preferably cyclopropyl; for example, but not limited to, [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0190] Embodiment 8.5.9: Two R attached to non-adjacent ring carbon atoms 12together form a bridging methylene or ethylene, a compound of Formula (I), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 8.4.4.

[0191] Aspect 8.5.10:R 12 A compound of Formula (I), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 8.4.4, wherein is CN.

[0192] Aspect 8.5.11:R 12 But -C 2-6 Alkenyl or -C 2-6 alkynyl, which are optionally halogen, CN or —C 1-6 and optionally substituted with alkoxy; for example, but not limited to, vinyl, propenyl, ethynyl, each of which is optionally substituted with halogen, CN, or —C 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, optionally substituted with alkoxy.

[0193] Aspect 8.5.12: Two R attached to the same carbon atom 12 But, =C(R c )2, where R c each independently represents H, F, Cl, Br, I, and —C optionally substituted with halogen; 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein alkyl is selected from; for example, but not limited to, =CH2, =CF2, =CCl2, =C(CH3)2, =C(CF3)2.

[0194] Aspect 8.5.13: Two R attached to the same carbon atom 12 But Spiro C 3-6Forming a cycloalkyl or spiro 4-7 membered heterocycloalkyl, such as, but not limited to, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spiroazetidine, spiroazolidine, which optionally contain halogen (preferably F) or -C 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, optionally substituted with alkyl, said alkyl being optionally substituted with halogen (preferably -CF3).

[0195] Aspect 8.5.14:R 12 is H, halogen, -OH, N(R a )2, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C 1-6 Alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein said C 1-6 Alkyl or C 3-6 Cycloalkyl at each occurrence is independently optionally selected from halogen and -OC 1-6 may be substituted with alkyl, Alternatively, two R's bonded to adjacent ring carbon atoms 12 together with the carbon atom to which they are attached form a C3-4 cycloalkyl, Alternatively, two R's attached to non-adjacent ring carbon atoms 12 together form a bridging methylene or ethylene, a compound of Formula (I), a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 8.4.4.

[0196] Aspect 8.5.15:R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl, optionally substituted with halogen -OC 1-6alkyl, for example, but not limited to, H, F, CN, -C≡CH, -CHF, -CHF, -O-CH; Alternatively, two R bonded to the same carbon atom 12 = C(R c )2, where R c are each independently H, halogen, and —C optionally substituted with halogen. 1-6 A compound of Formula (I) according to any one of Aspects 1 to 8.4.4, wherein alkyl is selected from, for example, but not limited to, =CH2, =CF2, =CCl2, =C(CH3)2, =C(CF3)2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0197] Aspect 8.5.16:R 12 The ring carbon atom to which is attached is R 13 is attached to the ring carbon atom, and the ring NR 11 is not adjacent to [ka] , preferably [ka] A compound of Formula (I) according to any one of Aspects 1 to 8.5.15, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein:

[0198] Aspect 9.1: Structural Fragment [ka] Z in is selected from C, O, and Se; k is 0 or 1; R 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 alkyl; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, Alternatively, two R bonded to the same carbon atom 12 = C(R c )2, where R c are independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl; R 13 is H, halogen, and —C optionally substituted with halogen 1-6 alkyl; R 14 is H; or Z is selected from C, O, and Se; k is 0 or 1; R 11 is -C substituted with one or more hydrogen isotopes, e.g., D 1-6 alkyl; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 -OC optionally substituted with alkyl and halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are independently H, halogen, and C optionally substituted with halogen. 1-6 alkyl; R 13 is H, halogen, and —C optionally substituted with halogen 1-6 alkyl; R 14 is H or a hydrogen isotope, for example D, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof of a compound of Formula (I) according to any one of Aspects 1 to 6.3.

[0199] Aspect 9.2: Structural Fragment [ka] Examples of, but not limited to, [ka] [ka] [ka] [ka] [ka] A compound of formula (I) according to any one of Aspects 1 to 6.3, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, which includes

[0200] Aspect 9.3: Structural Fragment [ka] but, [ka] ,for example, [ka] where R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen or D 1-6 alkyl, preferably -C optionally substituted with one or more D 1-3 alkyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 or two R bonded to the same carbon atom; 12But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; and / or R 14 are independently selected from H and D; and / or R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; where R 12 is preferably -C optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen; R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; According to one embodiment, the structural fragment is [ka] where R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6Forms a cycloalkyl, R c are each H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen; R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl, compounds of Formula (I) according to any one of Aspects 1 to 6.3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0201] Aspect 9.4: Structural Fragment [ka] but [ka] ,for example [ka] where R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl, halogen or D 1-6 alkyl, preferably -C optionally substituted with one or more D 1-3 alkyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6alkyl, or two R bonded to the same carbon 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; and / or R 14 are each independently selected from H and D; and / or R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; where R 12 is preferably -C optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon 12 But, =C(R c )2, where R c are each independently selected from H and halogen; R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, acetylenyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl; According to one embodiment, the structural fragment is [ka] where R 11 But -C 1-6 Alkyl, -C 2-6 alkenyl, or optionally -OC 1-6 -C3-6 cycloalkyl optionally substituted with alkyl or halogen, examples of which include methyl, ethyl, cyclopropyl, propenyl, isopropyl, fluoroethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 -OC optionally substituted with alkyl and halogen1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably -C optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen; R 12 Specific examples of include fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl. Compounds of Formula (I) according to any one of Aspects 1 to 6.3, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0202] Aspect 10.1: The following subgeneric formula: [ka] wherein each substituent has the meaning defined in the corresponding embodiment above, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0203] Aspect 10.1.1: Y is O; G is CH or N; M is C-R4; Z is selected from C, Se and O; W is -OH or -NH; R1 and R1' together form -(CH2) t -formed; R2 is H; R3 is a halogen; R4 is a halogen; R5 is selected from H and halogen; R6 is halogen, -C 1-6 Alkyl, and -C 2-6 alkynyl; R7 and R8 are each independently selected from H, halogen, CN, and NO2; R 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 is alkyl; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl; R 13 is H, halogen, and —C optionally substituted with halogen 1-6 alkyl; R 14 is H; k is selected from 0 or 1; m and n are each independently selected from integers of 0 to 2; Compounds of formula (I) according to embodiment 10.1, wherein t is selected from 1 or 2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0204] Aspect 10.1.2: The following formula [ka] (In the ceremony Z is selected from C and O; W is -OH or -NH; R5 is selected from H and halogen, preferably halogen, most preferably F; R6 is halogen, -C 1-6 Alkyl and -C 2-6 Alkynyl, preferably -C 2-6 alkynyl, most preferably ethynyl; R8 is selected from H and halogen, preferably H or F; R 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 alkyl, preferably -CH3, -CH2CH3, -CH2CH2-O-CH3, -CH2CH2-OF; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl, optionally substituted with halogen -OC 1-6 alkyl, preferably selected from H, F, CN, -C≡CH, -CHF, -CHF, -CH, and -O-CH, or two R bonded to the same carbon atom; 12 But, =C(R c )2, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, preferably selected from =CH2, =CF2, =CCl2, =C(CH3)2, =C(CF3)2; R 13 is H, halogen, and —C optionally substituted with halogen 1-6 alkyl, preferably selected from H, F, and —CH; k is selected from 0 or 1; Compounds of Formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof according to embodiments 10.1 to 10.1.1, wherein m is selected from the integers 0 to 2.

[0205] Aspect 10.1.3: The following formula: [ka] ,for example [ka] wherein R5 is halogen, preferably F; and / or R6 is -C 2-6 alkynyl, preferably ethynyl; and / or R4 is halogen, preferably F; and / or R 14 are each independently selected from H and D; and / or R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen or D 1-6 alkyl, preferably -C optionally substituted with one or more D 1-3 alkyl, preferably methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably C optionally substituted with halogen (preferably F). 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(Rc )2, where R c are each independently selected from H and halogen (preferably F); R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl; R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD alkyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C substituted with halogen (preferably F). 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12 Illustrative examples of include, but are not limited to, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl, compounds of formula (I) according to embodiment 10.1, stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.

[0206] Aspect 10.1.4: The following formula: [ka] (In the formula, R 11 However, optionally -OC 1-6 optionally substituted with alkyl or halogen; 1-6 Alkyl, -C 2-6 Alkenyl or -C 3-6 cycloalkyl, examples of which include methyl, ethyl, cyclopropyl, propenyl, isopropyl, and fluoroethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; R 12 Illustrative examples of include fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethyl, methylene, difluoro, spirocyclopropyl, dimethyl; or R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD alkyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; R 12 Specific examples of R include fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; and / or two R 14 The H not shown in the figure is replaced with D.) A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0207] Aspect 10.1.5: The following formula: [ka] ,for example [ka] (In the formula, R2, R5, R6, R 13 , R 14 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R5 is halogen, preferably F; and / or R6 is -C 2-6 alkynyl, preferably ethynyl; and / or R 14 are each independently selected from H and D; R 13 But -C 1-6 Alkyl, preferably -C 1-3 and / or R2 is H, -C 2-6 Alkynyl, optionally substituted with halogen or D -C 1-6 Alkyl and -OC 1-6 alkyl optionally substituted with halogen or D; and / or R11 However, optionally -OC 1-6 -C optionally substituted with alkyl, halogen, or D 1-6 alkyl, preferably -C 1-3 Alkyl is optionally substituted with one or more D, preferably -CD, methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C optionally substituted with halogen (preferably F). 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl; specifically, R2 is H, optionally substituted with halogen or D; 1-6 Alkyl, -C 2-6 Alkynyl and -OC optionally substituted with halogen or D 1-6 alkyl, where R2 is preferably H, -C 2-6Alkynyl and -OC optionally substituted with halogen or D 1-6 alkyl; and / or R 11 optionally labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, R c are independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably -C optionally substituted with halogen (preferably F). 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0208] Aspect 10.1.6: The following formula: [ka] (In the formula, R2, R11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; R2 is preferably H, optionally substituted with halogen, -C 1-6 -OC optionally substituted with alkyl and halogen 1-6 alkyl; R 11 but preferably optionally -OC 1-6 optionally substituted with alkyl or halogen; 1-6 Alkyl, -C 2-6 Alkenyl or -C 3-6 cycloalkyl, examples of which include methyl, ethyl, cyclopropyl, propenyl, isopropyl, and fluoroethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; R 12 Specific examples of include fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, acetylenyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; or R2 is preferably H, optionally substituted with halogen -C 1-6 Alkyl, -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl; R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6alkyl, preferably -CD; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl, optionally substituted with halogen -OC 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; R 12 Specific examples of R include fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; and / or two R 14 The H not shown in the figure is replaced with D.) Compounds of formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof according to embodiment 10.1.

[0209] Aspect 10.1.7: The following formula: [ka] ,for example [ka] (In the formula, W, R4, R7, R8, R 13 , R 14 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 14 are each independently H or D; and / or W is H, -C1-6 and / or R7 and R8 are both H, or both H, or one of them is H and the other is H, or one of them is H and the other is H, or one of them is H and the other is H, or C substituted with H, or 1-6 alkyl; and / or R4 is halogen (preferably F or Cl), CN, and -C optionally substituted with halogen (preferably F). 1-6 alkyl; and / or R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen or D 1-6 alkyl, preferably -C 1-3 Alkyl is optionally substituted with one or more D, preferably -CD, methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C substituted with halogen (preferably F); 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl; specifically, W is selected from H and halogen; and / or R7 and R8 are both H, or both halogen (preferably F), or one of them is H and the other is halogen (preferably F), or one of them is H and the other is halogen (preferably F), substituted with C 1-6 alkyl; and / or R 11 optionally labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD3; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; wherein the halogen is preferably F; and wherein R 12 is preferably —C substituted with halogen (preferably F); 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0210] Aspect 10.1.8: The following formula: [ka] (In the formula, W, R7, R8, R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, W is selected from H and halogen; R7 and R8 are both H, or both halogen, or one of them is H and the other is halogen, or one of them is H and the other is optionally substituted with halogen. 1-6 alkyl; R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C 1-3 alkyl, preferably methyl or ethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6alkyl, m is selected from 1 or 2, where halogen is preferably F; R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, acetylenyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; or preferably W is selected from H and halogen; R7 and R8 are both H, or both halogen, or one of them is H and the other is halogen, or one of them is H and the other is optionally substituted with halogen. 1-6 alkyl; R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, m is selected from 1 or 2, wherein the halogen is preferably F; R 12 Illustrative examples of R include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; and / or two R 14 The H not shown in the figure is replaced with D.) A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0211] Aspect 10.1.9: The following formula: [ka] ,for example [ka] (In the formula, W, R2, R7, R8, R 13 , R 14 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 14 are each independently H or D; and / or W is H, -C 1-6 and / or R7 and R8 are both H, or both H (preferably F), or one of them is H and the other is H (preferably F), or one of them is H and the other is H (preferably F), or C substituted with H and the other is H (preferably F). 1-6 and / or R2 is H, -C 2-6 Alkynyl, optionally substituted with halogen -C 1-6 alkyl or D, or -OC optionally substituted with halogen 1-6 alkyl or D, and / or R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen or D 1-6 Alkyl, preferably -C substituted with one or more D 1-3 alkyl, preferably -CD3, methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C substituted with halogen (preferably F); 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl; specifically, W is selected from H and halogen; and / or R7 and R8 are both H, or both halogen (preferably F), or one of them is H and the other is halogen (preferably F), or one of them is H and the other is halogen (preferably F), substituted with C 1-6 alkyl; and / or R2 is -C optionally substituted with H, halogen or D. 1-6 Alkyl, -C 2-6 Alkynyl and -OC optionally substituted with halogen or D 1-6 alkyl, where R2 is preferably H or -C optionally substituted with halogen or D; 2-6 Alkynyl and -OC 1-6 alkyl; and / or R 11 optionally labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD; and / or R 12is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably —C substituted with halogen (preferably F); 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen (preferably F); R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0212] Aspect 10.1.10: The following formula: [ka] Here, W, R2, R7, R8, R 11 and R 12are each as defined generally or specifically in the corresponding embodiment above; preferably, W is selected from H and halogen; R7 and R8 are both H, or both halogen, or one of them is H and the other is halogen, or one of them is H and the other is halogen, or C substituted with H and halogen. 1-6 alkyl; R2 is H, optionally halogen-substituted -C 1-6 -OC optionally substituted with alkyl and halogen 1-6 alkyl; R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C 1-3 alkyl, preferably methyl or ethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, m is selected from 1 or 2, where halogen is preferably F; R 12 Illustrative examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, acetylenyl, cyanyl, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; or preferably W is selected from H and halogen; R7 and R8 are both H, or both halogen, or one of them is H and the other is halogen, or one of them is H and the other is optionally substituted with halogen. 1-6alkyl; R2 is H, optionally halogen-substituted -C 1-6 Alkyl, -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl; R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, m is selected from 1 or 2, where halogen is preferably F; R 12 Illustrative examples of R include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl; and / or two R 14 The H not shown in the figure is replaced with D.) A compound of formula (I) according to embodiment 10.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0213] Aspect 10.2: The following formula: [ka] (wherein each substituent has the meaning defined in the corresponding embodiment above). A compound of formula (I) according to embodiment 1, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, having the formula:

[0214] Aspect 10.2.1: Y is O; G is CH or N; M is C-R4; Z is selected from C, Se and O; W is -OH or -NH; R1 and R1' together form -(CH2) t -formed; R2 is H; R3 is a halogen; R4 is a halogen; R7 is H; R8 is H, CN, halogen, NO2, -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2 and -C(O)OR a Selected from -C 1-6 The alkyl may optionally be a halogen or -N(R a )2, where R a is —C optionally substituted with H and halogen; 1-6 alkyl; R9 is -Si(R b )3, -C 1-6 Alkyl, and -(CH2) n -C 3-6 cycloalkyl, wherein —C 1-6 Alkyl and -C 3-6 Each cycloalkyl is independently optionally selected from halogen, -Se-C 1-6 alkyl, and optionally halogen-substituted -C 1-6 may be substituted with alkyl, and R b each of which is optionally substituted with halogen; 1-6 Alkyl and -C 2-6 alkenyl; R 10 is halogen and -C1-6 alkyl; R 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 is alkyl; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl; R 13 is H, halogen, and —C optionally substituted with halogen 1-6 alkyl; R 14 is H; k is selected from 0 or 1; m and n are each independently selected from integers of 0 to 2; Compounds of Formula (I) according to embodiment 10.2, wherein t is selected from 1 or 2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0215] Aspect 10.2.2: The following subgeneric formula: [ka] (In the formula, Z is selected from C and O; W is -OH or -NH; R8 is H, CN, halogen, NO2, -C 1-6 Alkyl, -N(R a )2, -C(O)N(R a )2, and -C(O)OR aSelected from -C 1-6 The alkyl may optionally be a halogen or -N(R a )2, where R a is —C optionally substituted with H and halogen; 1-6 alkyl; R9 is -Si(R b )3, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, wherein —C 1-6 Alkyl and -C 3-6 Each cycloalkyl is independently optionally selected from halogen or -Se-C 1-6 may be substituted with alkyl, R b -C 1-6 Alkyl and -C 2-6 alkenyl; R 10 is halogen and -C 1-6 alkyl, preferably Cl and -CH; R 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C 1-6 alkyl, more preferably -CH; R 12 is H, halogen, CN, -C optionally substituted with halogen 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl, and -OC 1-6 alkyl, preferably H, F, CN, -C≡CH, -CHF, -CHF, CH, -O-CH, or two R bonded to the same carbon atom; 12 But, =C(R c )2, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, preferably =CH2, =CF2, =CCl2, =C(CH3)2, =C(CF3)2; R 13is H, halogen, and —C optionally substituted with halogen 1-6 alkyl, preferably H, F, and -CH; R 14 is H; k is selected from 0 or 1; m is selected from integers of 0 to 2. A compound of formula (I) according to embodiment 10.2 or 10.2.1, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0216] Aspect 10.2.3: The following formula: [ka] ,for example [ka] (In the formula, R7, R 10 , R 13 , R 14 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 14 are each independently H or D; and / or R7 is selected from H and halogen; and / or R 10 -C 1-6 alkyl and halogen; and / or R 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen or D 1-6 alkyl, preferably -C optionally substituted with one or more D 1-3 alkyl, preferably -CD3, methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably C optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon 12 But, =C(R c )2, where R c are each independently selected from H and halogen; wherein the halogen is preferably F or Cl; R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0217] Aspect 10.2.4: The following formula: [ka] (In the formula, R7, R 10 , R 11 and R 12 are each as generally or specifically defined in the corresponding embodiment above; preferably, R7 is selected from H and halogen; R 10 -C 1-6 R is selected from alkyl and halogen; 11 is optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C1-3 alkyl, preferably methyl, ethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; wherein the halogen is preferably F or Cl; R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0218] Aspect 10.2.5: The following formula: [ka] ,for example [ka] (In the formula, R2, R7, R 10 , R 13 , R 14 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R 13 But -C 1-6 Alkyl, preferably -C 1-3 alkyl; and / or R 14are independently H or D; and / or R2 is H, -C 2-6 Alkynyl optionally substituted with halogen or D -C 1-6 alkyl, and —OC optionally substituted with halogen or D; 1-6 alkyl; and / or R7 is selected from H and halogen; and / or R 10 -C 1-6 alkyl and halogen; and / or R 11 But -C 1-3 Alkyl is optionally substituted with one or more D, preferably -CD, methyl, ethyl; and / or R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, and m is selected from 1 or 2; 12 is preferably C optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2, where R c are each independently selected from H and halogen; wherein the halogen is preferably F or Cl; R 12 Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, acetylenyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0219] Aspect 10.2.6: The following formula: [ka] (In the formula, R2, R7, R 10 , R 11 and R 12 are each as defined generally or specifically in the corresponding embodiment above; preferably, R2 is H, -C optionally substituted with halogen. 1-6 -OC optionally substituted with alkyl and halogen 1-6 alkyl; R7 is selected from H and halogen; R 10 -C 1-6 R is selected from alkyl and halogen; 11 However, optionally -OC 1-6 -C optionally substituted with alkyl or halogen 1-6 Alkyl, preferably -C 1-3 alkyl, preferably methyl or ethyl; R 12 is halogen, CN, optionally halogen-substituted -C 1-6 alkyl, optionally substituted with halogen -C 2-6 Alkynyl and -OC optionally substituted with halogen 1-6 alkyl, or two R bonded to the same carbon atom 12 But, =C(R c )2 or Spiro C 3-6 Forms a cycloalkyl, where R c are each independently selected from H, halogen, and —C optionally substituted with halogen. 1-6 alkyl, m is selected from 1 or 2; wherein the halogen is preferably F or Cl; R 12Specific examples of include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, and dimethyl. A compound of formula (I) according to embodiment 10.2, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, having the formula:

[0220] Aspect 10.2.7:R 11 -C labeled with one or more hydrogen isotopes, e.g., D 1-6 alkyl, preferably -CD; and / or two R 14 Compounds of Formula (I) according to embodiment 10.2 or 10.2.6, wherein the unshown H is replaced with D, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

[0221] Embodiment 11: A compound selected from the following exemplary compounds, or a pharmaceutically acceptable salt or solvate thereof:

[0222] The compounds of the present invention include each of the above-described independent aspects or specific aspects, as well as aspects formed by any combination or subcombination of the above-described aspects or specific aspects, and further include aspects formed by any combination of the above-described preferred or exemplified aspects.

