WO2024207892A1 - Compounds having activity against kras-mutant tumors - Google Patents

Abstract

Provided in the present invention are compounds having the structure of formula (I) useful as KRAS inhibitors, a pharmaceutical composition comprising such compounds, a method for preparing the compounds, and the use of the compounds in treatment of cancers.

Description

Compounds with activity against KRAS mutant tumors

Cross-references

This application claims priority to Chinese patent application 2023103552845 filed on April 4, 2023, Chinese patent application 2023110575381 filed on August 22, 2023, Chinese patent application 2024100268659 filed on January 8, 2024, and Chinese patent application 2024101768252 filed on February 8, 2024.

Technical Field

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

Background Art

Ras, or rat sarcoma oncogene homolog, represents a group of closely related monomeric globular 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 is responsible for regulating cell growth, survival, migration, and differentiation. These regulatory functions of Ras are carried out through the conversion between the GDP-bound state and the GTP-bound state, i.e., a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13: 394-401). Ras bound to GDP is in an inactive form and is in a dormant or closed state. At this time, the signal system is closed. It will be activated when exposed to some pro-growth stimuli. For example, it can be induced by guanine nucleotide exchange factor (GEF) to release GDP and bind to GTP. As a result, Ras is "turned on" and converted into an active form of Ras, which recruits and activates various downstream effectors for signal transduction. It can transmit signals on the cell surface to the cytoplasm, thereby controlling many key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).

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

Among human tumor-related genes, there are three ubiquitously expressed Ras genes, H-RAS, K-RAS and N-RAS, which encode highly homologous HRas, NRas and KRas proteins of about 21KDa, respectively. In 1982, researchers first discovered that Ras was activated by mutation in cancer cell lines (Chang, EH et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large-scale genome sequencing studies in different cancer types revealed that Ras protein mutated in more than 30% of cancer types, especially in pancreatic cancer (>90%), colon cancer (45%) and lung cancer (35%). Transgenic and genetically engineered mouse models have also revealed that Mutated Ras proteins are sufficient to drive and trigger many types of cancer, and Ras oncogenes are also critical for the maintenance and progression of tumors in many cancer types. For example, in Ras mutant cancer cell lines and cancer animal models, RNA intervention has been shown to slow tumor growth. These studies have made Ras tumor proteins a very attractive anti-cancer drug target widely accepted in the pharmaceutical field.

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

However, the past few decades of drug development for Ras have shown that due to the smooth surface of Ras protein, the lack of obvious groove or pocket structure for binding small molecule inhibitors, and its very high affinity for guanine substrates (picomolar level), the development of its small molecule inhibitors has fallen into an intractable dilemma, and thus Ras has long been considered an "undruggable" target in the industry. At the same time, there is still a great need for compounds with more structural types or patterns as KRas inhibitors to provide more treatment options, or to provide further improved inhibitory activity relative to existing Kras inhibitors, thereby providing more potent therapeutic drugs for clinical use.

The present invention solves these and other needs. The present invention provides novel structural inhibitor compounds with KRas mutant protein inhibitory activity. These compounds of the present invention have an improved structural pattern, and compared with the existing KRas mutant protein inhibitors in the prior art, have enhanced KRas mutant protein inhibitory activity and related tumor inhibitory activity, and have good pharmacokinetic properties, thus having good drugability, such as being easier to absorb in the body after administration in a convenient manner, and having reduced toxic and side effects, improved drug resistance and safety, and reduced risk of drug interactions.

Brief description of the invention

The present invention provides a compound having structural formula (I) as defined herein below, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof:

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

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

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

The present invention also provides compounds of the present invention or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, which are used as inhibitors of Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplified cells.

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

The present invention also provides the use of the compounds of the present invention or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising the same, for treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplification.

The present invention also provides the use of the compound of the present invention or its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.

The present invention also provides a method for treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising the same.

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

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

The present invention also provides a pharmaceutical combination comprising a compound of the present invention or its stereoisomers, tautomers, stable isomers, isotopic variants, pharmaceutically acceptable salts or solvates and one or more other pharmaceutically active agents.

The present invention also provides processes for preparing the compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

definition

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

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

The term "Ras mutation" or "Ras mutant protein" as used herein refers to a protein encoded and expressed by a Ras gene in which one or more codons are mutated, typically including but not limited to a Ras protein in which a glycine at codon 12, a glycine at codon 13, or a glutamine at codon 61 of Ras is mutated, such as a mutant HRas, NRas, or KRas. These residues are located in the active site of Ras, and their mutations can impair the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the continued presence of Ras bound to GTP.

For the purposes of the present invention, "Ras mutation" or "Ras mutant protein" and "Ras" in describing inhibitory activity are used interchangeably and generally refer to mutant HRas, NRas or KRas, such as but not limited to KRas-G12C (mutation of glycine to cysteine at codon G12), KRas-G12D (mutation of glycine to aspartic acid at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12), 2 (mutation of glycine to valine at codon G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); in particular, it refers to KRas mutant proteins, more particularly, it refers to KRas-G12C mutant protein, KRas-G12D mutant protein, KRas-G12V mutant protein, KRas-G12A mutant protein, KRas-G12R mutant protein, KRas-G12S mutant protein, KRas-G13D mutant protein and KRas-Q61H mutant protein.

The term "treatment" as used herein refers to administering one or more compounds of the present invention described herein or pharmaceutically acceptable salts or solvates thereof to a subject, such as a mammal, such as a human, who suffers from the disease or has symptoms of the disease, to cure, alleviate, mitigate or affect the disease or symptoms of the disease. Preferably, the treatment is curative or ameliorative.

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

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

The term "Ras mutation-mediated disease" as used herein refers to a disease in which Ras mutation promotes the occurrence and development of the disease, or in which inhibition of Ras mutation reduces the incidence of the disease, reduces or eliminates the symptoms of the disease. For the present invention, "Ras mutation-mediated disease" preferably refers to a KRas mutation-mediated disease, and more preferably a KRas mutation-mediated cancer or tumor.

As used herein, the term "cancer" or "tumor" refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. For various aspects of the present invention, the cancer or tumor includes, but is not limited to, lung adenocarcinoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region 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 cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma.

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

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

The term "therapeutically effective amount" as used herein refers to an amount or dosage that is generally sufficient to produce a beneficial therapeutic effect on the "Ras mutation-mediated disease" such as cancer or tumor patients in need of treatment. Those skilled in the art can determine the effective amount or dosage of the active ingredient in the present invention by conventional methods and in combination with conventional influencing factors.

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

The term "pharmaceutically acceptable" as used herein means that when administered in appropriate amounts to animals, such as humans, no adverse effects are produced. Molecular entities and compositions that cause allergic or other adverse reactions.

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

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

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

The compound structural formula or structural fragment used in this article Indicates the absolute configuration of a stereocenter, i.e., a chiral center. Accordingly, in the naming of the compounds or intermediates provided by the present invention, R or S is used to indicate the absolute configuration of the chiral center. In the definition of some compounds of the present invention, axial chirality may also be used to indicate the configuration of the compound. The determination of these configurations uses the Cahn-Ingold-Prelog rule well known to those skilled in the art. The absolute configuration of axial chirality in the two example structures shown in the figure below is described as follows:

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

The structural fragments used in this article The bonds indicated to be crossed are the bonds connecting the structural fragment to the rest of the molecule.

The substituents shown as crossing chemical bonds in the cyclic structure fragments referred to herein are, for example, The -(R ₃ ) _m in the formula (a) means that the one or more R ₃ substituents can substitute at any chemically feasible one or more substitution sites, including Z, in the ring.

Compounds of the present invention include unlabeled forms of compounds of the present invention and isotope-labeled forms thereof. The isotope-labeled form of a compound is a compound in which only one or more atoms are replaced by corresponding isotope-enriched atoms. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of, for example, hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁷ Cl and ¹²⁵ I. Such isotope-labeled compounds can be used as probes, analytical tools or as therapeutic agents in, for example, bioassays.

In certain embodiments, the compounds of the invention are provided in unlabeled form. In certain embodiments, the compounds of the invention are provided in isotopically labeled form, such as compounds in which one or more H atoms are replaced by deuterium atoms (D), such as In the above, two hydrogen atoms of the methylene group attached to the rest of the molecule may be optionally replaced by isotopes, for example by deuterium, for example as represented by Wherein R ₁₂ is independently H or D, and/or the -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -C _3-6 cycloalkyl in R ₄ can be optionally substituted by one or more isotopes, such as deuterium. For another example, the -C _1-6 alkyl optionally substituted by halogen, -OC _1-6 alkyl optionally substituted by halogen and -C _2-6 alkynyl optionally substituted by halogen of R ₁₁ as a substituent on the fused ring, wherein the alkyl or alkynyl can be optionally substituted by one or more isotopes, such as deuterium.

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

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

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

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

The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to ₆ carbon atoms, examples of which are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, etc.

The term "alkoxy" as used herein means an alkyl group as defined herein that is connected to the rest of the molecule via an oxygen atom. Specifically, the alkoxy group has 1-10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C _1-6 alkoxy" refers to a straight or branched saturated hydrocarbon group having 1 to ₆ carbon atoms that is connected to the rest of the molecule via an oxygen atom, examples of which are, for example, -O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O-n-hexyl, 2-methylpentyl-O-, etc.

As used herein, the term "C _{1-6 alkyl} optionally substituted by halogen" refers to the C _1-6 alkyl described above, wherein one or more (e.g., 1, 2, 3, 4 or 5) hydrogen atoms are optionally replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of "C _1-6 alkyl substituted by halogen" include, for example, -CH ₂ F, -CHF _{2 ,} -CF ₃ , -CCl ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ CF ₃ or -CF(CF ₃ ) ₂ , etc.

The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one double bond. Specifically, the alkenyl group has 2-8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term " _{C2-6 alkenyl} " refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, pentenyl, etc., and the carbon atom in the alkenyl group that is connected to the rest of the molecule can be saturated or an olefinic carbon atom.

The term "alkynyl" as used herein refers to a straight or branched chain radical consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Unsaturated hydrocarbon groups. Specifically, alkynyl groups have 2-8, such as 2 to 6, 2 to 5, 2 to ₄ or 2 to 3 carbon atoms. For example, as used herein, the term " _C2-6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, propargyl, butynyl, etc., and the carbon atom in the alkynyl group that is connected to the rest of the molecule can be saturated or can be an acetylenic bond carbon atom.

As used herein, the term "cycloalkyl" means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure with a specified number of ring carbon atoms. Cycloalkyl may have 3 to 12 carbon atoms (i.e., C _3-12 cycloalkyl), such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkyls include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or polycyclic (e.g., bicyclic) structures, including spirocyclic, fused or bridging systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octanyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl or bicyclo[3.2.1]octanyl, etc. For example, the term "C _3-6 cycloalkyl" as used herein refers to a monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

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

For the compounds of the present invention, exemplary heterocycloalkyl groups include, but are not limited to, the following: It is to be understood that structures having asymmetric centers encompass racemic and/or single enantiomeric forms thereof, e.g. Can represent and/or

Preferred heterocycloalkyl groups are

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

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

As used herein, the term "optionally substituted", unless otherwise indicated, means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for the group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 identical or different substituents. In another embodiment, the optionally substituted group has 3 identical or different substituents. In another embodiment, the optionally substituted group has 4 identical or different substituents. In another embodiment, the optionally substituted group has 5 identical or different substituents. base.

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

Unless otherwise specified, Cn _-n+m or _Cn - _Cm in the definition of the compounds of the present invention includes various cases of n to n+m carbon atoms, for example, _C1-6 includes _C1 , _C2 , _C3 , _C4 , _C5 and _C6 , and also includes any range from n to n+m, for example, _C0-6 includes _C1 , _C2 , _C3 , _C4 , _C5 , _C6 , _C0-1 , _C0-2 , _C0-3 , _C0-4 , _C0-5 , _C1-2 , _C1-3 , _C1-4 , _C2-3 , etc., and _C1-6 includes _C1-2 , _C1-3 , _C1-4 , _C2-6 , _C3-6 , etc. Similarly, the n-membered to n+m-membered in the definition of the compounds of the present invention means that the number of ring atoms is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 12-membered ring, etc., and also includes any range of n to n+m-membered, for example, 3-12-membered ring includes 3-6-membered ring, 3-8-membered ring, 3-9-membered ring, 4-10-membered ring, 4-7-membered ring, 4-5-membered ring, 5-6-membered ring, 5-7-membered ring, 5-8-membered ring, 5-9-membered ring, 6-7-membered ring, 6-8-membered ring, 6-10-membered ring and 6 to 12-membered ring, etc.

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

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

It should be understood that the dosages referred to herein when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits, and related uses and methods thereof, are based on the weight of the free form and do not include any salt, hydrate or solvate thereof, unless the specification states that the dosage is based on the weight of the salt, hydrate or solvate.

Problems to be solved by the present invention

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

Solutions to the problem

Through extensive and in-depth research, the inventors have developed a group of compounds with significant inhibitory activity against Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplified cells. Through structural modification and activity verification, the inventors found that at several specific sites of the benzopyrimidine ring and quinazoline of the KRas inhibitor structure, a specific type of substituent modification was performed, and the specific combination of several substitution sites and substituent types implemented obtained a further improved inhibitory activity against KRas mutant proteins compared to the prior art inhibitors, and the modified compounds thus obtained have good safety, reduced risk of drug interactions, and good or even further improved pharmacokinetic properties, so that they can be administered in a convenient manner.

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

The present invention thus provides the following technical solutions.

Compounds of the present invention

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

Therefore, the above-mentioned various isomers and derivatives of the compounds of the present invention are thus included within the scope of the present invention, and their respective meanings, preparations and specific examples are as defined in the "Definitions" section above, or are well known in the art. However, preferably, the compounds of the present invention and/or their pharmaceutically acceptable salts or solvates.

The present invention also encompasses N-oxides of the compounds of the present invention, as long as these compounds contain basic nitrogen atoms such as nitrogen atoms present in nitrogen-containing heterocycles and are chemically and biologically feasible. Some compounds of the present invention can exist in polymorphic or amorphous forms, so they also fall within the scope of the present invention.

The present invention provides the following compound embodiments:

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

in:

M is selected from N or CR ₇ ;

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;

Y is selected from O, S and Se;

W is selected from OH and NH ₂ ;

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

Q is selected from in

Z is selected from N, C, O, S and Se;

k is selected from 0 or 1;

m and n are each independently selected from an integer from 0 to 2;

R ₁ is selected from -C _1-6 alkyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, each independently optionally substituted by halogen or C _1-6 alkoxy;

R ₂ is selected from H, -C _1-6 alkyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl is each independently optionally substituted by halogen or C _1-6 alkoxy,

Or two _R2 attached to the same carbon atom together with the carbon atom to which they are attached form a _{C3-4 cycloalkyl} group;

_R3 is selected from H, halogen, -CN, -OH, _-OC1-6alkyl , _{-OC3-6cycloalkyl , -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl and -(CH2)n-C3-6cycloalkyl, wherein each occurrence of C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl or C3-6cycloalkyl is each independently optionally substituted by halogen ,} CN or _C1-6alkoxy ,

or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , spiro C _3-6 cycloalkyl optionally substituted by halogen, or spiro 4-7 membered heterocycloalkyl optionally substituted by halogen, wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen,

or R ₁ and R ₃ attached to adjacent ring carbon atoms or two R ₃ attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C _{3-4 cycloalkyl} group;

or two _R3 attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;

R ₄ is selected from H, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein the C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl or C _3-6 cycloalkyl are each independently optionally substituted by deuterium, halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ ;

_R5 is selected from H and halogen;

R ₆ is selected from H, halogen, -C _1-6 alkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -Se-C _1-6 alkyl and -C _2-6 alkynyl, each independently optionally substituted by halogen;

R ₇ is selected from H, halogen, CN and -C _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted with halogen or CN;

R ₈ is selected from -OH, halogen, -CN, -B(OH) ₂ , -C _1-6 alkyl, -OC _1-6 alkyl,

-CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl),

-PO(C _1-6 alkyl) ₂ , -PO(C _1-6 alkyl)(C _2-6 alkenyl), -PO(C _1-6 alkyl)(C _2-6 alkynyl),

-SO-N(C _1-6 alkyl) ₂ , -SO-N(C _1-6 alkyl)(C _2-6 alkenyl), -SO-N(C _1-6 alkyl)(C _2-6 alkynyl),

-SO ₂ -N(C _1-6 alkyl) ₂ , -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkenyl) and -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkynyl),

wherein -C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally substituted by halogen or CN;

_R9 and _R10 are each independently selected from H, halogen and _C1-6 alkyl optionally substituted by halogen;

R ₁₁ is selected from H, halogen, -C _1-6 alkyl optionally substituted by halogen or deuterium, -OC _1-6 alkyl optionally substituted by halogen or deuterium, and -C _2-6 alkynyl optionally substituted by halogen or deuterium;

R ₁₂ is each independently selected from H and deuterium; and

t is selected from an integer of 1 to 4.

Embodiment 1.1: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotope variant a pharmaceutically acceptable salt or solvate, wherein

Q is selected from

R ₄ is selected from H, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein the C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl or C _3-6 cycloalkyl are each independently optionally substituted by halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ ;

R ₁₁ is selected from H, halogen, -C _1-6 alkyl optionally substituted by halogen, -OC _1-6 alkyl optionally substituted by halogen, and -C _2-6 alkynyl optionally substituted by halogen.

Embodiment 1.2: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein

Q is selected from

_R3 is selected from H, halogen, -CN, -OH, _-OC1-6alkyl , _{-OC3-6cycloalkyl , -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl and -(CH2)n-C3-6cycloalkyl, wherein each occurrence of C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl or C3-6cycloalkyl is each independently optionally substituted by halogen ,} CN or _C1-6alkoxy ,

or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , spiro C _3-6 cycloalkyl or spiro 4-7 membered heterocycloalkyl, wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen,

or R ₁ and R ₃ attached to adjacent ring carbon atoms or two R ₃ attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C _{3-4 cycloalkyl} group;

or two _R3 attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;

R ₄ is selected from H, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein the C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl or C _3-6 cycloalkyl are each independently optionally substituted by halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ ;

R ₁₁ is selected from H, halogen, -C _1-6 alkyl optionally substituted by halogen, and -OC _1-6 alkyl optionally substituted by halogen.

Embodiment 1.3: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which is the following formula (I-1),

in:

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;

Y is selected from O, S and Se;

W is selected from OH and NH ₂ ;

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

Q is selected from in

Z is selected from N, C, O, S and Se;

k is selected from 0 or 1;

m and n are each independently selected from an integer from 0 to 2;

R ₁ is selected from -C _1-6 alkyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, each independently optionally substituted by halogen or C _1-6 alkoxy;

R ₂ is selected from H, -C _1-6 alkyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl is each independently optionally substituted by halogen or C _1-6 alkoxy,

Or two _R2 attached to the same carbon atom together with the carbon atom to which they are attached form a _{C3-4 cycloalkyl} group;

R ₃ is selected from H, halogen, -OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -C _1-6 alkyl and -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein each occurrence of C _1-6 alkyl or C _3-6 cycloalkyl is independently optionally substituted by halogen or C _1-6 alkoxy,

or R ₁ and R ₃ attached to adjacent ring carbon atoms or two R ₃ attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C _{3-4 cycloalkyl} group;

or two _R3 attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;

R ₄ is selected from H, -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl and -(CH 2 ) _n -C 3-6 cycloalkyl, wherein C _1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH ₂ ) n -C _3-6 cycloalkyl _C2-6 alkenyl, _-C2-6 alkynyl or _C3-6 cycloalkyl are each independently optionally substituted by halogen, CN, _-C1-6 alkoxy or -O-CON( _C1-6 alkyl) ₂ ;

_R5 is selected from H and halogen;

R ₆ is selected from H, halogen, -C _1-6 alkyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -Se-C _1-6 alkyl and -C _2-6 alkynyl, each independently optionally substituted by halogen;

R ₇ is selected from H, halogen, CN and -C _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted with halogen or CN;

R ₈ is selected from -OH, halogen, -CN, -B(OH) ₂ , -C _1-6 alkyl, -OC _1-6 alkyl,

-CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl),

-PO(C _1-6 alkyl) ₂ , -PO(C _1-6 alkyl)(C _2-6 alkenyl), -PO(C _1-6 alkyl)(C _2-6 alkynyl),

-SO-N(C _1-6 alkyl) ₂ , -SO-N(C _1-6 alkyl)(C _2-6 alkenyl), -SO-N(C _1-6 alkyl)(C _2-6 alkynyl),

-SO ₂ -N(C _1-6 alkyl) ₂ , -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkenyl) and -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkynyl),

wherein -C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally substituted by halogen or CN;

_R9 and _R10 are each independently selected from H, halogen and _C1-6 alkyl optionally substituted by halogen; and

t is selected from an integer of 1 to 4.

Embodiment 2.1: The compound of formula (I) according to Embodiment 1 or 1.3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein p is 1 and X is C, i.e. the fused bicyclic moiety where X is located is

Embodiment 2.1.1: A compound of formula (I) of Embodiment 2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₅ is H; or R ₅ is a halogen selected from F, Cl, Br, I; preferably R ₅ is a halogen, most preferably F.

Embodiment 2.1.2: A compound of formula (I) according to Embodiment 2.1 or 2.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R6 is H; or _R6 is a halogen selected from F, Cl, Br, I.

Embodiment 2.1.3: The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₆ is -C _1-6 alkyl, -OC _1-6 alkyl, -SC _1-6 alkyl _-C1-6 alkyl, optionally substituted with halogen, 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-CH ₂ CH ₃ , -SeCH ₃ .

Embodiment 2.1.4: A compound of formula (I) according to Embodiment 2.1 or 2.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₆ is -C _2-6 alkynyl, optionally substituted with halogen, for example but not limited to Best

Embodiment 2.1.5: A compound of formula (I) according to any one of Embodiments 2.1 to 2.1.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₉ and R ₁₀ are each H, i.e., the fused bicyclic moiety where X is located is Alternatively, _R9 and _R10 are each halogen, preferably F.

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 isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of _R9 and _R10 is H and the other is selected from halogen, preferably F; preferably _R10 is H and _R9 is selected from halogen, preferably F, as exemplified above.

Embodiment 2.1.7: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 2.1 to 2.1.6, wherein W is -OH.

Embodiment 2.1.8: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 2.1 to 2.1.6, wherein W is _-NH2 .

Embodiment 2.1.9: The compound of formula (I) of Embodiment 2.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the fused bicyclic moiety where X is located is Wherein _R5 is halogen, preferably F, and _R6 is selected from _-C1-6 alkyl, _-C2-6 alkynyl and halogen, preferably selected from _-C1-6 alkyl and _-C2-6 alkynyl, for example

Embodiment 2.2: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein p is 0 and X is S, that is, the fused bicyclic part where X is located is

Embodiment 2.2.1: A compound of formula (I) according to Embodiment 2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₅ is H; or R ₅ is a halogen selected from F, Cl, Br, I; preferably R ₅ is a halogen, most preferably F.

Embodiment 2.2.2: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R6 is H; or _R6 is a halogen selected from F, Cl, Br, I.

Embodiment 2.2.3: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R6 is _-C1-6 alkyl, _{-OC1-6 alkyl} , _-SC1-6 alkyl, -Se- _C1-6 alkyl, optionally substituted with halogen, 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 , -CH 2} CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -O-CH ₃ , -O-CH ₂ CH ₃ , -SCH ₃ , -S-CH ₂ CH ₃ , -SeCH ₃ .

Embodiment 2.2.4: A compound of formula (I) according to Embodiment 2.2 or 2.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₆ is -C _2-6 alkynyl, optionally substituted with halogen, for example but not limited to Best

Embodiment 2.2.5: A compound of formula (I) according to any one of Embodiments 2.2 to 2.2.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₉ and R ₁₀ are each H; or R ₉ and R ₁₀ are each halogen, preferably F.

Embodiment 2.2.6: A compound of formula (I) according to any one of Embodiments 2.2 to 2.2.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein one of R ₉ and R ₁₀ is H and the other is Preferably R ₁₀ is H and R ₉ is selected from halogen, as exemplified above.

Embodiment 2.2.7: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 2.2 to 2.2.6, wherein W is -OH.

Embodiment 2.2.8: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 2.2 to 2.2.6, wherein W is _-NH2 .

Embodiment 2.2.9: The compound of formula (I) of Embodiment 2.2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the fused bicyclic moiety where X is located is For example

Embodiment 3.1: A compound of formula (I) according to any one of Embodiments 1 to 2.2.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 5-7 membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, P, Se and S, connected to the pyrimidine ring portion of the molecule via a nitrogen heteroatom, such as but not limited to wherein each Z in each ring may be C, or at most two of them may be heteroatoms selected from N, O, P, Se and S, such as 5-7 membered heterocycloalkyl containing 1-3 nitrogen atoms, 5-7 membered heterocycloalkyl containing 1 nitrogen atom and 1-2 heteroatoms selected from O, P, Se and S, 5-7 membered heterocycloalkyl containing 2 nitrogen atoms and 1 heteroatom selected from O, P, Se and S, 5-7 membered heterocycloalkyl containing 1 nitrogen atom and 1 O atom, such as but not limited to Each is substituted by 1-4 R ₈ , preferably substituted by 1-2 R ₈ , more preferably R ₈ is substituted on a ring carbon atom.

Embodiment 3.1.1: Compounds of formula (I) of Embodiment 3.1, stereoisomers, tautomers, stable isomers thereof A variant, a pharmaceutically acceptable salt or a solvate of Substituted by 1-2 R ₈ , preferably substituted by R ₈ at the meta position of N, for example but not limited to

Embodiment 3.1.1.1: The compound of formula (I) of Embodiment 3.1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the substituent R ₈ on B is in a stereoisomeric form, such as R or S configuration, as long as it is chemically feasible.

Embodiment 3.1.2: Compounds of formula (I) according to Embodiments 3.1 to 3.1.1.1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein the substituents R ₈ carried on B are each independently selected from -OH, halogen, CN, -C _1-6 alkyl and -OC _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted with halogen or CN; preferably, one of the two R ₈ attached to the same ring carbon atom is -OH and the other is -C 1-6 alkyl optionally substituted with halogen or CN, preferably methyl; more preferably, two R ₈ are attached to the meta-ring carbon atom of the N atom attached to the rest of the molecule (e.g., pyrimidine ring), one of which is -OH and the other is -C _1-6 alkyl, preferably methyl, for _example , B is Best

Embodiment 3.1.3: A compound of formula (I) according to Embodiments 3.1 to 3.1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R ₈ carried on B is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , _-CON (C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN; preferably -CON(C _1-6 alkyl) ₂ , for example -CON(CH ₃ ) ₂ , for example B is

Embodiment 3.1.4: Compounds of formula (I) of Embodiments 3.1 to 3.1.1.1, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein the substituent _R8 carried on B is selected from -PO( _C1-6 alkyl) ₂ , -PO( _C1-6 alkyl)( _C2-6 alkenyl) and -PO( _C1-6 alkyl)( _C2-6 alkynyl), wherein _-C1-6 alkyl, _C2-6 alkenyl and _C2-6 alkynyl are optionally substituted by halogen or CN.

Embodiment 3.1.5: A compound of formula (I) according to Embodiments 3.1 to 3.1.1.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R ₈ carried on B is selected from -SO-N(C _1-6 alkyl) ₂ , -SO-N(C _1-6 alkyl)(C _2-6 alkenyl), -SO-N(C _1-6 alkyl)(C _2-6 alkynyl), -SO ₂ -N(C _1-6 alkyl) ₂ , -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkenyl) and -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN; preferably -SO-N(C _1-6 alkyl)(C _2-6 alkynyl) or -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkynyl), for example -SO ₂ -N(CH ₃ )(C≡CH), for example, B is

Embodiment 3.1.6: The compound of formula (I) of Embodiment 3.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is substituted by 1-2 R ₈ , preferably substituted by R ₈ at the meta position between N and O, R ₈ being independently selected from -OH, halogen, CN, -C _1-6 alkyl and -OC _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted by halogen or CN; preferably one of the two R ₈ attached to the same ring carbon atom is -OH and the other is -C _1-6 alkyl optionally substituted by halogen or CN, preferably methyl; more preferably two R ₈ are substituted on the meta ring carbon atom of the N atom attached to the rest of the molecule (e.g., pyrimidine ring), i.e. One of them is -OH and _{the other is -C 1-6 alkyl} , preferably -C _1-3 alkyl, more preferably methyl, for example B is Best

Embodiment 3.1.6.1: The compound of formula (I) of Embodiment 3.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the substituent R ₈ on B is in a stereoisomeric form, such as R or S configuration, as long as it is chemically feasible.

