Compound having pkmyt1 inhibition effect

Abstract

The present invention provides a PKMYT1 inhibitor compound and a pharmaceutical composition thereof, and a use. The compound has a structure represented by formula (I). The compound and the pharmaceutical composition can be used for preventing or treating PKMYT1-mediated diseases, conditions or disorders.

Description

Compounds with PKMYT1 inhibitory activity Technical Field

[0001] The present invention relates to compounds that inhibit PKMYT1 kinase or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, methods for preparing the same and pharmaceutical compositions containing the same, and the use of the compounds and pharmaceutical compositions for preventing or treating diseases, conditions or disorders mediated by PKMYT1. Background Art

[0002] Amplification of CCNE1 in cancer cells is a hallmark of some difficult-to-treat ovarian, endometrial, and bladder cancers. Recent studies have found that the membrane-associated tyrosine / threonine kinase 1 (PKMYT1) is essential in CCNE1-amplified cancer cells but not in otherwise healthy cells. Increasing CCNE1 dosage results in inhibition of PKMYT1, a negative regulator of CDK1.

[0003] PKMYT1 kinase, also known as PKMYT1, is a member of the WEE family of kinases. It inhibits CDK1 phosphorylation during cell cycle transitions, significantly impacting tumor cell proliferation, migration, and xenograft tumor formation. PKMYT1 inhibitors can lead to selective, unplanned CDK1 activation in CCNE1-overexpressing cells, promoting early mitosis, where DNA synthesis occurs. CCNE1 overexpression disrupts CDK1 homeostasis, at least in part, through premature activation of the MMB-FOXM1 mitotic transcriptional program.

[0004] Furthermore, PKMYT1 inhibitors are synthetically lethal to FBXW7 deletions or other specific mutations.

[0005] Therefore, inhibition of PKMYT1 is a promising strategy for treating CCNE1-amplified cancers and FBXW7-loss-of-function tumors. Therefore, the development of new PKMYT1 inhibitors is needed. Summary of the Invention

[0006] The present invention provides novel PKMYT1 inhibitory compounds. These compounds have high affinity for PKMYT1 and are capable of inhibiting PKMYT1, thus showing potential for preventing and treating PKMYT1-mediated diseases, disorders, or conditions. These compounds also exhibit superior properties, including improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and reduced resistance to drug resistance.

[0007] In one aspect, the present invention provides a compound represented by formula (I) as defined below:

[0008] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof.

[0009] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, for use as a drug, preferably as a PKMYT1 inhibitor.

[0010] In another aspect, the present invention provides use of the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, in the preparation of a drug, preferably a PKMYT1 inhibitor.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0012] In another aspect, the present invention provides a method for treating an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition. In some embodiments, the individual suffers from and requires treatment for a disease, disorder, or condition with symptoms of cell hyperproliferation. In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a cancer that overexpresses CCNE1.

[0013] In another aspect, the present invention provides a method for preventing or treating a PKMYT1-mediated disease, disorder, or condition in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound, or prodrug thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is selected from uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer, and endometrial cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, and prostate cancer.

[0014] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition in the preparation of a medicament for preventing or treating a PKMYT1-mediated disease, disorder or condition in an individual. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is selected from uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer and endometrial cancer. In some embodiments, the cancer is selected from liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer and prostate cancer.

[0015] In another aspect, the present invention provides a method for inhibiting PKMYT1 in a cell expressing PKMYT1, the method comprising contacting the cell with a compound of formula (I). In some embodiments, the cell overexpresses CCNE1. In some embodiments, the cell is in a subject.

[0016] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has been previously determined to be a cancer that overexpresses CCNE1.

[0017] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer is a cancer that overexpresses CCNE1.

[0018] In another aspect, the present invention provides a method of inducing cell death in a cancer cell that overexpresses CCNE1, the method comprising contacting the cell with an effective amount of a compound disclosed herein.

[0019] In some embodiments, the cell is in a subject. In some embodiments, the cancer overexpressing CCNE1 is uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer. In some embodiments, the cancer overexpressing CCNE1 is liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, or prostate cancer.

[0020] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has previously been identified as a cancer having an inactivating mutation in the FBXW7 gene.

[0021] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0022] In another aspect, the present invention provides a method for inducing cell death in a cancer cell harboring an FBXW7 mutation, the method comprising contacting the cell with an effective amount of a compound of Formula (I). In some embodiments, the cell is in an individual. In some embodiments, the cancer harboring an FBXW7 mutation is uterine cancer, colon cancer, breast cancer, lung cancer, esophageal cancer, colorectal cancer, gastric cancer, ovarian cancer, or endometrial cancer. DETAILED DESCRIPTION

[0023] definition

[0024] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0025] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0026] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0027] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 8 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 1-6 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 1-4 Alkyl", "C 1-3 Alkyl" and "C 1-2 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl is optionally substituted with one or more (such as one to three) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl", for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0028] As used herein, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0029] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, an alkenyl group has 2-6 carbon atoms ("C 2-6 alkenyl”), for example 2-4 carbon atoms (“C 2-4The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0030] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0031] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic fused hydrocarbon groups having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. The ring includes, but is not limited to, cyclopropyl (ring), cyclobutyl (ring), cyclopentyl (ring), cyclohexyl (ring), cycloheptyl (ring), cyclooctyl (ring), cyclononyl (ring), cyclobutenyl (ring), cyclopentenyl (ring), cyclohexenyl (ring), cycloheptenyl (ring), cyclooctenyl (ring), cyclononenyl (ring), etc.

[0032] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ). The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6. The cycloalkyl and cycloalkylene groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., methyl or halogen), for example, a methyl-substituted cyclopropyl group.

[0033] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6. The cycloalkenyl and cycloalkenylene are optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopentenyl.

[0034] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monovalent monocyclic or bicyclic fused ring structure having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(O), S(O)2, and NR', wherein R' is a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 The heterocyclic group may be linked to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g., 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituted by one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, OH, NH2, oxo (=O), C 1-6 Alkyl, C 1-6 Examples include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, and azooctenyl.

[0035] As used herein, "heterocyclyl," "heterocycle," and "heterocyclylene" are also referred to as "nitrogen-containing heterocyclyl" or "nitrogen-containing heterocycle" when they have one or more nitrogen atoms in the ring; or as "oxygen-containing heterocyclyl" or "oxygen-containing heterocycle" when they have one or more oxygen atoms in the ring; or as "sulfur-containing heterocyclyl" or "sulfur-containing heterocycle" when they have one or more sulfur atoms in the ring. The nitrogen-containing heterocycle can be attached to the rest of the molecule via a nitrogen atom in the ring. The nitrogen-containing heterocycle is preferably saturated ("nitrogen-containing heterocycloalkyl" or "nitrogen-containing heterocycle"), and more preferably monocyclic. In particular, the 3- to 10-membered nitrogen-containing heterocycle is a group having 3-10 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0036] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-14 "Aryl" means an aromatic group containing 6 to 14 (e.g. 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (e.g. 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0037] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O). One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). A heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzo The heteroaryl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0038] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0039] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0040] If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0041] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0042] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0043] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0044] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any substitutable ring atom in the ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, such substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0045] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and13 N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0046] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0047] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0048] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0049] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0050] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0051] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0052] In this article, solid lines (——), solid wedges or virtual wedge Depicting chemical bonds of compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. In some embodiments, the straight solid line is used to depict bonds to asymmetric carbon atoms. and a straight dashed line Represents the relative configuration of a stereocenter. Unless otherwise indicated, the compounds of the present invention are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformers, epimers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs). It should be understood that certain molecules may exist in multiple tautomeric forms. The present invention includes all tautomers, even though only one tautomer may be indicated in the examples.

[0053] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0054] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer excess or enantiomeric excess (ee value) is 80%.

[0055] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0056] As used herein, a wavy line crossing a bond extending from a substituent Indicates the point of attachment of the substituent to another group.

[0057] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0058] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0059] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0060] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0061] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0062] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0063] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0064] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0065] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0066] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting group can be removed at an appropriate subsequent stage using methods known in the art. The term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "thiol-protecting group." The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0067] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0068] Compound

[0069] In a first aspect, the present invention provides a compound represented by formula (I):

[0070] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0071] in:

[0072] Q is N or CR 1a ;

[0073] X is N or CR 1b ;

[0074] Y is N or CR 1c ;

[0075] Z is N or CR 1d ;

[0076] R 1 -C(O)NHR 2 、-C(O)R 3 or -S(O)2R 3 ;

[0077] R 2 For hydrogen, C 1-6 Alkyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 1-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl, C 3-6 Cycloalkyl, or 5-14 membered heteroaryl;

[0078] Each R 3 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-10 aryl;

[0079] R 1a 、R 1b 、R 1c and R 1d Each independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3- 6-ring hydrocarbon group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 1g 、-SR 1g 、-NR 1g R 1h 、-NHC(O)R 7 、-NHS(O)R 7 、-NHS(O)2R 7 、-C(O)R 1g 、-C(O)OR 1g 、-C(O)NR 1g R 1h 、-OC(O)R 1g、-S(O)R 1g 、-S(O)OR 1g 、-S(O)NR 1g R 1h 、-S(O)2R 1g 、-S(O)2OR 1g 、-S(O)2NR 1g R 1h 、-OS(O)2R 1g 、-NR 1g -C(O)R 1h 、-NR 1g -C(O)OR 1h 、-NR 1g -S(O)2-R 1h 、-NR 1g -C(O)-NR 1g R 1h 、-C 1-6 Alkylene-R 1g 、-C 1-6 Alkylene-OR 1g and -C 1-6 Alkylene-NR 1g R 1h ;

[0080] Ring A is selected from C 6-10 Aryl and 5-14 membered heteroaryl;

[0081] Ring B is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, phenyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl have 1 or 2 heteroatoms independently selected from N, O, and S;

[0082] "a" and "b" are used to indicate the common carbon atoms of ring B and ring D;

[0083] m and n are each 0, 1, 2, 3, 4 or 5;

[0084] R a In each occurrence, independently selected from C 1-6 Alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC(O)R 7 、-NHS(O)R 7 、-NHS(O)2R 7 、-NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-14 membered heteroaryl,

[0085] Optionally, when m is 2, 3, 4 or 5 and there are two adjacent R a When the two R a Together with the two ring atoms to which they are attached, they form a ring C selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-14 membered heteroaryl;

[0086] R b is independently selected at each occurrence from halogen, =O, CN, NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C 1-6 Alkylene-(5-10 membered heteroaryl), -OR 5 、-SR 5 、-NR 5 R 6 、-C 1-6 Alkylene-OR 5 、-C 1-6 Alkylene-NR 5 R 6 and -OC 1-6 Alkylene-NR 5 R 6 ;

[0087] R 1g and R 1h Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and -C 1-6 Alkylene-C 6-10 Aryl and -C 1-6 Alkylene-5-14 membered heteroaryl;

[0088] Any of the above alkyl, alkylene, alkenyl, alkynyl, alkynylene, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups is optionally substituted at each occurrence, wherein the “optionally substituted” means optionally substituted with 1, 2, 3 or more substituents independently selected from the following groups:

[0089] Halogen, =O, CN, NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -C 1- 6-alkylene-C 6-10 Aryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C 1-6 Alkylene-(5-14 membered heteroaryl), -C(O)R 5 、-OC(O)R 5 、-C(O)OR 5 、-OR 5 、-SR 5 、-S(O)R 5 、-S(O)2R 5 、-S(O)2NR 5 R 6 、-NR 5 R 6 、-C(O)NR 5 R 6 、-NR 5 -C(O)R 6 、-NR 5 -C(O)OR 6 、-NR 5 -S(O)2-R 6 、-NR 5 -C(O)-NR 5 R 6 、-C 1-6 Alkylene-OR 5 、-C 1-6 Alkylene-NR 5 R 6 and -OC 1-6 Alkylene-NR 5 R 6 wherein the alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, =O, -C(O)O-tert-butyl, NH2, CN, NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and -C 1- 6-alkylene-C 6-12 Aralkyl;

[0090] R5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and -C 1-6 Alkylene-C 6-12 aralkyl; and

[0091] R 7 Each occurrence is independently selected from C 1-6 Alkyl and halogenated C 1-6 alkyl,

[0092] Provided that: the compound represented by formula (I) is not:

[0093] In some embodiments, Y is CR 1c .