[0223] Beneficial Effects of the Invention As mentioned above, mutant Ras proteins, particularly mutant KRas proteins, are known to be involved in tumorigenesis and various other diseases. We have surprisingly discovered that the compounds of the present invention having the above-described structural features potently inhibit cell proliferation in KRas mutant proteins (e.g., KRas mutant proteins such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D), and thus have potential value as antiproliferative, apoptosis-inducing, and / or anti-invasive agents in the prevention, suppression, and treatment of associated tumor diseases. In particular, the compounds of the present invention are expected to be used for the prevention or treatment of diseases or conditions caused by mutant Ras proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), particularly KRas-G12D mutant proteins. Alternatively, it is expected that the compounds can be used in the prevention or treatment of diseases or conditions that are ameliorated by inhibition of Ras mutations (such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), particularly KRas-G12D mutant proteins, such as cancers or tumors as defined in the present disclosure.

[0224] Specifically, as a result of investigation, it has been found that the compound of the present invention can achieve one or more of the following technical effects.

[0225] High mutant protein inhibitory activity: The compounds of the present invention, particularly the compounds specifically exemplified in this disclosure, exhibit growth inhibitory activity against KRas G12D mutant cells in a KRAS G12D mutant cell AGS cell growth inhibition test. As shown in Activity Example 1, their IC 50 The value is in the range of 10 pM to 10 μM, for example, 10 pM to 5 μM, 100 pM to 5 μM, 500 pM to 1 μM, 0.001 to 10 μM, 100 pM to 1 μM, 100 pM to 0.5 μM, 0.001 to 5 μM, 0.01 to 1 μM, preferably 100 pM to 1 μM, 0.001 to 0.5 μM, more preferably 100 pM to 0.5 μM, 0.001 to 0.1 μM, and most preferably 1 to 50 nM, 100 pM to 0.1 μM.

[0226] The compounds of the present invention, particularly the compounds specifically exemplified in this disclosure, also exhibit potent growth inhibitory activity against KRAS G12D mutant cells in a KRAS G12D mutant cell AGS (3D) cell growth inhibition test. As shown in Activity Example 5, their IC 50 The value is in the range of 0.001 to 5 μM, for example, 0.001 to 1 μM, preferably 0.001 to 0.5 μM, more preferably 0.001 to 0.1 μM, and most preferably less than 1 nM to 50 nM.

[0227] Good pharmacokinetic properties, e.g., T 1 / 2 The prolongation of AUC allows for the extension of the dosing interval. The long half-life improves patient compliance. As shown in Example 2, AUC 0-t It has the highest overall safety / activity data, excellent drug properties, and high bioavailability.

[0228] As shown in Activity Example 3, it has been shown to have a very satisfactory safety profile, a reduced risk of drug interactions, and no significant inhibitory effects on the major CYP subtypes involved in drug metabolism.

[0229] It has excellent in vivo pharmacodynamic properties, favorable safety profile, and significantly suppresses tumor volume. For example, as shown in Activity Examples 4 and 7, it exhibited excellent target-related tumor suppression activity in a human pancreatic cancer AsPC-1 xenograft mouse model and a human pancreatic cancer cell HPAC subcutaneous xenograft tumor NOD / SCID mouse model, without any significant changes in mouse body weight.

[0230] Based on the above beneficial effects of the compounds of the present invention, the present invention also provides the following technical solutions in various aspects.

[0231] Compounds of the Invention as Therapeutic Agents or Pharmaceuticals According to one aspect, the present invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.

[0232] 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 (such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more particularly as a RAS G12D inhibitor.

[0233] In yet another aspect, the present invention provides compounds of the present invention, preferably pharmaceutically acceptable salts or solvates thereof, for the treatment and / or prevention of diseases or disorders mediated by Ras mutant proteins, particularly KRas mutant proteins (such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more particularly KRAS G12D mutant proteins, or compounds for the treatment and / or prevention of diseases or disorders ameliorated by inhibition of Ras mutations, more particularly KRas mutant proteins (such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more particularly KRAS G12D mutant proteins.

[0234] In a specific embodiment, the present invention provides compounds of the present invention for the treatment and / or prevention of diseases in which Ras mutant proteins, specifically KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more specifically KRAS G12D mutant proteins, promote the onset and development of the disease. Alternatively, the present invention provides treatment and / or prevention of diseases in which the incidence of the disease is reduced and symptoms of the disease are alleviated or eliminated by inhibiting Ras mutant proteins, specifically KRas mutant proteins (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more specifically KRAS G12D mutant proteins. Such diseases include, for example, tumors and cancers. Specific examples include, but are not limited to: lung cancer, lung adenocarcinoma, osteosarcoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland 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 (CNS) tumors, primary CNS lymphoma, spinal cord tumors, brain stem glioma, or pituitary adenoma.

[0235] In particular, the present invention provides compounds of formula (I), or isomers thereof, and 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 patients suffering from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, bile duct cancer.

[0236] Pharmaceutical Compositions and Their Administration In another aspect, the present invention provides a pharmaceutical composition comprising a compound defined by formula (I) 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 for the treatment or prevention of diseases caused by Ras mutations, particularly KRas mutations, particularly diseases caused by KRas G12D mutations, particularly KRas G12C, KRas G12D, KRas G12V, G12A, G12R, G12S, or KRas G13D mutations, such as tumors and cancers.

[0237] The pharmaceutical compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th Edition. For example, they can be formulated into tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. The compositions may contain conventional ingredients in pharmaceutical formulations, such as diluents (e.g., glucose, lactose, mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavors, flavorings, other known additives, and other active agents. Suitable carriers and excipients are 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.

[0238] The administration and application of the pharmaceutical composition of the present invention are carried out in accordance with good medical practice.Factors to be considered in this context include the specific disease to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the administration schedule, and other factors well known to physicians.The optimal dosage and frequency of administration of the compound or pharmaceutical composition of the present invention can be determined by one skilled in the art through standard tests in the field of pharmaceutical research.

[0239] The compositions of the present invention can be administered by any suitable method, including oral, topical (e.g., buccal, sublingual, etc.), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intratracheal, intradermal, intrathecal, inhalation, epidural, and intranasal administration. They can also be administered intralesionally for localized treatment, if necessary. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, and subcutaneous administration. In some embodiments, the pharmaceutical compositions of the present invention are administered orally.

[0240] For a human subject weighing 70 kg, a suitable dosage range for the compounds of the present invention can be routinely determined by one skilled in the art, but is, for example, 1 to 1000 mg per day.

[0241] When describing dosage amounts of a drug or a pharmaceutically acceptable salt thereof in this disclosure, it should be understood that the dosage is based on the weight of the free base and does not include hydrates or solvates thereof, unless the specification expressly states that the dosage is based on the weight of the salt, hydrate, or solvate.

[0242] Treatment methods and uses As described above, the compounds of the present invention, and various specific embodiments thereof, particularly the compounds specifically prepared and characterized in the Examples, exhibit inhibitory effects against Ras mutations, particularly KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, G12A, G12R, G12S or KRas G13D mutations, particularly KRas G12D mutations.

[0243] Thus, according to another aspect, the present invention provides a method for inhibiting a Ras mutation, particularly a KRas mutation, preferably a KRas G12D mutation, in a cell, comprising contacting the cell with a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to inhibit the activity of a Ras mutation, particularly a KRas mutation (such as a G12C mutation, a G12D mutation, a G12V mutation, a G12A mutation, a G12R mutation, a G12S mutation, and a G13D mutation), preferably a KRas G12D mutation, in the cell.

[0244] Based on the same properties, the present invention also provides a method for inhibiting abnormal cell proliferation in a mammal, which method comprises 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.

[0245] According to another aspect, the present invention provides a method for treating and / or preventing a disease mediated by a Ras mutation, in particular a disease mediated by a KRas mutation (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation, etc.), preferably a disease mediated by a 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.

[0246] According to another aspect, the present invention provides the use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for inhibiting Ras mutations in cells, in particular KRas mutations, preferably KRas G12D mutations, or for inhibiting abnormal cell proliferation in a mammal, or for treating and / or preventing a disease mediated by a Ras mutation, in particular a disease mediated by a KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, most preferably KRas G12D mutation.

[0247] According to another aspect, the present invention provides the use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment and / or prevention of a disease mediated by a Ras mutation, in particular a disease mediated by a KRas mutation (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation and G13D mutation), preferably a KRas G12D mutation.

[0248] For each of the technical solutions of the methods and uses provided by the present invention as described above, the abnormal cell proliferation or disease mediated by Ras mutation, particularly KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, most preferably KRas G12D mutation, particularly refers to cancer or tumor. Examples of cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, osteosarcoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland 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 (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, or pituitary adenoma.

[0249] For each of the technical solutions of the methods and uses provided by the present invention as described above, the abnormal cell proliferation or disease mediated by Ras mutation, particularly KRas mutation (e.g., 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; and most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and bile duct cancer.

[0250] Therefore, in a preferred embodiment of this aspect, the present invention provides technical solutions of methods and uses for treating or preventing cancer or tumors by inhibiting KRas G12V and / or KRas-G12D mutations. In a further preferred embodiment, the present invention provides technical solutions of methods and uses for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer by inhibiting KRas-G12D mutations.

[0251] The present invention also provides the use of the compounds of the present invention, preferably pharmaceutically acceptable salts or solvates thereof, as research tool compounds in the study of KRas inhibitors (e.g., inhibitors of G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), particularly for inhibiting KRas G12D. Accordingly, the present invention relates to the in vitro use of the compounds of the present invention, preferably pharmaceutically acceptable salts or solvates thereof, as KRas inhibitors, particularly KRas G12D inhibitors, and particularly relates to the in vitro use of the compounds of the present invention, preferably pharmaceutically acceptable salts or solvates thereof, as research tool compounds that function as KRas inhibitors, particularly KRas G12D inhibitors. The present invention also relates to The present invention also relates to methods, in particular in vitro methods, for inhibiting KRas (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), in particular KRas G12D, which methods comprise applying a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, to a sample (e.g., a biological sample). Of course, the term "in vitro" is used in the specific context of "outside a living human or animal body," and includes in particular experiments performed with cells, cell extracts, or subcellular extracts, and / or with biomolecules in aqueous solutions or media provided in an artificial environment, such as a flask, test tube, culture dish, microtiter plate, etc.

[0252] Pharmaceutical combinations The compounds of the invention can be administered as the sole active ingredient or in combination with other drugs or therapies.

[0253] Thus, in another aspect, the present invention provides a pharmaceutical combination comprising or consisting of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, and another active agent, for use in inhibiting abnormal cell proliferation in a mammal or for treating and / or preventing a disease mediated by a Ras mutation, preferably a KRas mutation (e.g., G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations), and most preferably a KRas-G12D mutation.

[0254] The other active agents can be one or more additional compounds of the invention, or second or additional (e.g., third) compounds that are compatible with the compounds of the invention, i.e., do not adversely affect each other, or have complementary activities. For example, these active agents can be compounds known to modulate other biologically active pathways, compounds that modulate a different component of a biologically active pathway involved with the compounds of the invention, or compounds that overlap with the biological target of the compounds of the invention.

[0255] In certain embodiments, 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 radiation therapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, topoisomerase inhibitors, antihormones, angiogenesis inhibitors, and cytotoxic agents.

[0256] Other active agents used in combination with the present invention can be administered simultaneously with the compounds of the present invention, separately, or sequentially, by the same or different administration routes. The other active agents can be co-administered with the compounds of the present invention in a single pharmaceutical composition, or can be administered separately from the compounds of the present invention, for example, as a combined preparation, preferably in the form of a kit. When administered separately, they can be administered simultaneously or sequentially, and sequential administration can be performed at close or distant intervals in time. They may be prepared and / or formulated by the same manufacturer or by different manufacturers. Furthermore, when the compounds of the present invention and other active ingredients are combined as a combination therapy, (i) they can be added before the combined product is sent to the physician (e.g., in the case of a kit containing the compounds of the present invention and other drugs), (ii) they can be added by the physician (or under the physician's guidance) immediately before administration, or (iii) they can be added by the patient himself, for example, when the compounds of the present invention and other active agents are administered sequentially.

[0257] The compounds of the present invention may also be used in combination with anti-tumor therapies, including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, etc.

[0258] Thus, 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 invention, or a pharmaceutically acceptable salt or solvate thereof, and further comprising a device for separately containing the compositions, for example, a container, a dispenser bottle, or individual foil packaging such as a blister pack for packaging tablets, capsules, etc., and instructions for use. Kits of the present invention are particularly suitable when different dosage forms are to be administered, such as oral and parenteral dosage forms, or when the different compositions are to be administered at different dosing intervals.

[0259] With regard to the technical solution of the pharmaceutical composition, pharmaceutical combination or kit of the present invention as described above, the abnormal cell proliferation or disease mediated by Ras mutation, in particular KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, and most preferably KRas G12D mutation, is as defined above for the method and use of the present invention.

[0260] In the pharmaceutical compositions, methods, uses, pharmaceutical combinations or kits of the present invention described above, the compounds shown in the examples are preferred.

[0261] Methods for preparing the compounds of the present invention According to another aspect, the present invention also provides a process for the preparation of the compounds defined in the present invention.

[0262] The compounds of the present invention can be prepared by a variety of methods, including the general methods set forth below, methods disclosed in the Examples, or methods analogous thereto.

[0263] Standard synthetic methods and procedures for the preparation of organic compounds and the addition and manipulation of functional groups are known in the art, and reference can be made to standard textbooks, for example Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 7th edition, Wiley, 2013). For each reaction step of each general synthetic scheme, suitable reaction conditions are well known to those skilled in the art and can be determined by routine work. Each step of the method for synthesizing the compounds of the present invention is carried out under reaction conditions known per se (for example, those specifically mentioned), in the absence or usually in the presence of a solvent or diluent (for example, a solvent or diluent that is inert to the reagents used and capable of dissolving the reagents used), or a catalyst, condensing agent, or neutralizing agent (for example, H +The reaction can be carried out in the absence or presence of an ion exchanger (e.g., a cation exchanger of the type), at low, room temperature, or elevated temperature (e.g., about −100° C. to about 190° C., e.g., about −78° C. to about 150° C., e.g., about 0° C. to about 125° C., room temperature, −20° C. to 40° C., or reflux temperature, etc.), depending on the nature of the reaction and / or the reactants, at atmospheric pressure, or, if necessary, under pressure in a sealed vessel, and / or in an inert atmosphere such as argon or nitrogen.

[0264] Unless otherwise specified, the starting materials and reagents used in the preparation of the compounds are commercially available, are known compounds in the literature, or can be prepared by the methods described below, or methods similar to those described below, or by standard methods known to those skilled in the art. Unless otherwise specified in the description of the methods, the solvents used are conventional solvents suitable for the type of reaction and well known to those skilled in the art. Examples include water, esters, ethers, liquid aromatic hydrocarbons, alcohols, nitriles, halogenated hydrocarbons, amides, bases, carboxylic acid anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for post-treatments such as chromatographic purification or fractional purification.

[0265] If necessary, the starting materials and intermediates in the synthetic reaction steps can be separated and purified by conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. If intermediates and final products are obtained as solids, they can also be purified by recrystallization or aging. Materials can be characterized by conventional methods, such as physical constants, spectroscopic data, and the like. Reaction mixtures can be worked up by conventional methods, such as mixing with water, phase separation, and purifying the crude product by chromatography, if necessary.

[0266] Those skilled in the art will recognize whether the compounds of the present invention have stereocenters. At all reaction stages, the resulting isomers can be separated into individual isomers, such as diastereoisomers or enantiomers, or any mixture of isomers, such as a racemate or a mixture of diastereoisomers. See, for example, EL Eliel, SH Wilen, and LN Mander's "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

[0267] If a mixture of stereoisomers is produced during the preparation of the compounds of the present invention, individual stereoisomers of the compounds of the present invention can be obtained by resolution. For example, optically active substances can be obtained from compounds of the present invention obtained as a mixture of stereoisomers using well-known methods, such as forming diastereomeric pairs, forming salts with optically active acids followed by fractional crystallization and regeneration of the free base, or performing chiral preparative chromatography. Alternatively, optically pure or enantiomerically enriched synthetic intermediates can be obtained using starting materials or intermediates with established stereochemistry, or by any known chiral separation method. The synthetic intermediates obtained can be used directly in subsequent steps at various stages of the above-mentioned synthetic processes.

[0268] In certain cases, it may be necessary to protect a particular reactive group using an appropriate protecting group to prevent reaction with other reactive groups. Suitable protecting groups and methods for protection and deprotection using such suitable protecting groups are well known to those skilled in the art. For examples, see T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999).

[0269] The synthetic schemes shown below are only general synthetic schemes for synthesizing the compounds of the present invention. Other methods and other reactants or intermediates known to those skilled in the art can also be used to obtain the compounds of the present invention.

[0270] For clarity, in the synthesis examples described below, unless otherwise specified, R1 to R2 appearing in the structural formula of each intermediate compound are 14 , X, Y, Z, M, G, W, k, n, m, and t have the same meaning as defined above for the compounds of the invention, where PG represents a suitable protecting group, which can be determined by one skilled in the art of organic chemistry.

[0271] Synthetic Scheme A Some of the compounds of the present invention represented by general formulas IA and IB can be synthesized according to the following schemes or appropriate modified reaction schemes thereof, wherein, unless otherwise specified, each symbol has the same meaning as above.

[0272] [ka]

[0273] Some representative compounds of the present invention can be synthesized according to the above scheme. Compound 1 may be commercially available or may be synthesized according to the method used in the embodiments described herein or a similar method. In step A, compound 1 is subjected to an aromatic nucleophilic substitution reaction (when G is N) or a metal-catalyzed coupling reaction (when G is C) to obtain compound 2. Typical conditions for aromatic nucleophilic substitution include, for example, DIEA / THF, NaH / THF, etc. Typical metal-catalyzed coupling reactions include the Suzuki coupling reaction and the Negishi coupling reaction. In step B, compound 2 is fluorinated by a halogen exchange reaction under conditions such as KF / DMSO to obtain compound 3. In step C, compound 4 or 5 is obtained by introducing a phenol or an aromatic amine compound into compound 3 and subjecting the resulting compound to a metal-catalyzed coupling reaction. In step D, compound 4 or 5 is subjected to an aromatic nucleophilic substitution reaction with an alcohol, thiol, or selenium compound under conditions such as DIEA / dioxane, NaH / THF, or DABCO / CsCO / ACN to obtain compound 6 or 7. If compound 6 or 7 has a protecting group, it is removed in step E to give a compound of general formula IA or IB.

[0274] It should be noted that the removal of the protecting groups in step E can be adjusted depending on the protecting groups possessed by the molecule, and may be a single-step or multi-step reaction. A conventional PG1 protecting group can be removed under conditions such as trifluoroacetic acid or hydrochloric acid; a conventional PG2 protecting group such as Boc, e.g., MOM, can also be removed under conditions such as trifluoroacetic acid or hydrochloric acid; a conventional PG2 protecting group such as TIPS can be removed under conditions such as CsF / DMF; a conventional PG2 protecting group such as PMB can be removed under conditions such as trifluoroacetic acid; and a conventional PG2 protecting agent such as Me can be removed under conditions such as boron tribromide.

[0275] Synthetic Scheme B Some of the compounds of the present invention represented by general formulas IA and IB can also be synthesized according to the following schemes or appropriate modifications thereof.

[0276] [ka]

[0277] In step A, compound 2 can be synthesized according to synthetic scheme A. In step B, compound 2 is subjected to an aromatic nucleophilic substitution reaction to obtain compound 8. In step C, a phenol or aromatic amine fragment is introduced into compound 8, followed by a metal-catalyzed coupling reaction to obtain compound 6 or 7. In step D, the protecting group of compound 6 or 7 is removed to obtain a compound of general formula IA or IB. Typical conditions for the coupling reaction, nucleophilic substitution reaction, and protecting group removal reaction involved in this synthetic scheme are similar to the corresponding reaction conditions described in synthetic scheme A, and can be carried out with reference thereto.