Embodiment 3.2: A compound of formula (I) according to any one of Embodiments 1 to 2.2.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is a 6-12 membered polycyclic heterocycloalkyl group (e.g., a 6-10 membered, 6-9 membered, 6-8 membered, 6-7 membered polycyclic heterocycloalkyl group) containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S, connected to the pyrimidine ring portion of the molecule via a nitrogen heteroatom, such as a group containing 1 to 4 nitrogen atoms, a group containing 1 nitrogen atom and 1 to 3 heteroatoms selected from O, S, P and Se, a group containing 2 nitrogen atoms and 1 to 2 heteroatoms selected from O, S, P and Se, a group containing 3 nitrogen atoms and 1 heteroatom selected from O, S, P and Se, such as but not limited to Each is substituted by 1-4 R ₈ , preferably substituted by 1-2 R ₈ , more preferably R ₈ is substituted on a ring carbon atom.

Embodiment 3.2.1: The compound of formula (I) of Embodiment 3.2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein B is Replaced by 1 R ₈ , such as but not limited to or replaced by 2 independently selected _R8 , such as but not limited to

Embodiment 3.2.2: A compound of formula (I) according to Embodiment 3.2 or 3.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein a substituent R ₈ carried on B is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN; preferably -CON(C _1-6 alkyl) ₂ , more preferably -CON(C _1-3 alkyl) ₂ , for example -CON(CH ₃ ) ₂ , for example B is For example Or when B carries two R ₈ substituents, for example, B is wherein R ₈ ortho to the N heteroatom is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted by halogen or CN, preferably -CON(C _1-6 alkyl) ₂ , more preferably -CON(C _1-3 alkyl) ₂ , for example -CON(CH ₃ ) ₂ , and another R ₈ is selected from halogen such as fluorine or chlorine, or cyano, for example

Embodiment 3.2.3: The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein the substituent _R8 carried on B is selected from -PO( _C1-6 alkyl) ₂ , -PO( _C1-6 alkyl)( _C2-6 alkenyl) and -PO( _C1-6 alkyl)( _C2-6 alkynyl), wherein _-C1-6 alkyl, _C2-6 alkenyl and _C2-6 alkynyl are optionally substituted with halogen or CN; or when B carries two _R8 substituents, one of them is selected from -PO( _C1-6 alkyl) ₂ , -PO( _C1-6 alkyl)( _C2-6 alkenyl) and -PO( _C1-6 alkyl)( _C2-6 alkynyl), wherein _-C1-6 alkyl, _C2-6 alkenyl and C2-6 alkynyl are optionally substituted with halogen or CN. _2-6 Alkynyl is optionally substituted by halogen or CN, the other being selected from halogen, such as fluorine or chlorine, or CN.

Embodiment 3.2.4: A compound of formula (I) according to Embodiment 3.2 or 3.2.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the substituent R ₈ carried on B is selected from -SO-N(C _1-6 alkyl) ₂ , -SO-N(C _1-6 alkyl)(C _2-6 alkenyl), -SO-N(C _1-6 alkyl)(C _2-6 alkynyl), -SO ₂ -N(C _1-6 alkyl) ₂ , -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkenyl) and -SO ₂ -N(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN; preferably -SO-N(C _1-6 alkyl)(C _2-6 alkynyl) or -SO ₂ -N(C 1-6 alkyl) _1-6 alkyl) (C _2-6 alkynyl), such as -SO ₂ -N(CH ₃ )(C≡CH), for example, B is

Embodiment 3.3: A compound of formula (I) according to any one of Embodiments 1 to 2.2.9, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein B is Wherein one of R ₈ is -OH and the other is -C _1-6 alkyl, preferably -C _1-3 alkyl, more preferably methyl, for example B is Best Or B is wherein R ₈ adjacent to the nitrogen heteroatom is selected from -CONH (C _1-6 alkane wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are _optionally substituted by _halogen or CN, preferably -CON(C _1-6 alkyl) _{2, more preferably -CON(C 1-3 alkyl) 2 , for example -CON(CH 3 ) 2 , another R 8 is selected from} H or cyano or halogen such as fluorine or chlorine, for example B _is

Embodiment 4.1: A compound of formula (I) according to any one of Embodiments 1 to 3.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is

Embodiment 4.2: A compound of formula (I) according to any one of Embodiments 1 to 3.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is For example

Embodiment 4.2.1: A compound of formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁ is -C _1-6 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl _3. -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.2.2: The compound of formula (I) of Embodiment 4.2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₁ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.2.3: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R2 is H.

Embodiment 4.2.4: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein at least one R ₂ is -C _1-6 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.2.5: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein at least one R ₂ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.2.6: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two _R2 together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group.

Embodiment 4.2.7: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is H.

Embodiment 4.2.8: Compounds of formula (I) according to any one of Embodiments 4.2 to 4.2.6, stereoisomers, tautomers thereof The invention relates to a pharmaceutically acceptable salt or solvate of the present invention, wherein R ₃ is a halogen selected from F, Cl, Br, I; preferably F.

Embodiment 4.2.9: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.2 to 4.2.6, wherein R ₃ is -OH.

Embodiment 4.2.10: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -C _1-6 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.2.11: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R3 is _-OC1-6alkyl , optionally substituted with halogen or _C1-6alkoxy , for example but not limited to _-O - _CH3 , -O- _CH2CH3 , -O- _CH2CH2CH3 , -O-CH( _CH3 ) ₂ , -O- _{CH2F ,} -O- _CH2Cl , -O- _{CHF2 , -O} - _CF3 , -O- _CH2CH2F , -O- _CH2CHF2 , -O- _{CH2CF3 ,} -O _{- CH2CH2CF3} , -O- _{CH2 -} O _{- CH3} , -O- _CH2CH2 - _O - _CH3 .

Embodiment 4.2.12: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.2.13: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -OC _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.2.14: A compound of formula (I) according to any one of Embodiments 4.2.8 to 4.2.13, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein at least one R ₃ is present; preferably there is one R ₃ , more preferably the one R ₃ is adjacent to R ₁ , for example the one R ₃ is selected from halogen such as F, -C _1-6 alkyl such as methyl, -C _1-6 alkoxy such as methoxy.

Embodiment 4.2.15: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R1 and _R3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a _{C3-4 cycloalkyl} group.

Embodiment 4.2.16: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.6, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two _R3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a _{C3-4 cycloalkyl} .

Embodiment 4.2.17: A compound of Formula (I) according to any one of Embodiments 4.2 to 4.2.16, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R4 is H.

Embodiment 4.2.18: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.16, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R4 is _-C1-6 alkyl, optionally substituted with halogen, CN, _-C1-6 alkoxy or -O- _CON ( _C1-6 alkyl) ₂ , 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} , -CH(CH ₃ )CH ₂ -OCH ₃ , -CH ₂ CH(CH ₃ )-OCH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH(CH ₃ )F, -CH(CH ₃ )CH ₂ F, -CH ₂ CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ , -CH ₂ CN, -CH ₂ CH ₂ CN,

Embodiment 4.2.19: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.16, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₄ is -C _2-6 alkenyl or -C _2-6 alkynyl, such as but not limited to ethenyl, propenyl, ethynyl, each optionally substituted with halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ .

Embodiment 4.2.20: A compound of formula (I) according to any one of Embodiments 4.2 to 4.2.16, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₄ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ , for example but not limited to

Embodiment 4.2.21: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.2 to 4.2.16 wherein _R4 is methyl.

Embodiment 4.2.22: A compound of formula (I) according to Embodiment 4.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁ is -C _1-6 alkyl, R ₂ is H, R ₃ is selected from halogen, C _1-6 alkyl and C _1-6 alkoxy, and R ₄ is C _1-6 alkyl, for example Q is For example

Embodiment 4.3: A compound of formula (I) according to any one of Embodiments 1 to 3.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is For example Where m is 1, or m is 1 or 2.

Embodiment 4.3.1: The compound of formula (I) of Embodiment 4.3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein k is 0, then Q is For example For example and each fragment formed by replacing two H atoms on the methylene group connected to the rest of the molecule in each exemplary fragment by deuterium, preferably

Embodiment 4.3.2: The compound of formula (I) of Embodiment 4.3, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein k is 1, then Q is For example For example and each fragment formed by replacing two H atoms on the methylene group attached to the rest of the molecule in each example fragment with deuterium.

Embodiment 4.3.3: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁ is -C _1-6 alkyl, preferably -C _1-3 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH 2 _{CH 2} CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -C _{2 F 5 ,} -C ₂ Cl ₅ , -CF ₍ CF ₃ ) ₂ ; preferably -CH ₃ .

Embodiment 4.3.4: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.3.5: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R1 and _R3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a _{C3-4 cycloalkyl} group, and the corresponding structural fragments are, for example but not limited to

Embodiment 4.3.6: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is H.

Embodiment 4.3.7: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is a halogen selected from F, Cl, Br, I, preferably F.

Embodiment 4.3.7.1: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.3 to 4.3.5, wherein R ₃ is CN.

Embodiment 4.3.8: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.3 to 4.3.5, wherein R ₃ is -OH.

Embodiment 4.3.9: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -C _1-6 alkyl, preferably -C _1-3 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH 2 _{CH 2} CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.3.9.1: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -C _2-6 alkenyl or -C _2-6 alkynyl, Optionally substituted with halogen, CN or -C _1-6 alkoxy; for example but not limited to ethenyl, propenyl, ethynyl, each of which is optionally substituted with halogen, CN or -C _1-6 alkoxy.

Embodiment 4.3.10: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R3 is _-OC1-6alkyl , optionally substituted with halogen or _C1-6alkoxy , for example but not limited to _-O - _CH3 , -O- _CH2CH3 , -O- _CH2CH2CH3 , -O-CH( _CH3 ) ₂ , -O- _{CH2F ,} -O- _CH2Cl , -O- _{CHF2 , -O} - _CF3 , -O- _CH2CH2F , -O- _CH2CHF2 , -O- _{CH2CF3 ,} -O _{- CH2CH2CF3} , -O- _{CH2 -} O _{- CH3} , -O- _CH2CH2 - _O - _CH3 .

Embodiment 4.3.11: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.3.12: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -OC _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.3.13: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two _R3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a _{C3-4 cycloalkyl} , preferably a cyclopropyl; the corresponding ring is for example but not limited to

Embodiment 4.3.13.1: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein each R ^c is independently selected from H, F, Cl, Br, I, -C _1-6 alkyl optionally substituted with halogen; for example, but not limited to, =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ .

Embodiment 4.3.13.2: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two _R3 attached to the same carbon atom form a spiro _C3-6 cycloalkyl or a spiro 4-7 membered heterocycloalkyl, such as but not limited to spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spiroazetidine, spiroazetidine.

Embodiment 4.3.14: A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.3 to 4.3.5, wherein two _R3 attached to non-adjacent ring carbon atoms are taken together to form a bridged methylene or ethylene group.

Embodiment 4.3.14.1: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is selected from halogen, CN, OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -C _1-6 alkyl, -C _2-6 alkynyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein each occurrence of C _{1- 6} alkyl, -C _2-6 alkynyl or C _3-6 cycloalkyl is each independently optionally substituted with halogen or -OC _1-6 alkyl;

or two _R3 attached to the same ring carbon atom together with the carbon atom to which they are attached form a _{C3-4 cycloalkyl} group,

or two R ₃ attached to the same carbon atom form ＝C(R ^c ) ₂ , wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen, such as but not limited to ＝CH ₂ , ＝CHF, ＝CF ₂ , ＝CCl ₂ , ＝C(CH ₃ ) ₂ , ＝C(CF ₃ ) ₂ ;

Preferably,

R ₃ is -C _1-3 alkyl substituted by halogen, such as -CHF ₂ , for example m=1; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein each R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ , preferably =CHF.

Embodiment 4.3.14.2: A compound of formula (I) according to Embodiment 4.3.14.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the ring carbon atom to which R ₃ is attached is adjacent to the ring carbon atom to which R ₁ is attached. The carbon atoms are adjacent and not adjacent to the ring NR ₄ , e.g.

Embodiment 4.3.15: A compound of Formula (I) according to any one of Embodiments 4.3 to 4.3.14.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R4 is H.

Embodiment 4.3.16: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.14.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R4 is _-C1-6 alkyl, optionally substituted with halogen, CN, _-C1-6 alkoxy or -O-CON( _C1-6 alkyl) ₂ , or optionally substituted with _one or more deuterium; for example, but not limited to _-CH3 , _{-CH2CH3 , -CH2CH2CH3} , _-CH ( _CH3 )( _CH3 ), -CH2CH2CH2CH3, -CH2CH( _CH3 ) _{CH3 ,} -C( _CH3 ) ₃ , _{-CD3 , -CH2} - _OCH3 , _{-CH2 - O} - _CH2CH3 , _{-CH2CH2 - O} - _CH3 , _{-CH 2} CH ₂ -O-CH ₂ CH ₃ , -CH(CH ₃ )CH ₂ -OCH ₃ , -CH ₂ CH(CH ₃ )-OCH ₃ , -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH(CH ₃ )F, -CH(CH ₃ )CH ₂ F, - CH ₂ CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ , -CH ₂ CN, -CH ₂ CH ₂ CN,

Preferably, R ₄ is -C _1-3 alkyl, such as methyl, ethyl;

Preferably, R ₄ is -C _1-3 alkyl substituted by one or more deuterium, for example -CD ₃ .

Embodiment 4.3.17: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.14.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₄ is -C _2-6 alkenyl or -C _2-6 alkynyl, such as but not limited to ethenyl, propenyl, ethynyl, each optionally substituted with halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ .

Embodiment 4.3.18: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.14.2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₄ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen, CN, -C _1-6 alkoxy or -O-CON(C _1-6 alkyl) ₂ , for example but not limited to

Embodiment 4.3.19: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.3 to 4.3.14.2, wherein _R4 is methyl; or _R4 is ethyl; or _R4 is _-CD3 .

Embodiment 4.3.20: A compound of formula (I) of Embodiment 4.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is selected from C, Se and O, _R1 is _-C1-6 alkyl, _R3 is selected from H, halogen, _C1-6 alkyl and _C1-6 alkoxy, and _R4 is _C1-6 alkyl; preferably Z is selected from C.

Embodiment 4.3.21: A compound of formula (I) of Embodiment 4.3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is selected from C, R ₁ is -C _1-6 alkyl, R ₃ is selected from halogen, CN, OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -C _1-6 alkyl, -C _2-6 alkynyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, wherein each occurrence of C _1-6 alkyl, -C _2-6 alkynyl or C _3-6 cycloalkyl is each independently optionally substituted with halogen or -OC _1-6 alkyl,

or two R ₃ attached to the same ring carbon atom together with the carbon atom to which they are attached form a spiro C _{3-4 cycloalkyl} group optionally substituted by halogen,

or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; and

_R4 is _C1-6 alkyl;

Preferably, Z is C, R ₃ is -C _1-3 alkyl, substituted by halogen, such as -CHF ₂ ; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; R ₄ is -C _1-3 alkyl, or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ , ethyl;

More preferably, Q is wherein R ₁ is -C _1-3 alkyl, R ₃ is -C _1-3 alkyl substituted by halogen, such as -CHF ₂ , and m is 1; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is each independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ , preferably =CHF; more preferably (R ₃ ) _m is selected from -CHF ₂ and =CHF; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuteriums, such as methyl, -CD ₃ , ethyl;

Most preferably, Q is For example wherein R ₃ and R ₄ each have the general or preferred meanings defined above, preferably Q is Wherein R ₃ is -C _1-3 alkyl, substituted by halogen, such as -CHF ₂ .

Embodiment 4.3.21.1: A compound of formula (I) according to any one of Embodiments 4.3 to 4.3.21, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two hydrogen atoms of the methylene group connected to Y in the Q moiety are optionally replaced by deuterium.

Embodiment 4.3.22: The compound of formula (I) of Embodiment 4.3.1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein examples of Q include but are not limited to

Best

Embodiment 4.3.23: A compound of Formula (I) according to Embodiment 4.3.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is For example wherein R ₁ , R ₃ and R ₄ are each as defined in Embodiment 1, preferably as defined in any one of Embodiments 4.3.3, 4.3.6 to 4.3.19; more preferably, wherein R ₄ is -C _1-6 alkyl optionally substituted by -OC _1-6 alkyl or halogen, preferably -C _1-3 alkyl; R ₃ is selected from halogen, CN, -C _1-6 alkyl optionally substituted by halogen, -C _2-6 alkynyl optionally substituted by halogen and -OC _1-6 alkyl optionally substituted by halogen, or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ or spiro C _3-6 cycloalkyl optionally substituted by halogen, wherein R ^c is each independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen, and m is selected from 1 or 2; R Specific examples of ₃ include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl;

Most preferably, R ₃ is -C _1-3 alkyl substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ , ethyl;

wherein two hydrogen atoms of the methylene group attached to Y are optionally replaced by deuterium;

More preferably, R ₃ is attached to a ring carbon atom para to the ring nitrogen atom; (R ₃ ) _m is selected from -CHF ₂ and =CHF.

Embodiment 4.3.23: Compounds of formula (I) of Embodiment 4.3.1, stereoisomers, tautomers, stable isomers thereof isotropic variant, pharmaceutically acceptable salt or solvate, wherein Q is wherein R ₃ and R ₄ are each as defined in Embodiment 1, preferably as defined in Embodiments 4.3.6 to 4.3.19, respectively; more preferably, wherein R ₄ is -C _1-6 alkyl optionally substituted by -OC _1-6 alkyl or halogen, preferably -C _1-3 alkyl; R ₃ is selected from halogen, CN, -C _1-6 alkyl optionally substituted by halogen, -C _2-6 alkynyl optionally substituted by halogen and -OC _1-6 alkyl optionally substituted by halogen, or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ or spiro C _3-6 cycloalkyl optionally substituted by halogen, wherein R ^c is each independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen, and m is selected from 1 or 2; R Specific examples of ₃ include, but are not limited to, fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl;

Most preferably, R ₃ is -C _1-3 alkyl substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ , ethyl;

wherein two hydrogen atoms of the methylene group attached to Y are optionally replaced by deuterium;

More preferably (R ₃ ) _m is selected from -CHF ₂ and =CHF.

Embodiment 4.4: A compound of formula (I) according to any one of Embodiments 1 to 3.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is

Embodiment 4.4.1: A compound of Formula (I) according to Embodiment 4.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Q is selected from

Embodiment 4.4.2: A compound of Formula (I) according to Embodiment 4.4 or 4.4.1, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein _R2 is H.

Embodiment 4.4.3: A compound of formula (I) according to Embodiment 4.4 or 4.4.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein at least one R ₂ is -C _1-6 alkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O- CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F , -CH ₂ Cl , -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , - C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.4.4: A compound of formula (I) according to Embodiment 4.4 or 4.4.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein at least one R ₂ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.4.5: A compound of formula (I) according to Embodiment 4.4 or 4.4.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two _R2 together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group, for example Q is For example

Embodiment 4.4.6: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is H.

Embodiment 4.4.7: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is a halogen selected from F, Cl, Br, I; preferably F.

Embodiment 4.4.8: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.4 to 4.4.5, wherein R ₃ is -OH.

Embodiment 4.4.9: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable _{salt or a solvate thereof, wherein R3 is -C1-6 alkyl, optionally substituted with halogen or C1-6 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 - _{CH3, -CH2CH2-O-CH2CH3 , -CH2F , -CH2Cl , -CHF2 , -CF2 3.} -CCl ₃ , -CH ₂ CH ₂ F , -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , -C ₂ Cl ₅ , -CF(CF ₃ ) ₂ .

Embodiment 4.4.10: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R3 is _-OC1-6alkyl , optionally substituted with halogen or _C1-6alkoxy , for example but not limited to _-O - _CH3 , -O- _CH2CH3 , -O- _CH2CH2CH3 , -O-CH( _CH3 ) ₂ , -O- _{CH2F ,} -O- _CH2Cl , -O- _{CHF2 , -O} - _CF3 , -O- _CH2CH2F , -O- _CH2CHF2 , -O- _{CH2CF3 ,} -O _{- CH2CH2CF3} , -O- _{CH2 -} O _{- CH3} , -O- _CH2CH2 - _O - _CH3 .

Embodiment 4.4.11: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -(CH ₂ ) _n -C _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.4.12: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₃ is -OC _3-6 cycloalkyl, optionally substituted with halogen or C _1-6 alkoxy, for example but not limited to

Embodiment 4.4.13: A compound of Formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 4.4.7 to 4.4.12 wherein at least one R ₃ is present; preferably one R ₃ is present.

Embodiment 4.4.14: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein the two _R3 together with the carbon atom to which they are attached form a _{C3-4 cycloalkyl} group.

Embodiment 4.4.15: A compound of formula (I) according to any one of Embodiments 4.4 to 4.4.5, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein two _R3 attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group, for example Q is

Embodiment 4.4.16: A compound of formula (I) of Embodiment 4.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is selected from C, Se and O, two _R2 together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl group, and _R3 is selected from H, halogen, _C1-6 alkyl and _C1-6 alkoxy.

Embodiment 5.1: A compound of formula (I) according to any one of Embodiments 1 to 4.4.15, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

Embodiment 5.2: A compound of formula (I) according to any one of Embodiments 1 to 4.4.15, wherein Y is S, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

Embodiment 5.3: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 4.4.15 wherein Y is Se.

Embodiment 6a: A compound of formula (I) according to any one of Embodiments 1 to 5.3, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein M is N.

Embodiment 6b: A compound of formula (I), stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 5.3, wherein M is CR ₇ .

Embodiment 6.1: A compound of Formula (I) according to Embodiment 6b, wherein R ₇ is H, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

Embodiment 6.2: A compound of formula (I) according to Embodiment 6b, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₇ is a halogen selected from F, Cl, Br and I; preferably F or Cl.

Embodiment 6.3: A compound of Formula (I) according to Embodiment 6b, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₇ is CN.

Embodiment 6.4: A compound of formula (I) according to Embodiment 6b, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein _R7 is _-C1-6 alkyl _, optionally substituted by halogen or CN; for example, but not limited to _-CH3 , _-CH2CH3 , _-CH2F , _-CH2Cl , _-CHF2 , _-CF3 , _-CCl3 , _-CH2CH2F , _{-CH2CHF2 , -CH2CF3} , _-CH2CN , _-CH2CH2CN ; preferably _R7 is _-C1-3 alkyl, optionally substituted by one or more halogen _, preferably substituted by _F , _more preferably _-CF3 .

Embodiment 6.5: The compound of formula (I) of Embodiment 6b, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein _R7 is selected from H, halogen, CN and _-C1-6 alkyl optionally substituted by one or more halogen (preferably F); preferably H, halogen, CN and _-C1-3 alkyl substituted by one or more halogen (preferably F); more preferably H, F, Cl, CN, _-CF3 .

Embodiment 7a: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is H.

Embodiment 7b: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is halogen, preferably F.

Embodiment 7c: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is -C _1-6 alkyl optionally substituted by halogen, for example but not limited to -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )(CH ₃ ), -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -C(CH ₃ ) ₃ , -CH ₂ -OCH ₃ , -CH ₂ -O-CH ₂ CH ₃ , -CH ₂ CH ₂ -O-CH ₃ , -CH ₂ CH ₂ -O-CH ₂ CH ₃ , -CH ₂ F, -CH ₂ Cl , -CHF ₂ , -CF ₃ , -CCl ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH 2 CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -C ₂ F ₅ , _{-C 2 Cl 5} , -CF(CF ₃ ) ₂ , preferably -CH ₃ .

Embodiment 7d: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is -OC _1-6 alkyl optionally substituted by halogen, for example but not limited to -O-CH ₃ , -O-CH ₂ CH ₃ , -O-CH ₂ CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , -O-CH ₂ F, -O-CH ₂ Cl, -O-CHF ₂ , -O-CF ₃ , -O-CH ₂ CH ₂ F, -O-CH ₂ CHF ₂ , -O-CH ₂ CF ₃ , -O-CH ₂ CH ₂ CF ₃ , -O-CH ₂ -O-CH ₃ , -O-CH ₂ CH ₂ -O-CH ₃ , preferably -O-CH ₃ ; or

R ₁₁ is -OC _1-6 alkyl optionally substituted by deuterium, preferably -OC _1-3 alkyl optionally substituted by one or more deuterium groups, for example, -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CD ₃ .

Embodiment 7e: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is -C _2-6 alkynyl optionally substituted by halogen, preferably ethynyl.

Embodiment 7e: A compound of formula (I) according to any one of Embodiments 1 to 6.4, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein R ₁₁ is selected from H, -OC _1-6 alkyl and -OC _1-6 alkyl substituted by deuterium, preferably H and -OC _1-3 alkyl optionally substituted by one or more deuterium, for example H, -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CD ₃ .

Embodiment 7: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which has the following sub-formula:

wherein each substituent has the meaning defined in the above respective embodiments.

Embodiment 7.1: A compound of formula (I) according to Embodiment 7, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein:

Y is O;

B is selected from

Z is selected from C, Se and O, preferably O or C;

W is -OH; or W is NH ₂ ;

R ₁ is C _1-6 alkyl, preferably methyl;

_R2 is H, or two _R2 attached to the same carbon atom together form a cyclopropyl group,

R ₃ is selected from H, C _1-6 alkyl, -OC _1-6 alkyl and halogen, preferably C _1-6 alkyl, -OC _1-6 alkyl and halogen, such as methyl, ethyl, methoxy, ethoxy and F; or

For formula (IA-2), (IB-2), (IC-2) or (ID-2), R ₃ is selected from halogen, CN, -C _1-6 alkyl optionally substituted by halogen, -C _2-6 alkynyl optionally substituted by halogen and -OC _1-6 alkyl optionally substituted by halogen, or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ or spiro C _3-6 cycloalkyl optionally substituted by halogen, wherein R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen; preferably, R ₃ is -C _1-3 alkyl, substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; more preferably, R ₃ is attached to the ring carbon atom in the para position to the ring nitrogen atom, and (R ₃ ) _m is selected from -CHF ₂ and =CHF;

R ₄ is selected from H and C _1-6 alkyl, preferably C _1-6 alkyl, such as methyl or ethyl; more preferably, R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ ;

R ₅ is selected from H and halogen, preferably halogen, such as F;

R ₆ is selected from halogen, C _1-6 alkyl and C _2-6 alkynyl, preferably F, ethyl or ethynyl;

R ₇ is selected from H, halogen, CN and halogen-substituted C _1-6 alkyl, preferably H, F, Cl, CN, CF ₃ ;

R ₈ is selected from -OH, halogen, -CN, -C _1-6 alkyl, -OC _1-6 alkyl and -CON(C _1-6 alkyl) ₂ ;

_R9 and _R10 are each independently H or halogen, for example, each independently H or F, or both are H, or both are halogen, for example, F;

R ₁₁ is selected from H, halogen, C _1-6 alkyl optionally substituted by halogen, C _1-6 alkoxy optionally substituted by halogen, and -C _2-6 alkynyl optionally substituted by halogen; preferably H, halogen, C _1-6 alkyl, C _1-6 alkoxy and -C _2-6 alkynyl;

or R ₁₁ is selected from H, C _1-6 alkoxy optionally substituted by deuterium, preferably H and C _1-3 alkoxy optionally substituted by one or more deuterium, more preferably H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ;

n is selected from 0, 1 and 2, k is selected from 0 and 1, m and t are each independently selected from 1 or 2, preferably 2;

wherein two hydrogen atoms of the methylene group of Q connected to Y are optionally replaced by deuterium.

Embodiment 8: A compound of formula (I) according to Embodiment 7 or 7.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, which has the following sub-formula:

Preferably, wherein

R ₈ is selected from -OH and -C _1-6 alkyl, preferably one of them is -OH and the other is C _1-6 alkyl, such as -CH ₃ ;

Y is O;

_R9 is H;

_R5 is selected from halogen, preferably F; and

R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl;

For formula (I-A'-2), (I-B'-2), (I-C'-2) or (I-D'-2), R ₃ is -C _1-3 alkyl substituted by halogen, such as -CHF ₂ ; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ , preferably =CHF; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ ;

More preferably, R ₃ is attached to a ring carbon atom para to the ring nitrogen atom, and (R ₃ ) _m is selected from -CHF ₂ and =CHF;

R ₇ is selected from H, halogen, CN and -C _1-3 alkyl substituted by one or more halogens; preferably H, F, Cl, CN, -CF ₃ ;

One of R ₈ is -C _1-6 alkyl, preferably -C _1-3 alkyl, more preferably methyl, and the other is OH;

R ₁₁ is selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy; or R ₁₁ is selected from H, C _1-6 alkoxy optionally substituted by deuterium, preferably H and C _1-3 alkoxy optionally substituted by one or more deuterium, more preferably H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ;

k is selected from 0, m is selected from 1 or 2;

wherein two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.