[0094] In some embodiments, R 1g and R 1h Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -C 1-6 Alkylene-C 6-10 Aryl and -C 1-6 In some preferred embodiments, R 1g and R 1h Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -C 1-4 Alkylene-C 6-10 Aryl and -C 1-4 In some more preferred embodiments, R 1g and R 1h Each occurrence is independently selected from H and C 1-6 alkyl.

[0095] In some of the embodiments described above, R 1a 、R 1b 、R 1c and R 1d Each independently selected from H, halogen, CN, NO2, C 1- 6 alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 1g 、-SR 1g 、-NR 1g R 1h 、-NHC(O)R 7 、-NHS(O)R 7 、-NHS(O)2R 7 、-C(O)OR 1g 、-C(O)NR 1g R 1h 、-S(O)OR 1g 、-S(O)2R 1g 、-S(O)2NR 1g R 1h 、-C 1-6 Alkylene-R 1g 、-C 1-6 Alkylene-OR 1g and -C 1-6 Alkylene-NR 1g R 1h ,

[0096] where R 1g and R 1h Optionally, each independently selected at each occurrence from H and C 1-6 alkyl, and

[0097] wherein any of the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted at each occurrence by 1, 2 or 3 groups independently selected from halogen, C 1-6 Alkyl, -OR 5 、-SR 5 and -NR 5 R 6 substituted by a substituent, wherein R 5 and R 6 Each occurrence is independently H.

[0098] In some preferred embodiments, R 1a 、R 1b 、R 1c and R 1d Each independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, OH, -OC1-6 Alkyl, NH2, -NHC 1-6 Alkyl and -N(C 1-6 alkyl) 2, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted at each occurrence by 1, 2 or 3 independently selected from halogen, C 1-6 Alkyl, OH and NH2 substituents.

[0099] In some preferred embodiments, R 1a 、R 1b 、R 1c and R 1d are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, -OC 1-6 Alkyl, OH, CN, NO2, NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 and 5-10 membered heteroaryl, wherein the -OC 1-6 The alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH.

[0100] In some preferred embodiments, R 1a 、R 1b 、R 1c and R 1d are each independently selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -OC 1-6 Alkyl, OH, CN, NO2, NH2, -NHC 1-6 Alkyl and -N(C 1-6 alkyl)2 and 5-10 membered heteroaryl.

[0101] In some preferred embodiments, R 1b H or C 1-6 Alkyl, preferably H or C 1-4 In some preferred embodiments, R 1b More preferably, it is H.

[0102] In some preferred embodiments, R 1c Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, OH, CN, NO2, NH2 and 5-6 membered heteroaryl, more preferably H, halogen, C 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 alkyl, CN, imidazolyl, thiazolyl and oxazolyl.

[0103] In some preferred embodiments, R 1c More preferably selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, OH, CN, NO2, NH2 and 5-6 membered heteroaryl, further more preferably selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl, CN, imidazolyl, thiazolyl and oxazolyl.

[0104] In some preferred embodiments, R 1d More preferably, each independently selected from H, halogen, OH, CN, NH2, -NHC 1-6 Alkyl and -N(C 1-6 Alkyl)2.

[0105] In some of the embodiments described above, Q is N.

[0106] In some of the embodiments described above, X is CR 1b .

[0107] In some of the embodiments described above, Z is CR 1d .

[0108] In some of the embodiments described above, R 1 -C(O)NHR 2 .

[0109] In some of the embodiments described above, R 2 is hydrogen or C 1-6 Alkyl, preferably H.

[0110] In some of the embodiments described above, the compound of formula (I) has the structure shown in the following formula (IA):

[0111] In some of the embodiments described above, R 1c Selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, OH, CN, NO2, NH2, C 3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, OH and NH2. In some preferred embodiments, R 1c Selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, imidazolyl, thiazolyl and oxazolyl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, imidazolyl, thiazolyl and oxazolyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and OH. In some more preferred embodiments, R 1c Selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and OH.

[0112] In some embodiments, R 1c Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl, OH, CN, NO2, NH2 and 5-6 membered heteroaryl. In some preferred embodiments, R 1c Selected from H, halogen, C 1-4 Alkyl, halogenated C 1-4 In some more preferred embodiments, R 1c Selected from H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, CN,

[0113] In some of the embodiments described above, R 1d is NH2.

[0114] In some of the embodiments described above, the ring A is selected from C 6-10aryl, 5- or 6-membered monocyclic heteroaryl, and 8-, 9- or 10-membered bicyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl and the 8-, 9- or 10-membered bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S. In some preferred embodiments, the ring A is selected from phenyl, 5- or 6-membered monocyclic heteroaryl, and 8-, 9- or 10-membered bicyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl and the 8-, 9- or 10-membered bicyclic heteroaryl each have 0, 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S, and one or more ring carbon atoms in the 5- or 6-membered monocyclic heteroaryl or the 8-, 9- or 10-membered bicyclic heteroaryl are optionally replaced by C(O).

[0115] In some more preferred embodiments, the ring A is phenyl or a 5- or 6-membered monocyclic heteroaryl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 0, 1 or 2 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S, and one or more ring carbon atoms in the 5- or 6-membered monocyclic heteroaryl group are optionally replaced by C(O). Preferably, the 5- or 6-membered monocyclic heteroaryl group is independently selected from furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl and pyridazinyl at each mention, more preferably

[0116] In some of the embodiments described above, Ring A is Among them A 1 、A 2 and A 3 are each independently CH or N, and A 1 、A 2 and A 3 Not all N.

[0117] In some of the embodiments described above, the compound of formula (I) or (IA) has the structure shown in the following formula (IB):

[0118] In some of the embodiments described above, the ring A is selected from

[0119] In some of the embodiments described above, R a In each occurrence, independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -O-halogenated C1-6 Alkyl, -SC 1-6 Alkyl, -S-halogenated C 1-6 Alkyl, C 3-6 In some preferred embodiments, R a In each occurrence, independently selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and C 3-6 In some more preferred embodiments, R a In each occurrence, independently selected from C 1-3 Alkyl, halogenated C 1-3 In some more preferred embodiments, R a is independently selected at each occurrence from methyl, ethyl, isopropyl, CHF2, CH2F, CF3, F, Cl, OH, NH2, and cyclopropyl. In some of the embodiments described above, when m is 2, 3, 4, or 5 and there are two adjacent R a When the two R a Together with the two ring atoms to which they are attached they form said Ring C.

[0120] In some of the embodiments described above, m is 3 or 4.

[0121] In some of the embodiments described above, the compound of Formula (I), (IA) or (IB) has the structure shown in the following Formula (IC):

[0122] where R 8a and R 8b Each is R a , as defined in any of the above embodiments;

[0123] p is 1 or 2;

[0124] A 1 、A 2 and A 3 are each independently CH or N, and A 1 、A 2 and A 3 Not all N; and

[0125] in:

[0126] Optionally, when there is an R a With R 8aWhen adjacent, the R a With the R 8a together with the two ring atoms to which they are attached, form Ring C as described in any of the above embodiments; or

[0127] Optionally, when there is an R a With R 8b When adjacent, the R a With R 8b together with the two ring atoms to which they are attached, form Ring C as described in any of the above embodiments; or

[0128] Optionally, when there are two R a When adjacent, the two R a Together with the two ring atoms to which they are attached, they form Ring C as described in any of the above embodiments.

[0129] In some preferred embodiments, the compound has a structure shown in Formula (ID), (IE), (IF) or (Ix):

[0130] where R 8a 、R 8b 、R 8c 、R 8d and R 8e Each is R a , as defined in any of the above embodiments;

[0131] q is 0, 1, or 2; and

[0132] Wherein, optionally, R in (ID) or (IF) 8a With R 8c , or R in (IE) or (IF) 8b With R 8d , together with the two ring atoms to which they are attached, form Ring C as described in any of the above embodiments.

[0133] In some preferred embodiments, the compound has a structure shown in formula (Iy):

[0134] where R 8a 、R 8b 、R 8c and R 8e Each is R a , as defined in any of the above embodiments;

[0135] q is 0 or 1; and wherein R 8a With R 8cTogether with the two ring atoms to which they are attached, they form Ring C as described in any of the above embodiments.

[0136] In some embodiments, R in Formula (IC), (ID), (IE), (IF) or (Ix) 8a With R 8b Neither OH nor SH.

[0137] In some embodiments, R in Formula (Iy) 8a With R 8b Neither OH nor SH.

[0138] In some of the embodiments described above, when the ring C is not formed, at least one R in the formula (IC) a , R in the formula (ID) 8c , R in the formula (IE) 8d , R in the formula (IF) 8c and R 8d At least one of, or R in the formula (Ix) 8e It's OH.

[0139] In some of the embodiments described above, the ring C is selected from optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 3-6 Heterocycloalkenyl, optionally substituted phenyl, optionally substituted 5- or 6-membered monocyclic heteroaryl, and optionally substituted 8-, 9-, or 10-membered bicyclic heteroaryl, wherein the 3-6 membered heterocycloalkyl, the C 3-6 The heterocycloalkenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8-, 9-, or 10-membered bicyclic heteroaryl group each have 0, 1, 2, 3, or 4 nitrogen atoms as ring members and 0, 1, or 2 ring members independently selected from O and S;

[0140] In some preferred embodiments, the ring C is selected from optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 3-6 membered heterocycloalkenyl, optionally substituted 5 or 6 membered monocyclic heteroaryl, and optionally substituted 8, 9 or 10 membered bicyclic heteroaryl, wherein the 3-6 membered heterocycloalkyl, the 3-6 membered heterocycloalkenyl, the 5 or 6 membered monocyclic heteroaryl and the 8, 9 or 10 membered bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S;

[0141] In some more preferred embodiments, the ring C is an optionally substituted 5- or 6-membered heterocycloalkyl, an optionally substituted 5- or 6-membered heterocycloalkenyl, or an optionally substituted 5- or 6-membered monocyclic heteroaryl, wherein the 5- or 6-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkenyl, or the 5- or 6-membered monocyclic heteroaryl each has 1, 2, 3, or 4 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S;

[0142] In some more preferred embodiments, the ring C is an optionally substituted 5-membered heterocycloalkyl, an optionally substituted 5-membered heterocycloalkenyl, or an optionally substituted 5- or 6-membered monocyclic heteroaryl, wherein the 5-membered heterocycloalkyl, the 5-membered heterocycloalkenyl, or the 5- or 6-membered monocyclic heteroaryl each has 1, 2, or 3 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S;

[0143] In some more preferred embodiments, the ring C is selected from pyrrolidinyl, 2,3-dihydro-1H-pyrrolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, each of which is optionally substituted;

[0144] In some more preferred embodiments, the ring C is an optionally substituted 5-membered monocyclic heteroaryl group having 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring members independently selected from O and S, preferably an optionally substituted pyrazolyl or imidazolyl group (e.g. ), more preferably optionally substituted pyrazolyl (e.g. );

[0145] In some more preferred embodiments, the structural unit formed by ring C and ring A is selected from

[0146] wherein the term "optionally substituted" independently has the meaning described in any of the above embodiments at each occurrence.

[0147] In some of the embodiments described above, Part of it is:

[0148] Preferred

[0149] In some embodiments, Some can also be

[0150] In some of the embodiments described above, the compound of formula (ID) has the structure shown in the following formula (IG):

[0151] include

[0152] In some of the embodiments described above, the compound of formula (IE) has the structure shown in the following formula (IH):

[0153] include

[0154] In some of the embodiments described above, the compound of formula (ID) has the structure shown in the following formula (IJ):

[0155] include

[0156] In some of the embodiments described above, the compound of formula (IF) has the structure shown in the following formula (IK):

[0157] include

[0158] In some of the embodiments described above, the compound of formula (Ix) has the structure shown in the following formula (I-x1):

[0159] In some of the embodiments described above, the compound of formula (Iy) has the structure shown in the following formula (I-y1):

[0160] In some of the embodiments described above, particularly those according to Formula (IC), (ID), (IE), (IF), (Ix), (IG), (I-G1), (IH), (I-H1), or (I-x1), R 8a and R 8b Each is independently methyl, ethyl, CHF2, CH2F, CF3, F or Cl, preferably methyl.

[0161] In some of the embodiments described above, particularly embodiments of compounds according to Formula (IJ), (I-J1), (IK), (I-K1), (Iy) or (I-y1), R 8b Each is independently methyl, ethyl, CHF2, CH2F, CF3, F or Cl, preferably methyl.