[0278] Synthetic Scheme C [ka]

[0279] Some representative compounds of the present invention (G = N) can be synthesized according to the above-described scheme. Compound 9 may be commercially available or can be obtained by the method used in the examples described in this disclosure or by a similar method. In Step A, compound 9 is subjected to an amination reaction in the presence of a condensing agent (e.g., BOP, PyAOP, etc.) to obtain compound 10. In Step B, compound 10 is subjected to a metal-catalyzed coupling reaction to introduce the corresponding B fragment, thereby obtaining compound 11 or 12. In Step C, compound 11 or 12 is treated with an oxidizing agent (e.g., mCPBA, etc.) to obtain compound 13a / 13b (or a mixture of 13a and 13b) or 14a / 14b (or a mixture of 14a and 14b), respectively. The resulting compound 13a / b or 14a / b can be subjected to a nucleophilic aromatic substitution reaction to obtain compound 6 or 7, which is then subjected to Step E to remove the protecting agent to obtain compound I-A' or I-B'.

[0280] It should be noted that typical reaction conditions and reagents for the metal-catalyzed coupling reaction, aromatic nucleophilic substitution reaction, and protecting reagent removal reaction constituting the above synthesis scheme are well known in the art and within the ordinary experience of a person skilled in the art, or can be determined by a person skilled in the art by making appropriate modifications based on typical conditions for corresponding reactions in the art and methods for identifying the starting materials and target materials used. [Example]

[0281] Synthesis Example The present invention will be further described below with reference to examples, but it should be noted that the following examples are for illustrative purposes only and are not intended to limit the scope of protection of the present invention.

[0282] The following abbreviations are used in describing the embodiments and specific examples in this disclosure: ACN (acetonitrile); Boc (tert-butoxycarbonyl); BAST (bis(2-methoxyethyl)aminosulfur trifluoride); 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 in methanol); HLM (human liver microsomes); H2O (water); H2SO4 (sulfuric acid); IV (intravenous); K2CO3 (potassium carbonate); LCMS (liquid chromatography mass spectrometry); LC-MS / MS (liquid chromatography-mass spectrometry-mass spectrometry online); MeOH (methanol) methanol-d4 (tetradeuterated methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimol); MOM (methoxymethyl ether); MTBE (methyl tert-butyl ether); m / z (mass-to-charge ratio); N2 (nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); Na2SO3 (sodium sulfite); Na2SO4 (sodium sulfate); NCS (chlorobutanimide); NHC l (Ammonium chloride); NMR (Nuclear Magnetic Resonance); PdCl2(dtbpf) or Pd(dtbpf)Cl2 (1,1'-bis(di-tert-butylphosphino)ferrocene palladium chloride); PdCl2(dppf) or Pd(dppf)Cl2 (1,1'-bisdiphenylphosphinoferrocene palladium dichloride); Pd(OAc)2 (Palladium acetate); Pd(PPh3)4 (Tetraphylphosphonium palladium); PE (Petroleum Ether); PO (Oral); 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·HO (p-toluenesulfonic acid monohydrate); μL (microliter); μM (micromolar concentration); μmol (micromolar).

[0283] In the examples below, the names and structures of the synthesized target compounds are provided. Any discrepancies between the name and the structure are unintentional and in such cases the structure takes precedence.

[0284] In the following examples, experimental methods for which no specific conditions are given are generally carried out according to conventional conditions for such reactions or according to manufacturer's recommendations. Unless otherwise specified, percentages and parts are by weight. Unless otherwise specified, liquid ratios are by volume.

[0285] The experimental materials and reagents used in the following examples are either commercially available, according to prior art methods, or prepared by methods analogous to those disclosed in this application, unless otherwise specified.

[0286] In the following examples: 1 H-NMR spectra were recorded using a Bruker (400 MHz) with chemical shifts relative to deuterated solvents (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 plus an Aglient G6100 mass spectrometer (LCMS liquid chromatography-mass spectrometry system).

[0287] Chiral analysis methods: SFC-1: Waters UPCC, analytical column: Daicel Chiralpak (登録商標)IC, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% DEA); Flow rate: 1.5 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending: 0-0.5 min A / B = 95 / 5, 0.5-5.0 min A / B = 95 / 5-60 / 40, 5.0-8.0 min A / B = 60 / 40. キラル analysis 2: Agilent 1260 Infinity, separation カラム: Daicel Chiralpak (登録商標) IG, 4.6 x 100 mm, 5 μm; Mobile phase A: n-Hekisan, Mobile phase B: ETOH / DCM = 9 / 1 (0.1% DEA); Flow rate: 1.0 mL / min; Cell temperature: 35°C; Blending: 0-20 min, A / B = 60 / 40. SFC-3: Waters UPCC, Analysis カラム: Daicel Chiralpak (登録商標) IG, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH; Flow rate: 1.5 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 90 / 10. SFC-4:Waters UPCC,Analysis: Daicel Chiralpak (登録商標) IG, 100 x 4.6 mm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% DEA); Flow rate: 2.0 mL / min; Cell temperature: 40°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 60 / 40. Chiral analysis 5: SHIMADZU LC-20AD, separation card: Daicel Chiralpak (登録商標) IA, 150 x 4.6 mm, 5 μm; Mobile phase A: n-Hekisan, Mobile phase B: ETOH (+ 0.1% DEA); Flow rate: 1.0 mL / min; Cell temperature: 35°C; Blending: 0-10 min, A / B = 90 / 10. SFC-6: Waters UPCC, Analysis: Daicel Chiralpak (登録商標) OZ, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% DEA); Flow rate: 1.5 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 70 / 30. SFC-7:Waters UPCC,Analysis カラム:Daicel ChiralCEL (登録商標) IC, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH; Flow rate: 2.0 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 60 / 40. SFC-8:Waters UPCC,Analysis カラム:Daicel ChiralCEL (登録商標) IC, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: IPA (+ 0.1% 7.0 mol / l Anmonia); Flow rate: 1.5 mL / min; Caramel temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 55 / 45. SFC-9: Waters UPCC, Analysis カラム: Daicel Chiralpak (登録商標) IG, 100 x 3mm, 3μm; Mobile phase A: CO2, Mobile phase B: IPA (0.1% DEA); Flow rate: 1.5 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 70 / 30. SFC-10:Waters UPCC,Analysis カラム:Daicel ChiralCEL (登録商標) OZ, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% DEA); Flow rate: 1.5 mL / min; Cell temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 70 / 30. SFC-11:Waters UPCC,Analysis: Daicel ChiralCEL (登録商標) OZ, 100 x 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (+0.1% 7.0 mol / l Anmonia); Flow rate: 1.5 mL / min; Caramel temperature: 35°C; Back pressure: 1800 psi; Blending time: 0-8.0 min, A / B = 60 / 40. SFC-12: Waters UPCC, analytical column: REGIS(S,S)WHELK-O1,100 * 3 mm 3 μm; mobile phase A: CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l ammonia); flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; gradient: 0-5.0 min A / B = 80 / 20. SFC-13: Waters UPCC, analytical column: Daicel ChiralCEL (登録商標) ID, 100 * 3mm 3μm; Mobile phase A: CO2, Mobile phase B: IPA (+0.1% DEA); Flow rate: 1.5mL / min; Column temperature: 35℃; Back pressure: 1800psi; Gradient: 0-5.0min A / B=70 / 30. SFC-14: Waters UPCC, analytical column: Daicel ChiralCEL (登録商標) IC, 100 * 3mm 3μm; Mobile phase A: CO2, Mobile phase B: IPA (+0.1% DEA); Flow rate: 1.5mL / min; Column temperature: 35℃; Back pressure: 1800psi; Gradient: 0-8.0min A / B=70 / 30. SFC-15: Waters UPCC, analytical column: Daicel ChiralCEL (登録商標) IC,100 * 3mm 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (+0.1% DEA); Flow rate: 1.5mL / min; Column temperature: 35℃; Back pressure: 1800psi; Gradient: 0-8.0min A / B=85 / 15. SFC-16: Waters UPCC, analytical column: (S,S)WHELK-O1,100 * 3 mm 3 μm; mobile phase A: CO2, mobile phase B: MeOH (+0.1% DEA); flow rate: 1.5 mL / min; column temperature: 35 °C; back pressure: 1800 psi; gradient: 0-5.0 min A / B = 70 / 30.

[0288] Intermediate A-1 [ka] 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

[0289] [ka]

[0290] Step A: Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2,2-trichloroacetyl)ureido)benzoate Methyl 2-amino-4-bromo-3,5-difluorobenzoate (34 g, 128 mmol) and THF (500 mL) were added to a round-bottom flask equipped with a magnetic stir bar at room temperature. After stirring at room temperature, 2,2,2-trichloroacetyl isocyanate (28.9 g, 153 mmol) was added dropwise to the system. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (crude) as a brown solid, which was used directly in the next step. LCMS (m / z): 452.8 (M + H).

[0291] Step B: 7-Bromo-6,8-difluoroquinazoline-2,4-diol At room temperature, methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2,2-trichloroacetyl)ureido)benzoate obtained in the previous step was added to a round-bottom flask equipped with a magnetic stir bar, followed by the addition of NH3 (400 mL, 7 M MeOH solution). The resulting mixture was stirred at room temperature for 2 hours and monitored by LCMS until the reaction was complete. After concentration under reduced pressure, the resulting solid was slurried with methyl tert-butyl ether and filtered to give 7-bromo-6,8-difluoroquinazoline-2,4-diol (32 g, 90% overall yield for two steps) as a pale yellow solid. LCMS (m / z): 277.0 (M + H).

[0292] Step C: 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline 7-Bromo-6,8-difluoroquinazoline-2,4-diol (6 g, 22 mmol) and POCl3 (50 mL) were added to a round-bottom flask equipped with a magnetic stir bar. DIEA (12 mL) was added dropwise while stirring at room temperature. After the dropwise addition was complete, the system was heated to 110 °C and stirred overnight. The reaction solution was concentrated under reduced pressure to approximately 30 mL and then poured into water (500 mL), resulting in the formation of a precipitate. The resulting solid was collected by filtration and dried to give 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (5 g, 74% yield) as a yellow solid. LCMS (m / z): 312.9 (M + H).

[0293] Intermediate B-1 [ka] 7-Bromo-2,4-dichloro-8-fluoroquinazoline

[0294] [ka]

[0295] Step A: 7-Bromo-8-fluoroquinazoline-2,4(1H,3H)-dione 2-Amino-4-bromo-3-fluorobenzoic acid (10.0 g, 42.7 mmol) and urea (25.7 g, 427.3 mmol) were mixed together at room temperature. The mixture was heated to 200 °C and stirred for 2 h. The reaction mixture gradually changed from a solid to a liquid and back to a solid. After completion of the reaction, the reaction was monitored by LCMS and washed with hot water (250 mL). The solid was collected by filtration to give 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (12 g, crude). LCMS (m / z): 258.9 (M + H).

[0296] Step B: 7-Bromo-2,4-dichloro-8-fluoroquinazoline DIPEA (13.5 mL, 77.2 mmol) was added to a mixture of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.0 g) and POCl3 (35.9 mL, 386.0 mmol) at room temperature. The mixture was heated to 100 °C and stirred for 5 h. After completion of the reaction, most of the solvent and base were removed by concentration. ACN (10 mL) was added for dilution. The resulting diluted solution was slowly added dropwise to water with stirring at room temperature, and a solid precipitated. The precipitate was filtered and dried to give 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.8 g, 83% yield) as a yellow solid. LCMS (m / z): 296.8 (M + H).

[0297] Intermediate C-1 and Intermediate C-1a [ka] 7-Chloro-2,4-dichloro-8-fluoropyrido[4,3-d]pyrimidine and tert-butyl (1R,5S)-3-(7-chloro-2-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate The preparation and characterization of Intermediate C-1 and Intermediate C-1a were carried out with reference to WO 2021 / 041671A1.

[0298] Intermediate A-1a [ka] tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0299] [ka]

[0300] Step A: tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (8.0 g, 26 mmol), DIEA (8.0 mL), and THF (80 mL) were added to a round-bottom flask equipped with a magnetic stir bar. With stirring at room temperature, tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.0 g, 28 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred for 1 hour. The reaction solution was concentrated, poured into water, and filtered. The filter cake was collected and dried to give tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.0 g, 72% yield) as a yellow solid. LCMS (ESI, m / z): 499.0 (M + H).

[0301] Intermediate A-1b [ka] tert-Butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0302] Step A: tert-Butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.0 g, 8.4 mmol), KF (21.4 g, 368 mmol), and DMSO (100 mL) was stirred at 100 °C overnight. After completion of the reaction, monitored by LCMS, the reaction solution was cooled to room temperature. With stirring, the reaction solution was slowly poured into water (1 L), causing the precipitation of a yellow solid. The solid was filtered, and the filter cake was washed with water (200 mL). The filter cake was collected and dried to give tert-butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.7 g, 88% yield) as a yellow solid. LCMS (m / z): 473.4 (M + H).

[0303] By reference to the above synthetic scheme, the following intermediates of the present invention were also synthesized:

[0304] [Table 1]

[0305] Intermediate A-1b-I [ka] tert-Butyl (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0306] [ka]

[0307] Step A: tert-butyl (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-Butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 6.34 mmol), (7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (4.13 g, 7.61 mmol), Pd(OAc) (71 mg, 0.32 mmol), BIDIME (209 mg, 0.63 mmol), and KPO (4.04 g, 19.02 mmol) were dissolved in tert-amyl alcohol (30 mL) at room temperature. The system was purged with N three times, then heated to 110 °C, and stirred overnight. Upon completion of the reaction (as detected by LCMS), the mixture was filtered through Celite and washed with EA (50 mL). The resulting organic phase was concentrated and purified by FCC (SiO, EA / PE = 0-50%) to give a yellow solid, tert-butyl (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.3 g, 41% yield). 1H NMR (400MHz, chloroform-d) δ 7.74 (dd,J=9.1, 5.6Hz,1H), 7.39 (dd,J=9.8, 1.7Hz,1H), 7.34 (d,J=2.6Hz,1H), 7.31 - 7.28 (m,1H), 7.10(d,J=2.6Hz,1H), 4.86 - 4.61 (m,1H), 4.54 - 4.26 (m,2H), 4.20 - 4.01 (m,1H), 3.92 - 3.69 (m,1H), 3.58 - 3.36 (m,1H), 2.11 - 1.97 (m,3H), 1.53 (s,9H), 1.36 - 1.23 (m,4H), 1.17 - 1.08 (m,18H), 0.95 - 0.79 (m,18H), 0.61 - 0.49 (m,3H). LCMS (m / z): 891.4 (M+H).

[0308] Intermediates A-1b-I1 and A-1b-I2 [ka]

[0309] This compound, tert-butyl (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate A-1b-I, 10 g), was resolved by SFC (SFC150, Waters) (separation column: DAICEL CHIRALPAK (登録商標) IC, 250 * 25 mm, 10 μm; mobile phase: CO2 / MeOH = 75 / 25; flow rate: 70 mL / min). The first eluted isomer 1 was identified as intermediate A-1b-I1 (4.5 g, with a shorter retention time). Chiral analysis method SFC-1, Rt = 3.855 min. LCMS (m / z): 891.4 (M + H). The second eluted isomer 2 was identified as intermediate A-1b-I2 (4.9 g, with a longer retention time). Chiral analysis method SFC-1, Rt = 4.198 min. 1H NMR (400MHz, chloroform-d) δ 7.74 (dd,J=9.1, 5.7Hz,1H), 7.40(dd,J=9.7, 1.7Hz,1H), 7.34 (d,J=2.5Hz,1H), 7.29 (d,J=8.7Hz,1H), 7.10(d,J=2.6Hz,1H), 4.81 - 4.64 (m,1H), 4.51 - 4.32 (m,2H), 4.18 - 4.03 (m,1H), 3.91 - 3.69 (m,1H), 3.52 - 3.32 (m,1H), 2.30 - 1.93 (m,3H), 1.53 (s,9H), 1.37 - 1.21 (m,4H), 1.16 - 1.05 (m,18H), 0.94 - 0.80(m,18H), 0.62 - 0.47 (m,3H). 19 F NMR (376 MHz, chloroform-d) δ −47.14, −105.65, −112.24, −120.80. LCMS (m / z): 891.4 (M + H).

[0310] Intermediate C-2 and Intermediate C-2a [ka] 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0311] [ka]

[0312] Step A: 4,6-Dichloro-5-fluoronicotinoyl chloride Thionyl chloride (2.25 mL, 31 mmol) was slowly added to a solution of 4,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.4 mmol) in DCM (100 mL) under stirring at room temperature, followed by the addition of DMF (175 mg, 2.4 mmol). The resulting reaction solution was stirred at 50 °C for 2 h. After completion of the reaction (as confirmed by TLC), the reaction mixture was concentrated and azeotroped with a small amount of toluene. 4,6-dichloro-5-fluoronicotinoyl chloride (4.5 g, 83% yield) was obtained as a yellow solid, which was used directly in the subsequent reaction.

[0313] Step B: (4,6-Dichloro-5-fluoronicotinoyl)carbamidothioate A mixture of 4,6-dichloro-5-fluoronicotinoyl chloride (4.5 g, 19.8 mmol) and 1,2-dimethoxyethane (20 mL) was slowly added dropwise to a mixture of 2-methylisothiourea sulfate (15 g, 49.5 mmol) and 1 M aqueous NaOH (70 mL) at 0 °C under stirring, and the mixture was stirred at the same temperature for 1 h. The precipitated solid was filtered and dried to give methyl (4,6-dichloro-5-fluoronicotinoyl)carbamidothioate (5.0 g, 90% yield). LCMS (m / z): 282.1 (M + H).

[0314] Step C: 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4,6-Dichloro-5-fluoronicotinoyl)carbamidothioate (5.0 g, 17.8 mmol) was dissolved in DMF (40 mL), and the solution was heated to 120 °C and stirred for 3 h. After completion of the reaction (as confirmed by LCMS), the reaction mixture was cooled to room temperature, and water (200 mL) was added. The precipitated solid was filtered and dried to give the desired product, (4,6-dichloro-5-fluoronicotinoyl)carbamidothioate (3.6 g, 82% yield). LCMS (m / z): 245.6 (M + H).

[0315] Step D: tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate At room temperature, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.9 mmol), BOP (2.3 g, 5.3 mmol), and DIEA (1.0 g, 8.1 mmol) were added to a solution of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.0 g, 4.0 mmol) in DMF (15 mL). The reaction solution was stirred at 50 °C for 2 h. After completion of the reaction (confirmed by LCMS), the reaction solution was poured into 100 mL of ice water to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EtOAc / PE = 0-20%) to give the yellow solid product tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (980 mg, 55% yield). LCMS (m / z): 440.1 (M + H).

[0316] Intermediate D-1, D-2, D-2a [ka]

[0317] [ka]

[0318] Step A: 2,6-Dichloro-3-fluoropyridin-4-amine Selectfluor (68 g, 180 mmol) was added to a solution of 2,6-dichloropyridin-4-amine (25 g, 154 mmol) in methanol / water (V / V = 5:1, 300 mL) at room temperature. The resulting mixture was stirred at 50 °C for 48 h, concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and brine, and dried over anhydrous sodium sulfate. The crude product was concentrated by filtration and purified by FCC (SiO2, EA / PE = 0-10%) to give 2,6-dichloro-3-fluoropyridin-4-amine (10 g) as a white solid. LCMS (m / z): 180.9 (M + H).

[0319] Step B: tert-butyl (tert-butoxycarbonyl) (2,6-dichloro-3-fluoropyridin-4-yl)carbamate At room temperature, 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) under stirring. The resulting mixture was heated to 60 °C and stirred for 16 h. Upon completion of the reaction (as confirmed by TLC), the crude product was obtained by concentration. After slurrying with methanol, tert-butyl (tert-butoxycarbonyl) (2,6-dichloro-3-fluoropyridin-4-yl)carbamate (16 g) was obtained as a white solid. LCMS (m / z): 381.2 (M + H).

[0320] Step C: tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate 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) under a dry ice ethanol bath. The resulting mixture was stirred for 1 h. Upon completion of the reaction (as confirmed by TLC), the reaction was quenched by adding an appropriate amount of acetic acid, diluted with EA, washed with water, and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was purified by FCC (SiO, EA / PE = 0-20%) to give tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13 g).

[0321] Step D: 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride 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 h. After completion of the reaction (confirmed by LCMS), the mixture was concentrated to give 4-amino-2,6-dichloro-5-fluoronicotinate hydrochloride (8 g). LCMS (m / z): 224.9 (M + H).

[0322] Step E: 5,7-Dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one A mixture of 4-amino-2,6-dichloro-5-fluoronicotinic acid (8 g, 30.8 mmol) and thionyl chloride (200 mL) was stirred at 50 °C for 3 h. The reaction mixture was then concentrated, and the residue was dissolved in acetone (50 mL) to give solution 1. At room temperature, a solution of ammonium thiocyanate (7 g, 92 mmol) in acetone (160 mL) was added dropwise to solution 1, and the resulting reaction mixture was continuously stirred at room temperature for 1 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was poured into water, filtered, and the filter cake was dried to give 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (5 g). LCMS (m / z): 265.9 (M + H).