Embodiment 8.1: The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment B in each sub-formula is

Embodiment 8.2: The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment B in each sub-formula can be replaced by Thus, compounds of the sub-general formulae (IA"'), (IA"'-1), (IA"'-2), (IA"'-3), (IA"'-4), (IB"'), (IB"'-1), (IB"'-2), (IB"'-3), (IB"'-4), (IC"'), (IC"'-1), (IC"'-2), (IC"'-3), (IC"'-4), (ID"'), (ID"'-1), (ID"'-2), (ID"'-3), (ID"'-4) are obtained accordingly, for example

Embodiment 8.3: The compound of formula (I) of Embodiment 8.2, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein in each sub-formula shown in the table:

Z is C;

W is OH or NH ₂ ;

R ₁ is -C _1-3 alkyl, preferably methyl;

R ₃ is -C _1-3 alkyl, substituted by halogen, preferably substituted by F; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c are each independently selected from H and halogen, preferably H and F; more preferably R ₃ is attached to the ring carbon atom in the para position to the ring nitrogen atom, (R ₃ ) _m is selected from -CHF ₂ and =CHF;

_R4 is _-C1-3 alkyl or _-C1-3 alkyl substituted by one or more deuteriums;

Y is O; two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium;

R ₅ is halogen, preferably F;

R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl;

R ₇ is selected from H, halogen, CN and -C _1-3 alkyl substituted by one or more halogens; preferably H, F, Cl, CN, -CF ₃ ;

One of R ₈ is -OH and the other is -C _1-3 alkyl, preferably for More preferred

_R9 is H;

R ₁₁ is selected from H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ;

m is selected from 1 or 2.

Embodiment 9: A compound of formula (I) according to Embodiment 7 or 7.1, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, which has the following sub-formula:

Wherein, each substituent or structural fragment is as defined in any of the above corresponding embodiments,

Preferably:

R ₈ ortho to the nitrogen heteroatom is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN, and another R ₈ is selected from H, halogen or CN;

Z is C; Y is O; R ₉ is H;

_R5 is selected from halogen, preferably F; and

R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl;

R ₁ is -C _1-3 alkyl, preferably methyl;

For formula (IA"-2), (IA"-2') or (IC"-2) and examples thereof, R ₃ is -C _1-3 alkyl substituted by halogen, such as -CHF ₂ ; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen, such as but not limited to =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ , preferably =CHF; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuterium, such as methyl, -CD ₃ ; more preferably R ₃ is attached to the ring carbon atom para to the ring nitrogen atom, (R ₃ ) _m is selected from -CHF ₂ and =CHF;

R ₇ is selected from H, halogen, CN and -C _1-3 alkyl substituted by one or more halogens;

R ₁₁ is selected from H, halogen, C _1-6 alkyl and C _1-6 alkoxy; or R ₁₁ is selected from H, C _1-6 alkoxy optionally substituted by deuterium, preferably H and C _1-3 alkoxy optionally substituted by one or more deuterium, more preferably H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ;

K is 0, m is selected from 1 or 2;

wherein two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.

More preferably:

Z is C; Y is O; R ₉ is H;

R ₈ ortho to the nitrogen heteroatom is -CON(C _1-6 alkyl) ₂ , preferably -CON(CH ₃ ) ₂ , and the other R ₈ is H or halogen or CN;

R ₃ is -C _1-3 alkyl, substituted by halogen, preferably substituted by F; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c are independently selected from H and halogen, preferably H and F; further preferably, R ₃ is attached to the ring carbon atom in the para position to the ring nitrogen atom, and (R ₃ ) _m is selected from -CHF ₂ and =CHF;

_R4 is _-C1-3 alkyl or _-C1-3 alkyl substituted by one or more deuteriums;

The two hydrogen atoms of the methylene group attached to O are optionally replaced by deuterium;

R ₅ is halogen, preferably F;

R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl;

R ₇ is selected from H, F, Cl, CN, CF ₃ ;

R ₁₁ is selected from H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ;

m is selected from 1 or 2.

Embodiment 10: A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,

in:

M is selected from N or CR ₇ ;

The fused bicyclic part where X is located is wherein R ₅ is halogen, and R ₆ is selected from -C _1-6 alkyl and -C _2-6 alkynyl;

W is selected from OH and NH ₂ ;

Y is selected from O, S and Se;

B with R ₈ is wherein one of R ₈ is -OH and the other is -C _1-6 alkyl; or

B with R ₈ is wherein R ₈ ortho to the nitrogen heteroatom is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN, and another R ₈ is selected from H or halogen;

Q is Or Q is in

m is selected from an integer from 0 to 2;

R ₁ is selected from -C _1-6 alkyl;

R ₃ is selected from -C _1-6 alkyl, optionally substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen;

R ₄ is selected from -C _1-6 alkyl, or R ₄ is -C _1-6 alkyl substituted by one or more deuteriums;

R ₇ is selected from H, halogen, CN and -C _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted with halogen or CN;

R ₁₁ is selected from H, halogen, -C _1-6 alkyl optionally substituted by halogen, -OC _1-6 alkyl optionally substituted by halogen; or R ₁₁ is -C _2-6 alkynyl optionally substituted by halogen, or R ₁₁ is -OC _1-6 alkyl substituted by one or more deuteriums.

Embodiment 11: A compound selected from the group consisting of the compounds of Examples 1-269 below or a pharmaceutically acceptable salt or solvate thereof.

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

Advantageous Effects of the Invention

As mentioned above, it is known that Ras mutant proteins, especially KRas mutant proteins, play a role in tumorigenesis and a variety of other diseases. We have surprisingly found that the compounds of the present invention having the above structural characteristics can strongly inhibit cell proliferation in cell lines carrying KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS wild-type amplification, thereby preventing, In terms of curbing and/or treating related tumor diseases, the compounds of the present invention have potential as anti-proliferation, pro-apoptosis and/or anti-invasive drug value. In particular, it is expected that the compounds of the present invention can be used to prevent or treat those Ras mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) or KRAS wild amplification-mediated or benefited from Ras mutations (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) or KRAS wild amplification inhibition diseases or conditions, such as cancers or tumors as defined herein.

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

● High mutant protein inhibitory activity: The compounds of the present invention, especially the compounds specifically exemplified herein, show proliferation inhibitory activity in KRAS mutant cells (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplified cell proliferation inhibition experiments, with IC50 values in the range of 0.0001-10 μM, preferably in the range of 0.0001-1 μM; for example, 0.0001-1 μM, 0.001-1 μM, 0.0001-0.5 μM, 0.001-0.5 μM, 0.0001-0.1 μM, 0.001-0.5 μM, 0.001-0.1 μM;

● Having good pharmacokinetic properties, such as having a longer t _1/2 , so that, for example, the dosing interval can be increased, a longer half-life can be achieved, and patients have better compliance; having AUC _0-t data with the best safety/activity combination, having better drugability, and higher bioavailability, as verified in Active Example 3; and/or

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

● Good pharmacokinetic properties bring a more convenient oral administration mode and show good pharmacodynamic effects, as verified in Active Example 7.

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

Compounds of the invention for use in therapy or as a medicament

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

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

On the other hand, the present invention provides a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use in treating and/or preventing diseases or disorders mediated by Ras mutant proteins, specifically KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplification or benefiting from Ras mutations, specifically KRas mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant proteins) and KRAS amplification inhibition.

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

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

Pharmaceutical compositions and their administration

On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, preferably a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S, KRas G13D mutations or KRas Q61H mutations, and KRAS amplification-mediated diseases, such as tumors or cancers.

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

The administration and use of the pharmaceutical composition of the present invention are in accordance with good medical practice. Factors to be considered in this context include the specific disorder treated, the specific mammal treated, the clinical condition of the individual patient, the cause of the disorder, the position of the agent delivery, the method of administration, the arrangement of administration, and other factors known to the physician practitioner. The optimal dose level and the frequency of administration of the compounds of the present invention or the pharmaceutical composition can be determined by those skilled in the art through standard tests in the field of pharmaceutical research.

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

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

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

Treatments and uses

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

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

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

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

On the other hand, the present invention provides the use of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, for inhibiting Ras mutations, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations, and KRAS amplification-mediated diseases in cells.

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

For the various methods and technical solutions for use provided by the present invention, the abnormal cell growth or diseases mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutation, and KRAS amplification, especially refers to cancer or tumor. Exemplary such cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma, or pituitary adenoma.

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

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

The present invention also provides the use of the compounds of the present invention, preferably their pharmaceutically acceptable salts or solvates, as research tool compounds for KRas inhibitors (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations and KRAS amplification inhibitors) in research. Therefore, the present invention relates to the in vitro use of the compounds of the present invention, preferably their pharmaceutically acceptable salts or solvates as KRas inhibitors, and in particular to the in vitro use of the compounds of the present invention, preferably their pharmaceutically acceptable salts or solvates as KRas inhibitors. The present invention also relates to methods for inhibiting KRas (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations and KRAS amplification), in particular in vitro methods, which include applying the compounds of the present invention, preferably their pharmaceutically acceptable salts or solvates, to a sample (e.g., a biological sample). . It will be understood that the term "in vitro" in this particular context is used in the sense of "outside a living human or animal body", which specifically includes experiments performed with cells, cellular or subcellular extracts and/or biomolecules in an artificial environment, such as aqueous solutions or culture media that may be provided in flasks, test tubes, petri dishes, microtiter plates, etc.

Drug combinations

The compounds of the present invention may be administered as the sole active ingredient or in combination with other drugs or therapies.

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

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

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

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

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

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

With respect to the technical solutions of the pharmaceutical composition, drug combination or drug kit of the present invention, the abnormal cell growth involved therein or the diseases mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutation, and KRAS amplification are as defined above for the methods and uses of the present invention.

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

Preparation method of the compound of the present invention

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

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

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

If not otherwise specified, the starting materials and reagents used in the preparation of the compounds are commercially available, or known compounds in the literature, or can be prepared by a person skilled in the art by the methods described below, by methods analogous to the methods given below, or by standard methods known in the art. Unless otherwise specified in the process description, suitable solvents are those conventional solvents well known to a person skilled in the art for the specific type of reaction involved, such as water, esters, ethers, liquid aromatic hydrocarbons, alcohols, nitriles, halogenated hydrocarbons, amides, bases, carboxylic anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for post-processing, such as post-processing by chromatography or partitioning.

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

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

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

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

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

For the sake of clarity, in the exemplary synthetic schemes described below, unless otherwise specified, R ₁ , R ₂ , R 3 , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , X, Y, Z, n, m and t appearing in the structural formula of each intermediate compound are as defined above for the compounds of the present invention, wherein PG represents a suitable protecting group that can be _determined by those skilled in the art based on knowledge of organic chemistry.

Synthesis Scheme A

The synthesis of the compounds of the present invention can be prepared according to the following scheme or appropriate variations thereof.

In step A, compound 1 is commercially available or can be obtained by the method used in the examples herein or a method analogous thereto. Compound 1 is subjected to an aromatic nucleophilic substitution reaction to introduce fragment B-(R ₈ ) _t to obtain compound 2. Typical aromatic nucleophilic substitution conditions are well known in the art, such as DIEA/THF and the like.

In step B, compound 2 is reacted with a corresponding amine compound under conditions such as DIEA/dioxane to obtain compound 3 or 4. The corresponding amine compound is commercially available, or can be obtained according to the method used in the examples herein or a method similar thereto, or can be obtained according to the method of the relevant literature in the field of organic chemistry. The latter is introduced into naphthalene or benzothiophene compounds by Suzuki-Miyaura coupling reaction in step C to obtain compound 5 or 6 or 7 or 8. In step D, the protecting groups of compounds 5 to 8 are removed to obtain compounds of general formula I-A-1, I-B-1, I-A-4 and I-B-4.

Typical Suzuki-Miyaura coupling conditions are well known in the art, and those skilled in the art are aware of a variety of conditions for promoting such cross-coupling reactions, such as Pd(dtbpf)Cl ₂ /K ₃ PO ₄ /dioxane/water, or Pd(OAc) ₂ /rac-BIDIME/K ₂ CO ₃ /toluene; suitable palladium catalysts also include XantPhos Pd G2, A Pd G3, bis(triphenylphosphine)palladium(II) chloride, Pd(dppf)Cl ₂ , Pd ₂ dba ₃ , tetraphenylphosphine palladium and palladium(II) acetate, etc.; if necessary, suitable ligands may include tricyclohexylphosphine and triphenylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide and potassium phosphate monohydrate, etc.

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

The synthesis of compounds of the general formula I-A-2, I-B-2, I-A-3, and I-B-3 of the present invention can be carried out by those skilled in the art similarly to the above scheme.

Synthesis Scheme B

The synthesis of compounds of general formula IA and IB of the present invention can also be prepared according to the following schemes or appropriate variations thereof.

In step A, compound 2 can be obtained by following the method described in synthesis scheme A. Compound 2 is reacted with halogen Exchange reaction, fluorination under conditions such as KF/DMSO or KF/MsOH/DABCO/DMSO, etc., to obtain compound 9. Compound 9 is then subjected to the Suzuki-Miyaura coupling reaction of step B, the aromatic nucleophilic substitution reaction of step C, and the protective group removal reaction of step D to obtain the final compounds IA-1, IB-1, IA-4 and IB-4. The typical conditions for the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protective group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.

The synthesis of the compounds of the general formula I-A-2, I-B-2, I-A-3, and I-B-3 of the present invention can be carried out by those skilled in the art with reference to the above scheme.

The synthesis of compounds of the general formula I-C and I-D of the present invention can be carried out by those skilled in the art using appropriate starting materials, referring to the above scheme, or as shown in the following scheme C.

Synthesis Scheme C

The synthesis of compounds of general formula IC and ID of the present invention are prepared according to the following schemes or appropriate variations thereof.

Compound 9 can be purchased commercially or obtained by referring to literature reports or the synthesis scheme and appropriate variants provided by the present invention. In step A, compound 9 is introduced into fragment B-(R ₈ ) _t by condensation reaction under conditions such as condensation agent BOP to obtain compound 10. In step B, compound 10 is introduced into naphthalene or benzothiophene compounds by Suzuki-Miyaura coupling reaction to obtain compound 11 or 12. In step C, the sulfide in compound 11 or 12 is oxidized to obtain sulfoxide or sulfone, or a mixture of sulfoxide and sulfone, to obtain compound 13 or 14. Then, in step D, YQ group is introduced by aromatic nucleophilic substitution reaction to obtain compound 15 or 16. In step E, compound 15 or 16 is freed from any protecting group it may have to obtain a compound of general formula IC or ID. The Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and Typical conditions for the removal of protecting groups are well known in the art and can be carried out similarly to the relevant reaction conditions described in Synthesis Scheme A.

Synthesis Example

The present invention is further described below with reference to the following examples. It should be noted that the following examples are exemplary and should not be regarded as limiting the scope of protection of the present invention.

In the description of the embodiments and the specific examples that follow, the following abbreviations are used herein:

ACN (acetonitrile); Boc (tert-butoxycarbonyl); BOP (benzotriazol-1-oxytris(dimethylamino)phosphine hexafluorophosphate); CDCl ₃ (deuterated chloroform); cataCXium A Pd G ₃ ([n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate); DABCO (1,4-diazabicyclo[2.2.2]octane); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d ₆ (hexadeuterated dimethyl sulfoxide); EA or EtOAc (ethyl acetate); EDTA-K2 (ethylenediaminetetraacetic acid dipotassium salt); EtOH (ethanol); FCC (flash column chromatography); g (gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl/MeOH (hydrogen chloride methanol solution); HLM (human liver microsomes); H ₂ O (water); H ₂ SO ₄ (sulfuric acid); IV (intravenous administration); K ₂ CO ₃ (potassium carbonate); LCMS (liquid chromatography-mass spectrometry); LC-MS/MS (liquid chromatography-mass spectrometry-mass spectrometry); MeOH (methanol); Methanol-d ₄ (tetradeuterated methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimole); MOM (methoxymethyl ether); MsOH (methanesulfonic acid); MTBE (methyl tert-butyl ether); m/z (mass-to-charge ratio); N ₂ (nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO ₃ (sodium bicarbonate); Na ₂ SO ₃ (sodium sulfite); Na ₂ SO ₄ (sodium sulfate); NCS (chlorosuccinimide); NH ₄ Cl (ammonium chloride); NMR (nuclear magnetic resonance); PdCl ₂ (dtbpf) or Pd(dtbpf)Cl ₂ (1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride); PdCl ₂ (dppf) or Pd(dppf)Cl ₂ (1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride); Pd(OAc) (palladium acetate); Pd(PPh ₃ ) ₄ (tetrakistriphenylphosphinepalladium); PE (petroleum ether); PO or po (oral administration); POCl ₃ (phosphorus oxychloride); rt (room temperature); Selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt); SiO ₂ (silica gel); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIPS (triisopropylsilyl); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); TsOH·H ₂ O (p-toluenesulfonic acid monohydrate); μL (microliter); μM (micromolar); μmol (micromolar).

In the following examples, the names of the synthesized target compounds and their structures are given. Any deviation between the names and structures is not intentional, in which case the structure is decisive.

The experimental methods in the following examples where specific conditions are not specified are usually carried out according to the conventional conditions of such reactions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts. Unless otherwise specified, the ratios of liquids are volume ratios.

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

In the following examples, ¹ H-NMR spectra were recorded using a Bruker (400 MHz) and chemical shifts were expressed in δ (ppm) relative to the deuterated solvent peaks (CDCl ₃ : δ=7.26 ppm; CD ₃ OD: δ=3.31 ppm; DMSO-d ₆ : δ=2.50 ppm); LC-MS The data were recorded by Aglient 1260 liquid chromatograph + Aglient G6125B mass spectrometer LCMS. The gas chromatograph-mass spectrometer was Shimadzu GCMS-QP2010SE for detection.

Intermediate A

7-Bromo-2,4-dichloro-8-fluoroquinazoline

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

At room temperature, 2-amino-4-bromo-3-fluorobenzoic acid (10.0 g, 42.7 mmol) and urea (25.7 g, 427.3 mmol) were mixed together, heated to 200°C, and stirred for 2 h. The reaction gradually changed from solid to liquid, and then continued to change to solid. After the reaction was completed, it was washed with hot water (250 mL) and filtered to collect the solid to obtain 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (12 g, crude product). LCMS (ESI, m/z): 258.9 (M+H).

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

At room temperature, DIPEA (13.5 mL, 77.2 mmol) was added to a mixture of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.0 g, 15.4 mmol) and POCl ₃ (35.9 mL, 386.0 mmol), and the mixture was heated to 100°C and stirred for 5 h. After the reaction was completed, most of the solvent and alkali were removed by concentration, and ACN (10 mL) was added for dilution. Under room temperature stirring, the obtained dilution was slowly added dropwise to water, and a solid was precipitated. After filtering and drying, a yellow solid 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.8 g, yield 83%) was obtained. LCMS (ESI, m/z): 296.8 (M+H).

Intermediate B

7-Bromo-2,4-dichloro-6,8-difluoroquinazoline

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

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

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

At room temperature, the methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate obtained in the previous step was added to a round-bottom flask equipped with a stirrer, and then NH ₃ (100 mL, 7M MeOH solution) was added. The resulting mixture was stirred at room temperature for 2 hours, and the reaction was complete after monitoring by LCMS. After concentration under reduced pressure, the resulting solid was slurried with methyl tert-butyl ether and filtered to obtain a light yellow solid 7-bromo-6,8-difluoroquinazoline-2,4-diol (14 g, crude product), which was used directly in the next step without further purification. LCMS (ESI, m/z): 277.0 (M+H).

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

7-Bromo-6,8-difluoroquinazoline-2,4-diol (14 g, crude product) and POCl ₃ (112 mL) were added to a round-bottom flask equipped with a stirrer. DIEA (28 mL) was added dropwise to the system under stirring at room temperature. After the addition was complete, the system was heated to 110°C and stirred overnight. The reaction solution was concentrated to about 30 mL under reduced pressure and poured into water (600 mL). The precipitate was filtered and collected. After drying, a yellow solid 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (11 g, crude product) was obtained, which was used directly in subsequent reactions. LCMS (ESI, m/z): 312.9 (M+H).

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

Intermediate G

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

Step A: 4,6-Dichloro-5-fluoronicotinoyl chloride

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

Step B: (4,6-Dichloro-5-fluoronicotinoyl)carbamide thiomethyl ester

Under stirring at 0°C, a mixed solution of 4,6-dichloro-5-fluoronicotinoyl chloride (4.5 g, 19.8 mmol) and ethylene glycol dimethyl ether (20 ml) was slowly added dropwise to a mixed solution of 2-methylisothiourea sulfuric acid (15 g, 49.5 mmol) and 1M NaOH aqueous solution (70 ml), and the temperature was maintained and stirred for 1 h. The precipitated solid precipitate was filtered and dried to obtain the product (4,6-dichloro-5-fluoronicotinoyl) carbamoyl thiomethyl ester (5.0 g, yield 90%). LCMS (m/z): 282.1 (M+H).

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

Dissolve (4,6-dichloro-5-fluoronicotinoyl)carbamide thiomethyl ester (5.0 g, 17.8 mmol) in DMF (40 mL), heat to 120 ° C and stir to react for 3 h. After the reaction is complete as monitored by LCMS, cool to room temperature and add water (200 mL). Filter and dry the precipitated solid to obtain the product 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.6 g, yield 82%). LCMS (m/z): 245.6 (M+H).

Intermediate I

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

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 with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Filtered and concentrated, the resulting crude product was purified by FCC (SiO ₂ , EA/PE=0-10%) to obtain 2,6-dichloro-3-fluoropyridin-4-amine (10 g) as a white solid. LCMS (m/z): 180.9 (M+H).

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

Under stirring 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). The resulting mixture was heated to 60 ° C and stirred for 16 h. The reaction was completed by TLC monitoring, and the crude product was concentrated to obtain a white solid (tert-butyloxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (16 g). LCMS (m/z): 381.2 (M+H).

Step C: tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

Under a dry ice ethanol bath, LDA (2.0M, 63mL, 126mmol) was slowly added to a solution of tert-butyl (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamate (16g, 42mmol) in THF (200mL), and the resulting mixture was stirred at the temperature for 1h. After TLC monitoring, the reaction was completed, and an appropriate amount of acetic acid was added to quench the reaction, diluted with EA, washed with water, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by FCC ( _SiO2 , EA/PE = 0-20%) to obtain tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (13g).

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 the reaction was completed as monitored by LCMS, the mixture was concentrated to give 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride (8 g). LCMS (m/z): 224.9 (M+H).

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

A mixed solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (8 g, 30.8 mmol) and thionyl chloride (200 mL) was stirred at 50 ° C for 3 h. Then concentrated, the residue was dissolved in acetone (50 mL) to obtain solution 1. A mixed solution of ammonium thiocyanate (7 g, 92 mmol) and acetone solution (160 mL) was dropped into solution 1 at room temperature, and the resulting reaction solution was stirred for 1 h at room temperature. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water, filtered, and the filter cake was dried to obtain 5,7-dichloro-8-fluoro-2-thiopyrido[4,3-d]pyrimidin-4(3H)-one (5 g). LCMS (m/z): 265.9 (M+H).

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

At room temperature, a mixed solution of 5,7-dichloro-8-fluoro-2-thiopyrido[4,3-d]pyrimidin-4-ol (5 g, 18.8 mmol), methanol (380 mL), sodium hydroxide aqueous solution (0.1 M, 380 mL, 380 mmol) and iodomethane (5.3 g, 380 mmol) was stirred for 2 h. After the reaction was completed by LCMS monitoring, 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 obtain the product 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (4 g). LCMS (m/z): 279.9 (M+H).

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

A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (6.0 g, 22 mmol), sodium methoxide (10.3 g, 330 mmol), DMA (100 mL) and methanol (10 mL) was stirred at 50°C for 16 h. After the reaction was completed as monitored by LCMS, it was diluted with water, adjusted to pH ~ 3 with concentrated hydrochloric acid, filtered, and the filter cake was collected and dried to obtain the product 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.5 g). LCMS (m/z): 276.0 (M+H).

Intermediate ID3

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

The synthesis of intermediate ID3 was based on intermediate I, except that CD ₃ ONa was used instead of CH ₃ ONa in step G. LCMS (m/z): 278.9 (M+H).

Intermediate J

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

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

Under room temperature, 2-chloro-3-fluoro-4-aminopyridine (25.0 g, 171 mmol) was dissolved in 250 mL of acetonitrile. Then NIS (35.4 g, 205 mmol) and p-toluenesulfonic acid monohydrate (3.24 g, 17.1 mmol) were added to the above system. The resulting mixture was heated to 70 ° C and stirred overnight. The reaction was monitored by LCMS. After cooling to room temperature, the reaction solution was poured into water (500 mL) for quenching and extracted with ethyl acetate (800 mL × 3). The organic phases were combined, washed with saturated NaHCO ₃ water, saturated Na ₂ S ₂ O ₃ water, and brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by FCC (SiO ₂ , EA/PE = 0-50%) to obtain a white solid 2-chloro-3-fluoro-5-iodopyridin-4-amine (42 g, yield 90%). LCMS(m/z):272.9(M+H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 6.69 (s, 2H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-138.90.

Step B: 4-amino-6-chloro-5-fluoronicotinate

Under room temperature, 2-chloro-3-fluoro-5-iodopyridin-4-amine (40 g, 147 mmol) was dissolved in 400 mL of anhydrous ethanol. The system was replaced with CO, and the process was repeated three times. Pd(PPh ₃ ) ₂ Cl ₂ (10.3 g, 14.7 mmol) and TEA (95.0 g, 735 mmol) were then added to the reaction flask, and the CO gas was replaced three times. The resulting mixture was heated to 80°C in a CO gas atmosphere and reacted overnight. LCMS monitored the completion of the reaction, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated to dryness to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain 4-amino-6-chloro-5-fluoronicotinate (30 g, yield 93%) as a white solid. LCMS (m/z): 219.0 (M+H).

Step C: 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid ethyl ester

Under stirring at room temperature, add Boc ₂ O (65.9 g, 302 mmol) dropwise to a solution of 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 is complete, heat to 45 ° C and react overnight. Add imidazole (9.33 g, 137 mmol) to the system, stir for half an hour, add saturated ammonium chloride solution for washing (300 mL × 3), separate the liquids, wash the organic phase with saturated brine (300 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a yellow solid 4-(bis (tert-butoxycarbonyl) amino)-6-chloro-5-fluoronicotinate (45.9 g, yield 80%). LCMS (m/z): 419.1(M+H).

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

A solution of 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 THF solution of TMPMgCl-LiCl (161 mL, 161 mmol, 1 M) was added dropwise. After the addition, the temperature was maintained and stirred for 4 h, and a solution of dibromotetrachloroethane (42.0 g, 129 mmol) in THF (100 mL) was added dropwise. The mixture was stirred at -40°C for 4 h. 500 mL of saturated ammonium chloride solution was added to quench the mixture, and then extracted with EtOAc (500 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by FCC (SiO ₂ , EA/DCM=0-50%) to obtain ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (17.0 g, yield 32%) as a white solid. LCMS (m/z): 497.0 (M+H).

Step E: 4-amino-2-bromo-6-chloro-5-fluoronicotinate ethyl HCl

At room temperature, 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (28.0 g, 56.3 mmol) was dissolved in 4M hydrochloric acid-dioxane (500 mL). Stirred at room temperature for 1 h, LCMS monitored the completion of the reaction, and the system was concentrated to dryness to obtain a crude product of white solid 4-amino-2-bromo-6-chloro-5-fluoronicotinate HCl (19.1 g, crude product). LCMS (m/z): 296.9 (M+H).

Step F: 4-Amino-2-bromo-6-chloro-5-fluoronicotinic acid

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

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

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

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

At room temperature, 0.1M NaOH (100mL, 10.0mmol) and iodomethane (1.42g, 9.98mmol) were added to a methanol (50mL) solution of 5-bromo-7-chloro-8-fluoro-2-thiopyrido[4,3-d]pyrimidin-4-ol (1.55g, 4.99mmol) in sequence. The resulting mixture was stirred at room temperature for 2h. After the reaction, the reaction solution was slowly poured into stirred water (400mL). 1M HCl was used to adjust the pH to neutral, and a white solid was precipitated. After stirring for about 15min, it was filtered and the filter cake was dried to obtain 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyridine [4,3-d]pyrimidin-4-ol (1.5 g, yield 93%). LCMS (m/z): 323.8 (M+H).