[0162] In some more preferred embodiments, Part of it is:

[0163] (include ), (include ), (include ), (include ), or

[0164] In some more preferred embodiments, Part of it is:

[0165] In some of the above-described embodiments, the ring B is selected from C 5-6 cycloalkenyl, 5 or 6 membered heterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, wherein the heterocycloalkenyl and heteroaryl have 1 or 2 heteroatoms independently selected from N, O and S. In some more preferred embodiments, the ring B is selected from C 5-6 Cycloalkenyl, 5- or 6-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl, wherein the heterocycloalkenyl and heteroaryl have 1 or 2 heteroatoms independently selected from N, O, and S.

[0166] In some more preferred embodiments, the ring B is selected from cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, phenyl, pyrrolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. In some more preferred embodiments, the ring B is selected from Wherein "a" and "b" are used to indicate the common carbon atoms of ring B and ring D. In some more preferred embodiments, ring B can also be selected from Wherein "a" and "b" represent the common carbon atoms of ring B and ring D.

[0167] In some of the embodiments described above, n is 0, 1, or 2.

[0168] In some of the embodiments described above, R b is independently selected at each occurrence from halogen, =O, CN, NO2, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkylene-C 6-10 Aryl, -C1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-(3-10 membered heterocyclic group), -C 1-4 Alkylene-(5-10 membered heteroaryl), -OR 5 、-SR 5 、-NR 5 R 6 、-C 1-4 Alkylene-OR 5 、-C 1-4 Alkylene-NR 5 R 6 and -OC 1-4 Alkylene-NR 5 R 6 wherein the alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by 1, 2, 3 or more independently selected from halogen, OH, ═O, —C(═O)O-tert-butyl, NH 2 , CN, NO 2 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -C 1-6 Alkylene-C 6-10 The aryl group is substituted with a substituent, and wherein R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, halogenated C 1-6 alkyl and 3-10 membered heterocycloalkyl.

[0169] In some preferred embodiments, R b is independently selected at each occurrence from halogen, CN, NO2, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -SC 1- 4-alkyl, -S-halogenated C 1-4 Alkyl, -NR 5 R 6 、-C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -C 1-4 Alkylene-NR 5 R 6 and -OC 1-4 Alkylene-NR 5R 6 , where R 5 and R 6 Each occurrence is independently selected from H and C 1-4 alkyl.

[0170] In some preferred embodiments, R b is independently selected at each occurrence from halogen, CN, NO2, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -SC 1-4 Alkyl, -S-halogenated C 1-4 Alkyl, -NR 5 R 6 、-C 1-4 Alkylene-OC 1- 4-alkyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -C 1-4 Alkylene-NR 5 R 6 and -OC 1-4 Alkylene-NR 5 R 6 , where R 5 and R 6 Each occurrence is independently selected from H and C 1-4 In some preferred embodiments, R b Also independently selected at each occurrence from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, heteroaryl has 1 or 2 heteroatoms independently selected from N, O and S.

[0171] In some more preferred embodiments, R b is independently selected at each occurrence from halogen, CN, NO2, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -SC 1-4 Alkyl, -S-halogenated C 1-4 Alkyl, -NR 5 R 6 、-C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -C1-4 Alkylene-NR 5 R 6 and -OC 1-4 Alkylene-NR 5 R 6 , where R 5 and R 6 Each occurrence is independently selected from H and C 1-4 wherein the heterocycloalkyl and heteroaryl groups each have 1 or 2 heteroatoms independently selected from N, O, and S.

[0172] In some more preferred embodiments, R b independently selected at each occurrence from F, Cl, Br, CN, NO2, OH, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl and -NR 5 R 6 , where R 5 and R 6 Each occurrence is independently selected from H and C 1-4 In some more preferred embodiments, R b Can also be independently selected at each occurrence

[0173] In some more preferred embodiments, R b is independently selected at each occurrence from the group consisting of F, Cl, Br, CN, NO2, OH, methyl, ethyl, -OCH3, -OCH2CH3, and -NH2. In some more preferred embodiments, R b Can also be independently selected at each occurrence

[0174] In some of the embodiments described above, the Some selected from: Wherein "a" and "b" are used to indicate the common carbon atoms of ring B and ring D. In some embodiments, Some may also be selected from: Wherein "a" and "b" represent the common carbon atoms of ring B and ring D.

[0175] In some embodiments, the compound of formula (I) is represented by formula (II) or (III):

[0176] wherein Ring B is independently at each occurrence

[0177] The phenyl carbon atom indicated by "#" is not R a replace;

[0178] R a Each occurrence is independently C 1-4 Alkyl or halogen;

[0179] s is independently 0, 1, 2, or 3 at each occurrence;

[0180] t is independently 0, 1, or 2 at each occurrence;

[0181] R 8d is a halogen; and

[0182] R 8e is a halogen; and

[0183] R b Each occurrence is independently H or C 1-4 alkyl;

[0184] n is independently 0 or 1 at each occurrence;

[0185] R 1c Each occurrence is independently selected from:

[0186] Halogen, OH, CN, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH and NH2.

[0187] In some such embodiments, Ring B is preferably independently at each occurrence

[0188] In some embodiments, R a Preferably, it is independently methyl, F or Cl at each occurrence, more preferably methyl or F.

[0189] In some embodiments, R 8d It is preferably F or Cl, and more preferably F.

[0190] In some embodiments, R 8e It is preferably F or Cl, and more preferably F.

[0191] In some embodiments, R b Each occurrence is independently H or methyl.

[0192] In the embodiments described above, the compound of formula (II) or (III) The moiety is preferably selected from:

[0193] More preferred

[0194] In some preferred embodiments, the compound of formula (I) is represented by formula (II-A), formula (II-B) or (III-A):

[0195] The phenyl carbon atoms indicated by "#" are not a replace.

[0196] In a preferred embodiment, the compound of formula (II), (II-A) or (II-B) Part of (include ),

[0197] In some preferred embodiments, the compound of formula (I) is represented by formula (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2) or (III-3):

[0198] in:

[0199] R 8a and R 8b Each occurrence is independently C 1-4 Alkyl, and

[0200] R 1c 、R b 、n、R 8d and R 8e Each is as defined above.

[0201] In the embodiments described above, the compound of formula (II-1), (II-2), (II-3), (II-5), (III-1), (III-2) or (III-3) Partially preferred

[0202] In some preferred embodiments, R 8a and R 8b Each occurrence is independently methyl.

[0203] In a preferred embodiment, the formula (II-1) Part of

[0204] In a preferred embodiment, the formula (II-2) Part of

[0205] In a preferred embodiment, the formula (II-3) or (II-4) Some include For example, (include ).

[0206] In a preferred embodiment, the formula (II-5) Part of

[0207] In a preferred embodiment, the formula (III) Part of (include ).

[0208] In a preferred embodiment, the formula (III-1) Part of

[0209] In a preferred embodiment, the formula (III-2) Part of

[0210] In a preferred embodiment, the formula (III-3) Some include For example, (include ).

[0211] In other embodiments, the compound of formula (I) is represented by formula (IV), (V) or (VI):

[0212] in:

[0213] Ring B is independently present at each occurrence

[0214] R 8b Each occurrence is independently C 1-4 alkyl;

[0215] R 8e is independently a halogen at each occurrence;

[0216] R b Each occurrence is independently H or C 1-4 Alkyl; and

[0217] R 1c Each occurrence is independently selected from:

[0218] Halogen, OH, CN, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH and NH2.

[0219] In some such embodiments, R 8b Preferably, it is independently methyl at each occurrence.

[0220] In some embodiments, R 8e Preferably, it is independently F or Cl at each occurrence, more preferably F.

[0221] In some embodiments, R b Preferably, each occurrence is independently selected from H or methyl.

[0222] In the embodiments described above, the formula (IV), (V) or (VI) The moiety is preferably selected from:

[0223] More preferred

[0224] In some preferred embodiments, the compound of formula (I) is represented by formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (V-1) or (VI-1):

[0225] In the embodiments described above, the (IV-1), (V-1) or (VI-1) Partially preferred

[0226] In a preferred embodiment, the formula (II-4) Part of

[0227] In a preferred embodiment, the formula (IV-2) Part of

[0228] In a preferred embodiment, the formula (IV-3) Part of

[0229] In a preferred embodiment, the formula (IV-4) Part of

[0230] In a preferred embodiment, the formula (IV-5) Part of

[0231] In a preferred embodiment, the compound of formula (IV), (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5) Some include For example, Preferably (include ).

[0232] In a preferred embodiment, the formula (V) or (V-1) Part of

[0233] In a preferred embodiment, the compound of formula (VI) or (VI-1) Part of

[0234] In a preferred embodiment, in any of (II), (III), (II-A), (II-B), (III-A), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2), (III-3), (IV), (V), (VI), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (V-1), and (VI-1) described above, R 1c Each occurrence is independently selected from: halogen, OH, CN, NO2, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and OH.

[0235] In a more preferred embodiment, R 1c Each occurrence is independently selected from: halogen, OH, CN, NO2, NH2, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -C 1-4 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkenyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein any of the above cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH.

[0236] In a further more preferred embodiment, R 1c is independently selected at each occurrence from the group consisting of: F, Cl, Br, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

[0237] In a preferred embodiment, in the compound represented by the formula (II), (III), (II-A), (II-B), (III-A), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2) or (III-3), R 1c is independently at each occurrence F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy or difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

[0238] In a preferred embodiment, in the compound represented by the formula (IV), (V), (VI), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (V-1) or (VI-1), R 1cis independently at each occurrence F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy or difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or

[0239] In some preferred embodiments, the compound of formula (II-3) is represented by formula (II-3A):

[0240] in

[0241] R 1c Halogen, OH, NH2, -OC 1-4 Alkyl or C 3-6 Cycloalkyl;

[0242] R 8a and R 8b Each independently is C 1-4 Alkyl; and

[0243] R 8e It is a halogen.

[0244] In such embodiments, R 1c Preferably halogen, -OC 1-4 Alkyl or C 3-6 Cycloalkyl, more preferably F, Cl, methoxy, ethoxy, cyclopropyl or cyclobutyl, further more preferably Cl, methoxy or cyclopropyl.

[0245] In some preferred embodiments, R 8a and R 8b are each independently methyl.

[0246] In some preferred embodiments, R 8e is F or Cl, more preferably F.

[0247] In a more preferred embodiment, Some include For example, (include ).

[0248] In some preferred embodiments, the compound of formula (IV-1) is represented by formula (IV-1A)

[0249] in

[0250] R 1c Halogen, OH, NH2, C 1-6 Alkyl, C 2-6 Alkenyl or C2-6 Alkynyl; and

[0251] R 8b C 1-4 alkyl.

[0252] In such embodiments, R 1c Preferably halogen or C 2-4 Alkynyl, more preferably F, Cl, ethynyl, prop-1-yn-1-yl, propargyl or butynyl, further more preferably Cl or prop-1-yn-1-yl.

[0253] In some preferred embodiments, R 8b It is methyl or ethyl, more preferably methyl.

[0254] In some preferred embodiments, Some include For example, (include ).

[0255] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0256] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0257] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0258] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0259] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0260] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0261] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0262] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0263] The compounds provided herein can be prepared by various synthetic methods well known to those skilled in the art, including the examples listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples below.

[0264] Pharmaceutical compositions and uses

[0265] The terms "CCNE1" and "cyclin E1," used interchangeably herein, refer to the G1 / S-specific cyclin E1 (gene name: CCNE1). A cell overexpressing CCNE1 is a cell that exhibits higher CCNE1 activity than a cell that normally expresses CCNE1. For example, a CCNE1-overexpressing cell is a cell that exhibits at least three copies of the gene, compared to a diploid normal cell that has two copies. Thus, a cell that exhibits a CCNE1 copy number greater than three is a cell that overexpresses CCNE1. CCNE1 overexpression can be measured by identifying the expression level of the gene product in the cell (e.g., CCNE1 mRNA transcript count or CCNE1 protein level).

[0266] As used herein, the term "FBXW7" refers to the F-box / WD Repeat-Containing Protein 7 gene, transcript, or protein. A mutant FBXW7 gene, also described herein as an FBXW7 gene with an inactivating mutation, is a gene that is unable to produce functional FBXW8 protein or produces a reduced amount of FBXW7 protein in cells.