[0323] Step F: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate D-1) 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 methyl iodide (5.3 g, 380 mmol) was stirred at room temperature for 2 h. After completion of the reaction (confirmed by LCMS), the reaction solution was poured into 1000 mL of water and acidified to pH ∼6 with concentrated hydrochloric acid. The solution was filtered, and the filter cake was dried to give the product, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (4 g). LCMS (m / z): 279.9 (M + H).

[0324] Step G: 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate D-2) A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (400 mg, 1.4 mmol), sodium methoxide (0.38 g, 7.5 mmol), DMA (10 mL), and methanol (2 mL) was stirred at 50 °C for 16 h. After completion of the reaction (as confirmed by LCMS), the reaction mixture was diluted with water, adjusted to pH ∼3 with concentrated hydrochloric acid, filtered, and the filter cake was collected and dried to give the product, 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (250 mg). LCMS (m / z): 276.0 (M + H).

[0325] Step H: tert-Butyl (1R,5S)-3-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediate D-2a) A mixture of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (250 mg, 0.91 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 1.4 mmol), BOP (620 mg, 1.4 mmol), and N,N-diisopropylethylamine (361 mg, 2.8 mmol) in DMF (5 mL) was stirred at 45°C for 3 h. After the reaction was completed by monitoring with LCMS, the reaction solution was poured into water, filtered, and the filter cake was collected and dried to obtain tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg). LCMS (m / z): 470.3 (M + H).

[0326] Intermediates D-3, D-3a and D-4, D-4a [ka]

[0327] Intermediates D-3, D-3a and D-4, D-4a were synthesized according to the synthesis of the above-mentioned intermediates D-2, D-2a.

[0328] Intermediates E-1, E-1a and E-1b [ka] 7-Bromo-2,4,6-trichloro-8-fluoroquinazoline (E-1) tert-Butyl ((1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (E-1a) tert-Butyl ((1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (E-1b)

[0329] [ka]

[0330] Step A: tert-Butyl ((1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate At room temperature, tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.77 g, 8.32 mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (CAS: 1698028-11-3, 2.50 g, 7.57 mmol), DIEA (1.96 g, 15.1 mmol), and THF (50 mL). The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was concentrated under reduced pressure and further purified by FCC (SiO, EA / PE = 0-30%) to give tert-butyl ((1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 52% yield) as a yellow solid. LCMS (m / z): 506.9.

[0331] Step B: tert-Butyl ((1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate KF (2.29 g, 39.5 mmol) was added to a mixture of tert-butyl ((1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 3.95 mmol) and DMSO (50 mL) at room temperature. The resulting mixture was heated to 110° C. and stirred for 16 h. After completion of the reaction (confirmed by LCMS), the reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was immersed in EA. The resulting mixture was extracted with 50 mL of HCl (50 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EA / PE = 0-25%) to give a yellow solid, tert-butyl ((1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 83% yield). LC-MS (m / z): 489.0 (M + H) and 491.0 (M + H).

[0332] Intermediate E-2b [ka] tert-Butyl (1R,5S)-3-(6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Intermediate E-2b was synthesized according to the protocol described for intermediate E-1b, except in step A, 7-bromo-2,4,6-trichloro-8-fluoroquinazoline was replaced with 2,4,6-trichloro-8-fluoroquinazoline (CAS: 2205387-69-3).

[0333] Intermediates F-1, F-1a and F-1b [ka] 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (F-1) tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (F-1a) tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (F-1b)

[0334] [ka]

[0335] Step A: 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid NIS (50.6 g, 225 mmol) was added to a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (50 g, 215 mmol) and DMF (500 mL) at room temperature, and the resulting mixture was stirred at 80 °C for 3 h. After completion of the reaction (confirmed by LCMS), the reaction solution was cooled, poured into water (2 L), and extracted with ethyl acetate (4 L). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (50 g, 65% yield) as a yellow solid. LCMS (m / z): 360.2 (M + H).

[0336] Step B: 7-Bromo-8-fluoro-6-iodoquinazoline-2,4-(1H,3H)-dione A mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (50 g, 139 mmol) and urea (168 g) was stirred at 200 °C for 2 h. After completion of the reaction, the system was cooled to room temperature, slurried with water, and the solid was collected by filtration. After drying, 7-bromo-8-fluoro-6-iodoquinazoline-2,4-(1H,3H)-dione (48 g, 90% yield) was obtained as a yellow solid. LCMS (m / z): 384.8 (M + H).

[0337] Step C: 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline DIEA (40 mL) was slowly added to a mixture of 7-bromo-8-fluoro-6-iodoquinazoline-2,4-(1H,3H)-dione (20 g, 52 mmol) and phosphorus oxychloride (160 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction (confirmed by TLC), the reaction solution was concentrated, slowly poured into water, and filtered to collect the filter cake. After drying, 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (18.5 g, 85% yield) was obtained as a yellow solid.

[0338] Step D: tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (18.5 g, 44 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.3 g, 44 mmol), DIEA (17 g, 132 mmol), and tetrahydrofuran (200 mL) was stirred at room temperature for 1 h. After completion of the reaction (confirmed by TLC), the reaction solution was poured into water (2 L), filtered, and the solid was collected and dried to give tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17.6 g, 67% yield) as a yellow solid. LCMS(m / z): 596.6 (M+H).

[0339] Step E: tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 g, 16.8 mmol), potassium fluoride (8 g, 138 mmol), and DMSO (100 mL) was stirred at 110 °C for 16 h. After completion of the reaction (as confirmed by LCMS), the reaction solution was poured into water (2 L), filtered, and the solid was collected. After drying, tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9 g, 92% yield) was obtained as a yellow solid. LCMS(m / z): 583.3 (M+H).

[0340] Step F: tert-Butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 1.7 mmol), methyl fluorosulfonyldifluoroacetate (660 mg, 0.44 mL, 3.4 mmol), cuprous iodide (1 g, 5.2 mmol), HMPA (2 mL), and DMF (10 mL) was heated to 110 °C by microwave irradiation for 1 h. After completion of the reaction, the reaction solution was filtered, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EA / PE = 0-20%) to give tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 45% yield) as a yellow solid. LCMS (m / z): 523.6 (M + H).

[0341] Intermediate F-1c [ka] tert-Butyl (1R,5S)-3-(7-bromo-6-cyano-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0342] [ka]

[0343] Step A: tert-butyl (1R,5S)-3-(7-bromo-6-cyano-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Under nitrogen protection, a mixture of tert-butyl (1R,5S)-3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.0 mmol), zinc cyanide (160 mg, 0.5 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), and DMF (10 mL) was stirred at 110 °C for 16 h. After completion of the reaction (confirmed by LCMS), the reaction solution was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EA / PE = 0-30%) to give tert-butyl (1R,5S)-3-(7-bromo-6-cyano-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 58% yield) as a yellow solid. LCMS (m / z): 480.0 (M + H).

[0344] Intermediates G-1 and G-1a [ka] 2,4,7-trichloro-8-fluoro-5-(triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine (G-1) tert-Butyl (1R,5S)-3-(2,7-dichloro-8-fluoro-5-(triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (G-1a)

[0345] [ka]

[0346] Step A: 2-chloro-3-fluoro-5-iodopyridin-4-amine At room temperature, 2-chloro-3-fluoro-4-aminopyridine (25.0 g, 171 mmol) was dissolved in 250 mL of acetonitrile. Subsequently, NIS (35.4 g, 205 mmol) and p-toluenesulfonic acid monohydrate (3.24 g, 17.1 mmol) were added to the above system, respectively. The resulting mixture was heated to 70 °C and stirred overnight. After completion of the reaction (confirmed by LCMS), the reaction mixture was cooled to room temperature. The reaction solution was poured into water (500 mL) to quench the reaction, and then extracted with ethyl acetate (800 mL × 3). The combined organic phase was washed successively with saturated NaHCO3 solution, saturated Na2S2O3 solution, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EA / PE=0-50%) to give 2-chloro-3-fluoro-5-iodopyridin-4-amine (42 g, 90% yield) as a white solid. LCMS (m / z): 272.9 (M + H). 1 H NMR (400MHz, DMSO-d6) δ 8.10(s,1H), 6.69 (s,2H). 19 F NMR (376MHz, DMSO-d6) δ-138.90.

[0347] Step B: Ethyl 4-amino-6-chloro-5-fluoronicotinate 2-Chloro-3-fluoro-5-iodopyridin-4-amine (40 g, 147 mmol) was dissolved in 400 mL of absolute ethanol at room temperature. The system was purged with CO three times. Subsequently, Pd(PPh3)2Cl2 (10.3 g, 14.7 mmol) and TEA (95.0 g, 735 mmol) were added to the reaction flask, and the system was purged with CO three times. The resulting mixture was heated to 80 °C and reacted overnight under a CO atmosphere. After completion of the reaction (confirmed by LCMS), the reaction mixture was cooled to room temperature. The reaction solution was filtered through Celite. The filtrate was concentrated, and the resulting crude product was purified by FCC (SiO2, EA / PE = 0-50%) to give ethyl 4-amino-6-chloro-5-fluoronicotinate (30 g, 93% yield) as a white solid. LCMS (m / z): 219.0 (M + H).

[0348] Step C: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate Under stirring at room temperature, BocO (65.9 g, 302 mmol) was added dropwise to a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (30.0 g, 137 mmol) and DMAP (3.4 g, 27.5 mmol) in anhydrous dichloromethane (600 mL). After the addition was complete, the mixture was heated to 45 °C and allowed to react overnight. Imidazole (9.33 g, 137 mmol) was added to the system. After stirring for 30 minutes, the mixture was washed with saturated ammonium chloride solution (300 mL × 3), and the organic phase was separated. The organic phase was further washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (45.9 g, 80% yield) as a yellow solid. LCMS(m / z): 419.1 (M+H).

[0349] Step D: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate A solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (45.0 g, 107 mmol) in anhydrous THF (450 mL) was cooled to −40° C. in a dry ice-acetonitrile bath. At this temperature, a solution of TMPMgCl-LiCl (161 mL, 161 mmol, 1 M) in THF was added dropwise with stirring. After the addition was complete, the mixture was continuously stirred at this temperature for 4 h. Subsequently, a solution of dibromotetrachloroethane (42.0 g, 129 mmol) in THF (100 mL) was added dropwise. The mixture was continuously stirred at −40° C. for 4 h. The reaction was quenched by adding 500 mL of saturated ammonium chloride solution, followed by extraction with EtOAc (500 mL × 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO, EA / DCM = 0-50%) to give ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (17.0 g, 32% yield) as a white solid. LCMS (m / z): 497.0 (M + H).

[0350] Step E: Ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate To a solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (9.5 g, 19.1 mmol) in dichloromethane (50 mL) was added in one portion at room temperature under stirring. After stirring at room temperature for 2 h, the mixture was concentrated to dryness. The residue was neutralized with 200 mL of saturated sodium bicarbonate solution and then extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (5.6 g, 99% yield) as a white solid. LCMS (m / z): 296.9 (M + H).

[0351] Step F: Ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate Ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (5.60 g, 18.8 mmol), Pd(PPh3)2Cl2 (1.32 g, 1.88 mmol), and CuI (717 mg, 3.76 mmol) were dissolved in anhydrous THF (150 mL) at room temperature. The reaction flask was evacuated and purged with nitrogen three times. Triisopropylsilylacetylene (4.46 g, 24.5 mmol) and TEA (5.71 g, 56.5 mmol) were added and purged with nitrogen three times. The resulting mixture was heated to 45 °C and reacted for 2 h. After completion of the reaction (confirmed by LCMS), the reaction was cooled to room temperature. The reaction solution was filtered through Celite. The filtrate was concentrated to dryness. The crude product was purified by FCC (SiO, EA / PE=0-10%) to give ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate (7 g, 93% yield) as a white solid. LCMS (m / z): 399.1 (M + H).

[0352] Step G: Ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)-2-((triisopropylsilyl)ethynyl)nicotinate 2,2,2-Trichloroacetyl isocyanate (3.97 g, 21.1 mmol) was added to a solution of ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate (7.00 g, 17.5 mmol) in anhydrous THF (150 mL) under stirring at room temperature. The resulting mixture was stirred at room temperature for 1 h. It was then concentrated to dryness to give ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)-2-((triisopropylsilyl)ethynyl)nicotinate (11 g, crude) as a white solid, which was used directly in the next step without purification. LCMS (m / z): 586.0 (M + H).

[0353] Step H: 7-chloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine-2,4-diol Ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)-2-((triisopropylsilyl)ethynyl)nicotinate (11 g, crude) was dissolved in ammonia-methanol solution (50 mL, 7 M, 350 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. It was then concentrated to dryness. The crude product was slurried with PE / EA (100 mL / 10 mL) and filtered to give 7-chloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine-2,4-diol (5.8 g, 84% yield) as a white solid. LCMS (m / z): 396.1 (M + H).

[0354] Step I: 2,4,7-trichloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine At room temperature, phosphorus oxychloride (1.55 g, 10.1 mmol) and TEA (1.31 g, 10.1 mmol) were added to a solution of 7-chloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine-2,4-diol (1.00 g, 2.53 mmol) in anhydrous toluene (20 mL). The resulting mixture was heated to 100 °C, stirred overnight, and then concentrated. The resulting crude 2,4,7-trichloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine (crude) was used directly in the next step.

[0355] Step J: tert-Butyl (1R,5S)-3-(2,7-dichloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Under a nitrogen atmosphere, a solution of 2,4,7-trichloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine (crude product obtained in Step I) in anhydrous dichloromethane (20 mL) was cooled to -40 °C. DIPEA (976 mg, 7.56 mmol) was added, followed by a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (534 mg, 2.52 mmol) in DCM (2 mL). The resulting mixture was stirred at -40 °C for 1 h. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL) and extracted with DCM (30 mL × 3). The combined organic phase was dried and concentrated. The crude product was purified by FCC (SiO, EA / PE = 0-10%) to give tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (960 mg, 63% yield over two steps) as a white solid. LCMS (m / z): 608.3 (M + H).

[0356] Intermediate k1 (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid [ka] [ka]

[0357] Step A: 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol TIPSCl (177 g, 920 mmol) was added dropwise to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (300 g, 837 mmol) and imidazole (119 g, 1.76 mol) in DCM (3 L) while stirring in an ice bath. After the addition was complete, the system was slowly warmed to room temperature and stirred for 6 h. Upon completion of the reaction (as confirmed by TLC), water (900 mL) was added, the mixture was stirred for 30 min, and then the layers were separated. The aqueous phase was extracted with DCM (900 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and concentration to dryness, the product was purified by silica gel plug (PE / EA=50:1) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol (397 g, 92% yield).

[0358] Step B: 7-Fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-trifluoromethanesulfonate Trifluoromethanesulfonic anhydride (326 g, 1.16 mol) was added dropwise to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-ol (397 g, 0.77 mol) and DIPEA (298 g, 2.31 mol) in DCM (4 L) at −45 to −35° C. After the addition was complete, the mixture was stirred at the same temperature for 0.5 h. Upon completion of the reaction (as confirmed by TLC), the system was added to water (800 mL), the layers were separated, and the aqueous phase was extracted with DCM (1.2 L). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. After purification on a silica gel plug (PE / EA=50:1), 7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-trifluoromethanesulfonate (469 g, 94% yield) was obtained.

[0359] Step C: (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid Under nitrogen protection, Pd(dppf)Cl (13.2 g, 18.2 mmol) was added to a solution of 7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-trifluoromethanesulfonate (235 g, 0.36 mol), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborinane) (164 g, 0.73 mol), and potassium acetate (107 g, 1.1 mol) in dioxane (2.4 L). The mixture was heated to 85 °C and stirred for 20 h. Upon completion of the reaction (as confirmed by TLC), it was cooled to room temperature, filtered through Celite, and rinsed with EA. After concentration, the product was purified on a silica gel column (EA / PE = 0-5%) to give the crude compound.

[0360] The crude compound thus obtained was dissolved in methanol (1.2 L) and 1N HCl (2.4 L) was added. The resulting mixture was stirred at room temperature for 30 min. EA (2.4 L) was added, and the mixture was stirred for an additional 2 h. After standing to separate the layers, the organic phase was washed successively with water (2.4 L) and saturated brine (2.4 L × 2). After concentration, (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (183 g, yield 92%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.66–7.60 (m, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.24–7.19 (m, 1H), 7.18 (d, J=2.5 Hz, 1H), 4.52 (s, 2H), 1.35–1.29 (m, 3H), 1.24–1.21 (m, 3H), 1.20–1.17 (m, 18H), 1.12 (d, J=7.3 Hz, 18H). LCMS (m / z): 543.3 (M + H).

[0361] Intermediates k2 and k3 [ka] tert-Butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (k3)

[0362] [ka]

[0363] Step A: Ethyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate Sodium hydride (60%, 0.73 g, 22 mmol) was added to a solution of 2-(2,6-dibromophenyl)acetonitrile (5.0 g, 18 mmol) in DMF (50 mL) in an ice bath under a nitrogen atmosphere. The reaction was stirred at 0 °C for 10 min. Ethyl isothiocyanatoformate (2.14 mL, 18 mmol) was slowly added to the reaction mixture. After the addition, the reaction was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then heated to 100 °C and stirred for 1 h. DMF was removed by concentration under reduced pressure. Water (100 mL) and ethyl acetate (10 mL) were added, and the resulting mixture was stirred at room temperature for 15 min. After stirring, a large amount of yellow solid precipitated. The solid was filtered, washed with water, and dried to give ethyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate (3.9 g) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 11.69 (s,1H), 7.93 (dd,J=8.0, 1.0Hz,1H), 7.60(dd,J=7.8, 1.0Hz,1H), 7.28 - 7.14 (m,1H), 4.24 (q,J=7.1Hz,2H), 1.29 (t,J=7.1Hz,3H).

[0364] Step B: 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile Sodium hydroxide (3.7 g, 93 mmol) was added to a solution of ethyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate (3.9 g, 12 mmol) in a mixture of DMSO (12 mL) and water (18 mL). The reaction was stirred at 125 °C for 16 h. The reaction was cooled to room temperature, poured into 100 mL of ice water, filtered, washed with water, and dried to give 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile (2.2 g) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 7.96 (s,2H), 7.70(dd,J=7.9, 1.0Hz,1H), 7.46 (dd,J=7.9, 1.0Hz,1H), 7.14 - 6.96 (m,1H).

[0365] Step C: tert-butyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate 4-Dimethylaminopyridine (104 mg, 0.85 mmol) and N,N-diisopropylethylamine (2.3 mL, 26 mmol) were added sequentially to a solution of 2-amino-4-bromobenzo[b]thiophene-3-carbonitrile (2.2 g, 8.7 mmol) in a mixture of DMF (29 mL) and THF (4.5 mL). Di-tert-butyl dicarbonate (2.2 mL, 9.5 mmol) was then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, water (100 mL) was added to the reaction mixture. A yellow solid precipitated. The solid was collected by filtration, washed with water, and dried to give tert-butyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate (1.4 g) as a pale yellow solid.

[0366] Step D: tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate tert-Butyl (4-bromo-3-cyanobenzo[b]thiophen-2-yl)carbamate (1.4 g, 3.9 mmol), bis(pinacolato)diboron (1.5 g, 5.9 mmol), potassium acetate (0.77 g, 7.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.3 g, 0.35 mmol) were added sequentially to a 50 mL round-bottom flask. 1,4-Dioxane (5 mL) was then added to the reaction flask. The reaction was then purged with nitrogen. The reaction was heated to 105 °C for 3 h. After completion of the reaction, the filtrate was collected by filtration and concentrated. The crude material was purified by FCC (SiO, petroleum ether / tetrahydrofuran 0-30%) to give tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (1.6 g) as a pale yellow solid. LCMS (m / z): 423.0 (M + Na).

[0367] Intermediate k4,k5,k5-A [ka] tert-Butyl (4-bromobenzo[b]thiophen-2-yl)carbamate (k4) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (k5)

[0368] [ka]

[0369] Step A: Methyl 4-bromobenzo[b]thiophene-2-carboxylate At room temperature, 2,6-dibromobenzaldehyde (15.7 g, 59.5 mmol), methyl mercaptoacetic acid (5.6 mL, 65.4 mmol), K2CO3 (15.7 g, 119.0 mmol), and DMF (200 mL) were added sequentially to a flask equipped with a magnetic stir bar, and the resulting mixture was heated to 110 °C and stirred for 10 h. After completion of the reaction (confirmed by TLC), the reaction solution was poured into 300 mL of water. A large amount of yellow solid precipitated and was filtered. The filter cake was washed with water and dried at 50 °C to give crude methyl 4-bromobenzo[b]thiophene-2-carboxylate (18 g). LCMS (m / z): 270.9 (M + H).