Intermediate K

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

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

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

Intermediate L

7-Chloro-5-ethoxy-8-fluoro-2-(methylthio)-3,4-dihydro-1,3,6-triaza-4-naphthalenone

Step A: 7-Chloro-5-ethoxy-8-fluoro-2-(methylthio)-3,4-dihydro-1,3,6-triaza-4-naphthalenone

At room temperature, sodium ethoxide (0.972 g, 14.3 mmol) was added to a DMAc/EtOH (44 mL, V/V = 10:1) solution of 5,7-dichloro-8-fluoro-2-(methylthio)-3,4-dihydro-1,3,6-triaza-4-naphthalenone (2.00 g, 7.14 mmol), and the resulting mixture was heated to 50°C and stirred for 1 h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into H ₂ O (400 mL), and the pH was adjusted to 3-4 with concentrated hydrochloric acid to precipitate a white solid product. The white solid was collected by filtration, rinsed with water, and finally dried to obtain a white solid 7-chloro-5-ethoxy-8-fluoro-2-(methylthio)-3,4-dihydro-1,3,6-triaza-4-naphthalenone (1.80 g, yield 87%). LCMS (m/z): 289.9.9 (M+H).

Intermediate AI

1-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

Step A: 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

A solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.40 g, 4.73 mmol) and DIEA (6.6 mL, 37.8 mmol) in DCM (20 mL) was cooled to 0°C. Under stirring, 3-methylpiperidin-3-ol hydrochloride (789 mg, 5.20 mmol) was added to the above system in batches. The resulting system was stirred for 2 h, slowly warmed to room temperature, and the reaction was completed after LCMS monitoring. DCM (20 mL) was added for dilution, washed with saturated aqueous ammonium chloride solution (30 mL), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a light yellow solid 1-(7-bromo-2-chloro-8-fluoroquinazoline-4-yl)-3-methylpiperidin-3-ol (1.42 g, yield 80%). LCMS (m/z): 374.0, 375.9 (M+H).

Intermediate A-II

5-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The synthesis of intermediate A-II is described in the synthesis of intermediate A-I, and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (prepared according to document WO2022132200) is used instead of 3-methylpiperidin-3-ol·hydrochloride in step A. LCMS (m/z): 467.0 (M+H)

Intermediate BI

1-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

The synthesis of intermediate B-I is described in the synthesis of intermediate A-I, and 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (intermediate B) is used instead of 7-bromo-2,4-dichloro-8-fluoroquinazoline (intermediate A) in step A. LCMS (m/z): 392.0 (M+H).

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

Intermediate E-II

5-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step A: 5-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide hydrochloric acid Salt (738mg, 3.03mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.00g, 3.03mmol), DIPEA (1.96g, 15.1mmol) and DMF/THF (12mL, 5:1), and the mixture was stirred at room temperature for 2h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into H ₂ O (100mL) and stirred for 10 minutes. At this time, a white solid product was precipitated. The white solid product was collected by filtration, washed with water, and dried to obtain a white solid product 5-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (1.5g, yield 99%). LCMS (m/z): 503.0 (M+H).

Intermediate BI-AF

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

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

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

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

At room temperature, (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (12.0 g, 30.6 mmol), KF (17.8 g, 306 mmol), DABCO (137 mg, 1.22 mmol), MsOH (117 mg, 1.22 mmol) were added to DMSO (60 mL) in sequence, and the temperature was raised to 65 ° C and stirred for 10 h. After the reaction was completed, the reaction solution returned to room temperature after LCMS monitoring. Then it was slowly poured into stirred water (600 mL) to produce flocculent insolubles, which were filtered and the filter cake was dried to obtain a yellow solid (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (11.3 g, yield 98%). LCMS (m/z): 378.0 (M+H).

Intermediate B-III-AF

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

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

At room temperature, DIPEA (1.55 mL, 8.92 mmol) was added to a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (700 mg, 2.23 mmol), (S)-6-methyl-1,4-oxazepane-6-ol hydrochloride (374 mg, 2.23 mmol) and THF (12 mL), and the resulting mixture was stirred for 2 h at room temperature. The reaction was completed by TLC and LCMS monitoring, and THF was removed by concentration, acetonitrile (2 mL) was added, and the mixture was slowly poured into stirred water (50 mL), and flocculent insoluble matter was produced. After filtering and drying the filter cake, a brown solid (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazoline-4-yl)-6-methyl-1,4-oxazepane-6-ol (720 mg, yield 79%) was obtained. LCMS (m/z): 409.9 (M+H).

Step B: (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

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

Intermediate EI-AF

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

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

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

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

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

Intermediate E-III-AF

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

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

At room temperature, HCl-dioxane (4M) (10 mL, 10 V) was added to (S)-6-hydroxy-6-methyl-1,4-oxol-4-carboxylic acid tert-butyl ester (1.00 g, 4.32 mmol) and stirred at room temperature for 1 h. LCMS monitored the completion of the reaction, and the reaction solution was concentrated to obtain The obtained product was (S)-6-methyl-1,4-oxacyclohexane-6-ol hydrochloride (840 mg, crude product) as a white solid. LCMS (m/z): 132.1 (M+H).

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

At room temperature, DIPEA (1.56 g, 12.1 mmol) was added to a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.00 g, 3.03 mmol), (S)-6-methyl-1,4-oxacyclohexane-6-ol hydrochloride (655 mg, 12.1 mmol) and THF (20 mL) and stirred at room temperature for 1 h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into a saturated NH ₄ Cl aqueous solution (50 mL) and extracted with EA (30 mL×3). The organic phase was collected, washed with a saturated NaCl aqueous solution (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a white solid (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol (1.2 g, yield 93%). LCMS (m/z): 425.9 (M+H).

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

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

Intermediate GIA

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

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

At room temperature, DIPEA (2.37 g, 18.3 mmol) was added to a mixture of 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.50 g, 6.11 mmol), (R)-3-methylpiperidin-3-ol hydrochloride (1.06 g, 7.02 mmol), BOP (5.40 g, 12.2 mmol) and DMF (20 mL). The reaction system was heated to 45 °C and stirred for 18 h. The reaction results were monitored by TLC. After the reaction mixture returned to room temperature, it was slowly poured into stirred _H2O (200 mL). Solid precipitated and was filtered. The filter cake was washed with _H2O (100 mL) and dried to give a brown solid (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2.0 g, yield 98%).

Intermediate G-II

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

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

Under stirring at room temperature, 6-methyl-1,4-oxazepane-6-ol hydrochloride (0.55 g, 3.2 mmol), DIPEA (1.4 mL, 8.16 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.14 g, 7.00 mmol) were added to DMF (8.0 mL) containing 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (0.57 g, 2.33 mmol) in sequence. The resulting mixture was heated to 45°C and stirred for 6 h. After the reaction was completed, water (30 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (30.0 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by FCC ( _SiO2 , EA/PE 0-50%) to give a pale yellow solid 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxacyclohexane-6-ol (0.77 g, yield 92%), LCMS (m/z) = 359.0 (M+H).

Intermediate G-II-A

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

The synthesis of intermediate G-II-A was carried out according to the scheme described for intermediate G-II, and in step A, (S)-6-methyl-1,4-oxo- Heterocycloheptan-6-ol·hydrochloride was used instead of 6-methyl-1,4-oxazepan-6-ol·hydrochloride.

Intermediate G-III

5-(7-chloro-8-fluoro-2-methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

Step A: 5-(7-chloro-8-fluoro-2-methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

At room temperature, 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (550 mg, 2.24 mmol), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide hydrochloride (1.09 g, 4.48 mmol), BOP (1.98 g, 4.48 mmol), DIEA (1.73 g, 13.4 mmol) were added to DMF (6 mL) solution and heated to 55 °C and stirred for 16 h. LCMS monitored the reaction to be complete, the reaction solution was poured into saturated sodium bicarbonate (50 mL), extracted with EA (30 mL×3), the organic phase was collected, washed with saturated brine (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and the crude product obtained by FCC (SiO ₂ , (EA/PE＝0-80%) was purified to obtain a yellow solid product 3 (900 mg, yield 92%). LCMS (m/z): 436.0 (M+H).

According to the above synthesis scheme, the following intermediates were prepared

Intermediate IIA

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

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

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

Intermediate ID3-IA

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

Referring to the synthesis of intermediate I-I-A, intermediate ID3 was used in step A instead of intermediate I, LCMS (m/z): 392.0 (M+H).

Intermediate I-II-A

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

The synthesis of intermediate I-II-A is carried out according to the scheme described for intermediate I-I-A, except that (R)-6-methylpiperidin-3-ol hydrochloride is used in step A instead of (S)-6-methyl-1,4-oxepan-6-ol hydrochloride.

Intermediate KIA

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

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

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

Intermediate K-II-A

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

The synthesis of intermediate K-II-A was carried out according to the scheme described for intermediate K-I-A, except that (S)-6-methyl-1,4-oxepan-6-ol hydrochloride was used in step A instead of (R)-3-methyl-3-hydroxypiperidine hydrochloride.

Intermediate L-II-A

(S)-4-[7-Chloro-5-ethoxy-8-fluoro-2-(methylthio)-1,3,6-triaza-4-naphthyl]-6-methyl-1,4-oxazepan-6-ol

Step B: (S)-4-[7-chloro-5-ethoxy-8-fluoro-2-(methylthio)-1,3,6-triaza-4-naphthyl]-6-methyl-1,4-oxazepan-6-ol

At room temperature, BOP (1.53 g, 3.45 mmol) was added to 7-chloro-5-ethoxy-8-fluoro-2-(methylthio)-3,4-dihydro-1,3,6-triaza-4-naphthalenone (500 mg, 1.73 mmol), (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (434 mg, 2.59mmol), DIPEA (1.12g, 8.63mmol) and DMF (20mL), the resulting mixture was heated to 50°C and stirred for 2h. LCMS monitored the completion of the reaction, poured the reaction solution into H ₂ O (400mL), stirred for 5min, and a yellow solid precipitated. The solid was collected by filtration, rinsed with water, and dried to obtain a yellow solid (S)-4-[7-chloro-5-ethoxy-8-fluoro-2-(methylthio)-1,3,6-triaza-4-naphthyl]-6-methyl-1,4-oxazacycloheptane-6-ol (477mg, yield 69%). LCMS (m/z): 403.1 (M+H).

Intermediate a

(3-Methoxy-1,2-dimethylpyrrolidin-2-yl)methanol

Step A: 1-(tert-Butyl)2-ethyl2-methyl-3-oxopyrrolidine-1,2-dicarboxylate

Under ice bath condition, CH ₃ I (5.52 g, 38.87 mmol) was added dropwise to a mixed solution of 1-(tert-butyl) 2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (5.0 g, 19.43 mmol), K ₂ CO ₃ (8.06 g, 58.30 mmol) and anhydrous ACN (50 mL). After the addition was completed, the reaction solution was heated to 40°C and stirred overnight. After the reaction was completed as monitored by TLC (PE:EA＝5:1, Rf＝0.6), the reaction solution was poured into a saturated NH ₄ Cl aqueous solution (200 mL) and extracted with EA (100 mL×3). The organic phase was washed with saturated aqueous NaCl solution (50 mL). The organic phases were collected, concentrated, and subjected to FCC (SiO ₂ , EA/PE=0-15%) to give a colorless oily liquid (1-(tert-butyl) 2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (3.8 g, yield 72%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.29–4.08 (m, 2H), 3.95–3.78 (m, 1H), 3.77–3.66 (m, 1H), 2.83–2.71 (m, 1H), 2.70–2.57 (m, 1H), 1.66–1.57 (m, 3H), 1.51–1.41 (m, 9H), 1.30–1.20 (m, 3H). LCMS (m/z): 294.0 (M+Na).

Step B: 1-(tert-Butyl) 2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate

Under ice bath stirring, NaBH ₄ (150 mg, 4.06 mmol) was added to a solution of 1-(tert-butyl) 2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (1.0 g, 3.69 mmol) in MeOH (10 mL), and the resulting mixture was stirred for 0.5 h at room temperature. After the reaction was completed, an excess of saturated aqueous ammonium chloride was added to the system, and the mixture was extracted with ethyl acetate EA (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a colorless liquid 1-(tert-butyl) 2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate (926 mg, yield 92%). LCMS (m/z): 296.0 (M+Na).

Step C: 1-(tert-Butyl)2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate

At room temperature, NaH (255 mg, 60% w/w, 6.37 mmol) was added to a THF (3 mL) solution of 1-(tert-butyl) 2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate (580 mg, 2.12 mmol), and the resulting mixture was stirred at room temperature for 0.5 h. CH ₃ I (904 mg, 6.36 mmol) was then added to the reaction system and the reaction was continued for 3 h. After the reaction was completed, Add an excess of saturated aqueous solution of ammonium chloride, extract with ethyl acetate EA (15 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The resulting crude product is purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain a colorless liquid 1-(tert-butyl) 2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate (200 mg, yield 34%). LCMS (m/z): 310.0 (M+Na).

Step D: (3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol

1-(tert-butyl) 2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate (200 mg, 0.70 mmol) was added to a reaction tube equipped with a magnetic stirrer, and LiAlH ₄ (3.5 mL, 1 M THF solution, 3.5 mmol) was added to the reaction system. The resulting mixture was heated to 70°C and refluxed with stirring for 3 h. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction system was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain a colorless liquid (3-methoxy-1,2-dimethylpyrrolidin-2-yl) methanol (110 mg, yield 99%), which was directly used in subsequent reactions without purification. LCMS (m/z): 160.1 (M+H).

Intermediate b

The compound 3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (120 g) was separated by SFC (SFC150, Waters) (separation column: DAICEL 250*50mm, 10μm; mobile phase: CO ₂ /MeOH=90/10; flow rate: 120mL/min), the first eluted isomer 1 was obtained, which was compound b (52.8g, relatively short retention time). Chiral analysis method-b (Waters UPCC, analytical column: Daicel 100*3mm 3μm; mobile phase A: CO ₂ , mobile phase B: MeOH; flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A/B＝90/10), Rt＝0.682min. ¹ H NMR (400MHz, Chloroform-d)δ4.59–4.42(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 isomer 2 eluted subsequently was compound b-1 (52.4 g, relatively long retention time). Chiral analysis method-b, 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).

Intermediate c

(3S)-(1,3,4-Trimethylpiperidin-3-yl)methanol

Step A: (S)-3-methyl-4-methylenepiperidin-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester

Under ice bath conditions, a THF solution of potassium tert-butoxide (5.25 mL, 1M, 5.25 mmol) was added dropwise to a toluene (10 mL) solution of methyl triphenylphosphonium bromide (1.89 g, 5.25 mmol), and the resulting system was stirred for 0.5 h under ice bath conditions. A toluene (5 mL) solution of (R)-3-methyl-4-oxopiperidin-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (1.00 g, 3.50 mmol) was added dropwise to the above system, and the temperature was maintained for 1 h. The temperature was then slowly raised to 110°C and the temperature was maintained for stirring and the reaction was continued overnight. The reaction was completed by TLC monitoring, cooled to room temperature, and concentrated to dryness under reduced pressure to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (750 mg, yield 75%). LCMS (m/z): 214.1 (M-56+H), 292.1 (M+Na).

Step B: (3S)-3,4-dimethylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester

Under nitrogen protection at room temperature, Pd/C (500 mg, 10% w/w, 0.47 mmol) was added to a methanol (20 mL) solution of (S)-3-methyl-4-methylenepiperidin-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (750 mg, 2.78 mmol). The system was replaced with a hydrogen balloon, and then stirred in a hydrogen atmosphere to react overnight. After the reaction was completed by TLC monitoring, it was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain a colorless oily product (3S)-3,4-dimethylpiperidin-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (600 mg, yield 79%). LCMS (m/z): 216.1 (M-56+H), 294.1 (M+Na). ¹ H NMR (400MHz, methanol-d ₄ ) δ4.08–4.02 (m, 0.23H), 3.98 (dd, J = 13.7, 1.5Hz, 1H), 3.91–3.78 (m, 1.23H), 3.72 (s, 0.69H), 3.67 (s, 3H), 3.21–2.76 (m, 2.46H) ), 2.20–2.06 (m, 0.23H), 1.81–1.29 (m, 14.9H), 1.20 (s, 3H), 1.07 (s, 0.69H), 1.02 (d, J = 6.6Hz, 3H), 0.86 (d, J = 6.8Hz, 0.69H).

Step C: (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol

At room temperature, LiAlH ₄ -THF (1M, 5.26mmol, 5.26mL) was added dropwise to a solution of (3S)-3,4-dimethylpiperidin-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (500mg, 1.75mmol) in THF (5mL), and the resulting system was heated to 70°C and stirred for 3h. After the reaction was completed as monitored by LCMS, Na ₂ SO ₄ ·10H ₂ O was added to quench the reaction until no gas was generated. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated under reduced pressure at low temperature (35°C) to obtain a colorless liquid (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol (250mg, yield 91%). LC-MS (m/z): 158.2 (M+H).

Intermediate d

(3S)-(4-Fluoro-1,3-dimethylpiperidin-3-yl)methanol

Step A: (S)-4-Fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester

Under ice bath conditions, BAST (19.57 g, 16.3 mL, 88.46 mmol) was added dropwise to a mixed solution of (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester (8.0 g, 29.49 mmol) and DCM (40 mL). After the addition was complete, the mixture was returned to room temperature and stirred overnight. After the reaction was completed by TLC monitoring, the reaction solution was slowly poured into a semi-saturated NaHCO ₃ (100 mL) solution and extracted with DCM (100 mL×3). The combined organic phases were concentrated and purified by FCC (SiO ₂ , EA/PE＝0-10%) to obtain a colorless oil (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (1.0 g, yield 12%). LCMS (m/z): 218.1 (M-56+H).

Step B: (S)-(4-Fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol

At room temperature, LiAH ₄ (4.02mL, 4.02mmol, 1M THF solution) was added to (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (500mg, 1.83mmol) and the temperature was raised to 70°C and stirred for 1h. After the reaction was completed, Na ₂ SO ₄ ·10H ₂ O was slowly added to the reaction solution under ice bath conditions to quench LiAH ₄ until the reaction no longer generated gas, and then anhydrous sodium sulfate was added to dry the solution, filtered, and the mother liquor was collected and concentrated to obtain a colorless oily liquid (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (284mg, yield 98%). LCMS (m/z): 160.1 (M+H).

Step C: (3S)-(4-Fluoro-1,3-dimethylpiperidin-3-yl)methanol

Under nitrogen protection at room temperature, Pd/C (5% w/w, 374 mg, 0.176 mmol) was added to a mixed solution of (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (280 mg, 1.76 mmol) and EA:MeOH=1:1 (20 mL), and the mixture was replaced with hydrogen, and then reacted at room temperature for 2 h under 60 psi _H2 pressure. After the reaction was completed by TLC monitoring, the reaction solution was filtered through diatomaceous earth, washed with EA (50 ml), and the organic phase was concentrated to obtain a colorless oily liquid (3S)-(4-fluoro-1,3-dimethylpiperidin-3-yl)methanol (220 mg, yield 78%). LCMS (m/z): 162 (M+H).

Intermediate e

(S,E)-(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

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

Dissolve (fluoromethylene) triphenylphosphine tetrafluoroborate (10.56g, 27.64mmol) in anhydrous THF (50mL) and replace with nitrogen three times. Under dry ice ethanol conditions, the temperature of the reaction solution was reduced to -70°C, and potassium tert-butoxide-tetrahydrofuran (27.64mL, 1M, 27.64mmol) solution was added dropwise to the reaction system. Keep the temperature and continue stirring for 1h. Then, a solution of (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.0g, 18.43mmol) in anhydrous tetrahydrofuran (15mL) was added dropwise to the reaction system. After the addition was completed, the resulting mixture was slowly heated to room temperature and stirred overnight. After the reaction was completed by TLC monitoring, the reaction solution was slowly poured into water (100mL) and extracted with ethyl acetate three times. After the organic phases were combined, they were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by FCC (SiO ₂ , EA/PE=0-15%) to give a colorless oily product (S,E)-1-tert-butyl-3-methyl-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate (1.98 g, yield 37%). LCMS (m/z): 232.1 (M-56+H). ¹ H NMR (400 MHz, Chloroform-d) δ 6.55 (d, J = 84.7, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.10-3.82 (m, 1H), 3.69 (s, 3H), 3.00-2.85 (m, 1H), 2.76 (d, J = 13.1 Hz, 1H), 2.71-2.60 (m, 1H), 2.31-2.08 (m, 1H), 1.46 (s, 9H), 1.29 (s, 3H); and a colorless oily product (S, Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester (600 mg, yield 11%). LCMS (m/z): 232.1 (M-56+H). ¹ H NMR (400MHz, Chloroform-d) δ6.43 (d, J = 83.7, 1H), 3.86–3.75 (m, 1H), 3.71 (s, 3H), 3.62–3.47 (m, 1H), 3.42–3.29 (m, 2H), 2.24–2.06 (m, 2H), 1.46 (s, 9H) ),1.43–1.39(m,3H).

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

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

Step C: (S,E)-4-(Fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester

At room temperature, (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (370 mg, 1.98 mmol) was dissolved in methanol (5 mL), triethylamine was added dropwise until the pH of the reaction solution was ~10, stirred for 10 minutes, and then glacial acetic acid was added dropwise until the pH of the reaction solution was ~4. Formaldehyde aqueous solution (481.15 mg, 5.93 mmol) was added to the reaction solution and stirred at room temperature for 30 min. Sodium cyanoborohydride (136.62 mg, 2.17 mmol) was added to the reaction solution and stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed by LCMS monitoring, and the anhydrous tetrahydrofuran was evaporated twice to obtain a white solid (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (380 mg, yield 96%). LCMS (m/z): 202.1 (M+H).

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

Under ice bath conditions, 1M LiAlH ₄ -THF solution (2.83mL, 107.5mg, 2.83mmol) was added dropwise to a solution of (E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (380mg, 1.89mmol) in anhydrous tetrahydrofuran (5mL). The resulting mixture was stirred at room temperature for 20min. After the reaction was completed by LCMS monitoring, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. About 5g of anhydrous sodium sulfate was added to remove water. The reaction solution was filtered with diatomaceous earth, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to obtain a colorless oily product (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (300mg, yield 92%). LCMS (m/z): 174.1 (M+H).

Intermediate f

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

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

The synthesis of step A was carried out as described in the synthesis of intermediate e step A.

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

Under nitrogen protection at room temperature, wet Pd/C (400 mg, 10% w/w) was added to (S,E)-4-(fluoromethylene)-3-methylpiperidin-1,3- A mixture of 1-tert-butyl dicarboxylate-3-methyl ester and (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate-1-tert-butyl ester-3-methyl ester (850 mg, 2.96 mmol) in methanol (10 mL) was added. The system was replaced with a hydrogen balloon and stirred in a hydrogen atmosphere overnight. After the reaction was completed by TLC monitoring, it was filtered with diatomaceous earth and the filtrate was concentrated to dryness to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-10%) to obtain a colorless oily product (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl)-3-methyl ester (600 mg, yield 70%). LCMS (m/z): 234.1 (M-56+H), 312.1 (M+Na). ¹ H NMR (400 MHz, methanol-d4) δ4.76–4.70 (m, 0.5H), 4.64–4.52 (m, 1H), 4.46–4.41 (m, 0.5H), 4.23 (d, J=13.7 Hz, 1H), 4.08–3.99 (m, 1H), 3.67 (s, 3H), 3.06–2.86 (m, 1H), 2.86–2.70 (m, 1H), 1.95–1.81 (m, 1H), 1.80–1.68 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H). ¹⁹ F NMR (376 MHz, methanol-d4) δ221.80.

Step C: (3S,4S)-4-(Fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride

At room temperature, 3M hydrochloric acid-dioxane (10mL, 30mmol) was added dropwise to a solution of (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl)-3-methyl ester (600mg, 2.07mmol) in ethyl acetate (10mL), and the resulting mixture was stirred at room temperature for 1h. The reaction was completed after LCMS monitoring, and the mixture was concentrated under reduced pressure to obtain a white solid (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (500mg, crude product). LCMS (m/z): 190.1 (M+H).

Step D: Methyl (3S,4S)-4-(Fluoromethyl)-1,3-dimethylpiperidine-3-carboxylate

At room temperature, (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (500 mg, crude product from the previous step) was dissolved in methanol (10 mL), and aqueous formaldehyde solution (2 mL, 35-40% w/w, ~24 mmol) was added, and stirred at room temperature for 2 h. Sodium cyanoborohydride (696 mg, 11.1 mmol) was added in batches, and the resulting mixture was stirred at room temperature for 2 h. LCMS monitored the completion of the reaction, saturated NH ₄ Cl aqueous solution was added to the reaction solution, and the product was extracted with ethyl acetate three times. The organic phases were combined and concentrated to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a colorless oily product (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (200 mg, yield 44%). LCMS (m/z): 204.1 (M+H).

Step E: ((3S,4S)-4-(Fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol

At room temperature, LiAlH ₄ -THF (1.7 mL, 1M, 1.7 mmol) was slowly added dropwise to a solution of (3S, 4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (200 mg, 0.869 mmol) in anhydrous THF (2 mL), and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by TLC, cooled in an ice bath, and sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated. An appropriate amount of ethyl acetate was added, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a colorless oily crude product ((3S, 4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (100 mg, yield 58%). LCMS (m/z): 176.1 (M+H).

Intermediate g

(S)-(1,3-Dimethyl-4-methylenepiperidin-3-yl)methanol

Step A: (S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol

At room temperature, LiAlH ₄ (0.7 mL, 2.5 M THF solution, 1.75 mmol) was added dropwise to a mixture of (S)-3-methyl-4-methylenepiperidin-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (150 mg, 0.56 mmol) and THF (2 mL). After the addition was complete, the mixture was heated to 70°C and stirred for 3 h. After the reaction was completed by TLC monitoring, Na ₂ SO ₄ ·10H ₂ O was added to quench the reaction, and then anhydrous sodium sulfate was added to dry, and the mixture was diluted with ethyl acetate. The reaction solution was filtered through diatomaceous earth to remove the solid, and the filtrate was concentrated to obtain a colorless oily liquid (S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol (120 mg, yield 80%), which was directly used in subsequent reactions.

Intermediate h

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

Step A: (S)-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester

Dissolve (R)-3-methyl-4-oxypiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (10.0 g, 36.86 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (10.68 g, 55.29 mmol) in anhydrous DMF (100 mL) and replace with nitrogen three times. Cool the system with a dry ice ethanol bath and drop 1 mol of potassium tert-butoxide tetrahydrofuran solution (66.34 mL, 66.34 mmol). The resulting mixture was stirred at the temperature for 2 h, then slowly warmed to room temperature and continued to stir for 3 h. After the reaction was completed by LCMS monitoring, the reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and water (200 mL) and DCM/MeOH (100 mL, v/v=10/1) were added for extraction 5 times. The product was washed with LiCl aqueous solution (100 mL, 4% w/w) for 3 times, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a light yellow oily product (5.2 g, yield 46%). LCMS (m/z): 250.1 (M-56+H).

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

At room temperature, (S)-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (6.20 g, 20.31 mmol) was dissolved in methanol (150 mL) and replaced with nitrogen three times. Palladium carbon (2.16 g, 10% w/w) was added and hydrogen was used to replace the mixture. Change three times. Stir at 30°C for 4h under 15Psi hydrogen atmosphere. After the reaction is completed, the reaction solution is filtered with diatomaceous earth and the filter cake is washed three times with methanol. The filtrate is collected and concentrated to dryness to obtain a colorless oily product (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.53g, yield 89%). LCMS (m/z): 252.1 (M-56+H).

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

Under room temperature, (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.53 g, 17.99 mmol) was dissolved in 4M HCl/dioxane (60 mL), and the resulting mixture was stirred at room temperature for 1 h, and concentrated to remove the acid solution to obtain a white solid (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (4.38 g, yield 100%). LCMS (m/z): 208.1 (M+H).

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

At room temperature, (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.58 g, 14.69 mmol) was dissolved in methanol (40 mL), and formaldehyde aqueous solution (3.58 g, 37% w/w, 44.07 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (1.11 g, 17.63 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 h. After LCMS monitoring, the system was concentrated to dryness, ethyl acetate was added to dissolve the crude product, and diatomaceous earth was filtered. The resulting filtrate was purified by FCC (SiO ₂ , MeOH/DCM (containing 0.3% DIEA) = 0-4%) to obtain a colorless oily product (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (3.0 g, yield 92%). LCMS (m/z): 222.1 (M+H).