[0267] In general, the present invention provides compounds, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and methods of use. The compounds of the present invention may be Myt1 inhibitors. These compounds can be used to inhibit Myt1 (gene name PKMYT1) in cells, such as cells in an individual (e.g., cells that overexpress CCNE1 or have an inactivating mutation in the FBXW7 gene). The individual may be in need of treatment for a disease or condition, such as a disease or condition characterized by excessive cell proliferation, such as cancer. The Myt1 inhibitory activity of the compounds disclosed herein can be used to treat an individual in need of cancer treatment.

[0268] Myt1 is a cell cycle-regulating kinase that is primarily localized to the endoplasmic reticulum and Golgi complex. It is part of the Wee kinase family, which includes Wee1 and Wee1b. It participates in the negative regulation of the CDK1-cyclin B complex, which promotes the transition from the G2 phase of the cell cycle into mitosis (M phase). In response to DNA damage, Myt1 drives the phosphorylation of CDK1 (Tyr15 and Thr14 of CDK1). As part of the G2 checkpoint response, Myt1, together with Wee1 (which mediates Tyr15 phosphorylation only), maintains the kinase complex in an inactive state in G2 and blocks entry into mitosis until the damage is repaired. Furthermore, it has been proposed that Myt1 directly interacts with the CDK1 complex in the cytoplasm and prevents its nuclear translocation, thereby inhibiting cell cycle progression.

[0269] Myt1 is considered a potentially important cancer target because it is essential for many cancer cells. Overexpression of Myt1 has been observed in various cancers, including hepatocellular carcinoma and clear cell renal cell carcinoma. Myt1 downregulation plays a minor role in unperturbed cells but plays a more significant role in cells exposed to DNA damage. Furthermore, in addition to defects in G1 checkpoint regulation, cells exhibiting high levels of replication stress may be particularly sensitive to loss of Myt1 function, as these cells are prone to premature mitosis entry with damaged genomic material, leading to mitotic catastrophe.

[0270] Myt1 inhibitors, a regulator of the G2-M transition, may be particularly useful in treating tumors harboring CCNE1 amplification or FBXW7 loss-of-function mutations using synthetic lethal therapy strategies.

[0271] Cyclin E1 (encoded by the CCNE1 gene) is involved in the G1 to S phase transition of the cell cycle. In the late G1 phase of the cell cycle, it complexes with cyclin-dependent kinase 2 (CDK2), promoting E2F transcription factor activation and entry into the S phase. Cyclin E1 levels are strictly regulated during the normal cell cycle, accumulating at the G1 / S transition and being completely degraded at the end of the S phase. Cyclin E1 cell cycle-dependent proteasomal degradation is regulated by SCF. FBW7 Mediated by a ubiquitin ligase complex. Once activated in late G1, the cyclin E1 / CDK2 complex promotes the transition to S phase through phosphorylation and inactivation of RB1 and subsequent release of E2F transcription factors. S phase is promoted by E2F-mediated transcription of many genes involved in DNA replication, including the pre-replication complex subunits ORC1, CDC6, CDT1, and MCM helicase factors.

[0272] CCNE1 is frequently amplified and / or overexpressed in human cancers. CCNE1 amplification has been reported in several cancers, including endometrial, ovarian, breast, and gastric cancers, with a frequency of 5–40%. Importantly, numerous studies have confirmed that cyclin E1 is a driver of tumorigenesis in these indications, with CCNE1 amplification observed in more aggressive subtypes, including uterine carcinosarcoma (UCS; approximately 40%), uterine serous carcinoma (USC; approximately 25%), high-grade serous ovarian cancer (HGSOC; approximately 25%), and triple-negative breast cancer (TNBC; approximately 8%). Patients with cyclin E2 overexpression in tumor biopsies, as determined by immunohistochemistry and / or genomic copy number analysis, have a lower overall survival rate compared to patients with normal cyclin E1 levels. Patients with HGSOC who overexpress cyclin E1 have a lower response rate to cisplatin, the current standard of care.

[0273] SCF FBW7Defective proteolysis of the cell cycle-regulating cyclin E1 by the ubiquitin ligase complex is another mechanism underlying CCNE1 overexpression observed in tumors. The F-box protein gene FBXW7 is frequently mutated in several cancer types, including endometrial, colorectal, and gastric cancers, with a frequency of 5–35%. Like CCNE1, driver mutations in FBXW7 are observed in more aggressive endometrial cancer subtypes, including UCS (approximately 35%) and USC (approximately 25%). FBXW7 has a diverse spectrum of loss-of-function mutations in cancer, including truncating mutations throughout the gene and missense mutations within cyclin E1 that recognize the WD40 repeats. FBW7 functions as a homodimer in the SCF complex, and many deleterious missense mutations within the WD40 repeats are mostly heterozygous and dominant-negative. Notably, several recurrent hotspot missense mutations were identified within the WD40 repeat, including R465, R479, and R505, all of which disrupted cyclin E1 binding and ubiquitination.

[0274] Overexpression of cyclin E1 and / or loss of FBXW7 function are thought to drive tumorigenesis by inducing genomic instability (e.g., increased origin firing, defective nucleotide pools, transcription-replication conflicts, and / or fork instability). Overexpression of cyclin E1 has been shown to induce replication stress, characterized by slowing or stalling of replication forks and loss of heterozygosity at fragile sites. The primary mechanism by which cyclin E1 overexpression leads to replication stress is increased origin firing in early S phase, followed by depletion of replication factors, including the nucleotide pool. Decreases in total replication proteins and nucleotides reduce fork progression and lead to stalling and subsequent collapse or reversal.

[0275] It has been shown that the compounds of the present invention exhibit excellent PKMYT1 kinase inhibitory activity in in vitro tests, with IC values ​​in the nm range. 50 values, some of the compounds have IC 50 Less than 50nm, IC of some compounds 50 Less than 30nm, IC of some compounds 50 Not less than nm, IC of some compounds 50 Less than 10nm, IC of some compounds 50 Less than 5nm, IC of some compounds 50 It has also been shown that the compounds of the present invention exhibit good cell viability inhibition in CCNE1 overexpressing cells (e.g., gastric cancer cells), with an IC of nm. 50 values, some of the compounds have IC 50 Less than 1000nm, IC of some compounds 50Less than 800nm, IC of some compounds 50 Less than 500nm, IC of some compounds 50 Less than 400nm, IC of some compounds 50 Less than 300nm, IC of some compounds 50 Less than 200nm, IC of some compounds 50 Less than 100nm, IC of some compounds 50 Less than 50nm, IC of some compounds 50 Less than 20nm, IC of some compounds 50 Less than 10nm.

[0276] The compounds of formula (I) described herein, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof, are PKMYT1 inhibitors that can inhibit the activity of PKMYT1. PKMYT1 has been found to be essential in cancer cells with CCNE1 amplification, but not in other healthy cells. PKMYT1 inhibitors are synthetically lethal to FBXW7 deletions or other specific mutations. Therefore, the compounds of the present invention can be used to prevent or treat PKMYT1-mediated diseases, conditions, or disorders, as well as diseases, conditions, or disorders associated with CCNE1 overexpression or inactivating mutations in the FBXW7 gene.

[0277] The compounds of the present invention can be used to treat diseases, disorders, or conditions that rely on Myt1 activity, such as cancers that overexpress CCNE1 or harbor inactivating mutations in the FBXW7 gene. The disease, disorder, or condition can have symptoms of excessive cell proliferation. For example, the disease, disorder, or condition can be cancer (e.g., cancers that overexpress CCNE1 or harbor inactivating mutations in the FBXW7 gene). Cancers with a high incidence of CCNE1 overexpression include, for example, uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, and prostate cancer. Cancers harboring inactivating mutations in FBXW7 include, for example, uterine cancer, colon cancer, breast cancer, lung cancer, esophageal cancer, colorectal cancer, gastric cancer, ovarian cancer, and endometrial cancer.

[0278] The compounds of the present invention can be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intracerebroventricular, intraspinal, intraperitoneal, intranasal, inhalation, intratumoral and topical administration.

[0279] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may be a solid preparation, a liquid preparation or a transdermal preparation.

[0280] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutically active agents.

[0281] In another aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, and another therapeutically active agent. In some embodiments, the additional therapeutically active agent is a known other anticancer chemotherapeutic agent, including but not limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.

[0282] In another aspect, the present invention provides a compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to the present invention, which is used as a drug, preferably as a PKMYT1 inhibitor.

[0283] In another aspect, the present invention provides use of the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, in the preparation of a drug, preferably a PKMYT1 inhibitor.

[0284] In another aspect, the present invention provides a method for treating an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition. In some embodiments, the individual suffers from and requires treatment for a disease, disorder, or condition with symptoms of cell hyperproliferation. In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a cancer that overexpresses CCNE1.

[0285] In another aspect, the present invention provides a method for preventing or treating a PKMYT1-mediated disease, disorder, or condition in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound, or prodrug thereof; or administering to the subject a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is selected from uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer, endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, and prostate cancer.

[0286] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition in the preparation of a medicament for preventing or treating a PKMYT1-mediated disease, disorder or condition in an individual. In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is selected from uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer, endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer and prostate cancer.

[0287] In another aspect, the present invention provides a method of inhibiting PKMYT1 in a cell expressing PKMYT1, the method comprising contacting the cell with a compound of formula (I). In some embodiments, the cell overexpresses CCNE1. In some embodiments, the cell is in a subject.

[0288] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has been previously determined to be a cancer that overexpresses CCNE1.

[0289] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer is a cancer that overexpresses CCNE1.

[0290] In another aspect, the present invention provides a method of inducing cell death in a cancer cell that overexpresses CCNE1, the method comprising contacting the cell with an effective amount of a compound disclosed herein.

[0291] In some embodiments, the cell is in an individual. In some embodiments, the cancer overexpressing CCNE1 is uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, and prostate cancer.

[0292] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has previously been identified as a cancer having an inactivating mutation in the FBXW7 gene.

[0293] In another aspect, the present invention provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0294] In another aspect, the present invention provides a method for inducing cell death in a cancer cell harboring an FBXW7 mutation, the method comprising contacting the cell with an effective amount of a compound of Formula (I). In some embodiments, the cell is in an individual. In some embodiments, the cancer harboring an FBXW7 mutation is uterine cancer, colon cancer, breast cancer, lung cancer, esophageal cancer, colorectal cancer, gastric cancer, ovarian cancer, or endometrial cancer.

[0295] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0296] As used herein, unless otherwise indicated, the terms "treat," ...

[0297] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0298] Technical Effects

[0299] The compounds of the present invention are inhibitors of PKMYT1 and can be used to prevent or treat diseases, conditions, or disorders mediated by PKMYT1. The compounds of the present invention have further advantageous properties, including good pharmacokinetic properties (e.g., good oral bioavailability, metabolic stability, suitable half-life and duration of action), good safety (low toxicity (e.g., low cardiotoxicity) and / or minimal side effects), and resistance to drug resistance.

[0300] Example

[0301] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0302] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) can be used, wherein the diffraction intensity data of the cultured single crystal is collected using a Bruker D8 venture diffractometer, using CuKα radiation as the light source, and the scanning mode is: After collecting relevant data, the crystal structure was further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0303] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0304] Intermediate Preparation Example

[0305] Preparation of intermediate C024-d

[0306] Step 1: Sulfuric acid (400 mL) was added to a three-necked flask (1 L). Compound C024-d1 (50 g, 412.6 mmol, 1 eq.) was slowly added dropwise to the sulfuric acid. The reaction temperature was controlled at approximately 0°C-10°C. After the addition was complete, nitric acid (20.5 mL) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was slowly warmed to room temperature and reacted for three hours. After the reaction was completed, the reaction solution was slowly poured into ice water. The pH of the mixture was adjusted to 10 with 6M hydrochloric acid (3 L). A large amount of solid precipitated. The mixture was filtered and dried under vacuum to obtain the product C024-d2 (50 g, 72.92% yield) as a yellow solid.

[0307] LCMS (ESI) m / z: 167.1 [M+H] + .