[0370] Step B: 4-Bromobenzo[b]thiophene-2-carboxylic acid LiOH·HO (5.4 mL, 129.7 mmol) and methyl 4-bromobenzo[b]thiophene-2-carboxylate (7.0 g, 25.9 mmol) were added sequentially to a mixture of THF (10 mL) and HO (2 mL). The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction (confirmed by LCMS), the pH of the system was adjusted to 3 with 1 M hydrochloric acid. The mixture was extracted with EA (60 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 1-benzothiophene-2-carboxylic acid (8.0 g). LCMS (m / z): 256.9 (M + H).

[0371] Step C: tert-butyl (4-bromobenzo[b]thiophen-2-yl)carbamate 4-Bromobenzo[b]thiophene-2-carboxylic acid (2.5 g), DPPA (3.2 mL, 14.7 mmol), DIEA (2.0 mL, 19.5 mmol), toluene (25 mL), and tert-butanol (1.4 mL, 14.7 mmol) were added sequentially to the reaction flask. The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was concentrated under reduced pressure. The crude product was purified by FCC (SiO, EA / PE = 0-30%) to give tert-butyl (4-bromo-1-benzothiophen-2-yl)carbamate (3.0 g). LCMS (m / z): 271.9 (M-56).

[0372] Step D: tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[b]thiophen-2-yl)carbamate tert-Butyl (4-bromobenzo[b]thiophen-2-yl)carbamate (2.9 g, 8.9 mmol), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborinane) (5.0 g, 22.3 mmol), DephosPdCl2 (0.64 g, 0.9 mmol), KOAc (2.6 g, 26.7 mmol), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. The system was purged with nitrogen three times. The reaction solution was stirred at 95 °C for 1 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was concentrated under reduced pressure. The crude product was purified by FCC (SiO2, EA / PE = 0-30%) to give tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[b]thiophen-2-yl)carbamate (3.1 g, yield 98%).

[0373] Intermediate k5-A was synthesized according to the protocol for intermediate k5, except that in step D, bis(pinacolato)diboron was used instead of 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborinane).

[0374] Intermediates k6 and k7 [ka] tert-Butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (k6) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (k7)

[0375] [ka]

[0376] Step A: Methyl 4-bromo-5-fluoro-1-benzothiophene-2-carboxylate Under a nitrogen atmosphere, potassium carbonate (37.5 g, 271.4 mmol) and methyl mercaptoacetic acid (17.3 g, 169.2 mmol) were added to a solution of 2-bromo-3,6-difluorobenzaldehyde (30 g, 135.7 mmol) in THF (500 mL) at room temperature. The resulting reaction solution was heated to 45 °C and stirred for 4 h, then heated to 90 °C and stirred for 16 h. After completion of the reaction (confirmed by LCMS), the reaction solution was concentrated to dryness. Water was added to the concentrated solution, followed by extraction with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by FCC (SiO2, DCM / PE = 0-8%) to give methyl 4-bromo-5-fluoro-1-benzothiophene-2-carboxylate (24.3 g, 62% yield) as an off-white solid. LCMS(m / z): 288.9 (M+H).

[0377] Step B: 4-Bromo-5-fluoro-1-benzothiophene-2-carboxylic acid Under a nitrogen atmosphere, lithium hydroxide monohydrate (10.6 g, 252.2 mmol) was added to a solution of methyl 4-bromo-5-fluoro-1-benzothiophene-2-carboxylate (24.3 g, 84.1 mmol) in THF (170 mL) and water (57 mL). The resulting mixture was continuously stirred at room temperature for 3 h. After completion of the reaction (confirmed by LCMS), the reaction solution was concentrated to dryness. Dilute aqueous hydrochloric acid (1 N) was added to the concentrated residue until the pH reached ∼5. After a solid precipitated, the mixture was continuously stirred at room temperature for 0.5 h and then filtered. The filter cake was rinsed with water and dried under vacuum to give 4-bromo-5-fluoro-1-benzothiophene-2-carboxylic acid (22.5 g, 98% yield) as an off-white solid. LCMS (m / z): 274.9 (M + H).

[0378] Step C: tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate Under a nitrogen atmosphere, triethylamine (11.6 g, 115.4 mmol) and diphenylphosphoryl azide (27.2 g, 98.9 mmol) were added to a solution of 4-bromo-5-fluoro-1-benzothiophene-2-carboxylic acid (22.5 g, 82.4 mmol) in anhydrous toluene (135 mL) and anhydrous tert-butanol (45 mL). The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was poured into 100 mL of saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by slurrying with EA / PE = 1 / 10 (80 mL) to give tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (28 g, 98% yield) as a yellow solid. LCMS(m / z): 289.9 (M+H).

[0379] Step D: tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate Under a nitrogen atmosphere, neopentyl glycol diborate (4.88 g, 21.7 mmol), potassium acetate (2.83 g, 28.9 mmol), and DPEphosPdCl (1.04 g, 1.45 mmol) were added to a solution of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (5 g, 14.5 mmol) in 1,4-dioxane (80 mL) at room temperature. The resulting reaction solution was heated to 90 °C and stirred for 16 h. After completion of the reaction (confirmed by LCMS), the reaction solution was filtered through Celite. The filter cake was rinsed with ethyl acetate, and the filtrate was concentrated to dryness. The crude product was purified by FCC (SiO, EA / PE = 0-10%) to give tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.2 g, 58% yield) as a white solid. LCMS (m / z): 256.0 (M + H-68-56). 1 H NMR (400MHz, DMSO-d6) δ 10.73 (s,1H), 7.86 - 7.77 (m,1H), 7.14 (d,J=0.7Hz,1H), 6.90(dd,J=9.8, 8.6Hz,1H), 3.81 (s,4H), 1.49 (s,9H), 1.02 (s,6H).

[0380] Intermediates k8 and k9 [ka] tert-Butyl (4-bromo-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate (k8) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate (k9)

[0381] [ka]

[0382] Step A: 1-(2-bromo-4-fluoro-6-methylphenyl)diazonium tetrafluoroborate A solution of sodium nitrite (9.5 g, 138.2 mmol) in water (20 mL) was slowly added to a solution of 2-bromo-4-fluoro-6-methylaniline (23.5 g, 115.2 mmol) in aqueous fluoroboric acid (140 mL, 50 wt%) at 0-5 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. After completion of the reaction (confirmed by LCMS), the reaction was filtered, and the filter cake was washed with aqueous fluoroboric acid (50 mL, 50 wt%) and ethyl acetate (50 mL). The filter cake was dried under vacuum to give an off-white solid product, 1-(2-bromo-4-fluoro-6-methylphenyl)diazonium tetrafluoroborate (31 g, 89% yield). LCMS (m / z): 216.9 (M + H).

[0383] Step B: 1-Bromo-2,5-difluoro-3-methylbenzene Under a nitrogen atmosphere, 1-(2-bromo-4-fluoro-6-methylphenyl)diazonium tetrafluoroborate was added to a single-necked flask equipped with a stir bar. The resulting mixture was heated to 170 °C and stirred for 7 h. After completion of the reaction (confirmed by LCMS), the crude product was purified by FCC (SiO2, PE) to give 1-bromo-2,5-difluoro-3-methylbenzene (16 g, 76% yield) as a colorless liquid. GCMS (m / z): 206.0 (M). 1 H NMR (400MHz, DMSO-d6) δ 7.55 - 7.48 (m,1H), 7.29 - 7.22 (m,1H), 2.28 (s,3H).

[0384] Step C: 2-Bromo-3,6-difluoro-4-methylbenzaldehyde To a solution of 1-bromo-2,5-difluoro-3-methylbenzene (16 g, 77.3 mmol) in anhydrous THF (150 mL) was slowly added dropwise LDA (46 mL, 2 M THF solution, 92.7 mmol) under a nitrogen atmosphere at −70 °C. After stirring the reaction at the same temperature for 40 min, anhydrous DMF (17 g, 231.9 mmol) was added to the reaction mixture. The resulting mixture was stirred at −70 °C for 1 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was poured into 100 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-4%) to give 2-bromo-3,6-difluoro-4-methylbenzaldehyde (15.5 g, 85% yield) as a pale yellow solid. LCMS(m / z): 236.9 (M+H).

[0385] Step D: Methyl 4-bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylate Potassium carbonate (18.2 g, 131.9 mmol) and methyl mercaptoacetic acid (8.4 g, 79.1 mmol) were added to a solution of 2-bromo-3,6-difluoro-4-methylbenzaldehyde (15.5 g, 66.0 mmol) in tetrahydrofuran (200 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 45 °C and stirred for 4 h, then heated to 90 °C and stirred for 16 h. After completion of the reaction (confirmed by LCMS), the reaction was concentrated to dryness, water was added to the residue, and then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the resulting crude product was purified by slurrying with EA (100 mL) to give methyl 4-bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylate (7.5 g, 37% yield) as a pale yellow solid. LCMS(m / z): 302.9 (M+H).

[0386] Step E: 4-Bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylic acid To a solution of methyl 4-bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylate (7.5 g, 24.7 mmol) in tetrahydrofuran (60 mL) and water (20 mL) was added lithium hydroxide monohydrate (3.1 g, 74.3 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction (as confirmed by LCMS), the reaction was concentrated. Dilute aqueous hydrochloric acid (1 N) was added to the concentrate until the pH reached ∼5, causing a solid to precipitate. The mixture was stirred at room temperature for an additional 0.5 h and then filtered. The filter cake was washed with water and dried under vacuum to give 4-bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylic acid (6.7 g, 94% yield) as an off-white solid. LCMS (m / z): 288.9 (M + H).

[0387] Step F: tert-butyl (4-bromo-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate Under a nitrogen atmosphere, triethylamine (3.3 g, 32.6 mmol) and diphenyl azidophosphate (7.7 g, 27.9 mmol) were added to a solution of 4-bromo-5-fluoro-6-methylbenzo[b]thiophene-2-carboxylic acid (6.7 g, 23.3 mmol) in anhydrous toluene (40 mL) and anhydrous tert-butanol (13 mL). The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction (as confirmed by LCMS), the reaction was poured into 100 mL of saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by slurrying with EA / PE = 1 / 10 (30 mL) to give tert-butyl (4-bromo-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate (7.1 g, 85% yield) as a yellow solid. LCMS (m / z): 303.9 (M + H-56).

[0388] Step G: tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate To a solution of tert-butyl (4-bromo-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate (3.0 g, 8.3 mmol) in 1,4-dioxane (48 mL) was added neopentyl glycol diborate (2.8 g, 12.5 mmol), potassium acetate (1.63 g, 16.6 mmol), and DPEphosPdCl (594 mg, 0.83 mmol) at room temperature. The resulting mixture was heated to 90 °C and stirred for 16 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was filtered through Celite, the filter cake was eluted with ethyl acetate, the filtrate was concentrated and dried, and the resulting crude product was purified by FCC (SiO, EA / PE = 0-10%) to give tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-6-methylbenzo[b]thiophen-2-yl)carbamate (1.5 g, 46% yield) as a white solid product. LCMS (m / z): 270.0 (M + H-68-56). 1 H NMR (400MHz, DMSO-d6) δ 10.65 (s,1H), 7.68 (d,J=7.1Hz,1H), 7.06 (s,1H), 3.80(s,4H), 2.24 (d, 3H), 1.48 (s,9H), 1.02 (s,6H).

[0389] Intermediates k10 and k11 [ka] tert-Butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (k10) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (k11)

[0390] [ka]

[0391] Step A: 2-Bromo-3,6-difluoro-5-nitrobenzaldehyde Concentrated sulfuric acid (90 mL) was slowly added dropwise to fuming nitric acid (42.7 g, 678.7 mmol) in a three-necked bottle with stirring at 0 °C, and the resulting mixture was stirred at the same temperature for 10 min. 2-Bromo-3,6-difluorobenzaldehyde (30 g, 135.7 mmol) was added batchwise to the reaction mixture, and the reaction mixture was stirred at 0 °C for 10 min. The resulting reaction solution was stirred at room temperature for 1 h. After completion of the reaction (confirmed by LCMS), the reaction solution was slowly poured into ice-cold water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by FCC (SiO2, EA / PE = 0-10%) to give 2-bromo-3,6-difluoro-5-nitrobenzaldehyde (31.3 g, 87% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.18 (s,1H), 8.61 (dd,J=8.0, 6.5Hz,1H)

[0392] Step B: Methyl 4-bromo-5-fluoro-7-nitrobenzo[b]thiophene-2-carboxylate Potassium carbonate (23.4 g, 169 mmol) and methyl mercaptoacetate (14.4 g, 135 mmol) were added to a solution of 2-bromo-3,6-difluoro-5-nitrobenzaldehyde (30.0 g, 113 mmol) in DMF (300 mL) at 0 °C. The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was slowly added to ice-cold water, filtered, and the filter cake was purified by slurrying (EA / PE = 2 / 1) to give methyl 4-bromo-5-fluoro-7-nitrobenzo[b]thiophene-2-carboxylate (15 g, 40% yield) as a yellow solid. LCMS (m / z): 333.9 (M + H).

[0393] Step C: Methyl 7-amino-4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate To a solution of methyl 4-bromo-5-fluoro-7-nitrobenzo[b]thiophene-2-carboxylate (15.0 g, 44.9 mmol) in ethanol (130 mL) and acetic acid (20 mL), iron powder (12.0 g, 224 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 2 h. After completion of the reaction (confirmed by LCMS), the reaction was filtered through Celite. The filtrate was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the target product, methyl 7-amino-4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (10.0 g, 74% yield). LCMS (m / z): 303.9 (M + H).

[0394] Step D: Methyl 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylate To a solution of methyl 7-amino-4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (9.5 g, 31.2 mmol) in tetrafluoroboric acid (80 mL, 40 wt% aqueous solution) was added sodium nitrite (4.1 g, 46.9 mmol), and the reaction was stirred at room temperature for 1 h. LCMS monitoring confirmed complete conversion of the starting material to the diazonium salt, and the reaction solution was filtered, and the filter cake was collected as a yellow solid. The resulting yellow solid was stirred at 200 °C for 20 min. After completion of the reaction (as confirmed by LCMS), the crude material was purified by FCC (SiO2, EA / PE = 0 - 45%) to give methyl 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylate (1.6 g, 17% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.03 (d,J=3.3Hz,1H), 7.81 (dd,J=9.8, 9.2Hz,1H), 3.93 (s,3H). 19 F NMR (376 MHz, DMSO-d) δ -106.95 to -106.97, -112.37 to -112.40 and 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid (1.4 g, yield 15%) were obtained. 1H NMR (400MHz, DMSO-d6) δ 14.11 (s,1H), 8.01 (d,J=3.3Hz,1H), 7.83 - 7.75 (m,1H). 19 F NMR (376MHz, DMSO-d6) δ-107.30-107.32,-112.50-112.52.

[0395] Step E: 4-Bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid To a solution of methyl 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylate (1.6 g, 5.2 mmol) in tetrahydrofuran (10 mL), methanol (3 mL), and water (3 mL) was added lithium hydroxide monohydrate (656 mg, 15.6 mmol), and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (as confirmed by LCMS), water (30 mL) and 1N hydrochloric acid solution (5 mL) were added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give crude 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid (1.4 g, 92% yield).

[0396] Step F: tert-butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate To a solution of 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid (2.8 g, 9.5 mmol) in toluene (40 mL) and tert-butanol (10 mL), triethylamine (2.9 g, 28.4 mmol) and phosphoryl azide diphenyl ether (3.7 g, 14.3 mmol) were added at room temperature. The resulting mixture was heated to 100 °C and stirred for 12 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was concentrated to dryness, and the resulting crude product was purified by FCC (SiO2, EA / PE = 0-15%) to give tert-butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (3.0 g, 86% yield) as a yellow solid. LCMS (m / z): 307.8 (M-56).

[0397] Step G: tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate Under a nitrogen atmosphere, neopentyl glycol diborate (2.0 g, 8.9 mmol), potassium acetate (2.0 g, 20.6 mmol), and DPEphosPdCl (501 mg, 0.7 mmol) were added to a solution of tert-butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (2.5 g, 6.8 mmol) in 1,4-dioxane (40 mL) at room temperature. The resulting mixture was heated to 90 °C and stirred for 5 h. After completion of the reaction (confirmed by GCMS), the reaction mixture was concentrated to dryness, and the resulting crude product was purified by FCC (SiO, EA / PE = 0-10%) to give tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (1.4 g, 51% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 10.98 (s,1H), 7.24 (d,J=3.8Hz,1H), 7.00 - 6.91 (m,1H), 3.80(s,4H), 1.01 (s,6H). 19 F NMR (376MHz, DMSO-d6) δ-103.69 --103.85,-111.30 --111.46.

[0398] Intermediates K12 and K13 [ka] tert-Butyl (4-bromo-7-fluorobenzo[b]thiophen-2-yl)carbamate (k12) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (k13) [ka]

[0399] Step A: Methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate At room temperature, 6-bromo-2,3-difluorobenzaldehyde (15 g, 68.2 mmol), methyl mercaptoacetic acid (6.7 mL, 75 mmol), K2CO3 (18.8 g, 13.6 mmol), and DMF (150 mL) were added, in order, to a reaction flask equipped with a stir bar. The resulting mixture was heated to 110 °C and stirred for 10 h. After completion of the reaction (as confirmed by TLC), the reaction mixture was poured into 300 mL of water. The large amount of precipitated yellow solid was filtered, and the filter cake was washed with water and dried at 50 °C to give methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (13 g, 66% yield). GCMS (m / z): 288 / 290 (M · + ). 1 H NMR (400 MHz, chloroform-d) δ 8.16–8.13 (m, 1H), 7.55–7.47 (m, 1H), 7.08–6.98 (m, 1H), 3.98 (s, 3H). 19 F NMR (376MHz, chloroform-d) δ-116.23.

[0400] Step B: 4-Bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid LiOH·HO (7.3 g, 173.6 mmol) and methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (10 g, 34.7 mmol) were added sequentially to a mixture of THF (100 mL) and HO (20 mL), and the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction (confirmed by LCMS), the pH of the system was adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with EA (80 mL × 3). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (9.3 g, 98% yield).

[0401] Step C: tert-butyl (4-bromo-7-fluorobenzo[b]thiophen-2-yl)carbamate 4-Bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (9.3 g), DPPA (11 mL, 51 mmol), DIPEA (8.8 mL, 51 mmol), toluene (100 mL), and tert-butanol (4.8 mL, 51 mmol) were added sequentially to the reaction flask, and the resulting mixture was stirred for 16 h at 100 °C. After completion of the reaction (confirmed by LCMS), the crude material was concentrated under reduced pressure and purified by FCC (SiO, EA / PE = 0-30%) to give tert-butyl (4-bromo-7-fluorobenzo[b]thiophen-2-yl)carbamate (10 g, 85% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.40–7.34 (m, 2H), 6.84–6.73 (m, 2H), 1.56 (s, 9H). 19 F NMR (376MHz, chloroform-d) δ-118.33.

[0402] Step D: tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-Butyl (4-bromo-7-fluorobenzo[b]thiophen-2-yl)carbamate (10 g, 29 mmol), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborinane) (24.9 g, 110 mmol), DPEPhosPdCl (2.1 g, 2.9 mmol), KOAc (8.5 g, 87 mmol), and 1,4-dioxane (150 mL) were added sequentially to a reaction flask and degassed three times with nitrogen. The resulting mixture was stirred at 95 °C for 1 h. After completion of the reaction (confirmed by LCMS), the crude material was concentrated under reduced pressure and purified by FCC (SiO, EA / PE = 0-30%) to give tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (12 g). LCMS (m / z): 255.9 (M + H-68-56).

[0403] Intermediate K14 [ka] tert-Butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0404] Intermediate k14 was synthesized and characterized according to the method described in WO 2021 / 118877A1.

[0405] Intermediate a1 [ka] (3-Fluoro-1-methylpiperidin-3-yl)methanol

[0406] [ka]

[0407] Step A: (3-fluoro-1-methylpiperidin-3-yl)methanol Under a nitrogen (N2) atmosphere, 2-methyltetrahydrofuran (5 mL) was added to methyl 3-fluoro-1-methylpiperidine-3-carboxylate (200 mg, 0.76 mmol). Subsequently, lithium aluminum hydride (1.5 mL, 1.5 mmol, 1.0 mol / L solution in tetrahydrofuran) was slowly added dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 5 hours. After completion of the reaction (confirmed by LCMS), the reaction was quenched by sequentially adding 1 mL of water and 30 mL of ethyl acetate. The resulting mixture was filtered through Celite, and the filtrate was concentrated and dried to give crude (3-fluoro-1-methylpiperidin-3-yl)methanol (130 mg, 77% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 4.89 (s,1H), 3.53 - 3.27 (m,3H), 2.48 - 2.22 (m,2H), 2.21 - 2.04 (m,4H), 1.65 - 1.42 (m,4H). 19F NMR (376MHz, DMSO-d6) δ-165.75.