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

Under ice bath conditions, 1M LiAlH ₄ -THF (17.63mL, 17.63mmol) was added dropwise to a solution of (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (3.0g, 13.56mmol) in anhydrous THF (30mL). The resulting mixture was stirred at 0°C for 15min. After the reaction was completed by LCMS monitoring, sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated. About 8g of anhydrous sodium sulfate was added. Filtered through diatomaceous earth, the filter cake was washed 3 times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to obtain a colorless solid product (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (2.6g, yield 99%). LCMS (m/z): 194.1 (M+H).

Intermediate i

(3S)-(4-Methoxy-1,3-dimethylpiperidin-3-yl)methanol

Step A: (3R)-4-Hydroxy-3-methylpiperidin-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester

Under ice bath condition, NaBH ₄ (279mg, 7.37mmol) was added in batches to a mixed solution of (R)-3-methyl-4-oxypiperidine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (2.0g, 7.37mmol) and MeOH (50mL), stirred under ice bath condition for 10min, TLC showed that the raw material disappeared. Then the reaction solution was poured into NH ₄ Cl (100mL), extracted with EA (100mL×3), the collected organic phase was washed with saturated NaCl aqueous solution (30mL), the organic phase was concentrated, and the obtained crude product was purified by FCC (SiO ₂ , EA/PE＝0％～40％) to obtain colorless oily liquid (3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (1.7g, yield 85％). LCMS (m/z): 218.1 (M+H-56). ¹ H NMR (400MHz, Chloroform-d) δ4.05–3.93(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).

Step B: (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester

Under ice bath conditions, NaH (439 mg, 10.94 mmol, 60%) was added to a mixed solution of (3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester (1.0 g, 3.66 mmol) and DMF (10 mL), and stirred for 20 minutes. Then CH ₃ I (1.56 g, 10.94 mmol) was added to the above reaction solution, and stirring was continued for 3 hours under ice bath conditions. After the reaction was completed by TLC monitoring, the reaction solution was poured into a saturated NH ₄ Cl aqueous solution (80 mL), and EA (50 mL×3) was added for extraction. The collected organic phase was washed with a saturated NaCl aqueous solution (20 mL). The concentrated crude product was purified by FCC (SiO ₂ , EA/PE=0-40%) to obtain a white solid (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (1.0 g, yield 95%). LCMS (m/z): 232.1 (M+H-56). ¹ H NMR (400MHz, Chloroform-d ₃ ) δ3.98–3.78(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).

Step C: (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol

At room temperature, LiAH ₄ (2.04mL, 2.04mmol, 1M in THF) was added to (3R)-4-methoxy-3-methylpiperidin-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester (200mg, 0.696mmol) and the temperature was raised to 70°C and stirred for 2h. After the reaction was completed, Na ₂ SO ₄ ·10H ₂ O was slowly added to the reaction solution under ice bath conditions to quench LiAH ₄ until the reaction no longer generated gas, and a small amount of EA was added to dilute, and then anhydrous sodium sulfate was added to dry, filtered, and the mother liquor was collected and concentrated to obtain a colorless liquid (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (120mg, yield 99%). LCMS (m/z): 174.1 (M+H). ¹ H NMR (400MHz, Chloroform-d ₃ ) δ3.95–3.53(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).

Intermediate j

(S)-(4,6-Dimethyl-6-azaspiro[2.5]octan-4-yl)methanol

Step A: (4S)-1,1-dichloro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic acid-6-tert-butyl-4-methyl ester

At room temperature, TEBAC (25.4 mg, 0.11 mmol) was added to a mixed solution of (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylic acid-1-(tert-butyl) ester-3-methyl ester (250 mg, 0.93 mmol), sodium hydroxide (7.5 mL, 50% wt) and CHCl ₃ (25 mL), and the mixture was heated to 80°C and stirred overnight. After the reaction was completed by LCMS monitoring, water (50 mL) and DCM (50 mL×3) were added for extraction. The organic phase was washed with saturated brine, the organic phase was collected, concentrated and further purified by FCC (SiO ₂ , EA/PE＝0-25%) to obtain a colorless liquid (4S)-1,1-dichloro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic acid-6-tert-butyl-4-methyl ester (320 mg, yield 98%). LC-MS (m/z): 296.0 (M-56).

Step B: (S)-(4,6-dimethyl-6-azaspiro[2.5]octan-4-yl)methanol

At room temperature, LiAlH ₄ (1M, 2.2mmol, 2.2mL) was added dropwise to a mixed solution of (4S)-1,1-dichloro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic acid-6-tert-butyl-4-methyl ester (130mg, 0.37mmol) and THF (2mL). After the addition was completed, the system was heated to 70°C and stirred overnight. After the reaction was completed by LCMS monitoring, Na ₂ SO ₄ ·10H ₂ O was added to quench the reaction until no gas was generated. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated at low temperature (35°C) to obtain a colorless liquid (S)-(4,6-dimethyl-6-azaspiro[2.5]octan-4-yl)methanol (40mg, yield 62%). LC-MS (m/z): 170.1 (M+H).

The following intermediates were prepared according to the above synthesis scheme or appropriate variations:

Intermediate e-d3

(S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methanol

Step A: Methyl (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidine-3-carboxylate

At room temperature, potassium carbonate (5.55 g, 40.2 mmol) was added to a mixed solution of (S, E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.00 g, 13.4 mmol), deuterated iodomethane (2.33 g, 16.1 mmol) and ACN (100 mL). After the addition, the mixture was heated to 90°C and stirred overnight. After the reaction was completed by LCMS monitoring, the mixture was filtered and the filter cake was rinsed with EA (50 mL). The filtrate was collected, concentrated and further purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a colorless liquid (S, E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidine-3-carboxylic acid methyl ester (1.9 g, yield 69%). LC-MS (m/z): 205.1 (M+H).

Step B: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methanol

Under ice bath, LiAlH ₄ (1M-THF, 9.3mmol, 9.3mL) was added dropwise to a mixed solution of (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidine-3-carboxylic acid methyl ester (1.9g, 9.3mmol) and THF (50mL), and stirred in ice bath at 0°C for 0.5h after the addition. After the reaction was completed as monitored by LCMS, the reaction was quenched with Na ₂ SO ₄ ·10H ₂ O until no gas was generated, and the reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated at low temperature (35°C) to obtain a colorless liquid 4-fluoromethylene-3-methyl-1-methyl-D3-piperidine-3-methanol (1.3g, 79% yield). LC-MS (m/z): 177.1 (M+H).

Intermediate e-d5

(S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methylene-d ₂ -ol

Step A: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methylene-d ₂ -ol

Under ice bath conditions, LiAlD ₄ powder (271.28 mg, 6.46 mmol) was added to a solution of (S, E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidine-3-carboxylic acid methyl ester (1.10 g, 5.39 mmol) in anhydrous tetrahydrofuran (15 mL). The resulting mixture was stirred at room temperature for 15 min. After the reaction was completed, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated by LCMS monitoring. About 5 grams of anhydrous sodium sulfate was added to the reaction solution to remove water. The reaction solution was filtered with diatomaceous earth, and the filter cake was washed three times with anhydrous tetrahydrofuran. The filtrate was collected and concentrated to dryness to obtain a colorless oily product (S, E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methylene-d ₂ -ol (951 mg, yield 99%). The product was used directly in the next step without purification. LCMS (m/z): 179.1 (M+H).

The following intermediates h-d3 and h-d5 were synthesized by referring to the above method.

Intermediate h-d3

((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methanol

Intermediate h-d5

((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methan-d ₂ -ol

Intermediate L

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

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

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

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

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

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

Under nitrogen protection, Pd(dppf)Cl ₂ (13.2 g, 18.2 mmol) was added to 7-fluoro-8-((triisopropylsilyl)acetylene) The mixture was added into a solution of 2,4-dioxane (2.4 L) of 1,2-di-((1,3,2-dioxaborane)-3-(((triisopropylsilyl)oxy)naphthalen-1-yl) trifluoromethanesulfonate (235 g, 0.36 mol), 5,5,5',5'-tetramethyl-2,2'-di(1,3,2-dioxaborane) (164 g, 0.73 mol) and potassium acetate (107 g, 1.1 mol). The system was heated to 85°C and stirred for 20 h. The reaction was monitored by TLC and completed. The mixture was cooled to room temperature, filtered through diatomaceous earth, rinsed with EA, concentrated, and purified by a silica gel column (EA/PE=0-5%) to obtain a crude compound.

The crude compound was dissolved in methanol (1.2 L), 1N HCl (2.4 L) was added, and the resulting mixture was stirred at room temperature for 30 min. EA (2.4 L) was added and stirring was continued for 2 h. The mixture was allowed to stand for separation, and the organic phase was washed with water (2.4 L) and saturated brine (2.4 L × 2) in turn, and concentrated to obtain (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (183 g, yield 92%). ¹ H NMR (400MHz, Chloroform-d) δ7.66–7.60(m,1H),7.34(d,J＝2.5Hz,1H),7.24–7.19(m,1H),7.18(d,J＝2.5Hz,1H),4.52(s,2H),1.35–1.29(m,3H),1.24–1. 21(m,3H),1.20–1.17(m,18H),1.12(d,J=7.3Hz,18H).LCMS(m/z):543.3(M+H).

Example 1

1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Step A: 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (191 mg, 1.20 mmol) and sodium hydride (64 mg, A solution of 60% w/w, 1.60mmol) in THF (10mL) was stirred at 0°C for 15min, and then 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (300mg, 0.80mmol) was added all at once. The resulting system was stirred for 1.5h and slowly warmed to room temperature. LCMS monitored the completion of the reaction, and saturated aqueous ammonium chloride solution (20mL) was added to the system, and extracted with ethyl acetate (15mL×2). The organic phases were combined, washed with saturated brine (20mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , MeOH/DCM=0-20%) to give 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol as a yellow solid (283 mg, yield 71%). LCMS (m/z): 497.0, 499.1 (M+H).

Step B: 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Under nitrogen protection, a solution of 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.40 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (349 mg, 0.64 mmol), Pd(dtbpf)Cl ₂ (26 mg, 0.04 mmol), and K ₃ PO ₄ (256 mg, 1.21 mmol) in 1,4-dioxane/water (V/V=4:1, 6 mL) was heated to 100° C. and stirred for 1.5 h. The reaction was completed after LCMS monitoring, and the system was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , EA/PE=0-100%) to give 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol as a brown solid (243 mg, yield 66%). LCMS (m/z): 915.4 (M+H).

Step C: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

A solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (240 mg, 0.26 mmol) and cesium fluoride (398 mg, 2.6 mmol) in DMF (2 mL) was heated to 50°C and the reaction was stirred for 1.5 h. The reaction was completed after LCMS monitoring, and the cesium fluoride solid was removed by filtration. The filtrate was purified by Pre-HPLC (C18E, ACN/(0.1% NH ₄ HCO ₃ /H ₂ O)=45-95%) to obtain a white solid 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (97 mg, yield 61%). ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.91–7.72(m,2H),7.44–7.34(m,1H),7.30–7.23(m,1H),7.21–7.15(m,1H),7.10–7.02(m,1H),5.28(d,J＝54.1Hz,1H),4.14–3.93(m,3H),3.91– 3.71(m,2H),3.16–3.06(m,2H),3.04–2.98(m,1H),2.88–2.78(m,1H),2.18–1.95(m,4H),1.87–1.57(m,6H),1.15(d,J＝6.2Hz,3H),1.02–0.96(m,3 H). ^19F NMR (376MHz, DMSO-d ₆ ) δ -111.75, -129.31, -172.02. LCMS (m/z): 603.1 (M+H).

Example 2

1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Step A: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Methanol (1 mL) was added to the compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (17 mg, 0.028 mmol). Pd/C (6.0 mg, 0.003 mmol) was added to the reaction system under _N2 conditions, and the reaction solution was replaced with _H2 (15 psi) three times, and the _H2 atmosphere was maintained and stirred at room temperature for 3 hours. The reaction was complete when monitored by LCMS. The reaction solution was filtered through diatomaceous earth, and the filtrate was filtered through a filter head, concentrated, and freeze-dried to obtain a white solid 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (7.0 mg, yield 41%). ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.91(dd,J＝8.5,6.6Hz,1H),7.73(dd,J＝9.1,6.0Hz,1H),7.38–7.24(m,3H),6.96–6.89(m,1H),5.27(d,J＝54.5Hz,1H),4.80–4.53(m,1H),4.13–4.07 (m,1H),4.05–3.95(m,2H),3.90–3.78(m,1H),3 .52(d,J＝13.0Hz,1H),3.12–3.05(m,2H),3.03–2.99(m,1H),2.88–2.76(m,1H),2.41–2.29(m,2H),2.15–1.98(m,4H),1.85–1.61(m,6H),1.15(d, J=14.4Hz, 3H), 1.05–0.92 (m, 1H), 0.76–0.67 (m, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -128.38, -172.12. LCMS (m/z): 607.3 (M+H).

Example 3

1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol formate

Step A: 1-(7-Bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

Under ice bath conditions, (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (100 mg, 0.8 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium hydrogen (40 mg, 60% w/w, 1.0 mmol) was slowly added to the reaction system, and the temperature was maintained and stirred for half an hour. 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.53 mmol) was added to the reaction system, and the resulting mixture was stirred and reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the system was poured into ice water (50 mL) to quench the reaction, and then extracted with ethyl acetate 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by FCC (SiO ₂ , MeOH/DCM=10-30%) to obtain a yellow oily product 1-(7-bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (170 mg, yield 68%). LCMS (m/z): 469.0 (M+H).

Step B: 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triisopropylsilyloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol

Under _N2 protection, compound 1-(7-bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.28 mmol) and (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (238 mg, 0.42 mmol) were dissolved in 1,4-dioxane/water (V/V=4:1, 6 mL). Then, Pd(dtbpf) _Cl2 (34 mg, 0.028 mmol) and potassium phosphate (126 mg, 0.56 mmol) were added under _N2 conditions. The resulting mixture was stirred at 110°C for 2 hours. The reaction was completed after LCMS monitoring, and the system was concentrated to dryness under reduced pressure. The crude product was purified by FCC (MeOH/DCM=0-10%) to give a yellow solid 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triisopropylsilyloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, yield 56%). LCMS (m/z): 885.5 (M+H).

Step C: 1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol formate

Under stirring at room temperature, 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triisopropylsilyloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (130 mg, 0.15 mmol) was dissolved in anhydrous DMF (2 mL), and cesium fluoride (223 mg, 1.5 mmol) was added. The temperature was raised to 50°C and stirred for 2 hours. The reaction was completed after monitoring by LCMS. The insoluble matter was removed by filtration, and the filtrate was purified by pre-HPLC (C18E, ACN/(0.1% FA/H ₂ O)=45-95%) to obtain a white solid 1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol formate (41 mg, yield 48%). ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.19(s,1H),7.96(dd,J＝9.2,5.9Hz,1H),7.83(dd,J＝32.3,8.6Hz,1H),7.51–7.41(m,1H),7.36(d,J＝2.6Hz,1H),7.26–7.16(m,1H),7.09(dd,J＝11.7, 2.6Hz,1H),4.27–4.15(m,2H),4.1 3–3.96(m,1H),3.93–3.75(m,3H),3.54–3.26(m,2H),2.97–2.88(m,1H),2.71–2.61(m,1H),2.33(s,3H),2.15–1.90(m,2H),1.76–1.58(m,6H),1 .16 (d, J=7.2Hz, 3H), 1.07 (d, J=1.5Hz, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -110.52, -128.59～-129.23. LCMS (m/z): 573.2 (M+H).

Example 4

1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate

Step A: 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Dissolve (3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (110 mg, 0.7 mmol) in THF (1 mL), and then add NaH (46.3 mg, 1.2 mmol) to the reaction system. Stir at room temperature for 30 minutes, and add 1-(7-bromo-2- The mixture was stirred for 3 h at room temperature. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with DCM (15 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by FCC (SiO ₂ , MeOH/DCM = 0-30%) to give a light yellow solid 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 26%). LCMS (m/z): 497.0 (M+H).

Step B: 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

Under nitrogen protection, to a solution of 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 0.12 mmol) in 1,4-dioxane/H ₂ O (V/V=4:1, 1.0 mL) were added (7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisomethylsilyl)oxy)naphthalen-1-yl)boric acid (131 mg, 0.24 mmol), PdCl ₂ (dtbpf) (7.8 mg, 0.012 mmol) and K ₃ PO ₄ (76.8 mg, 0.36 mmol) in sequence, and the mixture was reacted at 110° C. for 3 h. After concentration under reduced pressure, the crude product was purified by FCC (SiO ₂ , MeOH/DCM=0-30%) to give a pale yellow solid of 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (80 mg, yield 73%). LCMS (m/z): 916.4 (M+H).

Step C: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate

To a solution of 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (80.0 mg, 0.087 mmol) in DMF (1 mL) was added CsF (134 mg, 0.88 mmol). The resulting mixture was heated with stirring at 50°C for 2 h, cooled to room temperature, and the insoluble matter was removed by filtration. The filtrate was purified by Pre-HPLC (C18E, ACN/(0.1% FA/ _H2O )=45-95%) to give a light yellow solid 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate (30 mg, yield 57%). LCMS (m/z): 603.0 (M+H).

With reference to the synthetic method of the above compounds, the following examples were also prepared and characterized:

Examples 32-A-1 and 32-A-2

(3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

Step A: (R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol

At room temperature, (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (12.0 g, 31.9 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (22.5 g, 41.5 mmol), Pd(OAc) ₂ (716 mg, 3.19 mmol), BIDIME (2.11 g, 6.38 mmol) and K ₃ PO ₄ (27.1 g, 128 mmol) were added to anhydrous toluene (150 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 110°C and stirred overnight. The reaction was completed after monitoring by LCMS and TLC. The reaction solution was returned to room temperature, the palladium catalyst was removed by filtration through celite, the mother liquor was collected, water (100 mL) was added, and EA (150 mL×3) was used for extraction. The collected organic phase was washed with saturated NaCl (50 mL), and the crude product obtained by concentrating the organic solution was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a yellow solid (3R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (16.0 g, yield 64%). LCMS (m/z): 794.3 (M+H).

Step B: (R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol and (R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol

The above compound (R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (16.0 g) was separated by SFC (Waters SFC 150, separation column 250*50mm 10μm; mobile phase: _CO2 /MeOH (+0.1% 7.0mol/l _NH3 /MeOH) = 75/25; flow rate: 140mL/min), the first eluted isomer 1 was obtained as intermediate 32-A-P1, (R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (7.0g, relatively short retention time). Chiral analysis method SFC-32A, Rt = 2.539. The isomer 2 eluted subsequently was the intermediate 32-A-P2, (R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (7.0 g, relatively large retention time). Chiral analysis method SFC-32A, Rt=3.978.

Chiral analysis method SFC-32A: Waters UPCC (CA-352), analytical column: 100*3mm 3μm; mobile phase A: CO2, mobile phase B: MeOH (+0.1% DEA); flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A/B=80/20.

Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, NaH (30 mg, 60%, 756 umol) was added to a mixed solution of (((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (58 mg, 302 umol) and THF (10 mL) and stirred for 30 min. Then, ((R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (32-A-P1, 200 mg, 252 umol) was added to the reaction solution at once and stirred for 2 h. The reaction was completed after LCMS monitoring. The reaction solution was poured into half-saturated NH ₄ Cl solution (30 mL), extracted with EA (30 mL×3), the organic phase was collected, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , and the concentrated organic phase was purified by FCC (SiO ₂ , EA/PE＝0-80％) to obtain a yellow solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, yield 62％). LCMS (m/z): 484.2 (M/2+H).

Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, CsF (236 mg, 1.55 mmol) was added to a mixed solution of ((R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 155 umol) and DMF (3 mL). The temperature was raised to 50°C for 1 h. The reaction was completed after monitoring by LCMS and TLC. The reaction was analyzed by pre-HPLC (C18, CAN/(10 mmol NH ₄ HCO ₃ /H ₂ O)＝55-75％) was purified to give a white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 59％). LCMS (m/z): 655.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ ) δ7.97–7.78 (m, 1H), 7.65 (d, J＝9.8 Hz, 1H), 7.40–7.23 (m, 2H), 7.17–7.05 (m, 1H), 6.39–5.93 (m, 1H), 4.62–5.80 (m, 1H). 4.42(m,3H),4.32–4.18(m,1H),4.13–3.92(m,1H),3.57–3.46(m,1H),3.43–3.33(m,1H),3.26(s,1H),3.17–3.06(m,1H),3.02–2.89(m,1H),2.24 (s,3H),2.19–2.09(m,1H),2.07–1.92(m,1H),1.87–1.69(m,6H),1.27(s,3H),1.21(s,3H). ¹⁹ F NMR (376MHz, methanol-d ₄ )δ-111.60,-118.56,-119.53,-12 1.59,-125.79.

Step E: (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, NaH (30 mg, 60%, 756 umol) was added to a mixed solution of (((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (58 mg, 302 umol) and THF (10 mL) and stirred for 30 min. Then (3R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (32-A-P2, 200 mg, 252 umol) was added to the reaction solution at once and stirred for 2 h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into half-saturated NH ₄ Cl solution (30 mL), extracted with EA (30 mL×3), the organic phase was collected, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , and the concentrated organic phase was purified by FCC (SiO ₂ , EA/PE＝0-80％) to obtain a yellow solid (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, yield 62％). LCMS (m/z): 484.2 (M/2+H).

Step F: (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, CsF (236 mg, 1.55 mmol) was added to a mixed solution of (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 155 umol) and DMF (3 mL). The temperature was raised to 50°C for 1 h. The reaction was completed after monitoring by LCMS and TLC. The reaction was analyzed by pre-HPLC (C18, CAN/(10 mmol NH ₄ HCO ₃ /H ₂ O)＝55-75％) to give a white solid (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 59％). LCMS (m/z): 655.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ7.91–7.78(m,1H),7.62(d,J＝9.8Hz,1H),7.36–7.25(m,2H),7.18–7.09(m,1H),6.45–6.00(m,1H),4.62–4.48(m,3H),4.36–4.23(m,1H),4.14–4 .04(m,1H),3.53–3.45(m ,1H),3.41–3.34(m,1H),3.24(s,1H),3.14–3.06(m,1H),3.02–2.90(m,1H),2.23(s,3H),2.20–2.10(m,1H),2.05–1.92(m,1H),1.87–1.66(m,6H) ,1.25(s,3H),1.21(s,3H). ¹⁹ F NMR (376MHz, methanol-d ₄ )δ-111.63,-118.54,-119.85,-121.49,-126.12.

Example 32-1

(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (45 mg, 69 umol) was dissolved in methanol (20 mL), and Pd/C (15 mg, 10 wt%) and H ₂ balloons were replaced twice and stirred at room temperature for 4 hours. The reaction was completed by LCMS monitoring. The reaction solution was filtered to obtain a clear organic phase. After complete concentration, acetonitrile (2 mL) was added, followed by deionized water (20 mL). The mixture was lyophilized to obtain a white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((S)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (34 mg, yield 75%). LCMS (m/z): 659.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ7.75(d,J＝9.8Hz,1H),7.70–7.60(m,1H),7.27(d,J＝2.5Hz,1H),7.26–7.19(m,1H),7.01–6.94(m,1H),6.38–5.97(m,1H),4.62–4.46(m,2H),4.33 –4.21(m,1H),4.12–4.01(m,1H),3.58–3 .34(m,2H),3.14–3.03(m,1H),2.98–2.89(m,1H),2.63–2.34(m,2H),2.22(s,3H),2.19–2.13(m,1H),2.01–1.93(m,1H),1.87–1.69(m,7H),1.25( s, 3H), 1.21 (s, 3H), 0.79 (t, J = 7.4Hz, 3H). ¹⁹ F NMR (376MHz, methanol-d ₄ ) δ -118.19, -118.87, -118.95, -121.17, -121.30, -121.92, -124.72.

Example 32-2

(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (45 mg, 69 umol) was dissolved in methanol (20 mL), and Pd/C (15 mg, 10%, 14 umol) was added. ₂ balloons were replaced twice and stirred at room temperature for 4 hours. The reaction was completed by LCMS monitoring. The reaction solution was filtered to obtain a clear organic phase. After complete concentration, acetonitrile (2 mL) was added, followed by deionized water (20 mL). The mixture was lyophilized to obtain a white solid (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (39 mg, yield 86%). LCMS (m/z): 659.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ7.79(dd,J＝9.9,1.8Hz,1H),7.70–7.59(m,1H),7.27(d,J＝2.7Hz,1H),7.26–7.19(m,1H),6.97(d,J＝2.6Hz,1H),6.40–6.02(m,1H),4.63–4.46(m,2H) ,4.29–4.17(m,1H),4.13–3 .99(m,1H),3.54–3.36(m,2H),3.14–3.03(m,1H),3.00–2.88(m,1H),2.64–2.34(m,2H),2.22(s,3H),2.18–1.91(m,2H),1.90–1.68(m,7H),1.28 (s, 3H), 1.21 (s, 3H), 0.81 (t, 3H). ¹⁹ F NMR (376MHz, methanol-d ₄ ) δ -118.09, -118.75, -118.85, -121.16, -121.27, -121.92, -124.72.

Embodiment 49

(R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Step A: (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, DIPEA (717 mg, 5.55 mmol) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (350 mg, 1.39 mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (210 mg, 1.39 mmol) in THF (10 mL), and stirred at room temperature for 1 h. After the reaction was completed by LCMS monitoring, THF was removed by concentration at low temperature (35 ° C). EA (50 mL) and water (20 mL) were then added, the liquids were separated, and the aqueous phase was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a yellow solid (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (450 mg, yield 98%). LCMS (m/z): 331.0 (M+H).

Step B: (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Under ice bath condition, NaH (130 mg, 60%, 3.26 mmol) was added to a solution of (3S, 4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (200 mg, 1.14 mmol) in THF (10 mL) and stirred for 30 min. Keep ice bath, add (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (360 mg, 1.09 mmol) to the above reaction solution at once and stir for 5 h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into a saturated NH ₄ Cl solution (50 mL) and extracted with EA (50 mL×3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-20%) to obtain a yellow solid (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (180 mg, yield 35%). LCMS (m/z): 470.1 (M+H).

Step C: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1- 2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Under nitrogen protection, a solution of (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80 mg, 0.17 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (185 mg, 0.34 mmol), Pd(dtbpf) _Cl2 (11 mg, 0.017 mmol) and _K3PO4 (108 _mg , 0.51 mmol) in 1,4-dioxane/ _H2O (5.5 mL, V/V=4:1) was heated to 100°C and stirred for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was poured into water (50 mL), extracted with EA (50 mL×3), and the combined organic phases were washed with saturated NaCl (20 mL). The organic phase was concentrated under reduced pressure, and the resulting crude product was purified by FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-20%) to obtain a yellow solid (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 38%).

Step D: (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

CsF (98 mg, 0.64 mmol) was added to a solution of (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg, 0.064 mmol) in DMF (3 mL) at room temperature. The resulting mixture was heated to 50°C for 1 hour. After the reaction was completed as monitored by LCMS and TLC, the reaction solution was purified by FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-60%) to obtain a light yellow solid (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (35 mg, yield 88%). LCMS (m/z): 620.3 (M+H).

Embodiment 50

(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol

Pd/C (5 mg, 10%) was added to a solution of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.048 mmol) in methanol (20 mL) at room temperature under nitrogen protection. The system was replaced with _H2 balloon three times and stirred at room temperature overnight under _H2 balloon conditions. The reaction was completed by LCMS monitoring, and the reaction solution was filtered to remove Pd/C and then subjected to Pre.HPLC to obtain a white solid (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol (10 mg, yield 33%). LCMS (m/z): 624.3 (M+H). ¹ H NMR (400MHz, methanol-d ₄ ) δ7.55 (dd, J＝9.0, 5.8Hz, 1H), 7.19–7.09 (m, 2H), 6.96 (dd, J＝9.0, 2.6Hz, 1H), 4.69–4.31 (m, 4H), 4.14–3.78 (m, 4H), 3.70–3.37 (m, 3H),3.10–2.82(m,2H),2.56–2.34(m,1H),2.32–2.10(m,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84– 0.69(m,3H). ^1H NMR (400 MHz, methanol-d ₄ ) δ -76.94, -121.59, -149.95, -150.32.

Embodiment 51

(R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

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

At room temperature, DIPEA (2.11 g, 16.32 mmol) was added to a mixture of (R)-3-methylpiperidin-3-ol hydrochloride (949 mg, 6.26 mmol), 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.5 g, 5.44 mmol), BOP (4.81 g, 10.88 mmol) and DMF (20 mL). The resulting reaction system was heated to 45°C and stirred for 5 h. After the reaction was completed by LCMS monitoring, the reaction solution was returned to room temperature and slowly poured into stirred H ₂ O (300 mL). Filter, filter The cake was washed with water (100 mL), collected and dried to obtain a brown solid (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2.0 g, yield 99%). LCMS (m/z): 373.0 (M+H).