[0308] Step 2: Compound C024-d2 (25 g, 150.6 mmol, 1 eq) was added to a 1 L three-necked flask. Concentrated sulfuric acid (100 mL) was slowly added at 0°C. The mixture was stirred for 10 minutes. Sodium nitrite (12.5 g, 180.7 mmol, 1.2 eq) was added portionwise at 0°C. The mixture was reacted at 0°C for half an hour. The reaction solution was poured into ice water (500 mL), followed by potassium iodide (100 g, 602.4 mmol, 4 eq). The mixture was allowed to react at room temperature overnight. After the reaction, the mixture was extracted with ethyl acetate (150 mL*3). The organic phases were combined, washed with saturated sodium sulfite (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified on a silica gel column (petroleum ether) to obtain compound C024-d (18 g, 43.15% yield) as a white solid.

[0309] 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),2.53(s,3H),2.51(s,3H).

[0310] Preparation of intermediate C033-d

[0311] Compound C024-d2 (25 g, 150.6 mmol, 1 eq), cuprous bromide (18.66 g, 130.12 mmol, 1.2 eq), and acetonitrile (150 mL) were added to a three-necked flask (1 L). Isoamyl nitrite (22.36 g, 216.8 mmol, 2 eq) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was reacted at 60°C for one hour. After the reaction was completed, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (150 mL*3). The organic phases were combined, washed with saturated sodium sulfite (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a silica gel column (petroleum ether) to obtain compound C033-d (13 g, 37.69% yield) as a white solid.

[0312] 1 H NMR (400MHz, DMSO-d6) δ7.82 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.46 (s, 3H).

[0313] Preparation of intermediate INT1

[0314] Step 1: Dissolve compound 1 (500.0 mg, 1.28 mmol, 1.0 eq.), di-tert-butyl dicarbonate (419.0 mg, 1.92 mmol, 1.5 eq.), 4-dimethylaminopyridine (16 mg, 0.13 mmol, 0.1 eq.), and triethylamine (388 mg, 3.84 mmol, 3.0 eq.) in tetrahydrofuran (15 mL). The mixture was then purged with nitrogen and incubated at 50°C for 1 hour. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to afford compound 2 (350 mg, 46.19% yield) as a yellow solid.

[0315] LCMS (ESI) m / z: 592.2 [M+H] + .

[0316] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=6.0Hz,1H),8.50(s,1H),8.34(d,J=8.5Hz,1H),8.30( s,1H),8.23(d,J=6.0Hz,1H),7.77(d,J=8.4Hz,1H),1.98(d,J=2.8Hz,6H),1.37(s,18H).

[0317] Step 2: Dissolve compound 2 (350.0 mg, 0.59 mmol, 1.0 eq), iron powder (165.0 mg, 2.95 mmol, 5.0 eq.), and ammonium chloride (156.3 mg, 2.95 mmol, 5 eq.) in ethanol (20 mL) and water (4 mL). React at 80°C for 1 hour. After completion of the reaction, filter the filtrate, add water (50 mL), and extract with ethyl acetate (30 mL x 3). The organic phases are combined. The organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford crude compound 3 (330 mg, 100% yield) as a yellow solid.

[0318] LCMS (ESI) m / z: 562.2 [M+H] + .

[0319] Step 3: Compound 3 (330 mg, 0.58 mmol, 1.0 eq) was dissolved in anhydrous toluene (20 mL) and glacial acetic acid (1 mL). Isoamyl nitrite (135.6 mg, 1.15 mmol, 2.0 eq) was added dropwise at 0°C and reacted under nitrogen for 1 hour. Potassium acetate (170.8 mg, 1.74 mmol, 3.0 eq) was then added and the mixture was allowed to react overnight at room temperature under nitrogen. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined. The organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified on a silica gel column (methanol / dichloromethane = 3%) to afford compound 4 (150 mg, 45.18% yield) as a yellow solid.

[0320] LCMS (ESI) m / z: 573.3 [M+H] + .

[0321] Step 4: Dissolve compound 4 (400 mg, 0.84 mmol, 1.0 eq) and p-toluenesulfonic acid (22.36 mg, 0.13 mmol, 0.15 eq) in dichloromethane (10 mL). Slowly add 3,4-dihydro-2H-pyran (155.40 mg, 1.85 mmol, 2.2 eq.) at 0°C. The mixture is reacted at 25°C under nitrogen for 16 hours. LCMS monitors the reaction. The mixture is diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases are combined. The organic phases are washed again with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product is purified on a silica gel column (ethyl acetate / petroleum ether = 20%-100%) to afford compound INT1 (320 mg, 58.07% yield) as a yellow solid.

[0322] LCMS (ESI) m / z: 657.3 [M+1] + .

[0323] Example 1: Preparation of Compound C001

[0324] Preparation method

[0325] Step 1: C001-a (100 mg, 0.6 mmol, 1 eq.) was dissolved in DCM (5 mL). NCS (80 mg, 0.6 mmol, 0.9 eq.) was added at 0°C. The mixture was stirred at 25°C for 3 h, then quenched with saturated aqueous Na2S2O3 (15 mL). The mixture was extracted with DCM (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography (PE:EA = 5:1) to afford C001-b (60 mg, 48.3%). LCMS (ESI) m / z: 179.9 [M+H] + .

[0326] Step 2: Dissolve C001-b (60 mg, 0.33 mmol, 1 eq.) in DCM (5 mL), add NBS (53 mg, 0.29 mmol, 0.9 eq.), and stir at 25°C for 2 h. Quench with saturated aqueous Na2S2O3 (10 mL), and extract with DCM (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography (PE:EA = 7:1) to afford C001-c (52 mg, 60%). LCMS (ESI) m / z: 259.8 [M+H] +

[0327] Step 3: Dissolve C001-c (52 mg, 0.14 mmol, 1 eq.), potassium tert-butoxide (56 mg, 0.21 mmol, 1.5 eq.), and CuBr (5 mg, 0.016 mmol, 0.1 eq.) in xylene (3 mL). Add 2-iodo-4-methoxy-1,3-dimethylbenzene (92 mg, 0.17 mmol, 1.1 eq.). After fully displacing the nitrogen atmosphere, stir at 110°C for 3 h. Monitor the reaction by LCMS. Evaporate the dioxane in the reaction system, dissolve it in MeOH (2 mL), and separate and purify the mixture by preparative chromatography using a PE:EA = 7:1 ratio to afford C001-d (40 mg, 50.5%). LCMS (ESI) m / z: 394.0 [M+H] +

[0328] Step 4: Dissolve malononitrile (16 mg, 0.2 mmol, 2 eq.) in ultra-dry dioxane (2 mL), add sodium tert-butoxide (20 mg, 0.2 mmol, 2 eq.), and stir at 25°C for 30 min. C001-d (40 mg, 0.1 mmol, 1 eq.) and Pd(dppf)Cl2 (8 mg, 0.01 mmol, 0.1 eq.) dissolved in ultra-dry dioxane (2 mL) were added to the above system. The atmosphere was fully replaced with nitrogen and stirred at 110°C for 1 h. LCMS monitoring was used. The dioxane in the reaction system was evaporated to dryness and dissolved in MeOH (2 mL). Purification by preparative chromatography (PE:EA = 7:1) afforded C001-e (15 mg, 39.06%). LCMS (ESI) m / z: 378.1 [M+H] + .

[0329] Step 5: Dissolve C001-e (15 mg, 0.05 mmol, 1 eq.) and K2CO3 (47 mg, 0.15 mmol, 3 eq.) in DMSO (1.2 mL), then add a saturated aqueous solution of Na2CO3.H2O2 (0.4 mL) and stir at 25°C for 4 h. Monitor the reaction by LCMS. Add water (5 mL), extract with EA (3 × 10 mL), and dry the combined organic phases over anhydrous sodium sulfate to give C001-f (10 mg, 55.5%). LCMS (ESI) m / z: 396.1 [M+H] + .

[0330] Step 6: Dissolve C001-f (10 mg, 0.025 mmol, 1 eq.) in BBr3 (1 mL) and stir at 25°C for 1 h. Monitor the reaction by LCMS. Quench the reaction with methanol at 0°C, concentrate under reduced pressure, and dissolve in MeOH (0.5 mL). Preparative high-pressure liquid chromatography yields compound C001 (1.5 mg, 15.8%). LCMS (ESI) m / z: 382.1 [M+H] + . 1 H NMR (400MHz, CD3OD-d4) δ9.51(s,1H),8.71(s,1H),8.27(s,1H),7.08(d,J=8.0Hz,1H),6.93(d,J=8.0Hz,1H),1.81(s,3H),1.76(s,3H).

[0331] Example 2: Preparation of Compound C002

[0332] Preparation method

[0333] Step 1: Dissolve C001 (5 mg, 0.013 mmol, 1 eq.) in MeOH (2 mL), add Pd / C (2.5 mg) and K2CO3 (3.6 mg, 0.026 mmol, 2 eq.), replace the atmosphere three times with a hydrogen balloon, and react at room temperature for 3 h. Filter to remove the solid, concentrate the filtrate under reduced pressure, and analyze by TLC (EA:MeOH = 50:1) to obtain a crude product (5 mg). The crude product was slurried with EA (1 mL) and PE (3 mL) to obtain compound C002 (3.2 mg, 70%). LCMS (ESI) m / z: 348.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.38 (s, 1H), 8.66 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 1.82 (s, 3H), 1.78 (s, 3H).

[0334] Example 3: Preparation of Compound C005

[0335] Preparation method

[0336] Step 1: Dissolve C005-a (10 g, 54.9 mmol, 1 eq.) in THF (150 mL) and add BH3 dimethyl sulfide solution (137 mL, 137 mmol, 2.5 eq.) dropwise. React at 80°C for 8 h. Then evaporate the solvent and extract with DCM and water. Concentrate the organic phase to obtain C005-b (8 g, 87%). LCMS (ESI) m / z: 168.8 [M+H] + .

[0337] Step 2: Dissolve C005-b (2 g, 11.9 mmol, 1 eq.) in ACN (20 mL) and add DMP (5 g, 11.9 mmol, 1 eq.). Stir at 80°C for 16 h. The reaction is complete by TLC. Evaporate the solvent, extract with DCM and water, and concentrate the organic phase before column chromatography (EA:PE = 1:8) to yield C005-c (1 g, 51%).

[0338] Step 3: To a 250 mL autoclave, add C005-c (3.5 g, 21.1 mmol, 1 eq.), formamidine acetate (8.7 g, 84.3 mmol, 4 eq.), and methanol (100 mL). Heat to 120°C and stir for 3 h. Evaporate the solvent, extract with DCM and water, and concentrate the organic phase through a column chromatography (EA:PE = 1:15) to obtain C005-d (3 g, 81%). LCMS (ESI) m / z: 194.0 [M+H2O+H] + .

[0339] Step 4: Dissolve C005-d (2.9 g, 16.6 mmol, 1 eq.) in AcOH (20 mL), add Fe powder (9.3 g, 166 mmol, 10 eq.), and stir at 25°C for 2 h. Evaporate the solvent, adjust the pH to 9-10 by adding saturated sodium carbonate solution, extract with DCM and water, and concentrate the organic phase to obtain C005-e (1.9 g, 79%). LCMS (ESI) m / z: 146.1 [M+H] + .

[0340] Step 5: Dissolve C005-e (1 g, 6.90 mmol, 1 eq.) in DCM (10 mL), add acetic anhydride (1 g, 10.3 mmol, 1.5 eq.), and stir at 25°C for 2 h. Monitor the reaction by LCMS. Quench with methanol, evaporate the solvent, and filter through a column chromatography (EA:PE = 1:4) to obtain C005-f (1.2 g, 92%). LCMS (ESI) m / z: 187.8 [M+H] + .

[0341] Step 6: Dissolve C005-f (500 mg, 2.67 mmol, 1 eq.) in 10 mL of AcOH, add NBS (428 mg, 2.41 mmol, 0.9 eq.), and stir at 25°C for 5 h. Monitor by LCMS, evaporate the solvent, extract with EA and water, and concentrate the organic phase to obtain C005-g (680 mg, 96%). LCMS (ESI) m / z: 265.6 [M+H] + .

[0342] Step 7: Dissolve C005-g (850 mg, 3.24 mmol, 1 eq.), MeB(OH)2 (389 mg, 6.49 mmol, 2 eq.), Na2CO3 (688 mg, 6.49 mmol, 2 eq.), and Pd(dppf)Cl2 (237 mg, 0.324 mmol, 0.1 eq.) in 20 mL of dioxane and 10 mL of water. Stir at 110°C for 3 h, and extract with EA and water. The organic phase was concentrated and filtered through a column (EA:PE = 1:10) to give C005-h (440 mg, 68%). LCMS (ESI) m / z: 201.8 [M+H] + .