[0408] intermediate a2 [ka] (1,3-Dimethylpiperidin-3-yl)methanol

[0409] [ka]

[0410] Step A: (1,3-Dimethylpiperidin-3-yl)methanol Under a nitrogen (N2) atmosphere, 2-methyltetrahydrofuran (2 mL) was added to methyl 3-fluoro-1-methylpiperidine-3-carboxylate (300 mg, 1.23 mmol). Then, lithium aluminum hydride (2.5 mL, 2.5 mmol, 1.0 mol / L solution in tetrahydrofuran) was slowly added dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 4 hours. After completion of the reaction (confirmed by LCMS), the reaction was quenched by sequentially adding 1 mL of water and 30 mL of ethyl acetate. The resulting mixture was filtered through Celite, and the filtrate was concentrated to dryness to give crude (3-fluoro-1-methylpiperidin-3-yl)methanol (150 mg, 85% yield) as a colorless oil. LCMS (m / z): 144.0 (M + H).

[0411] Intermediate a3 [ka] (1-(2-Methoxyethyl)-3-methylpiperidin-3-yl)methanol

[0412] [ka]

[0413] Step A: 3-Methylpiperidine-3-carboxylic acid trifluoroacetate Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid (700 mg, 2.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to give a yellow solid crude product, 3-methylpiperidine-3-carboxylic acid trifluoroacetate (500 mg, crude), which was used directly in the subsequent reaction.

[0414] Step B: 2-Methoxyethyl 1-(2-methoxyethyl)-3-methylpiperidine-3-carboxylate To 3-methylpiperidine-3-carboxylic acid (300 mg) in DMF (5 mL), potassium carbonate (1.45 g, 10.5 mmol), and 1-bromo-2-methoxyethane (728 mg, 21.1 mmol) were added sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction was confirmed by TLC (100% EtOAc), the reaction was filtered, concentrated to dryness, and the crude product was purified by FCC (SiO, EtOAc / PE = 50-100%) to give crude 2-methoxyethyl 1-(2-methoxyethyl)-3-methylpiperidine-3-carboxylate (290 mg) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ 4.28 - 4.18 (m,2H), 3.59 (t,J=4.8Hz,2H), 3.49 (t,J=6.1Hz,2H), 3.38 (s,3H), 3.33 (s,3H), 3.14 - 3.02 (m,1H), 2.66 - 2.43 (m,3H), 2.26 - 1.87 (m,4H), 1.72 - 1.55 (m,2H), 1.15 (s,3H).

[0415] Step C: (1-(2-methoxyethyl)-3-methylpiperidin-3-yl)methanol Under a N2 atmosphere, anhydrous tetrahydrofuran (2 mL) was added to 2-methoxyethyl 1-(2-methoxyethyl)-3-methylpiperidine-3-carboxylate (230 mg, 0.09 mmol). Lithium aluminum hydride (2.2 mL, 2.2 mmol, 1.0 mol / L solution in tetrahydrofuran) was slowly added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. After completion of the reaction (confirmed by LCMS), the reaction was quenched by the sequential addition of 1 mL of water and 30 mL of ethyl acetate. The resulting mixture was filtered through Celite, and the filtrate was concentrated and dried to give crude (1-(2-methoxyethyl)-3-methylpiperidin-3-yl)methanol (110 mg, 66% yield) as a yellow oil. LCMS (m / z): 188.1 (M + H).

[0416] Intermediate a4 [ka] (1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol

[0417] [ka]

[0418] Step A: 2-Fluoroethyl 1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate Potassium carbonate (965 mg, 6.9 mmol) and 1-fluoro-2-iodoethane (607 mg, 3.5 mmol) were added sequentially to a solution of 3-methylpiperidine-3-carboxylic acid (200 mg, 1.4 mmol) in DMF (5 mL) at room temperature. The resulting solution was stirred at room temperature for 12 hours. After completion of the reaction (confirmed by TLC, 100% EtOAc), the reaction was filtered and concentrated to dryness. The resulting crude product was purified by FCC (SiO, EtOAc / PE = 50-100%) to give 2-fluoroethyl 1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate (180 mg, 55% yield). 1H NMR (400MHz, chloroform-d) δ 4.69 - 4.63 (m,1H), 4.62 - 4.57 (m,1H), 4.56 - 4.51 (m,1H), 4.49 - 4.44 (m,1H), 4.41 - 4.28 (m,2H), 2.74 - 2.59 (m,2H), 2.22 - 1.97 (m,4H), 1.75 - 1.53 (m,4H), 1.17 (s,3H). LCMS(m / z): 236.0(M+H).

[0419] Step B: (1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol Under a nitrogen (N2) atmosphere, anhydrous tetrahydrofuran (2 mL) was added to 2-fluoroethyl 1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate (180 mg, 0.76 mmol). Lithium aluminum hydride (2.3 mL, 2.3 mmol, 1.0 mol / L solution in tetrahydrofuran) was slowly added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 30 minutes. After completion of the reaction (confirmed by LCMS), the reaction was quenched by sequentially adding 1 mL of water and 30 mL of ethyl acetate. The resulting mixture was filtered through Celite, and the filtrate was concentrated and dried to give crude (1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol (100 mg, 74% yield) as a yellow oil. LCMS (m / z): 176.1 (M + H).

[0420] Intermediate a5 [ka] (4-Methoxy-1,3-dimethylpiperidin-3-yl)methanol

[0421] [ka]

[0422] Step A: 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate At room temperature, CHCl (13.79 g, 97.17 mmol) was added dropwise to a mixture of 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (5.0 g, 19.43 mmol), KCO (8.06 g, 58.30 mmol), and anhydrous acetonitrile (50 mL) with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature overnight. After completion of the reaction was confirmed by TLC, the reaction solution was poured into NHCl (100 mL) and extracted with EA (100 mL × 3). The combined organic phases were washed with saturated NaCl (50 mL), concentrated, and purified by FCC (SiO, EA / PE = 0-20%) to give 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate (4.85 g, 92% yield) as a colorless oil. LCMS (m / z): 216.0 (M + H-56). 1 H NMR (400 MHz, methanol-d4) δ 4.51 (d, J = 13.7 Hz, 1H), 4.23 - 4.05 (m, 1H), 3.73 (s, 3H), 3.47 - 3.27 (m, 1H), 3.17 (d, J = 13.7 Hz, 1H), 2.75 (s, 1H), 2.57 - 2.41 (m, 1H), 1.50 (s, 9H), 1.28 (s, 3H).

[0423] Step B: 1-(tert-butyl)3-methyl 4-hydroxy-3-methylpiperidine-1,3-dicarboxylate NaBH4 (230 mg, 6.08 mmol) was added to a mixture of 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate (1.5 g, 5.53 mmol) and MeOH (15 mL) in an ice bath, and the reaction mixture was stirred at room temperature for 15 min until the disappearance of the starting material was confirmed by TLC. The reaction mixture was poured into NH4Cl (50 mL) and extracted with EA (50 mL x 3). The collected organic phase was washed with saturated NaCl (30 mL). The organic solution was concentrated, and the crude product was purified by FCC (SiO2, EA / PE = 0-60%) to give 1-(tert-butyl) 3-methyl 4-hydroxy-3-methylpiperidine-1,3-dicarboxylate (800 mg, 53% yield) as a colorless oil. LCMS (m / z): 218.0 (M + H -56). 1 H NMR (400 MHz, methanol-d4) δ 3.91–3.83 (m,1H), 3.71–3.66 (m,3H), 3.64–3.47 (m,3H), 1.90–1.78 (m,1H), 1.73–1.56 (m,1H), 1.45 (s,9H), 1.14 (s,3H).

[0424] Step C: 1-(tert-butyl)3-methyl 4-methoxy-3-methylpiperidine-1,3-dicarboxylate NaH (219 mg, 5.49 mmol, 60%) was added to a mixture of 1-(tert-butyl) 3-methyl 4-hydroxy-3-methylpiperidine-1,3-dicarboxylate (500 mg, 1.83 mmol) and DMF (12 mL) and stirred in an ice bath for 20 min. CHCl (1.3 g, 9.15 mmol) was then added to the above solution and stirred in an ice bath for 3 h. After completion of the reaction (confirmed by TLC), the reaction mixture was poured into aqueous NHCl (80 mL) and extracted with EA (50 mL × 3). The combined organic phase was washed with saturated NaCl (20 mL), and the crude product obtained after concentration was subjected to FCC (SiO, EA / PE = 0-20%) to give 1-(tert-butyl) 3-methyl 4-methoxy-3-methylpiperidine-1,3-dicarboxylate (350 mg, 67% yield) as a colorless oily liquid. LCMS(m / z): 232.0(M + H-56).

[0425] Step D: (4-Methoxy-1,3-dimethylpiperidin-3-yl)methanol LiAH4 (5.39 mL, 5.39 mmol, 1 M in THF) was added to 1-(tert-butyl) 3-methyl 4-methoxy-3-methylpiperidine-1,3-dicarboxylate (310 mg, 1.08 mmol), and the reaction was heated to 70 °C and stirred for 2 h. After confirming the completion of the reaction by LCMS, the LiAlH4 was quenched by slowly adding Na2SO4·10H2O to the reaction mixture under ice-bath conditions until no further gas evolution was observed. Anhydrous sodium sulfate was then added to dry the solution. The solution was filtered, and the mother liquor was collected and concentrated to give (4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (170 mg, 91% yield) as a colorless liquid. LCMS (m / z): 174.0 (M + H). 1 H NMR (400MHz, methanol-d4) δ 3.69 - 3.52 (m,2H), 3.34 (s,3H), 3.22 - 3.03 (m,1H), 2.80 - 2.42 (m,2H), 2.33 - 2.17 (m,4H), 2.13 - 1.50(m,4H), 1.08 - 0.88(m,3H).

[0426] Intermediate a5A [ka]

[0427] The compound 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate (120 g) was separated by SFC (SFC150, Waters) (separation column: DAICEL CHIRALPAK (登録商標) IG, 250*50 mm, 10 μm; mobile phase: CO2 / MeOH=90 / 10; flow rate: 120 mL / min). The first eluted isomer (isomer 1) was obtained as compound a5A (52.8 g, with a shorter retention time). Chiral analytical method: SFC-3, Rt=0.682 min. 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 later-eluting isomer (isomer 2) was obtained as compound a5B (52.4 g, longer retention time). Chiral analysis method SFC-3, Rt = 1.035 min. 1 H NMR (400 MHz, chloroform-d) δ 4.60 - 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).

[0428] Intermediate a5A-1 [ka] (3S)-(4-Methoxy-1,3-dimethylpiperidin-3-yl)methanol

[0429] [ka]

[0430] Step A: 1-(tert-butyl) 3-methyl (3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylate Under ice bath, NaBH4 (279 mg, 7.37 mmol) was added batchwise to a solution of 1-(tert-butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate a5A, 2.0 g, 7.37 mmol) in MeOH (50 mL). The mixture was stirred under ice bath conditions for 10 min, and the disappearance of the starting material was confirmed by TLC. Subsequently, the reaction solution was poured into NH4Cl (100 mL) and extracted with EA (100 mL × 3). The collected organic phase was washed with saturated aqueous NaCl solution (30 mL). The crude product was concentrated, and the organic phase was purified by FCC (SiO, EA / PE = 0%-40%) to give 1-(tert-butyl) 3-methyl(3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylate (1.7 g, 85% yield) as a colorless oil. LCMS (m / z): 218.1 (M + H-56). 1 H NMR (400 MHz, chloroform-d) δ 4.05 - 3.93 (m, 1H), 3.78 - 3.70 (m, 3H), 3.69 - 3.59 (m, 2H), 3.35 - 3.22 (m, 1H), 3.20 - 3.10 (m, 1H), 1.97 - 1.82 (m, 1H), 1.77 - 1.63 (m, 1H), 1.54 - 1.40 (m, 9H), 1.29 - 1.18 (m, 3H).

[0431] Step B: 1-(tert-butyl) 3-methyl (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylate NaH (439 mg, 10.94 mmol, 60%) was added to a mixture of 1-(tert-butyl) 3-methyl(3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylate (1.0 g, 3.66 mmol) and DMF (10 mL). The reaction was stirred in an ice bath for 20 min. CHCl (1.56 g, 10.94 mmol) was then added to the mixture, and the mixture was stirred in an ice bath for an additional 3 h. After completion of the reaction (confirmed by TLC), the reaction was poured into saturated aqueous NHCl (80 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (20 mL) and concentrated. The crude product was purified by FCC (SiO, EA / PE = 0-40%) to give 1-(tert-butyl) 3-methyl (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylate (1.0 g, 95% yield) as a white solid. LCMS (m / z): 232.1 (M + H-56). 1 H NMR (400 MHz, chloroform-d3) δ 3.98 - 3.78 (m,1H), 3.75 - 3.61 (m,4H), 3.56 - 3.47 (m,1H), 3.46 - 3.36 (m,1H), 3.34 (s,1H), 3.30(s,2H), 3.19 - 2.86 (m,1H), 1.89 - 1.56 (m,2H), 1.45 (s,9H), 1.16 (s,3H).

[0432] Step C: (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol LiAH (2.04 mL, 2.04 mmol, 1M in THF) was added to 1-(tert-butyl) 3-methyl(3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylate (200 mg, 0.696 mmol) at room temperature, and the reaction was heated to 70 °C and stirred for 2 h. After completion of the reaction (as confirmed by LCMS), the reaction was quenched by slowly adding NaSO·10H O to the LiAH in an ice bath until no further gas evolution was observed. The mixture was diluted with a small amount of EA, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (120 mg, 99% yield) as a colorless liquid. LCMS (m / z): 174.1 (M + H). 1 H NMR (400 MHz, chloroform-d3) δ 3.95 - 3.53 (m,4H), 3.30 (s,2H), 3.27 (s,1H), 3.13 - 2.55 (m,2H), 2.16 (s,1H), 2.13 (s,2H), 2.04 - 1.81 (m,3H), 0.89 (s,1H), 0.83 (s,2H).

[0433] Intermediate a5A-2 [ka] ((3S)-1-Ethyl-4-methoxy-3-methylpiperidin-3-yl)methanol

[0434] Intermediate a5A-2 was synthesized according to the method described for intermediate a6A-2.

[0435] intermediate a6 [ka] (4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methanol

[0436] [ka]

[0437] Step A: 1-(tert-butyl)3-methyl 4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate DAST (4.87 mL, 5.94 g, 36.86 mmol) was added to a mixture of 1-(tert-butyl) 3-methyl-4-oxopiperidine-1,3-dicarboxylate (1.0 g, 3.69 mmol) and DCM (10 mL). The reaction mixture was heated to 50 °C at room temperature and allowed to react overnight. After completion of the reaction (confirmed by LCMS), the reaction mixture was cooled to room temperature, slowly poured into saturated aqueous NaHCO3, and extracted with EA (100 mL × 3). The combined organic phase was washed with saturated NaCl (50 mL). The crude product obtained by concentrating the organic solution was purified by FCC (SiO2, EA / PE = 0-10%) to give 1-(tert-butyl) 3-methyl 4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (290 mg, 27% yield) as a colorless oil. LCMS(m / z): 238.0(M + H-56).

[0438] Step B: (4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methanol LiAH (4.94 mL, 4.94 mmol, 1 M in THF) was added to 1-(tert-butyl) 3-methyl 4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (290 mg, 989 μmol) at room temperature. The reaction was heated to 70 °C and stirred for 2.5 h. After completion of the reaction (as confirmed by LCMS), NaSO·10H O was slowly added to the LiAH in an ice bath to quench the reaction until no further gas evolution was observed. The mixture was diluted with EA, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give (4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (170 mg, 96% yield) as a colorless liquid. LCMS (m / z): 180.0 (M + H).

[0439] Intermediate a6A-1 [ka] (S)-(4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methanol

[0440] [ka]

[0441] Step A: 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate BAST (19.57 g, 16.3 mL, 88.46 mmol) was added to a solution of 1-(tert-butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate a5A, 8.0 g, 29.49 mmol) in DCM (40 mL), and the reaction was stirred at 50 °C overnight. After completion of the reaction (confirmed by LCMS), the reaction was slowly poured into saturated aqueous NaHCO (100 mL) and extracted with DCM (100 mL × 3). The combined organic phases were concentrated and then purified (SiO, EA / PE = 0-10%) to give 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (3.2 g, 37% yield) as a colorless oil. LCMS (m / z): 238.1 (M-56 + H).

[0442] Step B: (S)-(4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methanol LiAH4 (18.62 mL, 18.62 mmol, 1M in THF) was added to 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (1.82 g, 6.21 mmol) at room temperature, and the mixture was heated to 70 °C and stirred for 2 h. After completion of the reaction (confirmed by LCMS), the reaction was quenched by slowly adding Na2SO4·10H2O to the LiAH4 in an ice bath until no further gas evolution was observed. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to give (S)-(4,4-difluoro-1,3-dimethylpiperidin-3-yl)methanol (1 g, 91% yield) as a colorless oil. LCMS (m / z): 180.1 (M + H).

[0443] Intermediate a6A-2 [ka] (S)-(4,4-Difluoro-1,3-dimethylpiperidin-3-yl)methanol

[0444] [ka]

[0445] Step A: 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate 1-(tert-Butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (a5A, 10 g, 36.86 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran and degassed with nitrogen three times. The reaction mixture was cooled to 0 °C in an ice bath, and [bis(2-methoxyethyl)amine] sulfur trifluoride (24.46 g, 20.39 mL, 110.57 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. After TLC showed the reaction was complete, the reaction solution was poured into 500 mL of half-saturated aqueous sodium bicarbonate and stirred for 10 min until no further bubbles were observed. This mixture was extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by FCC (SiO, EA / PE = 0-17%) to give a colorless oily product, 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (4.88 g, 43% yield). LCMS (m / z): 187.9 (M-56 + H). 1H NMR (400 MHz, chloroform-d) δ 4.09 - 3.79 (m, 1H), 3.74 (s, 3H), 3.70 - 3.15 (m, 3H), 2.60 - 2.18 (m, 1H), 2.07 - 1.91 (m, 1H), 1.45 (s, 9H), 1.33 (s, 3H).

[0446] Step B: Methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride 4 M HCl-dioxane (30 mL) was added to 1-(tert-butyl) 3-methyl (S)-4,4-difluoro-3-methylpiperidine-1,3-dicarboxylate (3.1 g, 10.57 mmol) at room temperature, and the resulting mixture was stirred for 1 h. The solution was concentrated under reduced pressure and then concentrated twice with EA (20 mL) to give methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride (2.3 g, 95% yield) as a white solid.

[0447] Step C: Methyl (S)-1-ethyl-4,4-difluoro-3-methylpiperidine-3-carboxylate Potassium carbonate (429.22 mg, 3.11 mmol) and iodoethane (484.38 mg, 3.11 mmol) were added sequentially to a solution of methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride (200 mg, 1.04 mmol) in acetonitrile (2 mL) at room temperature, and the resulting mixture was stirred at 90 °C overnight. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered through Celite, and the filter cake was washed twice with acetonitrile. The filtrate was collected, concentrated, and dried to give the oily product methyl (S)-1-ethyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (110 mg, 48% yield), which was used directly in the next step without further purification. LCMS (m / z): 222.1 (M + H).

[0448] Step D: (S)-(4,4-difluoro-1-(ethyl)-3-methylpiperidin-3-yl)methanol A 1M LiAlH4-THF solution (0.95 mL, 0.95 mmol) was added dropwise to a solution of methyl (S)-1-ethyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (110 mg, 0.474 mmol) in anhydrous tetrahydrofuran (5 mL) in an ice bath. The resulting mixture was stirred at room temperature for 20 minutes. After completion of the reaction (as confirmed by TLC), the reaction was quenched by the addition of Na2SO4·10H2O until no further bubbling was observed, and then dried by the addition of approximately 5 grams of anhydrous sodium sulfate. The resulting mixture was filtered through Celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected, concentrated, and dried to give the colorless oily product (S)-(4,4-difluoro-1-(ethyl)-3-methylpiperidin-3-yl)methanol (90 mg, 98% yield), which was used directly in the next step without further purification. LCMS(m / z): 194.1 (M+H).

[0449] Intermediate a6A-3 [ka] (S)-(4,4-Difluoro-1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol

[0450] [ka]

[0451] Step A: Methyl (S)-4,4-difluoro-1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate Potassium carbonate (429 mg, 3.11 mmol) and 1-fluoro-2-iodoethane (540 mg, 3.11 mmol) were added, in order, to a solution of methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride (200 mg, 1.04 mmol) in acetonitrile (2 mL), and the resulting mixture was stirred at 90 °C overnight. After completion of the reaction (confirmed by LCMS), the reaction mixture was filtered through Celite, and the filter cake was washed twice with acetonitrile. The filtrate was collected, concentrated, and dried to give the colorless oily product, methyl (S)-4,4-difluoro-1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate (180 mg, 73% yield), which was used directly in the next step without further purification. LCMS (m / z): 240.1 (M + H).