Step B: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Under nitrogen protection, a mixed solution of (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.60 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (391 mg, 0.72 mmol), cataCXium A Pd G ₃ (43.7 mg, 0.06 mmol), K ₃ PO ₄ (382 mg, 1.8 mmol) and 1,4-dioxane/H ₂ O (10 mL, V/V=4:1) was heated to 110° C. and stirred for 2 h. After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted with EA (60 mL × 3). The organic phase was combined and washed with saturated NaCl (20 mL). The organic phase was concentrated and the crude product was purified by FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-20%) to obtain a yellow solid (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (450 mg, yield 78%). LCMS (m/z): 835.4 (M+H).

Step C: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, m-CPBA (129 mg, 0.75 mmol) was added to a solution of (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (250 mg, 0.30 mmol) in DCM (15 mL) and stirred at room temperature for 2 h. After the reaction was completed as monitored by TLC and LCMS, DCM (50 mL) and half-saturated aqueous NaHCO ₃ solution (20 mL) were added in turn for washing. The liquid was separated and the aqueous phase was extracted with DCM (60 mL×3). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a brown solid (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (250 mg, yield 96%). LCMS (m/z): 867.3 (M+H).

Step D: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, NaH (17 mg, 60%, 0.41 mmol) was added to a mixed solution of ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (29 mg, 0.17 mmol) and THF (3 mL) and stirred for 30 min. Then (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg, 0.14 mmol) was added to the reaction solution at once and stirred for 3 h. After the reaction was completed by LCMS monitoring, the reaction solution was poured into a saturated NH ₄ Cl solution (50 mL). The mixture was extracted with EA (50 mL × 3), the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-40％) to give (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy 4-(4-(4-(4-methoxy-2-pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, yield 75%). LCMS (m/z): 962.5 (M+H).

Step E: (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, CsF (158 mg, 1.04 mmol) was added to a DMF (3 mL) solution of (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.10 mmol), and the resulting mixture was heated to 50 °C for 1 h. The reaction was completed after monitoring by LCMS. The reaction solution was subjected to Pre-HPLC to obtain a light yellow solid (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (30 mg, yield 44%). LCMS (m/z): 650.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ7.93–7.78(m,1H),7.39–7.19(m,3H),4.79–4.43(m,5H),4.10–3.95(m,3H),3.89–3.82(m,1H),3.79–3.67(m,1H),3.58–3.47(m,1H),3.27–3.16 (m,1H),3.13–3.06(m,1H),3.04–2.95(m,1H),2.38–2.24(m,3H),2.24–2.15(m,1H),2.12–2.01(m,1H),1.91–1.57(m,7H),1.38–1.28(m,1H),1. 22–1.14(m,5H). ^1H NMR (400 MHz, methanol-d ₄ ) δ -112.10, -150.97, -151.99, -223.17.

Embodiment 52

(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol

Under nitrogen protection at room temperature, Pd/C (9.8 mg, 10% wt) was added to a methanol (10 mL) solution of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (20 mg, 0.031 mmol). The resulting system was replaced with _H2 balloon three times and stirred at room temperature overnight under _H2 balloon conditions. After the reaction was completed by LCMS monitoring, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated and frozen The reaction mixture was dried to give (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol (9.3 mg, yield 46%) as a white solid. LCMS (m/z): 654.3 (M+H). ¹ H NMR (400MHz, methanol-d ₄ ) δ7.55 (dd, J＝9.0, 5.8Hz, 1H), 7.19–7.09 (m, 2H), 6.96 (dd, J＝9.0, 2.6Hz, 1H), 4.69–4.31 (m, 4H), 4.14–3.78 (m, 4H), 3.70–3.37 (m, 3H),3.10–2.82(m,2H),2.56–2.34(m,1H),2.32–2.10(m,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84– 0.69(m,3H). ^1H NMR (400 MHz, methanol-d ₄ ) δ -76.94, -121.59, -149.95, -150.32.

Embodiment 53

(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, a mixed solution of (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.20 g, 3.48 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 3.83 mmol), cataCXium A Pd G ₃ (507 mg, 696 μmol), K ₃ PO ₄ (2.22 g, 10.4 mmol) and 1,4-dioxane/H ₂ O (V/V=4/1, 15 mL) was replaced with N ₂ three times and the temperature was raised to 110° C. and stirred for 2 h. The reaction was completed after LCMS monitoring. The reaction solution was returned to room temperature, the palladium catalyst was removed by diatomaceous earth filtration, the mother liquor was collected, water (50 mL) was added, and EA (80 mL×3) was used for extraction. The combined organic phases were washed with saturated aqueous NaCl solution (20 mL), and the crude product obtained after concentration was purified by FCC (SiO ₂ , EA/PE＝0-40％) to obtain a yellow solid (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.1 g, yield 61％). LCMS (m/z): 541.0 (M+H).

Step B: (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, mCPBA (375 mg, 1.85 mmol) was added to (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (500 mg, 925 umol) and DCM. (20mL) solution and stirred at room temperature for 2h. TLC and LCMS monitored the completion of the reaction, the reaction solution was diluted with DCM (100mL), washed with half-saturated NaHCO ₃ aqueous solution (20mL), extracted with DCM (60mL×3), the combined organic phases were washed with saturated NaCl aqueous solution (30mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solution was concentrated to obtain a brown solid (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (510mg, yield 99%). LCMS (m/z): 557.2 (M+H).

Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At -40°C, NaHMDS (1.31 mL, 1 M THF solution, 1.31 mmol) was added dropwise to a mixed solution of (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (250 mg, 436 umol), ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (101 mg, 524 umol) and THF (10 mL) and stirred for 2 h. The reaction was completed after LCMS monitoring. The reaction solution was poured into a semi-saturated aqueous NH ₄ Cl solution (50 mL) and extracted with EA (50 mL×3). The organic phase was collected, washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the concentrated organic phase was purified by FCC (SiO ₂ , (EtOH/EA=1/3)/PE=0-40%) to give a yellow solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80 mg, yield 26%). LCMS (m/z): 686.3 (M+H).

Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

CF ₃ COOH (15 mL) was added to (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80 mg, 117 umol) at room temperature and stirred at room temperature for 1 h. The reaction was completed by LCMS monitoring. The reaction solution was concentrated to remove the acid solution, diluted with EA (30 mL), and a half-saturated aqueous NaHCO ₃ solution (30 mL) was added to adjust the pH to alkaline. The organic phase was collected and concentrated, and then purified by pre-HPLC (C18, CAN/(10 mmol NH ₄ HCO ₃ /H ₂ O)＝55-75％) to obtain a white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (19 mg, yield 25％). LCMS (m/z): 642.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ9.20(s,1H),7.67(dd,J＝9.1,5.8Hz,1H),7.33–7.28(m,1H),7.27–7.20(m,1H),7.13–7.00(m,1H),6.42–6.05(m,1H),4.59–4.51(m,3H),4.35–4.2 3(m,2H),3.73–3.56(m,1H),3.53–3.4 3(m,1H),3.13–3.04(m,1H),3.00–2.92(m,1H),2.55–2.43(m,1H),2.23(s,3H),2.19–2.11(m,2H),2.04–1.94(m,1H),1.87–1.76(m,6H),1.35–1 .26(m,3H),1.22(s,3H),0.88–0.75(m,3H). ¹⁹ F NMR (376MHz, methanol-d ₄ )δ-118.98,-121.17,-121.72,-139.21.

With reference to the synthetic method of the above compounds, the following examples were also prepared and characterized:

Example 93-A

(6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxacyclopentyl-6-ol

Step A: (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-1,4-oxazepan-6-ol

At room temperature, (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (500 mg, 1.27 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (1.04 g, 1.91 mmol), Pd(OAc) ₂ (29 mg, 127 umol), BIDIME (84 mg, 255 umol), and K ₃ PO ₄ (812 mg, 3.82 mmol) were added to anhydrous toluene (15 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 110° C. and stirred overnight. The reaction was completed after monitoring by LCMS and TLC. The reaction solution was returned to room temperature, the palladium catalyst and the base were removed by filtration through celite, and the crude product obtained by concentrating the organic solution was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a yellow solid (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-1,4-oxazepine Cycloheptan-6-ol (780 mg, yield 76%). LCMS (m/z): 810.2 (M+H).

Step B: (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, NaH (59 mg, 60 wt%, 1.48 mmol) was added to a mixed solution of ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (86 mg, 444 umol) and THF (15 mL) and stirred for 30 minutes. Then, (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-1,4-oxaazepan-6-ol (300 mg, 370 umol) was added to the reaction solution at once and stirred for 1.5 h. The reaction was completed after monitoring by TLC and LCMS. The reaction solution was poured into half-saturated NH ₄ Cl (50 mL) solution, extracted with EA (30 mL × 3), collected organic phase, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , concentrated organic phase and purified by FCC (EA/PE=0-90%) to give a yellow solid (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (270 mg, yield 74%). LCMS (m/z): 964.3 (M+H).

Step C: (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, CsF (417 mg, 2.75 mmol) was added to a mixed solution of (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (270 mg, 275 umol) and DMF (5 mL). The temperature was raised to 50°C for 1 h. The reaction was completed after monitoring by LCMS and TLC. The reaction was analyzed by pre-HPLC (C18, ACN/(10 mmol NH ₄ HCO ₃ /H ₂ O)＝50-70％) to give a white solid (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (85 mg, yield 46％). LCMS (m/z): 964.3 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.21(s,1H),8.19–7.94(m,2H),7.55–7.45(m,1H),7.42(d,J＝2.6Hz,1H),7.21–7.10(m,1H),6.50–6.12(m,1H),5.38–5.18(m,1H),4.52–4.19( m,4H),4.11–3.86(m,4H),3.81–3.66(m,1H),3.62–3.45(m,2H),2.94–2.71(m,2H),2.11(s,3H),2.03–1.53(m,5H),1.20–1.13(m,3H),1.11(s,3H) ). ^19F NMR(376MHz, DMSO-d ₆ )δ-110.19,-114.75–-116.33(m),-118.17–-119.09(m),-119.12–-119.84(m),-124.21–-125.19(m).

Embodiment 93

(6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (15 mg, 22 umol) was dissolved in methanol (10 mL), and Pd/C (5 mg, 10%, 4.5 umol) and H ₂ balloons were replaced twice and stirred at room temperature for 2 hours. The reaction was completed by LCMS monitoring. The reaction solution was filtered to obtain a clear organic phase. After complete concentration, acetonitrile (2 mL) was added, followed by deionized water (20 mL), and freeze-dried to obtain a white solid (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol (12 mg, yield 80%). LCMS (m/z): 675.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.36–8.18(m,1H),7.78(dd,J＝9.1,6.0Hz,1H),7.45–7.29(m,2H),7.10–6.95(m,1H),6.53–6.10(m,1H),5.37–5.19(m,1H),4.56–4.08(m,4H),4. ^{1 9} F NMR (376MHz, DMSO-d ₆ )δ-115.01–-116.01(m),-118.28–-119.20(m).-118.57–-118.80(m),-119.36,-123.83.

Example 93-1 and Example 93-2

Example 93, (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (25 mg) was separated by Pre-HPLC (C18, ACN/( ₁₀ mmol _NH4HCO3 / _H2O )=60-80%) to give the first eluting isomer 1 as Example 93-1 (4.8 mg, retention time 11.5 min), LCMS (m/z): 675.2 (M+H); the second eluting isomer 2 as Example 93-2 (8.4 mg, retention time 12.8 min), LCMS (m/z): 675.2 (M+H).

Examples 98-1 and 98-2

(6S)-4-(7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol trifluoroacetate and (6S)-4-(7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol trifluoroacetate

Step A: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (100 mg, 255 umol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (138 mg, 382 umol), Pd(OAc) ₂ (6 mg, 26 umol), BIDIME (17 mg, 51 umol) and K ₃ PO ₄ (162 mg, 765 mmol) were added to anhydrous toluene (8 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 105°C and stirred overnight. The reaction was completed after monitoring by LCMS and TLC. The reaction solution was returned to room temperature, the palladium catalyst was removed by filtration through celite, the mother liquor was collected and concentrated, and the obtained crude product was purified by FCC (SiO ₂ , EA/PE=0-60%) to obtain a yellow solid (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (40 mg, yield 29%). LCMS (m/z): 546.1 (M+H).

Step B: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, NaH (12 mg, 60%, 293 umol) was added to a mixed solution of (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (15 mg, 88 umol) and THF (5 mL) and stirred for 30 minutes. Then (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (40 mg, 73 umol) was added to the above reaction solution and stirred for 1 hour. The reaction was monitored by TLC. The reaction solution was poured into a semi-saturated NH ₄ Cl (30 mL) solution and extracted with EA (30 mL×3). The organic phase was collected, washed with saturated NaCl aqueous solution (30 mL), dried over anhydrous Na ₂ SO ₄ , and the concentrated organic phase was purified by FCC (SiO ₂ , EA/PE＝0-90％) to give a yellow solid (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (30 mg, yield 59％).

Step C: (6S)-4-(7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol trifluoroacetate and (6S)-4-(7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol trifluoroacetate

CF ₃ COOH (10 mL) was added to (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (30 mg, 43 umol) at room temperature and stirred at room temperature for 1 h. The reaction was completed by LCMS monitoring. The reaction solution was concentrated to remove the acid solution, diluted with EA (20 mL), and 15 mL of a half-saturated NaHCO ₃ solution was added. The pH was adjusted to alkaline, and extracted with EA (20 mL×3). The organic phase was collected, concentrated, and purified by pre-HPLC (C18, ACN/(0.1% TFA/H ₂ O)=35-45%). The first isomer 1 eluted was 98-1 (3 mg, yield 21%, retention time 8.20 min); the subsequent isomer 2 was 98-2 (2 mg, yield 14%, retention time 9.23 min). LCMS (m/z): 655.2 (M+H).

Embodiment 106

(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxy naphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

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

At room temperature, (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.38 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (207 mg, 0.58 mmol), potassium phosphate (243 mg, 1.14 mmol) and Pd(dtbpf)Cl ₂ (25 mg, 0.038 mmol) were added to a reaction bottle containing a magnetic bar. The atmosphere was replaced with nitrogen three times, and dioxane (4 mL) and water (1 mL) were added. The mixture was heated to 100°C and stirred overnight. The reaction was completed after LCMS monitoring, and the mixture was cooled to room temperature, quenched by adding 30 mL of saturated aqueous ammonium chloride solution, and then extracted with EtOAc (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by FCC (SiO ₂ , EA/PE＝0-100％) to obtain a white solid (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50 mg, yield 18％). LCMS (m/z): 721.0 (M+H).

Step B: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, m-CBPA (21 mg, 85% content, 0.10 mmol) was added to a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50 mg, 0.069 mmol) in DCM (5 mL) and the reaction was stirred at room temperature for 1 h. The reaction was completed by TLC monitoring. After adding an appropriate amount of DCM, the mixture was washed with saturated NaHCO ₃ and NaCl aqueous solutions, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product as a white solid (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (51 mg, crude product). LCMS (m/z): 737.0 (M+H).

Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50 mg) and ((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methan-d ₂ -ol (20 mg, 0.10 mmol) were dissolved in 2 mL of anhydrous THF. Under nitrogen protection, the mixture was cooled to -70°C, and t-BuONa (0.1 mL, 2M in THF, 0.2 mmol) was added dropwise. The resulting mixture was stirred at -70°C for 1 h. Saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (15 mL×3). The organic phases were combined, dried, and concentrated to give a crude product of white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl- _{d 3} )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg, crude product). LCMS (m/z): 871.0 (M+H).

Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg) was dissolved in 4M HCl-Dioxane (5 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by LCMS, the reaction was stopped and concentrated to dryness. The residue was neutralized with 20 mL of saturated sodium bicarbonate solution and extracted with EtOAc (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product of white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (57 mg, crude). LCMS (m/z): 827.3 (M+H).

Step E: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol

At room temperature, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol (57 mg) and cesium fluoride (52 mg, 0.34 mmol) were dissolved in DMF (2 mL) and stirred at 60° C. for 1 h. After the reaction was completed, the reaction solution _{was filtered and purified by pre-HPLC (C18, ACN/(0.1% NH4HCO3 / H2O} ) = 40-60%) to obtain a white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl- _d3 )piperidin- _3- yl)methoxy-d2)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.0 mg). LCMS (m/z): 671.4 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.96(s,1H),7.81–7.74(m,1H),7.40–7.31(m,2H),7.17–7.04(m,1H),6.46–6.11(m,1H),4.81–4.71(m,1H),4.64–4.23(m, 1H),3.76–3.46(m,3H),3.25–3.18(m,1H),2.89–2.75(m,2H),2.24–1.40(m,10H),1.26–0.99(m,6H),0.82–0.71(m,3H). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-116.07,-119.07,-119.23,-138.45.

Embodiment 110

(6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, NaH (40 mg, 60%, 987 umol) was added to a mixed solution of (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (51 mg, 296 umol) and THF (10 mL) and stirred for 30 minutes. Then, (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazole 4-Phenyl-1,4-oxazepane-6-ol (200 mg, 247 umol) was added to the above reaction solution at once and stirred for 1.5 h. The reaction was completed after monitoring by TLC. The reaction solution was poured into a semi-saturated NH ₄ Cl solution (30 mL) and extracted with EA (30 mL×3). The organic phase was collected and washed with a saturated NaCl solution (30 mL), dried over anhydrous Na ₂ SO ₄ , and the organic phase was concentrated and purified by FCC (SiO ₂ , EA/PE＝0-90％) to give a yellow solid (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (110 mg, yield 46％). LCMS (m/z): 482.3 (M/2+H).

Step B: (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, CsF (173 mg, 1.14 mmol) was added to a mixed solution of (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol (110 mg, 114 umol) and DMF (3 mL), and the mixture was heated to 50 °C for 1 h. The reaction was completed by monitoring by LCMS and TLC. The product was purified by pre-HPLC (C18, ACN/( _{10mmol NH4HCO3 / H2O} )=50-70%) to give a white solid (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35 mg, yield 47%). LCMS (m/z): 651.2 (M+H). ¹ H NMR (400MHz, DMSO- _d6 )δ10.23(s,1H),8.23–7.88(m,2H),7.60–7.35(m,2H),7.26–7.09(m,1H),6.97–6.44(m,1H),5.46–5.17(m,1H),4.70–4.50(m,1H),4.42–4.16(m, 3H),4.14–3.86(m,4H),3.80–3.50(m,4H),2.79–2.62(m,2H),2.35–2.09(m,4H),2.04–1.76(m,2H),1.21–1.13(m,3H),1.11(s,3H). ¹⁹ F NMR (376MHz, DM SO-d ₆ )δ-110.17,-117.83–-120.05(m),-124.89,-138.89.

Example 110-1 and Example 110-2

Example 110, (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (34 mg) was separated by SFC (Waters SFC 150, separation column: 250*25mm 10μm; mobile phase: CO ₂ /IPA (+0.1% 7.0mol/l NH ₃ /MeOH)=45/55; flow rate: 120mL/min), the first eluted isomer 1 was Example 110-1 (19 mg, relatively short retention time). Chiral analysis method 110, Rt=0.801, LCMS (m/z): 651.2 (M+H); the subsequent eluted isomer 2 was Example 110-2 (27 mg, relatively long retention time). Chiral analysis method 110, Rt=2.672, LCMS (m/z): 651.2 (M+H).

Chiral analysis method 110: Waters UPCC (CA-352), analytical column: 100*3mm 3 μm; mobile phase A: CO ₂ , mobile phase B: IPA (+0.1% DEA); flow rate: 1.5 mL/min; column temperature: 35° C.; back pressure: 1800 psi; gradient: 0-5.5 min A/B=60/40.

Embodiment 120

(S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

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

At room temperature, 4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-1,3,6-triaza-4-naphthyl)-6-methyl-1,4-oxazepan-6-ol (175 mg, 0.452 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (326 mg, 0.904 mmol), Pd(dtppf) ₂ Cl (52 mg, 0.045 mmol) and K ₃ PO ₄ (289 mg, 1.36 mmol) were added to a mixed solution of dioxane (4 mL) and water (1 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 100°C and stirred for 2 h. After the reaction was completed, the reaction solution was returned to room temperature, the palladium catalyst and the base were removed by filtration through celite, and the organic solution was concentrated. The crude product was purified by FCC (SiO ₂ , EA/PE=0-60%) to obtain a yellow solid (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (200 mg, yield 75%). LCMS (m/z): 587.1 (M+H).

Step B: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2-(methylsulfinyl)pyrrolidone 6-Methyl-1,4-oxazepane-6-ol (4,3-d-pyrimidin-4-yl)-6-methyl-1,4-oxazepane

At room temperature, m-CPBA (88 mg, 0.51 mmol) was added to a solution of (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (200 mg, 0.341 mol) and DCM (5 mL) and stirred at room temperature for 1 h. The reaction was completed by monitoring by TLC and LCMS. The reaction solution was diluted with DCM (15 mL), washed with half-saturated aq. NaHCO ₃ (20 mL), extracted with DCM (20 mL×2), and the collected organic phase was washed with saturated NaCl (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solution was concentrated to obtain a yellow solid (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (200 mg, yield 97%). LCMS (m/z): 603.1 (M+H).

Step C: (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Under -78°C dry ice ethanol bath condition, t-BuONa (0.5 mL, 2M THF solution, 1 mmol) was added dropwise to a mixed solution of (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (200 mg, 0.332 mmol), ((S)-(E)-4-fluoromethylene-1-methyl-3-methylpiperidin-3-yl)methanol (86 mg, 0.50 mmol) and THF (2 mL) and stirred for 1 h. The reaction was completed by LCMS monitoring. The reaction solution was poured into a half-saturated NH ₄ Cl aqueous solution (10 mL) and extracted with EA (20 mL×2). The organic phase was collected, washed with saturated NaCl solution, dried over _{anhydrous Na2SO4} , filtered, and concentrated to give a yellow solid (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, yield 64%). LCMS (m/z): 712.2 (M+1).

Step D: (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, TFA (2 mL) was added to a mixed solution of (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, 0.211 mol) and DCM (2 mL) and stirred for 1 h. The reaction was completed by monitoring by LCMS and TLC, and the product was purified by pre-HPLC (C18, ACN/( _{10mmol NH4HCO3} / _H2O )=40-60%) to obtain a white solid (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (8.4 mg, yield 6%). LCMS (m/z): 668.3 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.97–9.90(m,1H),7.79–7.54(m,1H),7.38–7.18(m,2H),7.11–6.96(m,1H),6.83–6.54(m,1H),4.69–4.59(m,1H),4.32–4.23(m,1H),4.01–3.8 6(m,6H),3.84–3.67(m,2H) ,3.53–3.38(m,2H),2.70–2.62(m,2H),2.46–2.35(m,1H),2.29–2.17(m,2H),2.17–2.08(m,3H),1.93–1.79(m,2H),1.31–1.19(m,2H),1.14–0.9 3(m,6H),0.88–0.69(m,3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ )δ-119.13–-120.20(m),-138.07–-139.06(m),-148.45–-149.26(m).

Embodiment 121

(S)-4-(7-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxapropane -6-ol

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

At room temperature, 4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-1,3,6-triazin-4-yl)-6-methyl-1,4-oxazepan-6-ol (530 mg, 1.37 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (1.5 g, 2.8 mmol), Pd(dtppf) ₂ Cl (100 mg, 0.0870 mmol) and K ₃ PO ₄ (871 mg, 4.11 mmol) were added to a mixed solution of dioxane (8 mL) and water (2 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 100°C and stirred for 2 h. The reaction was completed after LCMS monitoring, and the reaction solution was returned to room temperature. The palladium catalyst and the base were removed by diatomaceous earth filtration, and the organic solution was concentrated. The obtained crude product was purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain a yellow solid (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (720 mg, yield 62%). LCMS (m/z): 851.2 (M+H).

Step B: (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, m-CPBA (259 mg, 1.50 mmol) was added to a solution of (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (720 mg, 0.847 mol) and DCM (10 mL) and stirred at room temperature for 1 h. The reaction was completed by monitoring by TLC and LCMS. The reaction solution was diluted with DCM (50 mL), washed with half-saturated aq. NaHCO ₃ (50 mL), extracted with DCM (50 mL×2), and the collected organic phase was washed with saturated NaCl (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solution was concentrated to obtain a yellow solid (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (680 mg, yield 93%). LCMS (m/z): 866.5 (M+H).

Step C: (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl- 1,4-Oxazepan-6-ol

Under -78°C dry ice ethanol bath condition, t-BuONa (0.4 mL, 2M THF solution, 0.8 mmol) was added dropwise to a mixed solution of (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (220 mg, 0.254 mmol), ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methanol (53 mg, 0.31 mmol) and THF (5 mL) and stirred for 1 h. After completion of the reaction monitored by LCMS, the reaction solution was poured into a half-saturated aqueous NH ₄ Cl solution (10 mL) and extracted with EA (20 mL×2). The organic phase was collected, washed with saturated NaCl solution, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a yellow solid (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (180 mg, yield 73%). LCMS (m/z): 488.8 (M/2+1).

Step D: (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, CsF (180 mg, 1.18 mmol) was added to a mixed solution of (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (180 mg, 0.185 mmol) and DMF (2 mL), and the mixture was heated to 50 °C for 1 h. The reaction was completed by monitoring by LCMS and TLC, and the product was purified by pre-HPLC (C18, ACN/( _{10mmol NH4HCO3} / _H2O )=40-70%) to obtain a white solid (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (24 mg, yield 20%). LCMS (m/z): 664.3 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H),8.02–7.93(m,1H),7.51–7.43(m,1H),7.39(d,J＝2.6Hz,1H),7.27–7.20(m,1H),6.83–6.56(m,1H),5.09(d,J＝84.0Hz,1H),4.64–4. 54(m,1H),4.32–4.25(m,1H),4.16–4.02(m,2H),4.00–3.81(m,6H),3.79 –3.38(m,5H),2.70–2.64(m,2H),2.25–2.10(m,4H),1.95–1.78(m,2H),1. 14–0.97(m,6H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -110.27–-111.23(m), -138.17–-139.30(m), -149.09–-151.00(m).

Embodiment 125

(6S)-4-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-fluoromethylene-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step D: (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol

At room temperature, (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol (500 mg, 1.22 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (996 mg, 1.84 mmol), Pd(OAc) ₂ (27.5 mg, 0.122 mmol), BIDIME (80.8 mg, 0.245 mmol) and K ₃ PO ₄ (779 mg, 3.67 mmol) were added to anhydrous toluene (10 mL) in sequence. After N ₂ replacement three times, the temperature was raised to 110° C. and stirred for 16 h. After the reaction was completed by LCMS monitoring, the reaction solution was returned to room temperature, the palladium catalyst was removed by diatomaceous earth filtration, the mother liquor was collected and concentrated, and the crude product was subjected to FCC (SiO ₂ , THF/PE=0-30%) to obtain a yellow solid (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxacyclohexane-6-ol (570 mg, yield 56%). LCMS (m/z): 826.2 (M+H).

Step E: (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methoxy)-6-chloro-8-fluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxirane-6-ol

At room temperature, NaH (18.9 mg, 60%, 0.472 mmol) was added to a mixed solution of ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methanol (40.9 mg, 0.236 mmol) and THF (5 mL) and stirred for 20 minutes. Then, (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazole The reaction solution was stirred at room temperature for 1 hour. The reaction was monitored by TLC (EA/PE=1/2) to complete the reaction. The reaction solution was poured into a saturated NH ₄ Cl (30 mL) solution and extracted with EA (30 mL×3). The organic phase was collected and washed with a saturated _NaCl solution (70 mL). ₄ , dried, filtered and concentrated to give a brown solid (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methoxy)-6-chloro-8-fluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxirane-6-ol (150 mg, yield 97%). LCMS (m/z): 490.3 (1/2M+H).