[0343] Step 8: Dissolve C005-h (440 mg, 2.19 mmol, 1 eq.) in 2 mL of 30% HBr. Stir at 100°C for 2 h. Adjust the pH to 9-10 with Na2CO3. Extract with EA and water. Concentrate the organic phase to obtain C005-i (250 mg, 79%). LCMS (ESI) m / z: 160.0 [M+H] + .

[0344] Step 9: Dissolve C005-i (700 mg, 4.40 mmol, 1 eq.) in 10 mL of DCM, add NBS (700 mg, 3.96 mmol, 0.9 eq.), stir at room temperature for 2 h, and extract with DCM and water. The organic phase was concentrated and filtered through a column (EA:PE = 1:10) to obtain C005-j (600 mg, 57%). LCMS (ESI) m / z: 237.6 [M+H] + .

[0345] Step 10: Dissolve C005-j (100 mg, 0.418 mmol, 1 eq.), SO20 (132 mg, 0.502 mmol, 1.2 eq.), CuBr (60 mg, 0.418 mmol, 1 eq.), and t-BuOK (94 mg, 0.837 mmol, 2 eq.) in 5 mL of xylene. After nitrogen substitution, stir at 110°C for 4 h. Evaporate the solvent and filter through a column chromatography (EA:PE = 1:6) to obtain C005-k (35 mg, 22%). LCMS (ESI) m / z: 371.8 [M+H] + .

[0346] Step 11: Malononitrile (177 mg, 2.68 mmol, 5 eq.) was dissolved in ultra-dry dioxane (8 mL). NaH (107 mg, 2.68 mmol, 5 eq.) was added and stirred at 25°C for 30 min. C005-k (200 mg, 0.536 mmol, 1 eq.) and Pd(dppf)Cl2 (39 mg, 0.054 mmol, 0.1 eq.) were added and stirred at 110°C for 3 h. The dioxane in the reaction system was evaporated to dryness and MeOH (2 mL) was added for dissolution. The product was then purified by preparative chromatography (PE:EA = 3:1) to afford C005-1 (85 mg, 44%). LCMS (ESI) m / z: 358.0 [M+H] + .

[0347] Step 12: Dissolve C005-1 (85 mg, 0.238 mmol, 1 eq.) and K2CO3 (99 mg, 0.714 mmol, 3 eq.) in DMSO (6 mL), add H2O2 (2 mL), and stir at 25°C for 16 h. Monitor the reaction by LCMS. Extract with EA and water, and concentrate the organic phase to afford C005-m (80 mg, 90%). LCMS (ESI) m / z: 376.0 [M+H] + .

[0348] Step 13: Dissolve C005-m (120 mg, 0.32 mmol, 1 eq.) in 15 mL of DCM, add BBr3 (3 mL, 1 M in DCM), and stir at 25°C for 2 h. Monitor the reaction by LCMS. Evaporate the solvent, quench the reaction with methanol, slurry with saturated NaHCO3, filter, wash with water, and oven dry to obtain compound C005 (35 mg, 31%). LCMS (ESI) m / z: 362.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.29 (s, 1H), 8.58 (s, 1H), 7.89 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 2.74 (s, 3H), 1.73 (s, 3H), 1.69 (s, 3H).

[0349] Example 4: Preparation of Compound C006

[0350] Preparation method

[0351] Step 1: C006-a (2 g, 9.09 mmol, 1 eq.) was dissolved in THF (200 mL), and propylene glycol (1.38 g, 18.18 mmol, 2 eq.) and NaH (0.55 g, 13.64 mmol, 1.5 eq.) were added. The reaction was carried out at room temperature for 3 h. The organic phase was concentrated and filtered to obtain C006-b (1.5 g, 60%).

[0352] Step 2: Dissolve C006-b (5.1 g, 18 mmol, 1 eq.) in ACN (75 mL) and add 50 mL of Jones reagent dropwise. Stir at room temperature for 3 h, then cool to 0°C and add 75 mL of IPA dropwise. Filter. Evaporate the filtrate to dryness, extract with EA and water, and concentrate the organic phase before column chromatography to yield C006-c (3.2 g, 60%). LCMS (ESI) m / z: 311.7 [M+Na] + .

[0353] Step 3: Dissolve C006-c (2.7 g, 9.3 mmol, 1 eq.) in 27 mL of concentrated sulfuric acid, add P2O5 (2.6 g, 18.6 mmol, 2 eq.), and heat to 60°C with stirring for 1 h. Pour the reaction solution into ice water, filter, and dry to obtain C006-d (2.4 g, 94%).

[0354] Step 4: Dissolve C006-d (2.5 g, 9.1 mmol, 1 eq.) in ethanol (30 mL) and add Fe powder (1.0 g, 18.2 mmol, 2 eq.), NH4Cl (1.5 g, 27.3 mmol, 3 eq.), and 15 mL of water. Stir at 80°C for 3 h, filter, and adjust the pH to 9-10 by adding saturated sodium carbonate solution. Extract with EA and water, and concentrate the organic phase to obtain C006-e (2 g, 90%). LCMS (ESI) m / z: 241.6 [M+H] + .

[0355] Step 5: Dissolve C006-e (1.9 g, 7.85 mmol, 1 eq.) in MeOH (50 mL) and add sodium borohydride (2.4 g, 62.8 mmol, 8 eq.) portionwise. Stir at 25°C for 1 h. Monitor the reaction by LCMS. Evaporate the solvent, extract with DCM and water, and concentrate to afford C006-f (1.8 g, 94%). LCMS (ESI) m / z: 243.6 [M+H] + .

[0356] Step 6: Dissolve C006-f (1 g, 4.10 mmol, 1 eq.) in 10 mL of DCM, add TESiH (3.3 g, 28.7 mmol, 7 eq.), and add 10 mL of TFA dropwise at 0°C. After the addition is complete, react at room temperature for 16 h. Evaporate the solvent, extract with EA and water, and concentrate the organic phase to obtain C006-g (0.9 g, 97%). LCMS (ESI) m / z: 227.7 [M+H] + .

[0357] Step 7: Dissolve C006-g (600 mg, 2.63 mmol, 1 eq.), SO20 (827 mg, 3.16 mmol, 1.2 eq.), CuBr (376 mg, 2.63 mmol, 1 eq.), and t-BuOK (589 mg, 5.26 mmol, 2 eq.) in 10 mL of xylene. After N2 substitution, stir at 110°C for 16 h. Evaporate the solvent and filter through a column chromatography (EA:PE = 1:40) to obtain C006-h (170 mg, 18%). LCMS (ESI) m / z: 362.1 [M+H] + .

[0358] Step 8: Dissolve malononitrile (364 mg, 5.52 mmol, 10 eq.) in 5 mL of NMP, add NaH (221 mg, 5.52 mmol, 10 eq.), and stir at 25°C for 30 min. Add C006-h (200 mg, 0.552 mmol, 1 eq.) and Pd(dppf)Cl2 (40 mg, 0.055 mmol, 0.1 eq.), and stir at 110°C for 4 h. Extract with EA and water, concentrate the organic phase, and filter through a column chromatography (PE:EA = 6:1) to obtain C006-i (140 mg, 73%). LCMS (ESI) m / z: 346.0 [MH] - .

[0359] Step 9: Dissolve C006-I (180 mg, 0.519 mmol, 1 eq.) and K2CO3 (216 mg, 1.56 mmol, 3 eq.) in DMSO (6 mL), add H2O2 (2 mL), and stir at 25°C for 16 h. Monitor the reaction by LCMS. Extract with EA and water, concentrate the organic phase, and perform TLC (EA:PE = 1:1) to obtain C006-j (60 mg, 32%). LCMS (ESI) m / z: 366.2 [M+H] + .

[0360] Step 10: Dissolve C006-j (50 mg, 0.137 mmol, 1 eq.) in 8 mL of DCM, add BBr3 (1 mL, 1 M solution in DCM) at -10°C, and stir at 25°C for 2 h. Monitor the reaction by LCMS. Evaporate the solvent, quench the reaction with methanol, slurry with saturated NaHCO3, filter, wash with water, and prepare by TLC (EA:PE = 2:1) to obtain C006 (10 mg, 21%). LCMS (ESI) m / z: 352.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.04 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.79 (dd, J = 9.4, 8.2 Hz, 2H), 3.82–3.74 (m, 2H), 2.78 (t, J = 6.5 Hz, 2H), 1.87 (m, 5H), 1.81 (s, 3H).

[0361] Example 5: Preparation of Compound C007

[0362] Preparation method

[0363] Step 1: Dissolve C007-a (5 g, 34.7 mmol, 1 eq) in AcOH (50 mL), add PtO2 (394 mg, 1.74 mmol, 0.05 eq), and react at room temperature under 2 MPa H2 for 28 h. Evaporate the solvent, adjust the pH to 9-10 with Na2CO3, extract with EA and water, and concentrate the organic phase to give C007-b (4.8 g). LCMS (ESI) m / z: 148.7 [M+H] + .

[0364] Step 2: Dissolve C007-b (3.2 g, 21.6 mmol, 1 eq) in DCM (50 mL), add Ac2O (6.6 g, 64.9 mmol, 3 eq), and stir at room temperature for 2 h. Extract the organic phase with DCM and water, and concentrate to obtain C007-c (4.8 g). LCMS (ESI) m / z: 232.9 [M+H] + .

[0365] Step 3: Dissolve C007-c (8.3 g, 35.8 mmol, 1 eq) in 50 mL of AcOH, add NCS (4.3 g, 32.2 mmol, 0.9 eq), and heat to 50°C with stirring for 2 h. Evaporate the solvent, extract with EA and water, and concentrate the organic phase through a column (EA:MeOH = 100:2) to obtain C007-d (5 g). LCMS (ESI) m / z: 265.1 [MH]- .

[0366] Step 4: Dissolve C007-d (4 g, 15.0 mmol, 1 eq) in 30% HBr (30 mL) and stir at 80°C for 1 h. Add sodium carbonate to adjust the pH to 9-10, and extract with EA and water. The organic phase is concentrated and filtered through a column (EA:MeOH = 100:2) to afford C007-e (1 g). LCMS (ESI) m / z: 224.8 [M+H] + .

[0367] Step 5: Dissolve C007-e (1 g, 4.44 mmol, 1 eq) in ACN (20 mL) and add NBS (0.79 g, 4.44 mmol, 1 eq) in batches. Stir at 25°C for 2 h. Monitor the reaction by LCMS. Add 50 mL of water, filter, and dry to obtain C007-f (1.2 g). LCMS (ESI) m / z: 302.7 [M+H] + .

[0368] Step 6: Dissolve C007-f (500 mg, 1.65 mmol, 1 eq), 2-iodo-4-methoxy-1,3-dimethylbenzene (519 mg, 1.98 mmol, 1.2 eq), CuBr (236 mg, 1.65 mmol, 1 eq), and t-BuOK (370 mg, 3.30 mmol, 2 eq) in 10 mL of xylene. After N2 substitution, stir at 110°C for 16 h. Evaporate the solvent and filter through an EA column to obtain C007-g (200 mg). LCMS (ESI) m / z: 436.9 [M+H] + .

[0369] Step 7: Dissolve malononitrile (151 mg, 2.29 mmol, 10 eq) in 1 mL of NMP, add NaH (92 mg, 2.29 mmol, 10 eq), and stir at 25°C for 30 min. Then add C007-g (100 mg, 0.229 mmol, 1 eq) and Pd(dppf)Cl2 (17 mg, 0.023 mmol, 0.1 eq), and stir at 110°C for 6 h. Extract with EA and water, concentrate the organic phase, and filter through a column chromatography (PE:EA = 1:4) to obtain C007-h (50 mg). LCMS (ESI) m / z: 423.2 [M+H] + .

[0370] Step 8: Dissolve C007-h (430 mg, 1.02 mmol, 1 eq) in EtOH (18 mL), add 10% NaOH (9 mL), and stir at 60°C for 6 h. Monitor the reaction by LCMS. Extract with EA and water, and concentrate the organic phase to give C007-i (85 mg). LCMS (ESI) m / z: 379.0 [MH] - .