[0452] Step B: (S)-(4,4-difluoro-1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol Under ice-bath conditions, 1M LiAlH4-THF solution (1.5 mL, 1.50 mmol) was added dropwise to a solution of methyl (S)-4,4-difluoro-1-(2-fluoroethyl)-3-methylpiperidine-3-carboxylate (180 mg, 0.752 mmol) in anhydrous tetrahydrofuran (5 mL). The reaction was stirred at room temperature for 20 minutes. After completion of the reaction (confirmed by LCMS), Na2SO4·10H2O was added to quench the reaction until no more bubbles were observed. The resulting mixture was dried over approximately 5 grams of anhydrous sodium sulfate. The resulting mixture was filtered through Celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected, concentrated, and dried to give the colorless oily product (S)-(4,4-difluoro-1-(2-fluoroethyl)-3-methylpiperidin-3-yl)methanol (155 mg, 98% yield). This was used directly in the next step without purification. LCMS (m / z): 212.1 (M + H).

[0453] Intermediate a6A-4 [ka] (S)-(4,4-Difluoro-1-allyl-3-methylpiperidin-3-yl)methanol

[0454] [ka]

[0455] Step A: Methyl (S)-1-allyl-4,4-difluoro-3-methylpiperidine-3-carboxylate At room temperature, 3-bromopropyl-1-ene (316 mg, 2.61 mmol) was added to a mixture of methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride (200 mg, 0.871 mmol), K2CO3 (463 mg, 2.61 mmol), and ACN (5 mL). The reaction was heated to 90 °C and stirred overnight. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered through Celite. The collected filtrate was concentrated and purified by FCC (SiO2, EA / PE = 0-20%) to give the colorless oily product, methyl (S)-1-allyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (160 mg, 79% yield). LCMS (m / z): 234.1 (M + H).

[0456] Step B: (S)-(1-allyl-4,4-difluoro-3-methylpiperidin-3-yl)methanol LiAH4 (1.37 mL, 1.37 mmol, 1 M THF solution) was added to methyl (S)-1-allyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (160 mg, 0.686 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 10 min. After completion of the reaction (confirmed by TLC), the reaction mixture was quenched by slowly adding Na2SO4·10H2O to the LiAH4 under ice-bath conditions until no further gas evolution was observed. The resulting mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to give a colorless oily liquid (S)-(1-allyl-4,4-difluoro-3-methylpiperidin-3-yl)methanol (140 mg, 99% yield). LCMS (m / z): 206.1 (M + H).

[0457] Intermediate a6A-5 [ka] (S)-(4,4-Difluoro-1-cyclopropyl-3-methylpiperidin-3-yl)methanol

[0458] [ka]

[0459] Step A: Methyl (S)-1-cyclopropyl-4,4-difluoro-3-methylpiperidine-3-carboxylate A mixture of methyl (S)-4,4-difluoro-3-methylpiperidine-3-carboxylate hydrochloride (300 mg, 1.31 mmol), cyclopropyl borate (449 mg, 5.23 mmol), K2CO3 (542 mg, 3.92 mmol), and Cu(OAc)2 (23.73 mg, 0.131 mmol) in DCM (20 mL) was stirred at 40 °C for 3 days under an air atmosphere. After completion of the reaction (confirmed by LCMS), the reaction mixture was poured into H2O (20 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, concentrated, and purified by FCC (SiO2, EA / PE = 0-15%) to give colorless oily liquid methyl (S)-1-cyclopropyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (67 mg, 22% yield). LCMS (m / z): 234.1 (M + H). 1 H NMR (400MHz, CDCl3) δ 3.63 (s,3H), 3.04 (d,J=11.7Hz,1H), 2.82 - 2.63 (m,1H), 2.61 - 2.37 (m,2H), 2.35 - 2.12 (m,1H), 1.96 - 1.79 (m,1H), 1.64 - 1.53 (m,1H), 1.23 (s,3H), 0.44 - 0.32 (m,2H), 0.30 - 0.13 (m,2H). 19 F NMR (376MHz, C DCl3) δ-106.32,-106.96.

[0460] Step B: (S)-(4,4-Difluoro-1-cyclopropyl-3-methylpiperidin-3-yl)methanol LiAlH4 (0.18 mL, 0.18 mmol, 1 M THF solution) was added to a solution of methyl (S)-1-cyclopropyl-4,4-difluoro-3-methylpiperidine-3-carboxylate (42 mg, 0.18 mmol) in anhydrous THF (3 mL) at room temperature, and the reaction was stirred at room temperature for 10 min. After completion of the reaction (confirmed by TLC), the reaction was quenched by slowly adding Na2SO4·10H2O to the LiAlH4 under ice-bath conditions until no further gas evolution was observed. The resulting mixture was diluted with a small amount of EA, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give a colorless oily liquid (S)-(4,4-difluoro-1-cyclopropyl-3-methylpiperidin-3-yl)methanol (32 mg, 87% yield). LCMS (m / z): 206.1 (M + H).

[0461] intermediate a7 [ka] (3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol

[0462] [ka]

[0463] Step A: Methyl 7,7-dichloro-3-methyl-3-azabicyclo[4.1.0]heptane-1-carboxylate At room temperature, polyethylene glycol (1.0 g) was added to a mixture of methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate hydrobromide (1.3 g, 5.5 mmol), sodium hydroxide (45 mL, 50% wt), and CHCl3 (150 mL). After the addition, the mixture was heated to 80 °C and stirred overnight. After completion of the reaction (confirmed by LCMS), water (50 mL) was added, and the resulting mixture was extracted with DCM (50 mL × 3). The organic phase was washed with brine. The organic phase was collected, concentrated, and further purified by FCC (SiO2, EA / PE = 0 - 25%) to give colorless liquid methyl 7,7-dichloro-3-methyl-3-azabicyclo[4.1.0]heptane-1-carboxylate (150 mg, 11% yield). LC-MS(m / z): 238.0(M+H).

[0464] Step B: (3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol LiAlH4 (3.16 mL, 1 M THF solution, 3.16 mmol) was added dropwise to a solution of methyl 7,7-dichloro-3-methyl-3-azabicyclo[4.1.0]heptane-1-carboxylate (150 mg, 0.63 mmol) in THF (2 mL) at room temperature, and the reaction was heated to 70 °C and stirred overnight. After completion of the reaction (as confirmed by LCMS), the reaction was quenched with Na2SO4·10H2O until no gas evolution occurred. The reaction solution was filtered through Celite, and the resulting filtrate was concentrated at low temperature (35 °C) to give (3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol (40 mg, 45% yield) as a colorless liquid. This was used directly in the subsequent reaction. LC-MS (m / z): 142.0 (M + H).

[0465] Intermediate a8 [ka] (4-Fluoro-1,3-dimethylpiperidin-3-yl)methanol

[0466] Intermediate a8A-1 [ka] (3S)-(4-Fluoro-1,3-dimethylpiperidin-3-yl)methanol

[0467] [ka]

[0468] Step A: 1-(tert-butyl) 3-methyl (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylate Under ice-bath conditions, BAST (19.57 g, 16.3 mL, 88.46 mmol) was added dropwise to a solution of 1-(tert-butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate a5A, 8.0 g, 29.49 mmol) in DCM (40 mL), and the reaction mixture was stirred overnight at room temperature. After completion of the reaction (confirmed by TLC), the reaction mixture was slowly poured into half-saturated NaHCO solution (100 mL), and the resulting mixture was extracted with DCM (100 mL × 3). The combined organic phases were concentrated and purified by FCC (SiO, EA / PE = 0-10%) to give the colorless oily product 1-(tert-butyl) 3-methyl (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylate (1.0 g, 12% yield). LCMS (m / z): 218.1 (M-56 + H).

[0469] Step B: (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol LiAH4 (4.02 mL, 4.02 mmol, 1 M THF solution) was added to 1-(tert-butyl) 3-methyl (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylate (500 mg, 1.83 mmol) at room temperature. The reaction was heated to 70 °C and stirred for 1 h. After completion of the reaction (confirmed by LCMS), the reaction was quenched by slowly adding Na2SO4·10H2O to the LiAH4 under ice-bath conditions until no further gas evolution was observed. The resulting mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to give a colorless oily liquid (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (284 mg, 98% yield). LCMS(m / z): 160.1 (M+H).

[0470] Step C: (3S)-(4-fluoro-1,3-dimethylpiperidin-3-yl)methanol Under a nitrogen atmosphere, Pd / C (5% wt, 374 mg, 0.176 mmol) was added to a mixture of (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (280 mg, 1.76 mmol) in EA:MeOH = 1:1 (20 mL) at room temperature. The resulting mixture was purged with hydrogen and then reacted at room temperature for 2 h under 60 psi H2 pressure. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered through Celite, washed with EA (50 mL), and the organic phase was concentrated to give a colorless oily liquid (3S)-(4-fluoro-1,3-dimethylpiperidin-3-yl)methanol (220 mg, 78% yield). LCMS (m / z): 162 (M + H).

[0471] Intermediate a8A-2 [ka] ((3S)-1-Ethyl-4-fluoro-3-methylpiperidin-3-yl)methanol

[0472] [ka]

[0473] Step A: Methyl (S)-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate hydrochloride At room temperature, 4M HCl-dioxane (15 mL) was added to 1-(tert-butyl) 3-methyl (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylate (1 g, 3.66 mml), and the resulting mixture was stirred for 1 h. After completion of the reaction (as confirmed by LCMS), the reaction was concentrated under reduced pressure to remove the acid solution, affording methyl (S)-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate hydrochloride (760 mg, 99% yield) as a yellowish solid. LCMS (m / z): 174.1 (M + H).

[0474] Step B: Methyl (S)-1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate Iodoethane (1.7 g, 10.88 mmol) was added to a mixture of methyl (S)-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate hydrochloride (760 mg, 3.63 mmol), K2CO3 (1.5 g, 10.88 mmol), and ACN (10 mL) at room temperature, and the resulting mixture was stirred at 90 °C for 5 h. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered through Celite. The filtrate was collected, concentrated, and then purified by FCC (SiO2, EA / PE = 0-20%) to give the colorless oily product, methyl (S)-1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate (317 mg, 43% yield). LCMS (m / z): 202.1 (M + H).

[0475] Step C: (S)-(1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridin-3-yl)methanol LiAlH4 (1.58 mL, 1.58 mmol, 1 M THF solution) was added to a solution of methyl (S)-1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate (317 mg, 1.58 mmol) in THF (3 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. After completion of the reaction (confirmed by TLC), the LiAH4 was quenched by slowly adding Na2SO4·10H2O under ice-bath conditions until no further gas evolution was observed. The resulting mixture was diluted with an appropriate amount of EA and dried over anhydrous sodium sulfate. The resulting mixture was filtered and concentrated to give a colorless oily liquid (S)-(1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (250 mg, 92% yield). LCMS (m / z): 174.1 (M + H).

[0476] Step D: ((3S)-1-ethyl-4-fluoro-3-methylpiperidin-3-yl)methanol Under a nitrogen atmosphere at room temperature, Pd / C (10 wt%, 154 mg, 144 μmol) was added to a solution of (S)-(1-ethyl-4-fluoro-3-methyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (250 mg, 1.44 mmol) in MeOH (50 mL). The resulting mixture was degassed twice with hydrogen and stirred under a hydrogen balloon atmosphere at 25 °C for 2 h. After completion of the reaction (confirmed by LCMS), the reaction mixture was filtered through Celite, washed with EA (50 mL), and the combined filtrate was concentrated to give a colorless oily liquid ((3S)-1-ethyl-4-fluoro-3-methylpiperidin-3-yl)methanol (200 mg, 79% yield). LCMS (m / z): 176.1 (M + H).

[0477] Intermediate a9A-1 [ka] (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol

[0478] [ka]

[0479] Step A: 1-(tert-butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate Under ice bath conditions, a solution of potassium tert-butoxide in THF (5.25 mL, 1 M, 5.25 mmol) was added dropwise to a solution of methyltriphenylphosphonium bromide (1.89 g, 5.25 mmol) in toluene (10 mL). The mixture was stirred in an ice bath for 0.5 h. A solution of 1-(tert-butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate a5A, 1.00 g, 3.50 mmol) in toluene (5 mL) was added dropwise to the above mixture, and the resulting mixture was stirred at the same temperature for 1 h. Subsequently, the reaction system was slowly heated to 110 °C and stirred overnight. After completion of the reaction (confirmed by TLC), the reaction system was cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by FCC (SiO, EA / PE = 0-100%) to give the colorless oily product 1-(tert-butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate (750 mg, 75% yield). LCMS (m / z): 214.1 (M-56 + H), 292.1 (M + Na).

[0480] Step B: 1-(tert-butyl) 3-methyl(3S)-3,4-dimethylpiperidine-1,3-dicarboxylate Pd / C (500 mg, 10% w / w, 0.47 mmol) was added to a solution of 1-(tert-butyl) 3-methyl(S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate (750 mg, 2.78 mmol) in methanol (20 mL) at room temperature under a nitrogen atmosphere. The reaction was degassed with a hydrogen balloon and stirred overnight under a hydrogen atmosphere. After completion (confirmed by TLC), the reaction mixture was filtered through Celite. The filtrate was concentrated, and the crude product was purified by FCC (SiO2, EA / PE = 0-50%) to give 1-(tert-butyl) 3-methyl(3S)-3,4-dimethylpiperidine-1,3-dicarboxylate (600 mg, 79% yield) as a colorless oil. LCMS (m / z): 216.1 (M-56 + H), 294.1 (M + Na). 1 H NMR (400MHz, methanol-d4) δ 4.08 - 4.02 (m,0.23 H), 3.98 (dd,J=13.7, 1.5Hz,1H), 3.91 - 3.78 (m,1.23 H), 3.72 (s,0.69 H), 3.67 (s,3H), 3.21 - 2.76 (m,2.46 H), 2.20 - 2.06 (m,0.23 H), 1.81 - 1.29 (m,14.9 H), 1.20(s,3H), 1.07 (s,0.69H), 1.02 (d,J=6.6Hz,3H), 0.86 (d,J=6.8Hz,0.69H).

[0481] Step C: (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol LiAlH4-THF (1 M, 5.26 mmol, 5.26 mL) was added dropwise to a solution of 1-(tert-butyl) 3-methyl(3S)-3,4-dimethylpiperidine-1,3-dicarboxylate (500 mg, 1.75 mmol) in THF (5 mL) at room temperature. The resulting mixture was heated to 70 °C and stirred for 3 h. After completion of the reaction (confirmed by LCMS), the reaction was quenched by adding Na2SO4·10H2O until no further gas evolution was observed. The reaction solution was filtered through Celite to give colorless liquid (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol (250 mg, 91% yield). LC-MS (m / z): 158.2 (M + H).

[0482] Intermediate a9A-2 [ka] ((3S,4S)-1-Ethyl-3,4-dimethylpiperidin-3-yl)methanol

[0483] [ka]

[0484] Step A: Methyl (S)-3-methyl-4-methylenepiperidine-3-carboxylate hydrochloride 1-(tert-butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate (400 mg, 1.48 mmol) was added to HCl / dioxane (4 M) (5 mL) at room temperature and stirred for 1 hour. After confirming the completion of the reaction by LCMS, the mixture was concentrated to give methyl (S)-3-methyl-4-methylenepiperidine-3-carboxylate hydrochloride (304 mg, 100% yield) as a white solid. LC-MS (m / z): 170.1 (M + H).

[0485] Step B: Methyl (S)-1-ethyl-3-methyl-4-methylenepiperidine-3-carboxylate Potassium carbonate (1.02 g, 7.43 mmol) was added to a mixture of methyl (S)-3-methyl-4-methylenepiperidine-3-carboxylate hydrochloride (304 mg, 1.49 mmol) and iodoethane (695 mg, 4.45 mmol) in anhydrous acetonitrile (10 mL) at room temperature. The resulting mixture was heated to 90 °C and stirred overnight. After completion of the reaction (confirmed by LCMS), the reaction mixture was filtered and washed with EA (20 mL). The filtrate was collected, concentrated, and further purified by FCC (EA / PE = 0-80%) to give methyl (S)-1-ethyl-3-methyl-4-methylenepiperidine-3-carboxylate (120 mg, 48% yield) as a colorless liquid. LC-MS (m / z): 198.1 (M + H).

[0486] Step C: Methyl (3S,4S)-1-ethyl-3,4-dimethylpiperidine-3-carboxylate Pd / C (18 mg, 10% wt) was added to a mixture of methyl (S)-1-ethyl-3-methyl-4-methylenepiperidine-3-carboxylate (180 mg, 0.910 mmol) in MeOH (5 mL) at room temperature. After the addition, the mixture was stirred overnight at room temperature under H (60 Psi). After LCMS showed the reaction was complete, it was filtered and washed with MeOH (20 mL). The filtrate was collected and concentrated to give methyl (3S)-1-ethyl-3,4-dimethylpiperidine-3-carboxylate (150 mg, 82% yield) as a colorless liquid. LC-MS (m / z): 200.1 (M + H).

[0487] Step D: ((3S,4S)-1-ethyl-3,4-dimethylpiperidin-3-yl)methanol Under ice-bath conditions, LiAlH4 (1 M, 0.75 mmol, 0.75 mL) was added dropwise to a solution of methyl (3S)-1-ethyl-3,4-dimethylpiperidine-3-carboxylate (150 mg, 0.75 mmol) in THF (5 mL). The reaction mixture was stirred at the same temperature for 0.5 h. After completion of the reaction (as confirmed by LCMS), the reaction was quenched by adding Na2SO4·10H2O until no further gas evolution was observed. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated at 35 °C to give ((3S)-1-ethyl-3,4-dimethylpiperidin-3-yl)methanol (100 mg, 78% yield) as a colorless liquid. LC-MS (m / z): 172.1 (M + H).

[0488] Intermediate a10A-1 [ka] (S)-(1,3-Dimethyl-4-methylenepiperidin-3-yl)methanol

[0489] [ka]

[0490] Step A: (S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol LiAlH (0.7 mL, 2.5 M THF solution, 1.75 mmol) was added dropwise to a solution of 1-(tert-butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate (150 mg, 0.56 mmol) in THF (2 mL) at room temperature. After the addition was complete, the resulting mixture was heated to 70 °C and stirred for 3 h. After completion of the reaction (as confirmed by TLC), the reaction was quenched by adding NaSO·10H O, followed by drying with anhydrous sodium sulfate and dilution with ethyl acetate. The resulting mixture was filtered through Celite to remove solids, and the filtrate was concentrated to give (S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol (120 mg, 80% yield) as a colorless oily liquid, which was used directly in the subsequent reaction.

[0491] Intermediate a10A-2 [ka] ((S)-1-Ethyl-3-methyl-4-methylenepiperidin-3-yl)methanol

[0492] [ka]

[0493] Step A: ((S)-1-ethyl-3-methyl-4-methylenepiperidin-3-yl)methanol LiAlH (1 M, 0.66 mmol, 0.66 mL) was added dropwise to a solution of methyl (S)-1-ethyl-3-methyl-4-methylenepiperidine-3-carboxylate (130 mg, 0.66 mmol) in THF (5 mL) under ice bath conditions. After the addition, the mixture was stirred in the ice bath for 0.5 h. After monitoring the completion of the reaction by LCMS, the reaction was quenched by adding NaSO·10H O until no further gas evolution was observed. The reaction was filtered through Celite, and the resulting filtrate was concentrated at 35 °C to give ((S)-1-ethyl-3-methyl-4-methylenepiperidin-3-yl)methanol (90 mg, 81% yield) as a colorless liquid. LC-MS (m / z): 170.1 (M + H).

[0494] Intermediate a11A-1 [ka] (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0495] [ka]

[0496] Step A: 1-(tert-butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate and 1-(tert-butyl) 3-methyl (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (Fluoromethylene)triphenylphosphonium tetrafluoroborate (10.56 g, 27.64 mmol) was dissolved in anhydrous THF (50 mL), and the system was degassed with nitrogen three times. The reaction solution was cooled to -70 °C in a dry ice / ethanol bath, and potassium tert-butoxide tetrahydrofuran (27.64 mL, 1 M, 27.64 mmol) solution was added dropwise to the reaction system. The mixture was stirred at the same temperature for 1 hour. Then, a solution of 1-(tert-butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate a5A, 5.0 g, 18.43 mmol) in anhydrous THF (15 mL) was added dropwise to the reaction system. After the addition was complete, the resulting mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction (confirmed by LCMS), the reaction was slowly poured into water (100 mL) and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by FCC (SiO, EA / PE = 0-15%) to give 1-(tert-butyl) 3-methyl(S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (1.98 g, 37% yield) as a colorless oil. LCMS (m / z): 232.1 (M-56 + H). 1H NMR (400MHz, chloroform-d) δ 6.55 (d,J=84.7, 1H), 4.35 (d,J=13.2Hz,1H), 4.10 - 3.82 (m,1H), 3.69 (s,3H), 3.00 - 2.85 (m,1H), 2.76 (d,J=13.1Hz,1H), 2.71 - 2.60(m , 1H), 2.31 - 2.08 (m,1H), 1.46 (s,9H), 1.29 (s, 3H); The double bond configuration of compound a11A-1-1 was determined by the NOE signal between H1 and H2; 1-(tert-butyl) 3-methyl(S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (600 mg, 11% yield) was obtained as a colorless oil. LCMS (m / z): 232.1 (M-56 + H). 1 H NMR (400 MHz, chloroform-d) δ 6.43 (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); the double bond configuration of compound a11A-2-1 was determined by the NOE signal between H1 and H3.