Step F: (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methoxy)-6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxirane-6-ol

At room temperature, CsF (116 mg, 0.765 mmol) was added to a mixed solution of (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methoxy)-6-chloro-8-fluoro-7-(7-fluoro-3-(tri(isopropyl)methoxy)-8-(2-(tri(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxirane-6-ol (150 mg, 0.153 mmol) and DMF (3 mL), and the temperature was raised to 50°C for 1 h. The reaction was completed after LCMS monitoring. The reaction solution was filtered and purified by pre-HPLC (C18, ACN/(10 mmol NH ₄ HCO ₃ /H ₂ O) = 55-75% purification to give a white solid (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methoxy)-6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxirane-6-ol (14.7 mg, yield 14%). LCMS (m/z): 667.3 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.21(s,1H),8.52–8.27(m,1H),8.05–7.90(m,1H),7.52–7.43(m,1H),7.40(d,J＝2.6Hz,1H),7.14–6.99(m,1H),6.89–6.51(m,1H),5.37–5.20( m,1H),4.63–4.53(m,1H),4.33 –4.19(m,3H),4.06–3.90(m,3H),3.89–3.64(m,2H),3.61–3.50(m,3H),2.73–2.64(m,2H),2.30–2.18(m,1H),2.14(s,3H),1.95–1.78(m,2H),1.22 –1.14(m,3H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.36,-122.93,138.84.

Embodiment 132

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxypyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

In a dry ice ethanol bath at -78 °C, t-BuONa (0.78 mL, 2 M THF solution, 1.56 mmol) was added dropwise to (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (450 mg, 0.520 mmol), ((3S,4S)-4-(difluoromethyl)-1-(( 2 H ) 3 )methyl)-3-methyl-3-piperidin-1-yl)-2-(( ² H ) ₃ )methyl)-4-(trifluoromethyl)-3-piperidin-1-yl)-2-(( ² H ) 3 _{) ...} ) in a mixed solution of methanol (124 mg, 0.626 mmol) and THF (5 mL) and stirred for 1 h. After the reaction was completed as monitored by LCMS, the reaction solution was poured into a semi-saturated aqueous NH ₄ Cl solution (10 mL) and extracted with EA (20 mL×2). The organic phase was collected, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a yellow solid (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (300 mg, yield 57%). LCMS (m/z): 501.3 (M/2+1).

Step B: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, CsF (300 mg, 1.93 mmol) was added to a mixed solution of (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxypyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (300 mg, 0.347 mol) and DMF (3 mL), and the mixture was heated to 50° C. for 1 h. The reaction was completed by monitoring LCMS and TLC. The product was purified by pre-HPLC (C18, ACN/(10 _{mmol NH4HCO3 / H2O} )=50-70%) to give a white solid (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl- _d3 )piperidin- ₃ -yl)methoxy-d2)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridine pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35 mg, yield 15%). LCMS (m/z): 689.3 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.15 (s, 1H), 8.03–7.91 (m, 1H), 7.52–7.43 (m, 1H), 7.39 (d, J = 2.6Hz, 1H), 7.29–7.22 (m, 1H), 6.48–6 .12(m,1H),5.25–4.98(m,1H),4.17–4.04(m,2H),3.97–3.83(m,5H),3.81–3.37(m,5H),2.90–2.76(m,2H),1.91–1.55(m,5H),1.14–0.99(m,6H). ^19F NMR(376MHz, DMSO-d ₆ )δ-110.14–-110.90(m),-115.36–-119.56(m),-149.38–-150.27(m).

Embodiment 133

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin- ₃ -yl)methoxy- _d2 )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (25 mg, 37 umol) was dissolved in methanol (10 mL) at room temperature, Pd/C (10 mg, 10%, 9.0 umol) was added, _H2 balloon was replaced twice and stirred at room temperature for 2 h. The reaction was completed by LCMS monitoring, and the reaction solution was filtered to obtain a clear organic phase. After complete concentration, acetonitrile (2 mL) was added, and then deionized water (20 mL) was added, and lyophilization was performed to obtain a white solid (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy-d ₂ )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (20 mg, yield 79%). LCMS (m/z): 693.4 (M+H).

Embodiment 134

(3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid

Step A: (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, a mixed solution of (R)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (700 mg, 1.78 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (194 mg, 356 μmol), Pd(OAc) ₂ (40 mg, 178 μmol), BIDIME (118 mg, 356 μmol), K ₃ PO ₄ (1.14 g, 5.35 mmol) and 1,4-dioxane/H ₂ O (V/V=4/1, 15 mL) was replaced with N ₂ three times, heated to 110° C. and stirred for 16 h. The reaction was completed by LCMS monitoring. After cooling, the reaction solution was poured into water (100 mL) and extracted with EA (50 mL×3). The collected organic phase was washed with saturated NaCl (20 mL). The organic solution was concentrated. The crude product was subjected to FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-20%) to give a yellow solid (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (790 mg, yield 55%). LCMS (m/z): 810.3 (M+H).

Step B: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol

At 0°C, NaH (79 mg, 60 wt%, 1.97 mmol) was added to a mixed solution of (3S, 4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (143 mg, 740 μmol) and THF (3 mL) and stirred for 30 min. Then, (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 493 μmol) was added to the reaction solution at once and stirred at 25°C for 1 h. After the reaction was completed under LCMS monitoring, the reaction solution was poured into half-saturated NH ₄ Cl aqueous solution (50 mL), extracted with EA (50 mL×3), the organic phase was collected, washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na ₂ SO _4. Filtered, the organic phase was concentrated, and FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-40%) was used to obtain a yellow solid (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (370 mg, yield 76%). LCMS (m/z): 492.2 (M/2+H).

Step C: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid

At room temperature, CsF (300 mg, 1.97 mmol) was added to a solution of (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (370 mg, 376 μmol) and DMF (3 mL). The temperature was raised to 45° C. for reaction for 1 h. The reaction was monitored by LCMS. The reaction solution was purified by Pre-HPLC (CAN/(0.1% TFA/H ₂ O)=35-45%) to prepare Pale yellow solid (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid (180 mg, yield 71%). LCMS (m/z): 671.0 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ8.21–8.10(m,1H),7.86(dd,J＝9.2,5.7Hz,1H),7.38–7.27(m,2H),7.12–7.03(m,1H),6.43–6.11(m,1H),4.84–4.79(m,1H),4.69–4.55(m,1H),4. 43–4.35(m,1H),4.34–4.2 1 .32(s,3H),1.31–1.25(m,3H). ¹⁹ F NMR (376MHz, methanol-d ₄ )δ-77.29,-111.36,-120.83,-122.79,-126.34.

Embodiments 135 and 136

(3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid

Step A: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid

At room temperature, (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid (60 mg, 89.4 μmol) and Pt/C (50 mg, 10 wt%, 24.15 μmol) were dissolved in methanol (10 mL), the air was replaced twice with _H2 balloon, and the mixture was stirred at room temperature under _H2 balloon condition for 1 h. The reaction was completed by LCMS monitoring, and the reaction solution was filtered to obtain a clear organic phase, which was concentrated completely and then purified by Pre-HPLC (CAN/(0.1% TFA/H ₂ O)=35%-45%) to obtain a light yellow solid (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid (Example 135, 15 mg, yield 25%). LCMS (m/z): 675.2 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.27–8.19 (m, 1H), 7.68 (dd, J＝9.0, 5.8 Hz, 1H), 7.30 (d, J＝2.7 Hz, 1H), 7.28– 7.21(m,1H),6.93–6.85(m,1H),6.42–6.09(m,1H),4.53–4.42(m,1H),4.39–4.28(m,1H),4.27–4.18(m,1H),3.77–3.55(m,3H),3.51–3.39(m,1H) ),3.11–2.96(m,2H),2.91(s,3H),2.69–2.52(m,1H),2.38–2.11(m,5H),2.11–1.99(m,1H),1.91–1.71(m,3H),1.31–1.24(m,6H),0.81(q,J＝7.0Hz ,3H). ^19F NMR (376MHz, methanol-d ₄ )δ-77.21, -120.69, -121.15, -123.12, -124.23. And (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid (Example 136, 7 mg, yield 12%). LCMS (m/z): 641.2 (M+H). ¹ H NMR (400MHz, methanol-d ₄ )δ8.06(dd,J＝8.6,5.2Hz,1H),7.66(dd,J＝9.1,5.8Hz,1H),7.44–7.36(m,1H),7.31–7.20(m,2H),6.95(dd,J＝4.6,2.7Hz,1H),6.45–6.10(m,1H),4.56–4 .46(m,1H),4.40–4.32(m,1H),4.31–4.26(m,1H),3.73–3.59(m,3H),3. 53–3.44(m,1H),3.11–3.02(m,1H),3.02–2.97(m,1H),2.90(s,3H),2.49–2.40(m,1H),2.33–2.23(m,1H),2.20–2.15(m,2H),2.08–2.00(m,2H), 1.89–1.75(m,3H),1.64–1.55(m,1H),1.30–1.24(m,6H),0.79(q,J＝7.1Hz,3H). ¹⁹ F NMR(376MHz, methanol-d ₄ )δ-77.18,-121.06,-121.14,-122.96,-131.01 .

Embodiment 137

(3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate

Step A: (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

At 0°C, NaH (40 mg, 60 wt%, 987 μmol) was added to a mixed solution of ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methanol (64 mg, 370 μmol) and THF (5 mL) and stirred for 30 min. Then, (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 247 μmol) was added to the reaction solution at once and stirred at 25°C for 1 h. After the reaction was completed as monitored by LCMS, the reaction solution was poured into half-saturated NH ₄ Cl aqueous solution (20 mL), extracted with EA (20 mL × 3), collected the organic phase, washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na ₂ SO _4. Filtered, concentrated the organic phase and subjected to FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-40％) to obtain a yellow solid (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)acetylene) 1-((((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (170 mg, yield 72%). LCMS (m/z): 474.8 (M/2+H).

Step B: (3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate

At room temperature, CsF (150 mg, 987 μmol) was added to a solution of (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (170 mg, 176 μmol) and DMF (3 mL). The temperature was raised to 45°C for 1 h. The reaction was completed after LCMS monitoring. The reaction solution was purified by Pre-HPLC (CAN/(0.1% TFA/H ₂ O)＝35-45％) to prepare a light yellow solid (3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate (80 mg, yield 70％). LCMS (m/z): 651.3 (M+H). ¹ H NMR (400MHz, methanol-d ₄ )δ8.12–8.04(m,1H),7.85(dd,J＝9.2,5.7Hz,1H),7.37–7.27(m,2H),7.11–7.03(m,1H),7.02(s,0.5H),6.81(s,0.5H),4.76–4.59(m,1H),4.59–4.3 7(m,1H),4.35–4.16(m,1H),3.72–3.51(m,3H),3.51–3.32(m,2H),3.16–2.82(m,6H),2.71–2.48(m,1H),2.26–1.97(m,2H),1.91–1.69(m,3H),1. 33–1.22(m,6H). ¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.22, -111.46, -126.88, -134.15.

Embodiment 138

(3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate

Step A: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

At room temperature, a mixed solution of (R)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 1.02 mmol), 2-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (550 mg, 1.53 mmol), Pd(PPh ₃ ) ₄ (235 mg, 204 μmol), K ₃ PO ₄ (649 mg, 3.06 mmol) and 1,4-dioxane/H ₂ O (V/V=4:1, 15 mL) was replaced with N ₂ three times, and the mixture was heated to 100° C. and stirred for 8 h. The reaction was completed after LCMS monitoring. The reaction solution was poured into water (50 mL), extracted with EA (50 mL×3), and the collected organic phase was washed with saturated aqueous NaCl solution (20 mL). The crude product obtained after the organic solution was concentrated was subjected to FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-20%) to obtain a yellow solid (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 11%). LCMS (m/z): 804.2 (M+H).

Step B: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

At 0°C, NaH (14 mg, 60 wt%, 330 μmol) was added to a mixed solution of ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl)methanol (29 mg, 165 μmol) and THF (3 mL) and stirred for 30 min. Then, (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 110 μmol) was added to the reaction solution at once and stirred at 25°C for 1 h. The reaction was completed after LCMS monitoring. The reaction solution was poured into a semi-saturated aqueous solution of NH ₄ Cl (20 mL), extracted with EA (20 mL×3), and the organic phase was collected, washed with a saturated aqueous solution of NaCl (20 mL), and dried over anhydrous Na ₂ SO ₄ . The organic phase was concentrated by filtration and subjected to FCC (SiO ₂ , (EtOH:EA＝1:3)/PE＝0-40%) to give a yellow solid (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (50 mg, yield 65%). LCMS (m/z): 474.8 (M/2+H).

Step C: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate

At room temperature, (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (50 mg, 71.5 μmol) was dissolved in TFA (2 mL) and the solution was stirred at room temperature for 30 mins. The reaction was completed by LCMS monitoring. The reaction solution was concentrated to remove the acid solution. EA (10 mL) was diluted, and a half-saturated aqueous NaHCO ₃ solution (15 mL) was added to adjust the pH to weak alkaline, and EA (10 mL×3) was used for extraction. The organic phase was concentrated and purified by Pre-HPLC (CAN/(10 mM NH ₄ HCO ₃ )＝50-80％) to obtain a light yellow solid (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate (15 mg, yield 32％). LCMS (m/z): 655.3 (M+H). ¹ H NMR (400 MHz, methanol-d ₄ )δ8.10(dd,J＝15.8,1.6Hz,1H),7.65(dd,J＝9.1,5.9Hz,1H),7.27(d,J＝2.7Hz,1H),7.25–7.18(m,1H),6.89(d,J＝2.6Hz,1H),6.74(s,0.5H),6.52(s,0.5 H),4.67–4.58(m,1H),4.44–4.36(m,1H),4.28–4.18(m,1H),4.09–4.02(m,1H),4.00–3. 92(m,1H),3.58–3.40(m,2H),2.90–2.80(m,1H),2.80–2.70(m,1H),2.71–2.55(m,2H),2.39–2.27(m,1H),2.24(d,J＝2.0Hz,3H),2.21–2.10(m,1H ), 2.08–1.91 (m, 2H), 1.88–1.72 (m, 2H), 1.30–1.24 (m, 3H), 1.20 (s, 3H), 0.79 (q, J = 7.7Hz, 3H). ¹⁹ F NMR (376MHz, methanol-d ₄ ) δ-121.32, -122.40, -139.60.

The present invention also prepared the following compounds by referring to the above-mentioned synthetic schemes or appropriate variations.

Embodiment 186

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, (S)-4-[7-chloro-5-ethoxy-8-fluoro-2-(methylthio)-1,3,6-triaza-4-naphthyl]-6-methyl-1,4-oxazepan-6-ol (477 mg, 1.18 mmol), ((7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boric acid (964 mg, 1.78 mmol), Pd(dtbpf)Cl ₂ (153 mg, 0.237 mmol), and K ₃ PO ₄ (754 mg, 3.55 mmol) were added to a mixed solution of 1,4-dioxane (8 mL) and water (2 mL) in sequence. ₂ was replaced three times, and the temperature was raised to 110°C and stirred for 2h. After the reaction was completed by LCMS monitoring, the reaction was cooled to room temperature, quenched with 30mL saturated ammonium chloride aqueous solution, and then extracted with EtOAc (30mL×3). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated to dryness, and the crude product was purified by FCC (SiO ₂ , EA/PE＝0-50％) to obtain a white solid product (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (700mg, yield 68％). LCMS(m/z):865.3(M+H).

Step B: (6S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, m-chloroperbenzoic acid (246 mg, 85% w/w, 1.21 mmol) was added to a solution of compound (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (700 mg, 0.809 mmol) in dichloromethane (20 mL), and the mixture was stirred at the same temperature for 1 h. After the reaction was completed as monitored by LCMS, 20 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a white solid crude product (6S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (710 mg). LCMS (m/z): 881.2 (M+H).

Step C: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Under dry ice ethanol bath condition (-70°C), tBuONa (0.77 mL, 2M in THF, 1.54 mmol) was added to a mixed solution of (6S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (450 mg, 0.511 mmol), ((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl- _d3 )piperidin-3-yl)methanol (150 mg, 0.765 mmol) and anhydrous toluene (10 mL) and stirred for 1 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated NH ₄ Cl (30 mL) solution, extracted with EA (30 mL×3), and the organic phase was collected, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to dryness to obtain a white solid crude product (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (520 mg). LCMS (m/z): 1013.5 (M+H).

Step D: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

CsF (390 mg, 2.57 mmol) was added to (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin- The mixture was dissolved in DMF (5 mL) and heated to 50 °C for 1 h. The reaction was completed by LCMS monitoring, and the mixture was cooled to room temperature. The reaction solution was purified by pre-HPLC (C18, CAN/(10mmol NH ₄ HCO ₃ /H ₂ O)＝55-75％) to obtain white (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, yield 68％). LCMS (m/z): 701.2 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ10.17–10.13(m,1H),8.01–7.93(m,1H),7.50–7.42(m,1H),7.38(d,J＝2.6Hz,1H),7.25–7.21(m,1H),6.46–6.11(m,1H),5.34–4.96(m,1H),4.50 –4.25(m,4H),4.19–4.07(m,2H),4.01–3.35(m,7H),2.89–2.75(m,2H),1.89–1.57(m,5H),1.39–1.29(m,3H),1.14–0.98(m,6H). ¹⁹ F NMR (376MHz, DMSO-d ₆ )δ-110.58,-115.98,-118.94,-150.22.

Embodiment 187

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

At room temperature, (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl- _d3 )piperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (50 mg, 71 umol) was dissolved in methanol (10 mL), wet Pd/C (100 mg, 10%, 47 umol) was added, _H2 balloon was replaced twice and stirred at room temperature for 1 h. The reaction was monitored by LCMS. After the reaction solution was filtered with a filter membrane, a clear organic phase was obtained, which was concentrated to dryness and lyophilized to obtain a white solid product (30 mg, yield 60%). LCMS (m/z): 705.4 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.75–7.66(m,1H),7.35–7.22(m,2H),7.10–7.01(m,1H),6.45–6.13(m,1H),4.51–4.32(m,4H),4.09–3.70(m,6H),3.54–3 .42(m,2H),2.89–2.81(m,1H),2. 81–2.76(m,1H),2.46–2.38(m,1H),2.31–2.14(m,1H),1.88–1.57(m,5H),1.34(t,J＝7.0Hz,3H),1.14–1.06(m,3H),1.06–0.91(m,3H),0.84–0.72( m,3H).19F NMR (376MHz, DMSO-d ₆ )δ-115.85, -118.99,-120.31,-149.01.

Embodiment 188

(S)-4-(5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Under dry ice ethanol bath condition, tBuONa (0.43 mL, 2M THF solution, 0.86 mmol) was added to a mixed solution of (6S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (250 mg, 0.284 mmol), (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl- _d3 )piperidin-3-yl)methanol (75.0 mg, 0.426 mmol) and anhydrous toluene (5 mL) and stirred for 1 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated NH ₄ Cl (30 mL) solution, extracted with EA (30 mL×3), and the organic phase was collected, washed with saturated brine, dried over anhydrous Na ₂ SO _4, and concentrated to dryness to obtain a white solid crude product (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (290 mg). LCMS (m/z): 993.5 (M+H).

Step B: (S)-4-(5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

CsF (222 mg, 1.46 mmol) was added to a DMF (5 mL) solution of (S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl- _d3 )piperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (290 mg, 0.292 mmol), and the resulting mixture was heated to 50°C for 1 h. The reaction was completed by LCMS monitoring, and the mixture was cooled to room temperature. The reaction solution was purified by pre-HPLC (C18, CAN/(10mmol NH ₄ HCO ₃ /H ₂ O)=55-75%) and freeze-dried to obtain a white product (S)-4-(5-ethoxy-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d ₃ )piperidin-3-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (45 mg, yield 23%). LCMS (m/z): 681.2 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),8.01–7.92(m,1H),7.51–7.42(m,1H),7.38(d,J＝2.6Hz,1H),7.25–7.20(m,1H),6.83–6.56(m,1H),5.28–4.98(m,1H),4.64–4.54( m,1H),4.49–4.21(m,3H),4.20–4.04(m,2H),4.01–3.37(m,8H),2.73–2.62(m,2H),2.27–2.13(m,1H),1.93–1.78(m,2H),1.39–1.29(m,3H),1.1 4–0.98(m,6H). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-110.57,-138.75,-150.33.150.22.

Embodiment 189

(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

Under dry ice ethanol bath conditions, tBuONa (0.17 mL, 2M THF solution, 0.34 mmol) was added to a mixed solution of (6S)-4-(5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (100 mg, 0.113 mmol), ((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methanol (75.0 mg, 0.170 mmol) and anhydrous toluene (5 mL) and stirred for 1 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated NH ₄ Cl (30 mL) solution, extracted with EA (50 mL×3), and the organic phase was collected, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to dryness to obtain a white solid crude product (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane-6-ol (116.2 mg). LCMS (m/z): 1025.4 (M+H).

Step B: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol

CsF (86.0 mg, 0.566 mmol) was added to a solution of (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (116 mg, 0.113 mmol) in DMF (5 mL) and the mixture was heated to 50 °C for 1 h. The reaction was completed by LCMS monitoring, and the mixture was cooled to room temperature. The reaction solution was purified by pre-HPLC (C18, CAN/(10mmol NH ₄ HCO ₃ /H ₂ O)=50-75%) and freeze-dried to obtain a white product (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1-ethyl-3-methylpiperidin-3-yl)methoxy)-5-ethoxy-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35 mg, yield 43%). LCMS (m/z): 712.3 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H),8.01–7.93(m,1H),7.50–7.42(m,1H),7.41–7.36(m,1H),7.26–7.21(m,1H),6.46–6.11(m,1H),5.34–4.94(m,1H),4.50–4.26(m, 4H),4.21–4.07(m,2H),4.02–3.39(m,7H),3.00–2.84(m,2H),2.32–2.18(m,2H),1.93–1.56(m,5H),1.40–1.27(m,3H),1.15–0.99(m,6H),0.96– 0.89(m,3H). ^19F NMR(376MHz, DMSO-d ₆ )δ-110.57,-115.97,-118.98,-150.14.

The present invention also prepared the following compounds by referring to the above-mentioned synthetic schemes or appropriate variations.

Embodiment 220

5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

Step A: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

At room temperature, 5-(7-chloro-8-fluoro-2-methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide (500 mg, 1.15 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (CAS: 2621932-48-5, 620 mg, 1.72 mmol), cataCXiumA-Pd-G3 (167 mg, 0.229 mmol), K ₃ PO ₄ (730 mg, 3.44 mmol) were added to a solution of 1,4-dioxane (15 mL) and water (3 mL). After N ₂ replacement three times, the temperature was raised to 110 ° C and stirred for 2 h. The reaction was completed by LCMS monitoring, and the palladium catalyst was removed by filtration through diatomaceous earth. The mother liquor was collected, and water (50 mL) was added, and extracted with EA (30 mL×3). The collected organic phase was washed with saturated brine (70 mL), filtered and concentrated, and the crude product obtained by FCC (SiO ₂ , EA/PE=0-80%) was purified to obtain a yellow solid product 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide (600 mg, yield 83%). LCMS (m/z): 634.1 (M+H).

Step B: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

Under room temperature, magnesium monoperoxyphthalate hexahydrate (1.61 g, 2.84 mmol, 87% wt), 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine were added in sequence. -2-Formamide (600 mg, 0.947 mmol) was added to a mixed solution of toluene (20 mL) and water (4 mL) and stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction solution was poured into saturated sodium sulfite (50 mL), extracted with EA (30 mL×3), and the organic phase was collected, washed with saturated brine (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The crude product obtained by FCC (SiO ₂ , (THF/PE＝0-80%) was purified to obtain a yellow solid product 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide (320 mg, yield 51%). LCMS (m/z): 666.0 (M+H).

Step C: 5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

In a dry ice ethanol bath, t-BuONa (0.16 mL, 2 M in THF, 0.32 mmol) was added to 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine. The mixture was added into a mixed solution of -2-formamide (70 mg, 0.11 mmol), ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (30.5 mg, 0.158 mmol) and THF (2 mL) and stirred for 1.0 h. The reaction was completed after LCMS monitoring. The reaction solution was returned to room temperature and poured into a half-saturated NH ₄ Cl (50 mL) solution for quenching. The mixture was extracted with EA (30 mL×3). The organic phase was collected, washed with saturated brine (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a brown solid 5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide (80 mg, yield 98%). LCMS (m/z): 779.1 (M+H).

Step D: 5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine was reacted with 1% paraformaldehyde and 1% paraformaldehyde at room temperature. -2-Formamide (80 mg, 0.068 mmol) was added to a mixture of DCM/TFA (V/V=1:1, 4 mL) and stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated and quenched with saturated aqueous sodium bicarbonate solution (50 mL), then extracted with EA (30 mL×3). The organic phase was collected, washed with brine (70 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product, which was purified by pre-HPLC (C18, ACN/(10 mmol NH ₄ HCO ₃ /H ₂ O)=45-65%, RT=13.0 mins) to obtain a white solid 5-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide (28.6 mg, yield 38%). LCMS (m/z): 735.4 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.93(s,1H),9.20(s,1H),7.81–7.73(m,1H),7.40–7.30(m,2H),7.07–6.96(m,1H),6.61(s,1H),6.54–6.11(m,1H),5.37–5.12( m,2H),4.58–4.45(m,3H),4.44–4 .25(m,3H),3.24(s,3H),2.94(s,3H),2.90–2.74(m,2H),2.44–2.27(m,3H),2.24–2.14(m,1H),2.11(s,3H),1.89–1.57(m,5H),1.11(s,3H),0.72 (t, J=7.4Hz, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-115.22,-115.98,118.43,119.17,-119.64,-138.65.

Embodiment 221

(S,E)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Formamide

The synthesis of Example 221 was carried out according to the scheme described in Example 220, and (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol was used instead of ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol in step C. LCMS (m/z): 715.3 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.93(s,1H),9.19(s,1H),7.82–7.71(m,1H),7.40–7.31(m,2H),7.00(d,J＝2.6Hz,1H),6.86–6.78(m,0.5H),6.63(s,1H),6.61–6.58(m,0.5H),5 .34–5.11(m,2H),4.76–4.63(m,1H),4.57–4.45(m,2H),4. 41–4.19(m,3H),3.25(s,3H),2.95(s,3H),2.77–2.63(m,2H),2.57–2.50(m,1H),2.42–2.29(m,3H),2.26–2.17(m,1H),2.16(s,3H),2.14–2.04( m, 1H), 1.93–1.81 (m, 2H), 1.09 (s, 3H), 0.71 (t, J = 7.3Hz, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ119.64, -138.67, -138.70, -138.77.

Reference compound 3

5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The synthesis of reference compound 3 was carried out according to the scheme described in Example 220, and ((2R,7aS)-2-fluorotetrahydro -1H-pyrrolizine-7a(5H)-yl)methanol instead of ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol. LCMS (m/z): 701.3 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.93(s,1H),9.19(s,1H),7.82–7.70(m,1H),7.40–7.27(m,2H),7.06–6.97(m,1H),6.60(s,1H),5.41–5.12(m,3H),4.60–4.45(m,2H),4.39–4.24(m,2H),4.18–4.02(m ,2H),3.26(s,3H),3.15–3.05(m,2H),3.04–3.00(m,1H),2.94(s,3H),2.87–2.78(m,1H),2.42–2.28(m,3H),2.21–1.95(m,4H),1.89–1.73(m,3H) ), 0.71 (t, J=7.3Hz, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -119.62, -138.79, 171.98.

Embodiment 222

5-(6-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step A: (S,E)-5-(7-bromo-6-chloro-8-fluoro-2-((4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, 5-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (500 mg, 0.996 mmol), (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (224 mg, 1.29 mmol), DABCO (27.9 mg, 0.249 mmol), and Cs ₂ CO ₃ (973 mg, 2.99 mmol) were added to acetonitrile (10 mL) in sequence. After N ₂ replacement three times, the mixture was heated to 25° C. and stirred overnight. The reaction was completed by LCMS monitoring, and the reaction solution was poured into H ₂ O (200 mL) and stirred for 10 minutes. At this time, a white solid product was precipitated. The white solid product was collected by filtration, washed with water, and dried to obtain a white solid product (S,E)-5-(7-bromo-6-chloro-8-fluoro-2-((4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (600 mg, yield 94%). LCMS (m/z): 638.0 (M+H).

Step B: 5-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, (S,E)-5-(7-bromo-6-chloro-8-fluoro-2-((4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy To a mixed solution of 1,4-dioxane and water (5 mL, 5:1) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 0.313 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (169 mg, 0.470 mmol), Pd(dtbpf)Cl ₂ (20.3 mg, 0.031 mmol), and K ₃ PO ₄ (199 mg, 0.939 mmol). After N ₂ replacement three times, the temperature was raised to 80°C and stirred overnight. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature and directly concentrated to dryness. The crude product was purified by FCC (SiO ₂ , EA/PE=0-100%, and DCM/MeOH=10:1) to obtain a white solid product 5-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (230 mg, yield 93%). LCMS (m/z): 792.3 (M+H).