[0371] Step 9: Dissolve C007-i (100 mg, 0.263 mmol, 1 eq) and K2CO3 (109 mg, 0.787 mmol, 3 eq) in DMSO (6 mL), add H2O2 (2 mL), and stir at 25°C for 16 h. Monitor the reaction by LCMS. Extract with EA and water, concentrate the organic phase, and perform TLC (EA:PE = 1:1) to afford C007-j (45 mg). LCMS (ESI) m / z: 399.2 [M+H] + .

[0372] Step 10: Dissolve C007-j (40 mg, 0.10 mmol, 1 eq) in 10 mL of DCM and add BBr3 (1 mL, 1 min in DCM) at 0°C. Stir at 25°C for 1 h. Monitor the reaction by LCMS. Evaporate the solvent, quench with methanol, slurry with saturated NaHCO3, filter, wash with water, and prepare by TLC (DCM:MeOH = 10:1) to obtain compound C007 (8 mg). LCMS (ESI) m / z: 385.2 [M+H] + , 1 H NMR (400MHz, Methanol-d4) δ7.60(s,1H),7.07(d,J=8.3Hz,1H),6.92(d,J=8.3Hz,1H),3.3 2(d,J=3.1Hz,2H),2.98(t,J=6.1Hz,2H),2.83(t,J=6.1Hz,2H),1.89(s,3H),1.85(s,3H).

[0373] Example 6: Preparation of Compound C008

[0374] Preparation method

[0375] Step 1: Dissolve C008-a (5 g, 34.7 mmol, 1 eq) in AcOH (50 mL) and add PtO2 (394 mg, 1.74 mmol, 0.05 eq). The mixture is reacted at room temperature under 2 MPa of H2 for 28 h. The solvent is evaporated to dryness, and the pH is adjusted to 9-10 with Na2CO3. The mixture is extracted with EA and water, and the organic phase is concentrated to afford C008-b (4.8 g, 94%). LCMS (ESI) m / z: 148.7 [M+H] + .

[0376] Step 2: Dissolve C008-b (3.2 g, 21.6 mmol, 1 eq) in DCM (50 mL), add Ac2O (6.6 g, 64.9 mmol, 3 eq), and stir at room temperature for 2 h. Extract the organic phase with DCM and water, and concentrate to obtain C008-c (4.8 g, 95%). LCMS (ESI) m / z: 232.9 [M+H] + .

[0377] Step 3: Dissolve C008-c (8.3 g, 35.8 mmol, 1 eq) in 50 mL of AcOH, add NCS (4.3 g, 32.2 mmol, 0.9 eq), and heat to 50°C with stirring for 2 h. Evaporate the solvent, extract with EA and water, and concentrate the organic phase. Column chromatography (EA:MeOH = 100:2) affords C008-d (5 g, 52%). LCMS (ESI) m / z: 265.1 [MH] - .

[0378] Step 4: Dissolve C008-d (4 g, 15.0 mmol, 1 eq) in 30% HBr (30 mL), stir at 80°C for 1 h, add sodium carbonate to adjust the pH to 9-10, extract with EA and water, and concentrate the organic phase through a column (EA:MeOH=100:2) to obtain C008-e (1 g, 30%). LCMS (ESI) m / z: 224.8 [M+H] + .

[0379] Step 5: Dissolve C008-e (1 g, 4.44 mmol, 1 eq) in ACN (20 mL) and add NBS (0.79 g, 4.44 mmol, 1 eq) portionwise. Stir at 25°C for 2 h. Monitor the reaction by LCMS. Add 50 mL of water, filter, and dry to obtain C008-f (1.2 g, 89%). LCMS (ESI) m / z: 302.7 [M+H] + .

[0380] Step 6: Dissolve C008-f (500 mg, 1.65 mmol, 1 eq), SO20 (519 mg, 1.98 mmol, 1.2 eq), CuBr (236 mg, 1.65 mmol, 1 eq), and t-BuOK (370 mg, 3.30 mmol, 2 eq) in 10 mL of xylene. After N2 substitution, stir at 110°C for 16 h. Evaporate the solvent and filter through an EA column to obtain C008-g (200 mg, 28%). LCMS (ESI) m / z: 436.9 [M+H] + .

[0381] Step 7: Dissolve malononitrile (151 mg, 2.29 mmol, 10 eq) in 1 mL of NMP, add NaH (92 mg, 2.29 mmol, 10 eq), and stir at 25°C for 30 min. Add C008-g (100 mg, 0.229 mmol, 1 eq) and Pd(dppf)Cl2 (17 mg, 0.023 mmol, 0.1 eq), and stir at 110°C for 6 h. Extract with EA and water, concentrate the organic phase, and pass it through a column chromatography (PE:EA = 1:4) to obtain C008-h (50 mg, 51%). LCMS (ESI) m / z: 423.2 [M+H] + .

[0382] Step 8: Dissolve C008-h (430 mg, 1.02 mmol, 1 eq) in EtOH (18 mL), add 10% NaOH (9 mL), and stir at 60°C for 6 h. Monitor the reaction by LCMS. Extract with EA and water, and concentrate the organic phase to give C008-i (85 mg, 22%). LCMS (ESI) m / z: 379.0 [MH] - .

[0383] Step 9: Dissolve C008-i (100 mg, 0.263 mmol, 1 eq) and K2CO3 (109 mg, 0.787 mmol, 3 eq) in DMSO (6 mL), add H2O2 (2 mL), and stir at 25°C for 16 h. Monitor the reaction by LCMS. Extract with EA and water, concentrate the organic phase, and perform TLC (EA:PE = 1:1) to obtain C008-j (45 mg, 43%). LCMS (ESI) m / z: 399.2 [M+H] + .

[0384] Step 10: Dissolve C008-j (40 mg, 0.10 mmol, 1 eq.) in 10 mL of DCM and add BBr3 (1 mL, 1 M solution in DCM) at 0°C. Stir at 25°C for 1 h. Monitor the reaction by LCMS. Evaporate the solvent, quench with methanol, slurry with saturated NaHCO3, filter, and wash with water. Prepare the mixture by TLC (DCM:MeOH = 10:1) to obtain compound C008 (8 mg, 21%). LCMS (ESI) m / z: 385.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.60 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.32 (d, J = 3.1 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.83 (t, J = 6.1 Hz, 2H), 1.89 (s, 3H), 1.85 (s, 3H).

[0385] Example 7: Preparation of Compound C024

[0386] Preparation method

[0387] Step 1: Dissolve compound C024-a (13.20 g, 80.98 mmol, 1 eq.) in concentrated sulfuric acid (60 mL), then replace the atmosphere with nitrogen. Then, slowly add a pre-prepared potassium nitrate solution in concentrated sulfuric acid (9.80 g, 97.17 mmol, 1.2 eq. 40 mL) to the reaction flask, maintaining the temperature at 20-25°C. After the addition is complete, incubate the reaction mixture at 25°C for 1 hour. After the reaction is complete, slowly pour the reaction mixture into ice water and adjust the pH to 7 with aqueous ammonia. A solid precipitates, which is filtered and dried under vacuum to yield compound C024-b (11.10 g). LCMS (ESI) m / z: 209.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 8.87 (d, J = 6.0Hz, 1H), 8.46 (d, J = 8.4Hz, 1H), 8.22–8.18 (m, 2H).

[0388] Step 2: Dissolve C024-b (11.10 g, 53.36 mmol, 1 eq.) and stannous chloride (50.43 g, 266.82 mmol, 5.0 eq.) in ethanol and replace the atmosphere with nitrogen. The reaction mixture was stirred at 80°C for 4 hours. After the reaction, the reaction mixture was diluted with dichloromethane and the pH was adjusted to 13 with 2M sodium hydroxide solution. The mixture was filtered and the filtrate was extracted three times with dichloromethane. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound C024-c (7.0 g). LCMS (ESI) m / z: 179.1 [M+H] + .

[0389] Step 3: Dissolve C024-c (7.0 g, 39.33 mmol, 1 eq.), C024-d (10.89 g, 39.33 mmol, 1 eq.), tris(dibenzylideneacetone)dipalladium (3.60 g, 3.93 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.548 g, 7.86 mmol, 0.2 eq.), and cesium carbonate (38.44 g, 117.99 mmol, 3 eq.) in 1,4-dioxane (200 mL) and replace the atmosphere with nitrogen. The reaction mixture was stirred at 90°C for 12 hours. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to afford C024-e (6.1 g). LCMS (ESI) m / z: 328.2 [M+H] + .

[0390] Step 4: Dissolve C024-e (6.1 g, 18.65 mmol, 1 eq.) in acetonitrile (100 ml), then replace the atmosphere with nitrogen. Add N-bromosuccinimide (3.48 g, 19.58 mmol, 1.05 eq.) in portions at 0°C, and incubate the reaction mixture at 0°C for half an hour. After the reaction is complete, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The resulting crude product is purified by silica gel column chromatography (3% methanol / dichloromethane) to obtain compound C024-f (2.05 g). LCMS (ESI) m / z: 408.1 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.72(d,J=6.0Hz,1H),8.33(s,1H),8.08(s,1H),7.9 9(d,J=6.0Hz,1H),7.62(d,J=8.4Hz,1H),7.29(d,J=8.4Hz,1H),2.14(s,3H),2.06(s,3H).

[0391] Step 5: Dissolve C024-f (701 mg, 10.63 mmol, 2.1 eq.) in 1,4-dioxane (100 ml) and replace the atmosphere with nitrogen. Add sodium tert-butoxide (971 mg, 10.12 mmol, 2.0 eq.) at 0°C, and let the reaction sit at room temperature for 1 hour. Then, add malononitrile (2.05 g, 5.06 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (373 mg, 0.51 mmol, 0.1 eq.). Let the reaction sit at 90°C for 12 hours. After the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. Wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated in vacuo, and the resulting crude product is purified by silica gel column chromatography (3% methanol / dichloromethane) to yield compound C024-g (1.1 g). LCMS (ESI) m / z: 392.3 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ8.41(d,J=6.0Hz,1H),8.29(d,J=8.4Hz,1H),8.07(s,1H) ,8.02–7.98(m,2H),7.73(d,J=8.4Hz,1H),7.20(s,2H),2.08(s,3H),1.97(s,3H).

[0392] Step 6: Dissolve C024-g (500.0 mg, 1.28 mmol, 1.0 eq.), di-tert-butyl dicarbonate (419.0 mg, 1.92 mmol, 1.5 eq.), 4-dimethylaminopyridine (16 mg, 0.13 mmol, 0.1 eq.), and triethylamine (388 mg, 3.84 mmol, 3.0 eq.) in tetrahydrofuran. The atmosphere was purged with nitrogen, and the reaction mixture was incubated at 50°C for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C024-h (350 mg). LCMS (ESI) m / z: 492.2 [M+H] + .

[0393] Step 7: C024-h (350.0 mg, 0.71 mmol, 1.0 eq), iron powder (200.0 mg, 3.56 mmol, 5.0 eq) and ammonium chloride (188.9 g, 3.56 mmol, 5 eq) were dissolved in ethanol and water and reacted at 80°C under nitrogen for 1 hour. The reaction solution was filtered, the filtrate was added with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain crude C024-i (330 mg). LCMS (ESI) m / z: 462.2 [M+H] + .

[0394] Step 8: C024-i (330 mg, 0.71 mmol, 1.0 eq) was dissolved in anhydrous toluene (20 mL) and glacial acetic acid (1 mL). Isoamyl nitrite (166 mg, 1.42 mmol, 2.0 eq) was added dropwise at 0°C and reacted under nitrogen at 0°C for 1 hour. Potassium acetate (209.03 mg, 2.13 mmol, 3.0 eq) was then added and the reaction was allowed to proceed overnight at room temperature under nitrogen. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column (3% methanol / dichloromethane) to obtain C024-j (150 mg). LCMS (ESI) m / z: 473.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ13.50(s,1H),9.68(s,1H),8.55(d,J=6.0Hz,1H),8.36(s,1H),8.12(d,J=6.0Hz ,1H),8.02(s,1H),7.87(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.50(s,1H),1.98(s,3H),1.30(s,9H).

[0395] Step 9: Dissolve C024-j (150 mg, 0.32 mmol, 1.0 eq) in anhydrous ethanol (10 mL) and 6 M hydrochloric acid (5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C024-k (150 mg). LCMS (ESI) m / z: 373.2 [M+H] + .