[0497] [ka]

[0498] [ka]

[0499] [ka]

[0500] Step B: Methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride 4M HCl-dioxane (10 mL) was added to 1-(tert-butyl) 3-methyl(S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (600 mg, 2.09 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. The acid solution was concentrated to give methyl(S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (572 mg, 100% yield) as a white solid. LCMS (m / z): 188.1 (M + H).

[0501] Step C: Methyl (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (Methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate The hydrochloride salt (370 mg, 1.98 mmol) was dissolved in methanol (5 mL) at room temperature, and triethylamine was added dropwise to the reaction mixture until the pH reached ∼10. The reaction mixture was stirred for 10 min, and then glacial acetic acid was added dropwise until the pH reached ∼4. Aqueous formaldehyde (481.15 mg, 5.93 mmol) was added to the reaction mixture and stirred at room temperature for 30 min. Sodium cyanoborohydride (136.62 mg, 2.17 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. After completion of the reaction was confirmed by LCMS, the solvent was removed under vacuum. The residue was evaporated twice with anhydrous tetrahydrofuran to give methyl (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (380 mg, 96% yield) as a white solid. LCMS (m / z): 202.1 (M + H).

[0502] Step D: (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol Under ice-bath conditions, a solution of 1 M LiAlH4-THF (2.83 mL, 107.5 mg, 2.83 mmol) was added dropwise to a solution of methyl (E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylate (380 mg, 1.89 mmol) in anhydrous THF (5 mL). The resulting mixture was stirred at room temperature for 20 min. After completion of the reaction (as confirmed by LCMS), the reaction was quenched with sodium sulfate decahydrate until no further bubbles were observed. Approximately 5 g of anhydrous sodium sulfate was added to remove water. The resulting mixture was filtered through Celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected, concentrated, and dried to give (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).

[0503] Intermediate a11A-2 [ka] (S,Z)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0504] Intermediate a11A-2 was synthesized according to the protocol described for intermediate a11A-1, except that 1-(tert-butyl)3-methyl(S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (compound a11A-2-1) was used instead of 1-(tert-butyl)3-methyl(S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (compound a11A-1-1).

[0505] Intermediate a11A-3 [ka] (S,E)-(1-ethyl-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol

[0506] [ka]

[0507] Step A: Methyl (S,E)-1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate Potassium carbonate (370.73 mg, 2.68 mmol) and iodoethane (278.92 mg, 1.79 mmol) were added sequentially to a solution of methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate hydrochloride (200 mg, 0.894 mmol) in acetonitrile (6 mL) at room temperature, and the resulting mixture was heated to 90 °C and stirred overnight. After completion of the reaction (as confirmed by LCMS), the reaction mixture was filtered through Celite, and the filter cake was washed twice with acetonitrile. The filtrate was collected, concentrated to dryness, and the crude product was purified by FCC (SiO2, EA / PE = 0-90%) to give methyl (S,E)-1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (100 mg, 69% yield) as a colorless oil. LCMS(m / z): 216.1 (M+H).

[0508] Step B: (S,E)-(1-ethyl-4-(fluoromethylene)-3-methylpiperidin-3-yl)methanol Under ice-bath conditions, a 1M solution of LiAlH4-THF (0.7 mL, 0.7 mmol) was added dropwise to a solution of methyl (S,E)-1-ethyl-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (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 (confirmed by LCMS), sodium sulfate decahydrate was added to quench the reaction until no more bubbles were observed. Approximately 5 g of anhydrous sodium sulfate was then added for drying. The reaction solution was filtered through Celite, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected, concentrated, and dried to give (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).

[0509] Intermediate a12A-1 [ka] ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

[0510] [ka]

[0511] Step A: 1-(tert-butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate and 1-(tert-butyl) 3-methyl (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate The synthesis of Step A was carried out according to the synthesis method described for Step A of Intermediate a11A-1.

[0512] Step B: 1-(tert-butyl) 3-methyl (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate Wet Pd / C (400 mg, 10% w / w) was added to a 10 mL solution of 1-(tert-butyl) 3-methyl(S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate and 1-(tert-butyl) 3-methyl(S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (850 mg, 2.96 mmol) in methanol under a nitrogen atmosphere at room temperature. The reaction was degassed with a hydrogen balloon and stirred overnight under a hydrogen atmosphere. After completion of the reaction (confirmed by TLC), the reaction mixture was filtered through Celite, the filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO, EA / PE = 0-10%) to give 1-(tert-butyl) 3-methyl(3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (600 mg, 70% yield) as a colorless oil. LCMS (m / z): 234.1 (M-56 + H), 312.1 (M + Na). 1 H NMR (400MHz, methanol-d4) δ 4.76 - 4.70(m,0.5 H), 4.64 - 4.52 (m,1H), 4.46 - 4.41 (m,0.5 H), 4.23 (d,J=13.7Hz,1H), 4.08 - 3.99 (m,1H), 3.67 (s,3H), 3.06 - 2.86 (m,1H), 2.86 - 2.70(m,1H), 1.95 - 1.81 (m,1H), 1.80 - 1.68 (m,2H), 1.46 (s,9H), 1.27 (s,3H). 19 F NMR (376MHz, methanol-d4) δ 221.80.

[0513] Step C: Methyl (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride At room temperature, 3M hydrochloric acid in dioxane (10 mL, 30 mmol) was added dropwise to a solution of 1-(tert-butyl) 3-methyl(3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (600 mg, 2.07 mmol) in ethyl acetate (10 mL), and the resulting mixture was stirred at room temperature for 1 h. After completion of the reaction (confirmed by LCMS), the solvent was concentrated under reduced pressure to give methyl(3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (500 mg, crude) as a white solid. LCMS (m / z): 190.1 (M + H).

[0514] Step D: Methyl (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylate Methyl (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (500 mg, crude product from the previous step) was dissolved in methanol (10 mL) at room temperature, followed by the addition of aqueous formaldehyde (2 mL, 35-40% w / w, ∼24 mmol). The resulting mixture was stirred at room ...

Claims

1. Compounds of formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof 【Chemical 1】 (In the formula, R １ and R １ ’ together with the intracyclic bridge -(CH ２ ) ｔ - or CH ２ =CH ２ -forming; R ２ and R ３ are each independently H, halogen, or —C optionally substituted with halogen. １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl and / or —O—C optionally substituted with halogen １－６ alkyl; G is selected from CH and N; Y is selected from O, S and Se; M is N and C-R ４ Selected from: Z is selected from N, C, O, S and Se; B is, 【Chemistry 2】 Selected from: X is selected from C and S, and p is selected from 0 and 1, provided that when X is S, p is 0, and when X is C, p is 1; W is H, halogen, or —C １－６ Alkyl, OH or NH ２ Selected from: R ４ is H, halogen, CN, -C １－６ Alkyl or -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl and the -C ３－６ Each cycloalkyl is independently optionally substituted with halogen or CN; R ５ is H, halogen and NH ２ Selected from: R ６ is H, halogen, CN, -C １－６ Alkyl, —O—C １－６ Alkyl, —S—C １－６ Alkyl, -Se-C １－６ Alkyl or -C ２－６ alkynyl, wherein said -C １－６ Alkyl and the -C ２－６ Each alkynyl is independently optionally substituted with halogen; R ７ and R ８ are each independently H, a halogen, or —NO ２ , C.N., -C. １－６ Alkyl, —N(R ａ ) ２ , -C(O)N(R ａ ) ２ or -C(O)OR ａ wherein said -C １－６ The alkyl is optionally halogen or —N(R ａ ) ２ optionally substituted with; R ９ is -Si(R ｂ ) ３ , C.N., N.O. ２ , -C １－６ Alkyl, —O—C １－６ Alkyl, —S—C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－６ Cycloalkyl, -(CH ２ ) ｎ -5-6 membered heteroaryl or -(CH ２ ) ｎ -phenyl, wherein said -C １－６ alkyl, the aforementioned -C ２－６ alkenyl, the aforementioned -C ３－６ cycloalkyl, said 5-6 membered heteroaryl, and said phenyl each independently optionally include halogen, -Se-C １－６ alkyl and optionally halogen-substituted —C １－６ optionally substituted with a group selected from alkyl; R ａ is H and —C optionally substituted with halogen １－６ alkyl; R ｂ each optionally substituted with halogen, —C １－６ Alkyl and -C ２－６ alkenyl; R １０ is H, halogen, CN, -C １－６ Alkyl and -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl and the -C ３－６ Each cycloalkyl is independently optionally substituted with halogen or CN; R １１ is H, -C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl and -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ alkyl, the aforementioned -C ２－６ alkenyl, the aforementioned -C ２－６ Alkynyl or the C ３－６ Each cycloalkyl is independently optionally selected from halogen, —CN, —O—C １－６ Alkyl or —O—CON(R ａ ) ２ optionally substituted with; R １２ is H, halogen, —CN, —OH, —N(R ａ ) ２ , —O—C １－６ Alkyl, —O—C ３－６ Cycloalkyl, —C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl and -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl or C ３－６ Each occurrence of cycloalkyl is independently optionally selected from halogen, —CN, or —O—C １－６ may be substituted with alkyl, Alternatively, two R １２ But together = C (R ｃ ) ２ , Spiro C ３－６ cycloalkyl or spiro 4-7 membered heterocycloalkyl, where R ｃ are each independently H, halogen, or —C optionally substituted with halogen. １－６ alkyl, wherein said spiro C ３－６ The cycloalkyl or spiro 4-7 membered heterocycloalkyl is optionally halogen or -C optionally substituted with halogen. １－６ may be substituted with alkyl, Alternatively, two R bonded to adjacent ring carbon atoms １２ together with the ring carbon atoms, ３－４ forming a cycloalkyl, Alternatively, two R are bonded to non-adjacent ring carbon atoms. １２ together with the ring carbon atoms form a bridging methylene or ethylene; R １３ is H, -C １－６ Alkyl, and -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl or -C ３－６ Each cycloalkyl is independently optionally selected from halogen or —O—C １－６ optionally substituted with alkyl; Or, R １２ and R １３ are attached to adjacent ring carbon atoms, they together with the ring carbon atoms form -C ３－４ Forming a cycloalkyl; R １４ is H, -C １－６ Alkyl, and -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl or the aforementioned -C ３－６ Each cycloalkyl is independently optionally selected from halogen or —O—C １－６ Alternatively, two R １４ together with the ring carbon atoms form -C ３－４ Forming a cycloalkyl; k is selected from 0 or 1; m and n are each independently selected from integers from 0 to 2; t is selected from the integers 1 to 2.

2. B is 【Chemistry 3】 (In the formula, R ５ is a halogen, and R ６ is a halogen, -C １－６ Alkyl or -C ２－６ alkynyl, and R ７ and R ８ are each independently selected from H, and W is —OH.

2. A compound of formula (I) according to claim 1, wherein:

3. B is 【Chemistry 4】 (In the formula, R ５ is H or halogen, and R ６ is a halogen, -C ２－６ Alkynyl and —C １－６ alkyl, and R ７ and R ８ are each independently H, halogen, CN, and NO ２ and W is —OH; or R ５ is NH ２ and R ６ is -CN, and R ７ and R ８ are each independently selected from H or halogen, and W is H.

2. A compound of formula (I) according to claim 1, wherein:

4. B is 【Chemistry 5】 (In the formula, R ７ is H; R ８ is H, CN, halogen, NO ２ , -C １－６ Alkyl, —N(R ａ ) ２ , -C(O)N(R ａ ) ２ or -C(O)OR ａ wherein said -C １－６ The alkyl is optionally halogen or —N(R ａ ) ２ where R ａ is H and —C optionally substituted with halogen １－６ alkyl; R ９ is -Si(R ｂ ) ３ , NO ２ , C.N., -C. １－６ Alkyl, -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl and -C ３－６ Each cycloalkyl is independently optionally selected from halogen, -Se-C １－６ alkyl and optionally halogen-substituted —C １－６ may be substituted with alkyl; R １０ is a halogen and -C １－６ alkyl, and W is selected from -OH or -NH ２ It is.) 2. A compound of formula (I) according to claim 1, wherein:

5. G is N and R １ and R １ ’ Together -CH ２ -, -CH ２ CH ２ - or -CH ２ =CH ２ -, preferably -CH ２ CH ２ 5. A compound of formula (I) according to any one of claims 1 to 4, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, which forms -.

6. R ２ is H and R ３ is halogen, preferably F, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof.

7. M is N or C-R ４ and R ４ is halogen, CN, or —C substituted with halogen １－６ alkyl, preferably M is selected from N, C—F, C—Cl, C—CN and C—CF ３ A compound of formula (I) according to any one of claims 1 to 6, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof selected from:

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

9. R １４ are each independently H or D, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 8.

10. The following partial structure: 【Chemistry 6】 but, 【Chemistry 7】 , preferably 【Chemistry 8】 (In the formula, R １１ Ha-C １－６ alkyl, and —C １－６ The alkyl is optionally —O—C １－６ optionally substituted with alkyl or halogen or D, preferably one or more D; and / or R １２ is halogen, CN, optionally halogen-substituted —C １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl and —O—C optionally substituted with halogen １－６ alkyl, or two R bonded to the same carbon atom; １２ But, = C(R ｃ ) ２ or spiro-C ３－６ Forms a cycloalkyl, where R ｃ are each independently H, halogen, and —C optionally substituted with halogen. １－６ alkyl, m being selected from 1 or 2; and / or R １４ are each independently selected from H or D; and / or R １３ Ha-C １－６ Alkyl, preferably —C １－３ It is alkyl.) 10. The compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, wherein

11. The following sub-expressions: 【Chemistry 9】 (In the formula, Y is O; G is CH or N; M is C-R ４ and Z is selected from C, Se, and O; W is —OH or —NH ２ and R １ and R １ ’ together - (CH ２ ) ｔ -forming; R ２ is H; R ３ is a halogen; R ４ is a halogen; R ５ is selected from H and halogen; R ５ is a halogen, -C １－６ Alkyl, and -C ２－６ alkynyl; R ７ and R ８ are each independently H, halogen, CN, and NO ２ Selected from: R １１ is optionally —O—C １－６ -C optionally substituted with alkyl or halogen １－６ is alkyl; R １２ is H, halogen, CN, —C optionally substituted with halogen １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl, optionally substituted with halogen, —O—C １－６ alkyl, or two R bonded to the same carbon atom; １２ = C(R ｃ ) ２ where R ｃ are each independently H, halogen, and —C optionally substituted with halogen. １－６ alkyl; R １３ is H, halogen, and —C optionally substituted with halogen １－６ alkyl; R １４ is H; m and n are each independently selected from integers of 0 to 2; t is selected from 1 or 2.

2. A compound of formula (I) according to claim 1, having the formula:

12. R １１ but one or more hydrogen isotopes, preferably -CD ３ -C substituted with １－６ alkyl, and / or R １４ is D, a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, of the compound of formula (I) according to claim 11 .

13. The following formula: 【Chemistry 10】 (In the formula, R ２ is H, -C ２－６ Alkynyl, optionally substituted with halogen or D -C １－６ Alkyl or —O—C optionally substituted with halogen or D １－６ alkyl; R ５ is halogen, preferably F; and / or R ６ Ha-C ２－６ alkynyl, preferably ethynyl; and / or R ４ is halogen, preferably F; and / or R １４ are each independently selected from H and D; and / or R １３ Ha-C １－６ Alkyl, preferably —C １－３ alkyl; and / or R １１ is optionally —O—C １－６ -C optionally substituted with alkyl, halogen or D １－６ alkyl, preferably -C optionally substituted with one or more D １－３ alkyl; and / or R １２ is halogen, CN, optionally halogen-substituted —C １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl and —O—C optionally substituted with halogen １－６ alkyl, or two R bonded to the same carbon atom; １２ But together = C (R c ) ２ or Spiro C ３－６ Forms a cycloalkyl, where R c are each independently H, halogen, and —C optionally substituted with halogen. １－６ alkyl, and m is selected from 1 or 2.

2. A compound of formula (I) according to claim 1, having the formula:

14. The following formula: 【Chemistry 11】 (In the formula, R ２ is H, -C ２－６ Alkynyl, optionally substituted with halogen or D -C １－６ alkyl, or —O—C optionally substituted with halogen or D １－６ alkyl; and / or R ４ is a halogen (preferably F or Cl), CN, or —C optionally substituted with a halogen (preferably F); １－６ alkyl; and / or R ７ and R ８ are both H, or both halogen (preferably F), or one of them is H and the other is halogen (preferably F), or one of them is H and the other is halogen (preferably F) substituted C １－６ alkyl; and / or R １１ but optionally -O-C １－６ -C optionally substituted with alkyl, halogen or D １－６ alkyl, preferably -C optionally substituted with one or more D １－３ alkyl; and / or R １２ is halogen, CN, optionally halogen-substituted —C １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl, or —O—C optionally substituted with halogen １－６ alkyl, or two R bonded to the same carbon atom; １２ But together = C (R ｃ ) ２ or Spiro C ３－６ Forms a cycloalkyl, where R ｃ are each independently H, halogen, and —C optionally substituted with halogen. １－６ alkyl, and / or R １３ Ha-C １－６ Alkyl, preferably —C １－３ alkyl; and / or R １４ are each independently selected from H or D; and / or W is H; and m is selected from 1 or 2.

2. A compound of formula (I) according to claim 1, having the formula:

15. The following sub-expressions: 【Chemistry 12】 (In the formula, Y is O; G is CH or N; M is C-R ４ and Z is selected from C, Se, or O; W is —OH or —NH ２ and R １ and R １ ’ together - (CH ２ ) ｔ -forming; R ２ is H; R ３ is a halogen; R ４ is a halogen; R ７ is H; R ８ is H, CN, halogen, NO ２ , -C １－６ Alkyl, —N(R ａ ) ２ , -C(O)N(R ａ ) ２ , and —C(O)OR ａ wherein said -C １－６ The alkyl is optionally halogen or —N(R ａ ) ２ where R ａ is H and —C optionally substituted with halogen １－６ alkyl; R ９ is -Si(R ｂ ) ３ , -C １－６ Alkyl or -(CH ２ ) ｎ -C ３－６ cycloalkyl, wherein said —C １－６ Alkyl and the -C ３－６ Each cycloalkyl is independently optionally halogen, -Se-C １－６ -C optionally substituted with alkyl or halogen １－６ may be substituted with alkyl, where R ｂ each of which is optionally substituted with halogen; １－６ Alkyl or -C ２－６ alkenyl; R １０ is a halogen and -C １－６ alkyl; R １１ is optionally —O—C １－６ -C optionally substituted with alkyl and halogen １－６ alkyl; R １２ is H, halogen, CN, —C optionally substituted with halogen １－６ alkyl, optionally substituted with halogen -C ２－６ Alkynyl and —O—C optionally substituted with halogen １－６ alkyl, or two R bonded to the same carbon atom １２ But together = C (R ｃ ) ２ where R ｃ are independently H, halogen, and —C optionally substituted with halogen. １－６ alkyl; R １３ is H, halogen, and —C optionally substituted with halogen １－６ alkyl; R １４ is H; k is selected from 0 or 1; m and n are each independently selected from integers from 0 to 2; t is selected from 1 or 2.

2. A compound of formula (I) according to claim 1, having the formula:

16. A compound selected from the example compounds, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable excipient.

18. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 17, for use as a medicament for the treatment and / or prevention of a disease mediated by a KRas mutation, preferably a KRas G12V and / or a KRas G12D mutation.

19. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for the prevention and / or treatment of a disease mediated by a KRas mutation, preferably a KRas G12V and / or a KRas G12D mutation.

20. 20. The use according to claim 19, wherein the disease mediated by a KRas mutation, preferably a KRas G12V and / or KRas G12D mutation, is selected from pancreatic cancer, lung cancer, lung adenocarcinoma, osteosarcoma, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland 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 cord tumor, brainstem glioma, or pituitary adenoma.

21. The use according to claim 20, wherein the disease mediated by a KRas mutation, preferably a KRas G12V and / or a KRas G12D mutation, is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.

22. A method for treating and / or preventing a disease mediated by a Ras mutation, in particular a KRas mutation, preferably a KRas G12V and / or KRas G12D mutation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 17.

23. 23. The method of claim 22, wherein the disease mediated by a KRas mutation, preferably a KRas G12V and / or a KRas G12D mutation, is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.

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