Step C: 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, TFA (2.5 mL) was added to a solution of compound 5-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 0.137 mmol) in dichloromethane (7.5 mL), and the mixture was stirred at the same temperature for 1 h. After the reaction was completed as monitored by LCMS, the mixture was directly concentrated to dryness, and the residue was neutralized with 20 mL of saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a white solid crude product, which was then purified by pre-HPLC (C18, CAN/(10mmol NH ₄ HCO ₃ /H ₂ O)＝30-70％) and freeze-dried to obtain a white solid product 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.5 mg, yield 2％). LCMS(m/z):748.3(M+H). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.02(s,1H),7.77(dd,J＝9.1,6.1Hz,1H),7.40–7.30(m,2H),7.23(d,J＝7.0Hz,1H),6.91(d,J＝2.6Hz,1H),6.80(d,J＝7.4Hz,0.5H),6.62(s,1H),6.58 (d,J＝7.6Hz,0.5H),5.18–4.98(m,2H),4.63(dd,J＝19.2,10.6Hz,1H ),4.56–4.44(m,2H),4.29–4.11(m,3H),3.26(s,3H),2.95(s,3H),2.75–2.63(m,2H),2.45–2.38(m,1H),2.32–2.25(m,2H),2.14(d,J＝2.8Hz,5H),2 .06–1.93(m,1H),1.92–1.75(m,2H),1.08(s,3H),0.97(d,J=6.5Hz,3H). ¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-119.52,-121.08,-138.82.

Embodiment 223

5-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step A: 5-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, (S,E)-5-(7-bromo-6-chloro-8-fluoro-2-((4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 0.313 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (255 mg, 0.470 mmol), Pd(OAc) ₂ (10.5 mg, 0.047 mmol), rac-BI-DIME (31.0 mg, 0.094 mmol), K ₃ PO ₄ (199 mg, 0.939 mmol) was added to a 1,4-dioxane (5 mL) solution, and after N ₂ replacement three times, the temperature was raised to 110°C and stirred overnight. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature and directly concentrated to dryness. The crude product was purified by FCC (SiO ₂ , EA/PE=0-100%, and DCM/MeOH=10:1) to obtain a black solid crude product 5-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (300 mg, yield 90%). LCMS (m/z): 529.9 (M/2+H).

Step B: 5-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

At room temperature, CsF (216 mg, 1.42 mmol) was added to a solution of 5-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (300 mg, 0.242 mmol) and DMF (5 mL), and the mixture was heated to 50°C and stirred for 1 h. After the reaction was completed, the temperature was lowered to room temperature and filtered. The crude filtrate was purified by Pre-HPLC (C18, CAN/(10mmol NH ₄ HCO ₃ /H ₂ O)=40-75%) to obtain a white solid product 5-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (40 mg, yield 19%). LCMS (m/z): 744.2 (M+H). ¹ H NMR (400MHz, DMSO-d ₆ )δ10.22(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.94–7.84(m,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.06(d,J＝2.5Hz,1H),6.88–6.53(m,2H), 5.20–4.91(m,2H),4.71–4.44(m,3H),4.35–4.10(m,3H),4 .02–3.92(m,1H),3.67–3.53(m,1H),3.53–3.39(m,1H),3.28(s,3H),3.18–3.08(m,1H),2.96(s,3H),2.92–2.76(m,2H),2.74–2.62(m,1H),2.41 –2.25(m,2H),2.23–2.10(m,2H),1.95–1.78(m,1H),1.29(s,3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -110.34, -122.40, -138.86.

The present invention also prepared the following compounds by referring to the above-mentioned synthetic schemes or appropriate variations.

Active Examples

Example 1: Proliferation inhibition effect of the compounds of the present invention on NCI-H727 cells with KRAS G12V mutation

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

Method A: The following cell lines were used in this experiment:

The cells were cultured at 37°C, 5% CO2, and 95% humidity.

The following materials, instruments and reagents were used in this experiment: fetal bovine serum FBS (GIBCO, Cat#10091-148); CellTiter- Luminescent Cell Viability Assay (Promega, Cat# G7573); 96-well clear flat-bottom black wall plate ( Cat#3603); Envision multifunctional microplate reader, PE, 2105; CO ₂ incubator, Thermo Scientific, Model 371; biological safety cabinet, Thermo Scientific, Model 1300 Series A2; inverted microscope, Olympus, CKX53. NCI-H727 cell line was purchased from ATCC, catalog number CRL-5815.

The experiment was performed as follows:

Cell culture and inoculation: Harvest cells in the logarithmic growth phase and count them using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 μL of cell suspension to each 96-well plate; culture the cells in the 96-well plate at 37°C and 5% CO ₂ .

Drug dilution and drug addition were performed as follows: Single-point inhibition rate determination drug preparation: Prepare 10-fold drug solution, add 10 μL of drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is 1 μM, and set three replicates for each drug concentration. IC50 determination drug preparation: Prepare 10-fold drug solution, add 10 μL of drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, and set three replicates for each drug concentration. The cells in the 96-well plate that have been drugged were placed at 37°C and 5% _CO2 for 3 days, and then CTG detection was performed.

Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 10 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal and read the luminescence value.

The data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC50 value was calculated.

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

Method B: NCI-H727 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60182, adherent, culture medium RPMI-1640 + 10% FBS (GIBCO, Cat#10091-148)) were cultured at 37°C, 5% CO ₂ , and 95% humidity.

3D cell viability assay: harvest cells in the logarithmic growth phase and use a platelet counter to count the cells. Use the trypan blue exclusion method to detect cell viability and ensure that the cell viability is above 90%. Prepare RPMI-1640 medium containing 1% MC (methylcellulose, Sigma, Cat#M0512) and add 10% FBS to prepare 3D cell culture medium. Use 3D culture medium to adjust the cell concentration to about 14815 cells/mL and make the content of methylcellulose (MC) 0.65%; add 135 μL of cell suspension to 96-well transparent flat-bottom black wall plates (Greiner, Cat#655096) respectively; culture the cells in the 96-well plates overnight at 37°C and 5% _CO2 .

IC ₅₀ determination drug preparation: 10 times drug solution was prepared in culture medium, and 10 μL of drug solution was added to each well of the 96-well plate seeded with cells, so that the working concentration was up to 10 μM, 3× dilution, 9 concentrations, and 2 replicates were set for each drug concentration. The cells in the 96-well plate with drug were placed at 37°C and 5% CO ₂ for 7 days, and then CTG detection was performed ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).

Equilibrate the cell plate to room temperature for 30 minutes and melt the CTG reagent. Add 75 μl of CTG solution to each well for detection and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 25 minutes to stabilize the luminescence signal and read the luminescence. value( Multi-function microplate reader, PerkinElmer #2105).

GraphPad Prism software was used to analyze the data, and the dose-response-inhibition equation was used to fit the data to obtain the dose-effect curve, from which the IC50 value was calculated.

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

Representative compounds of the present invention showed satisfactory antiproliferative activity against NCI-H727 human lung cancer cells with KRAS G12V mutation. Some of the activity data are shown in the following table:

Example 2: Proliferation inhibition effect of the compounds of the present invention on AGS cells with KRAS G12D mutation

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

Method A: The following cell lines were used in this experiment:

The cells were cultured at 37°C, 5% CO2, and 95% humidity.

The following materials, instruments and reagents were used in this experiment: fetal bovine serum FBS (GIBCO, Cat#10099-141); CellTiter- Luminescent Cell Viability Assay (Promega, Cat# G7572); 96-well clear flat-bottom black-walled plate ( Cat#3603); Envision multifunctional microplate reader, PE, 2104; CO ₂ incubator, Thermo Scientific, Model 3100 Series; biological safety cabinet, Sujing Antai, Model 1300 Series A2; inverted microscope, Chongqing Optoelectronics, XDS-1B. AGS cell line was purchased from ATCC, catalog number CRL-1739.

The experiment was performed as follows:

Cell culture and inoculation: Harvest cells in the logarithmic growth phase and count the cells using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 μL of cell suspension to each 96-well plate; culture the cells in the 96-well plate at 37°C and 5% CO ₂ .

The drug dilution and dosing were performed as follows: Single-point inhibition rate determination drug preparation: 10-fold drug solution was prepared and Add 10 μL of drug solution to each well of the 96-well plate with cells, so that the working concentration is 1 μM, and set three replicates for each drug concentration. IC50 determination drug preparation: prepare 10 times drug solution, add 10 μL of drug solution to each well of the 96-well plate inoculated with cells, so that the working concentration is up to 10 μM, 3.16× dilution, 9 concentrations, and set three replicates for each drug concentration. Place the cells in the 96-well plate with _drug addition at 37°C and 5% CO2 for another 3 days, and then perform CTG detection.

Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal and read the luminescence value.

The data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC50 value was calculated.

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

Method B: AGS cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60476, adherent, culture medium (F12K Nutrient Mixture + 10% FBS (GIBCO, Cat#10091-148)) were cultured at 37°C, 5% CO ₂ , 95% humidity, 1500/well, cells in logarithmic growth phase were harvested and cell count and cell viability were detected using Countstar automatic cell counter based on the principle of classic trypan blue staining method to ensure that the cell viability was above 90%. Adjust the cell concentration; add 80 μL of cell suspension to 96-well transparent flat-bottom black wall plates (Greiner, Cat#655090) respectively, and culture the cells in the 96-well plates at 37°C and 5% CO ₂ .

IC ₅₀ determination drug preparation: Prepare 5 times drug solution in culture medium, add 20 μL drug solution to each well of the 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, and 2 replicates for each drug concentration. The cells in the 96-well plate with drug added were placed at 37°C and 5% CO ₂ for 3 days, and then CTG detection was performed.

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

GraphPad Prism software was used to analyze the data, and the dose-response-inhibition equation was used to fit the data to obtain the dose-effect curve, from which the IC50 value was calculated.

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

Representative compounds of the present invention showed satisfactory anti-proliferative activity against AGS human gastric adenocarcinoma cells with KRAS G12D mutation. Some of the activity data are shown in the table below.

Example 3-1: Pharmacokinetic properties of the compounds of the present invention in rats by cassette administration

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

This study used male SD rats, aged 6-8 weeks and weighing 220-250 g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and used the following reagents: Tolbutamide (Aladdin, Catalog No. H1401054); Sulfonbutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biological, Catalog No. 20191013); Propylene glycol (15) stearate (Solutol, Meilun Biological, Catalog No. S0206A); DMSO (Vetec, Catalog No. WXBD0293V); acetonitrile (Sigma-Aldrich, Catalog No. WXBD1744V); Methanol (Sigma-Aldrich, Catalog No. WXBD2831V).

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

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

Preparation of standard curve: aspirate 20 μL of 1 mg/mL DMSO stock solution for each compound, transfer it to 900 μL of 50% methanol working solution, dilute it step by step to obtain a standard curve working solution with a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20, 10 ng/mL; then aspirate 5 μL of the standard curve working solution and mix it with 45 μL of rat blank plasma to obtain a standard curve with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1 ng/mL for quantification of unknown samples.

Sample pretreatment: 50 μL of unknown plasma sample and standard curve sample, add 250 μL of acetonitrile containing tolbutamide as internal standard as precipitant, precipitate plasma protein, extract the test compound in plasma, centrifuge at low temperature for 20 minutes, take the supernatant, mix the supernatant with 0.1% formic acid aqueous solution, draw 5 μL for injection, and use LC-MS to analyze the blood drug concentration.

Mass spectrometry software Analyst 1.6.1 was used to draw standard curves and quantify unknown samples. Winnonlin 8.2 was used to calculate pharmacokinetic parameters based on the drug concentrations of unknown samples at each time point.

The experimental results show that in the cassette administration pharmacokinetic evaluation, the compounds of the present invention, such as the example compounds, show good pharmacokinetic properties.

Example 3-2: Pharmacokinetic properties of the compounds of the present invention in mice

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

[Experimental materials] Male CD-1 mice, age: 6-8 weeks, purchased from Zhejiang Weitonglihua Experimental Animal Co., Ltd.

[Experimental procedures] For the IV administration group, the compound was formulated into 20% Captisol (sulfobutyl β-cyclodextrin) in sodium acetate buffer (10 mM sodium acetate solution, pH adjusted to 4.0 with acetic acid) to make the final concentration of each compound 0.6 mg/mL. The drug preparation was injected into CD-1 mice through the tail vein at an injection volume of 5 mL/kg. Blood was collected from the submandibular vein or other appropriate methods at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were centrifuged at low temperature for 6 minutes, and the plasma was collected and stored at -80°C for testing. For the PO administration group, the compound was formulated into a solvent of 0.5% Tween80 and 99.5% (0.5% MC (400cp)) to make the final concentration of each compound 1 mg/mL. The drug preparation was orally administered to CD-1 mice at a dosage volume of 10 mL/kg. Blood was collected from the submandibular vein or other appropriate methods 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were centrifuged at low temperature for 6 minutes, and the plasma was collected and stored at -80°C for testing.

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

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

[Experimental results] The experimental results show that in the mouse pharmacokinetic evaluation, the compounds of the present invention, such as the example compounds, show good pharmacokinetic properties.

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

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

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

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

Prepare 400× test compound and positive control inhibitor:

Prepare the test compound solution: dissolve 8μL of 10mM test compound stock solution in 12μL acetonitrile; prepare the mixed solution of CYP1A2, CYP2C9 and CYP2D6 inhibitors: mix 12μL 1mM α-naphthoflavone, 10μL 40mM sulfaphenazole, 10μL 10mM quinidine and 8μL DMSO solution; prepare the CYP3A4 inhibitor solution: dissolve 8μL 2.5mM ketoconazole DMSO solution in 12μL acetonitrile; prepare the CYP2C19 inhibitor solution: dissolve 8μL 100mM omeprazole DMSO solution in 12μL acetonitrile.

Prepare 4× NADPH potassium phosphate solution: add 66.7 mg NADPH to 10 mL 0.1 M K-buffer, pH 7.4. Prepare 4× substrate potassium phosphate solution: add 10 mL 0.1 M K-buffer to 4 times the concentration required for the determination. Solution required.

Prepare 0.2 mg/mL human liver microsome (HLM) solution: add 10 μL 20 mg/mL human liver microsome into 990 μL K-buffer and store in ice bath until use.

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

【Experimental results】

The experimental results show that at the tested concentrations, the compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on key CYP subtypes of drug metabolism, and exhibit better safety for drug-drug interactions.

Example 5: Proliferation inhibition effect of the compounds of the present invention on NCI-H358 cells with KRAS G12C mutation

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

NCI-H358 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60136, adherent, culture medium RPMI-1640 + 10% FBS (GIBCO, Cat#10091-148)) were cultured at 37°C, 5% CO ₂ , and 95% humidity.

3D cell viability detection: harvest cells in the logarithmic growth phase and use a platelet counter to count the cells. Use the trypan blue exclusion method to detect cell viability and ensure that the cell viability is above 90%. Prepare RPMI-1640 medium containing 1% MC (Sigma, Cat#M0512) and add 10% FBS to prepare 3D cell complete medium. Use 3D medium to adjust the cell concentration to 12500 cells/mL and make the MC content 0.65%; add 80 μL of cell suspension to 96-well transparent flat-bottom black wall plates (Greiner, Cat#655096); culture the cells in the 96-well plates at 37°C and 5% _CO2 overnight.

IC50 determination drug preparation: prepare 5 times drug solution with culture medium, add 20 μL drug solution to each well of the 96-well plate inoculated with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, and 2 replicates for each drug concentration; or set the final test concentration to 0.1uM and 1.0uM, test the inhibition rate of some representative compounds at two concentrations, and infer the IC ₅₀ range of the compound. The cells in the 96-well plate with drug were placed at 37°C and 5% CO2 for 5 days, and then CTG detection ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).

Equilibrate the cell plate to room temperature for 30 minutes and melt the CTG reagent. Add 50 μl of CTG solution to each well for detection and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 25 minutes to stabilize the luminescence signal and read the luminescence value ( Multi-function microplate reader, PerkinElmer #2105).

The data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was used to fit the data. Dose-effect curves were constructed and IC50 values were calculated from them.

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

Representative compounds of the present invention showed satisfactory antiproliferative activity against KRAS G12C mutated NCI-H358 human lung cancer cells, with an IC50 range of <1uM, preferably <0.1uM.

Example 6: Proliferation inhibition effect of the compounds of the present invention on 7 tumor cell lines

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

The following materials, reagents, and instruments were used in this experiment: 6 cell lines were obtained from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. (NCI-H441, KC-0510; Capan-2, KC-0185; A549, KC-0284; HCT116, KC-0281; NCI-H460, KC-0512; EBC-1, KC-0195; A375, KC-0158); RPMI-1640 (Hyclone, SH30809.01); fetal bovine serum FBS (GIBCO, 10099-141); methylcellulose (SIGMA, 9004-67-5); phosphate buffered saline PBS (Solarbio, P1020-500); CellCounting-Lite 2.0 Luminescent Cell Viability Assay (Nanjing Novozyme, DD1101-04); 96-well transparent flat-bottom black wall plate (Thermo, 165305); multifunctional microplate reader (BMG LABTECH, Plus); CO2 incubator (Thermo Scientific, Model 3100 Series).

Experimental methods:

Prepare sterile 1% methylcellulose 3D culture medium in advance. Harvest cells in the logarithmic growth phase and use a platelet counter to count the cells. Use the trypan blue exclusion method to detect cell viability and ensure that the cell viability is above 90%. Adjust the cell concentrations of NCI-H441, A549, HCT116, NCI-H460, EBC-1 and A375 to make the final methylcellulose concentration of 0.65%, mix well and let stand; after there is no visible gas in the cell suspension, add 180 μL of cell suspension to each 96-well plate, for a total of 2500 cells. Use complete culture medium to adjust the capan-2 cell concentration, and add 180 μL of cell suspension to each 96-well plate, for a total of 3000 cells. Culture the cells in the 96-well plate overnight at 37°C, 5% CO2, and 95% humidity.

IC ₅₀ determination drug preparation: First, prepare 10mM DMSO stock solution of each compound. The first time, use DMSO as solvent, dilute 3.16 times, 9 concentrations, and prepare DMSO solutions of different concentrations of each compound. The second time, dilute 1:100 10-fold dilution of each compound, with complete medium as solvent. Finally, add 20 μL of each compound dilution to each well of the 96-well plate inoculated with cells, the final highest drug concentration is 10 μM, 9 concentrations, 3.16-fold dilution, and three replicates are set for each concentration; or set the final test concentrations to 0.1uM and 1.0uM, test the inhibition rate of some representative compounds at two concentrations, and infer the IC ₅₀ range of the compound.

Incubate the cells in the 96-well plate with the drug at 37°C and 5% _CO2 for 144 hours before performing CTG analysis. Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well. Shake on an orbital shaker for 5 minutes to lyse the cells. Leave the cell plate at room temperature for 20 minutes to stabilize the luminescence signal. Read the luminescence value and collect data.

The data were analyzed using GraphPad Prism 7.0 software, and the dose-effect curves were fitted using nonlinear S-curve regression to calculate the IC ₅₀ values (nM).

Cell survival rate (%) = (Lum test drug - Lum culture medium control) / (Lum solvent control - Lum culture medium control) × 100%

The cell activity data are shown in the table below, where A represents IC ₅₀ ≤100nM; B represents 100nM<IC ₅₀ ≤1000nM; and C represents IC ₅₀ >1000nM.

Reference compound 1 And reference compound 2 The preparation and characterization were carried out according to the method described in WO2022132200A1.

Example 7: Antitumor effect of the compounds of the present invention in a BALB/c nude mouse animal model with subcutaneous xenografts of human colon cancer cells GP2d with KRAS-G12D mutation

[Experimental Materials]: GP2d cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. BALB/c nude mice, female, were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.

[Experimental steps]: GP2d cells were cultured in a culture medium containing DMEM and 10% FBS, and cells in the logarithmic growth phase were collected and resuspended in PBS to an appropriate concentration for subcutaneous tumor inoculation in mice. The experimental mice were subcutaneously inoculated on the right rear back, and the GP2d cell inoculation amount was: 1×10 ⁷ /mouse, and the cells were resuspended in a 1:1 PBS and matrix gel (inoculation volume was 0.1mL). When the average tumor volume grew to ~150mm3, they were randomly divided and administered according to tumor size and mouse weight. Administration began immediately after grouping, and the day of administration was considered day 0. The drug was administered orally twice a day at a dose of 10 mg/kg, 30 mg/kg or solvent control (0.5% Tween 80 + 99.5% (0.5% MC (400 cp)). During the experiment, the body weight and tumor size of the mice were measured twice a week. The formula for calculating tumor size: tumor volume (mm ³ ) = 0.5 × (tumor long diameter × tumor short diameter ² ). Relative tumor inhibition rate TGI (%): TGI% = [1-(average tumor volume at the end of drug administration of a treatment group - average tumor volume at the beginning of drug administration of the treatment group)/(average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] × 100%.

[Experimental results]: The experimental results of 10 mg/kg are shown in the table below. Representative compounds of the present invention can significantly inhibit GP2d tumor Growth.

The results of the 30 mg/kg experiment are shown in the table below. Representative compounds of the present invention can significantly inhibit the growth of GP2d tumors.

Example 8: Antitumor effect of the compounds of the present invention in the subcutaneous xenograft NU/NU mouse model of human lung cancer cells with KRAS-G12V mutation NCI-H441

[Experimental Materials]: NCI-H441 cells were purchased from ATCC (Cat. No.: HTB-174). NU/NU mice, male, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[Experimental steps]: NCI-H441 cells were cultured in RPMI-1640 medium containing 10% FBS, cells in the logarithmic growth phase were collected, and PBS was resuspended to an appropriate concentration for subcutaneous tumor inoculation in mice. The experimental mice were subcutaneously inoculated on the right posterior back, with a cell inoculation volume of 1×10 ⁶ /mouse + Matrigel, and an inoculation volume of 0.1 mL. When the average tumor volume grew to 145 mm ³ , the mice were randomly divided into groups for administration according to tumor size and mouse weight. Administration began immediately after grouping, and the day of administration was considered day 0. The drug was administered orally twice a day at a dose of 30 mg/kg or solvent control (0.5% Tween 80 + 99.5% (0.5% MC (400 cp)). During the experiment, the body weight and tumor size of the mice were measured twice a week. The formula for calculating tumor size: tumor volume (mm ³ ) = 0.5 × (tumor long diameter × tumor short diameter ² ). Relative tumor inhibition rate TGI (%): TGI% = [1-(average tumor volume at the end of drug administration of a treatment group - average tumor volume at the beginning of drug administration of the treatment group) / (average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] × 100%.

[Experimental Results]: The experimental results at 30 mg/kg are shown in the table below. Representative compounds of the present invention can significantly inhibit the growth of NCI-H441 tumors.

Claims (22)

A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof,
in: M is selected from N or CR ₇ ; The fused bicyclic part where X is located is wherein R ₅ is halogen, and R ₆ is selected from -C _1-6 alkyl and -C _2-6 alkynyl; W is OH or NH ₂ ; Y is selected from O, S and Se; B with R ₈ is wherein one of R ₈ is -OH and the other is -C _1-6 alkyl; or B with R ₈ is wherein R ₈ ortho to the nitrogen heteroatom is selected from -CONH(C _1-6 alkyl), -CON(C _1-6 alkyl) ₂ , -CON(C _1-6 alkyl)(C _2-6 alkenyl), -CON(C _1-6 alkyl)(C _2-6 alkynyl), wherein -C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with halogen or CN, and another R ₈ is selected from H, halogen or CN; Q is Or Q is in m is selected from an integer from 0 to 2; R ₁ is selected from -C _1-6 alkyl; R ₃ is selected from -C _1-6 alkyl, optionally substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein each R ^c is independently selected from H, halogen and -C _1-6 alkyl optionally substituted by halogen; R ₄ is selected from -C _1-6 alkyl, or R ₄ is -C _1-6 alkyl substituted by one or more deuteriums; R ₇ is selected from H, halogen, CN and -C _1-6 alkyl, wherein -C _1-6 alkyl is optionally substituted with halogen or CN; R ₁₁ is selected from H, halogen, -C _1-6 alkyl optionally substituted by halogen, -OC _1-6 alkyl optionally substituted by halogen; or R ₁₁ is -C _2-6 alkynyl optionally substituted by halogen, or R ₁₁ is -OC _1-6 alkyl substituted by one or more deuteriums. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein the fused bicyclic part where X is located is Best A compound of formula (I) according to any one of claims 1 to 2, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof, wherein: Q is wherein m is 1, R ₃ is -C _1-3 alkyl substituted by halogen; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c are each independently selected from H, halogen and -C _1-3 alkyl optionally substituted by halogen; R ₄ is -C _1-3 alkyl or -C _1-3 alkyl substituted by one or more deuteriums; wherein two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium. The compound of formula (I) according to claim 3, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein Q is wherein m is 1, R ₃ is -C _1-3 alkyl substituted by halogen, or (R ₃ ) _m is =CH ₂ , =CHF, =CF ₂ , =CCl ₂ , =C(CH ₃ ) ₂ , =C(CF ₃ ) ₂ ; and R ₄ is selected from methyl, ethyl and -CD ₃ . The compound of formula (I) according to claim 3 or 4, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein Q is selected from: A compound of formula (I) according to any one of claims 1 to 5, wherein Y is O, a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof. The compound of formula (I) according to any one of claims 1 to 6, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein R ₇ is selected from H, halogen, CN and halogen-substituted C _1-3 alkyl, preferably H, F, Cl, CN or -CF ₃ . The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein B carrying R ₈ is Best The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein B carrying R ₈ is The R ₈ ortho to the nitrogen heteroatom is -CON(C _1-6 alkyl) ₂ , preferably -CON(C _1-3 alkyl) ₂ , most preferably -CON(CH ₃ ) ₂ , and the other R ₈ is selected from H, CN, fluorine and chlorine. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, wherein M is N; and R ₁₁ is H, or R ₁₁ is a C _1-6 alkoxy group optionally substituted by deuterium, preferably a C _1-3 alkoxy group optionally substituted by _one or more deuteriums, more preferably -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ . The compound of formula (I) of claim 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which has the following sub-formula:
wherein each substituent or structural fragment is as defined in any one of the preceding claims 1 to 9. The compound of formula (I) of claim 11, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein R ₃ is -C _1-3 alkyl, substituted by halogen, preferably substituted by F; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H and halogen, preferably H and F; more preferably (R ₃ ) _m is selected from -CHF ₂ and =CHF; _R4 is _-C1-3 alkyl or _-C1-3 alkyl substituted by one or more deuteriums; The two hydrogen atoms of the methylene group attached to O are optionally replaced by deuterium; R ₅ is halogen, preferably F; R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl; R ₇ is selected from H, F, Cl, CN, CF ₃ ; One of R ₈ is -OH and the other is methyl; preferably for R ₁₁ is selected from H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ; m is selected from 1 or 2. The compound of formula (I) of claim 1, its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, which has the following sub-formula:
wherein each substituent or structural fragment is as defined in any one of the preceding claims 1 to 9. The compound of formula (I) of claim 13, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein R ₃ is -C _1-3 alkyl, substituted by halogen, preferably substituted by F; or two R ₃ attached to the same carbon atom form =C(R ^c ) ₂ , wherein R ^c is independently selected from H and halogen, preferably H and F; more preferably (R ₃ ) _m is selected from -CHF ₂ and =CHF; _R4 is _-C1-3 alkyl or _-C1-3 alkyl substituted by one or more deuteriums; The two hydrogen atoms of the methylene group attached to O are optionally replaced by deuterium; R ₅ is halogen, preferably F; R ₆ is selected from C _1-6 alkyl and C _2-6 alkynyl, preferably ethyl or ethynyl; R ₇ is selected from H, F, Cl, CN, CF ₃ ; R ₈ ortho to the nitrogen heteroatom is -CON(C _1-3 alkyl) ₂ , preferably -CON(CH ₃ ) ₂ , and the other R ₈ is selected from H, CN, fluorine or chlorine; R ₁₁ is selected from H, -OCH ₃ , -OCD ₃ , -OCH ₂ CH ₃ ; m is selected from 1 or 2. A compound or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, which is a compound of Examples 92 to 102, 110 to 125-2, 127, 129 to 133, 140 to 161-2, 186 to 269. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable excipient. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition according to claim 16, for use as a medicament for treating and/or preventing diseases mediated by KRas mutation and KRAS amplification. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for preventing or treating diseases mediated by KRas mutation and KRAS amplification. The method of claim 18, wherein the disease mediated by KRAS mutation and KRAS amplification is selected from the group consisting of pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region 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 cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma. The use of claim 19, wherein the disease mediated by KRAS mutation and KRAS amplification is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer. A method for treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins and KRAS amplification, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 16. The method of claim 21, wherein the disease mediated by KRAS mutation and KRAS amplification is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.