[0396] Step 10: Dissolve C024-k (150 mg, 0.32 mmol, 1.0 eq.) in a mixed acid solution (4 mL) (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and stir at room temperature for 90 minutes. Add methionine (192 mg, 1.28 mmol, 4 eq.) to the reaction mixture and react at 40°C for 3 hours. After completion of the reaction, as monitored by LCMS, slowly add the reaction mixture dropwise to 5N aqueous sodium hydroxide solution and extract with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The residue is purified by HPLC to yield C024 (80 mg).

[0397] Step 11: The product C024 was prepared by chiral separation (SFC column: mobile phase: DAICEL CHIRALPAK AD-30 (250*30mm, 10mm); A (CO2) and B (isopropanol, containing 0.1% 7mmol / L ammonia methanol solution), gradient: B% = 35%) to obtain products C024A (30.91 mg, yield 19.6%) and C024B (23.67 mg, yield 15%).

[0398] C024-A: LCMS(ESI):m / z=391.2(M+H) + ,T=6.071min, 1 H NMR (400MHz, DMSO-d6) δ13.50(s,1H),8.55(s,1H),8.25(d,J=6.0Hz,1H),7.93–7.89(m,2H),7. 85(d,J=8.8Hz,1H),7.59(d,J=8.4Hz,1H),7.55(s,1H),7.08(s,2H),6.74(s,2H),2.04(s,3H).

[0399] C024-P2: LCMS(ESI):m / z=391.2(M+H) + ,T=6.070min, 1 H NMR (400MHz, DMSO-d6) δ13.50(s,1H),8.55(s,1H),8.25(d,J=6.0Hz,1H),7.93–7.89(m,2H),7. 85(d,J=8.8Hz,1H),7.59(d,J=8.4Hz,1H),7.55(s,1H),7.08(s,2H),6.74(s,2H),2.04(s,3H).

[0400] Example 8: Preparation of Compound C026A

[0401] Preparation method

[0402] Compound C024A (12.0 mg, 0.030 mmol, 1 eq.), palladium on carbon (10 mg, 0.093 mmol, 3.1 eq.), and triethylamine (0.32 mL) were dissolved in tetrahydrofuran (2 mL), followed by hydrogen exchange. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by high performance liquid chromatography to afford C026A (3.40 mg).

[0403] LCMS (ESI): m / z=357.3(M+H)+, T=5.362min.

[0404] 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),8.42(s,1H),8.34(d,J=8.4Hz,1H),8.10(d,J=5.6Hz,1H),7.87–7.81(m,2H),7. 72(d,J=5.6Hz,1H),7.64(d,J=8.8Hz,1H),7.58(d,J=8.8Hz,1H),7.51(s,1H),6.98(s,2H),6.63(s,2H),2.03(s,3H).

[0405] Example 9: Preparation of Compound C027

[0406] Preparation method

[0407] Step 1: Dissolve compound C027-a (13.20 g, 80.98 mmol, 1.0 eq) in concentrated sulfuric acid and replace the atmosphere with nitrogen. Then, slowly add a solution of potassium nitrate (9.80 g, 97.17 mmol, 1.2 eq) in concentrated sulfuric acid (40 mL) to the reaction flask, maintaining the temperature at 20°C-25°C. After the addition is complete, the reaction solution is incubated at 25°C for 1 hour. After the reaction is complete, pour the reaction solution into ice water, adjust the pH to 7 with aqueous ammonia, filter, and concentrate in vacuo to obtain C027-b (11.10 g). LCMS (ESI) m / z: 209.1 [M+H] + .

[0408] Step 2: C027-b (11.10 g, 53.36 mmol, 1.0 eq) and stannous chloride (50.43 g, 266.82 mmol, 5.0 eq) were dissolved in ethanol and replaced with nitrogen. The reaction solution was reacted at 80°C for 4 hours. After the reaction was completed, dichloromethane was added to dilute it, and the pH was adjusted to 13 with a 2M aqueous sodium hydroxide solution. The solution was filtered and the filtrate was extracted three times with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain C027-c (7.0 g). LCMS (ESI) m / z: 179.1 [M+H] + .

[0409] Step 3: C027-c (4 g, 22.39 mmol, 1.0 eq), C027-d (7.53 g, 26.87 mmol, 1.2 eq), Pd2(dba)3 (1.03 g, 1.12 mmol, 0.05 eq), Xantphos (1.30 g, 2.24 mmol, 0.1 eq), and cesium carbonate (14.6 g, 44.79 mmol, 2.0 eq) were dissolved in 1,4-dioxane and reacted overnight at 90°C under nitrogen. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%) to obtain C027-e (3.42 g, yield: 46.2%). LCMS (ESI) m / z: 331.2 [M+1] + .

[0410] Step 4: C027-e (3.42 g, 10.34 mmol, 1.0 eq) was dissolved in tetrahydrofuran, and N-bromosuccinimide (1.93 g, 10.86 mmol, 1.05 eq) was added at -78°C. The reaction mixture was reacted under nitrogen at -78°C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (ethyl acetate / petroleum ether = 10%) to obtain C027-f (2.38 g, yield: 56.1%). LCMS (ESI) m / z: 409.3 [M+1] + .

[0411] Step 5: Dissolve malononitrile (3.10 g, 46.87 mmol, 6.0 eq) in 1,4-dioxane. Add sodium hydroxide (60% dispersion in mineral oil) (1.87 g, 46.87 mmol, 6.0 eq) at 0°C and react at room temperature under nitrogen for 0.5 h. Then add C027-f (3.2 g, 7.81 mmol, 1.0 eq) and Pd(dppf)Cl2 (572 mg, 0.78 mmol, 0.1 eq). React at room temperature under nitrogen for 10 min and then at 90°C under nitrogen overnight. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and the crude product is purified on a silica gel column (ethyl acetate / petroleum ether = 30%) to yield C027-g (2.5 g). LCMS (ESI) m / z: 395.3 [M+1] + .

[0412] Step 6: Dissolve C027-g (1.65 g, 4.18 mmol, 1.0 eq) in methanesulfonic acid:sulfuric acid:water (86:13:1) (40 mL) and react at room temperature for 1 hour. Add DL-methionine (2.49 g, 16.72 mmol, 4.0 eq) and react at 40°C overnight. The reaction mixture was neutralized with 5 M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was concentrated to dryness, and the resulting crude product was purified on a silica gel column (methanol / dichloromethane = 6%) to obtain compound C027 (990 mg). LCMS (ESI) m / z: 399.2 [M+1] + .

[0413] Step 7: Compound C027 (980 mg, 2.46 mmol, 1.0 eq) was subjected to chiral separation to obtain compounds C027A (402.80 mg, yield 41.1%) and C027B (454.04 mg, yield 46.3%).

[0414] C027A:LCMS(ESI)m / z:399.2[M+1] + , 1 H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.50 (s, 1H), 8.34 (d, J = 6.0Hz, 1H), 8.18 (s, 1H), 7.94 ( d,J=6.0Hz,1H),7.32(d,J=11.6Hz,1H),7.05(s,2H),6.79(s,2H),1.79(s,3H),1.74(s,3H);

[0415] C027B:LCMS(ESI)m / z:399.2[M+1] + , 1H NMR (400MHz, DMSO-d6) δ9.93 (s, 1H), 8.50 (s, 1H), 8.34 (d, J = 6.0Hz, 1H), 8.17 (s, 1H), 7.94 ( d,J=6.0Hz,1H),7.32(d,J=11.6Hz,1H),7.05(s,2H),6.79(s,2H),1.79(s,3H),1.74(s,3H).

[0416] Example 10: Preparation of Compound C031

[0417] Preparation method

[0418] Step 1: Compound C024-h (500 mg, 0.846 mmol, 1 eq.), methylboronic acid (76 mg, 1.269 mmol, 1.5 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (70 mg, 0.0846 mmol, 0.1 eq.), and potassium phosphate (538 mg, 2.538 mmol, 3.0 eq.) were dissolved in toluene (10 mL) and water (0.5 mL), then the atmosphere was replaced with nitrogen and the reaction was carried out at 90°C for 16 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified on a silica gel column (ethyl acetate / petroleum ether = 20%) to obtain compound C031-b (380 mg). LCMS (ESI) m / z: 572.2 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=6.0Hz,1H),8.32(d,J=8.4Hz,1H),8.26(s,1H),8. 08–8.03(m,2H),7.76(d,J=8.4Hz,1H),2.76(s,3H),1.97(s,6H),1.37–1.36(m,18H).

[0419] Step 2: Dissolve C031-b (380 mg, 0.806 mmol, 1.0 eq), iron powder (225.6 mg, 4.03 mmol, 5.0 eq), and ammonium chloride (213.56 g, 4.03 mmol, 5 eq) in ethanol (10 mL) and water (2 mL) and react at 80°C for 1 hour. The reaction mixture was filtered hot, and the filter cake was washed with ethyl acetate (10 mL*3). The filtrate was added with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed again with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain crude compound C031-c (350 mg, containing 40% mono-Boc product), which was used directly in the next step. LCMS (ESI) m / z: 542.2 [M+H] + .

[0420] Step 3: Dissolve C031-c (350 mg, 0.647 mmol, 1.0 eq) in anhydrous toluene (10 mL) and glacial acetic acid (0.53 mL). Add isoamyl nitrite (151 mg, 1.294 mmol, 2.0 eq) dropwise at 0°C. The atmosphere is purged with nitrogen three times at 0°C and allowed to react at 0°C for 1 hour. Potassium acetate (190 mg, 1.94 mmol, 3.0 eq) is then added, the atmosphere is purged with nitrogen three times, and the reaction is allowed to proceed at room temperature overnight. The reaction mixture is quenched with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The crude product is purified on a silica gel column (methanol / dichloromethane = 3%) to afford compound C031-d (170 mg, containing bis-Boc product). LCMS (ESI) m / z: 453.3 [M+H] + .

[0421] Step 4: Dissolve C031-d (170 mg, 0.375 mmol, 1.0 eq) in anhydrous ethanol (5 mL) and 6 M hydrochloric acid (2.5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C031-e (120 mg). LCMS (ESI) m / z: 353.2 [M+H] + .

[0422] Step 5: Dissolve C031-e (120 mg, 0.34 mmol, 1.0 eq.) in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water in 12 mL of methanesulfonic acid) and stir at room temperature for 90 minutes. Add methionine (203 mg, 1.36 mmol, 4 eq.) to the reaction mixture and react at 40°C for 12 hours. After completion of the reaction, as monitored by LCMS, slowly add the reaction mixture dropwise to 5N sodium hydroxide solution and extract with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The residue is purified by HPLC to yield C031 (70 mg).

[0423] Step 6: Separation and purification by SFC (chromatographic column: DAICEL CHIRALPAK IG (250*25mm 10μm); mobile phase A (CO2) and B (isopropanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 40%) to obtain products C031A (9.61 mg) and C031B (11.81 mg):

[0424] C031A: LCMS (ESI): m / z=371.3(M+H)+, T=5.700min, 1 H NMR (400MHz, CD3OD) δ8.19(s,1H),8.11(d,J=6.0Hz,1H),8.00(s,1H),7.89(d,J=6.0Hz, 1H),7.83(d,J=8.4Hz,1H),7.62(d,J=8.8Hz,1H),7.55(s,1H),2.78(s,3H),2.15(s,3H).

[0425] C031B: LCMS (ESI): m / z=371.1(M+H)+, T=5.695min, 1 H NMR (400MHz, CD3OD) δ8.18(s,1H),8.11(d,J=6.0Hz,1H),8.00(s,1H),7.88(d,J=6.0Hz, 1H),7.83(d,J=8.4Hz,1H),7.62(d,J=8.8Hz,1H),7.55(s,1H),2.78(s,3H),2.14(s,3H).

[0426] Example 11: Preparation of Compound C032

[0427] Preparation method

[0428] Step 1: Dissolve compounds C032-a (25 g, 100 mmol, 1 eq.) and C032-b (19.4 g, 200 mmol, 2 eq) in ethanol and react at 80 ° C for 16 hours. The reaction solution was cooled to room temperature, and sodium cyanoborohydride (6.3 g, 100 mmol, 1 eq) was slowly added under an ice bath, and then acetic acid was slowly added dropwise. The reaction was stirred at room temperature for 1 hour, and the reaction was completed by LCMS detection. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether) to obtain C032-c (25 g). LCMS (ESI) m / z: 293.8 [M+H]; 1 H NMR (400MHz, CDCl3) δ7.50-7.46(m,1H),7.27(s,1H),7.21-7.17(m,1H),6.8 8-6.82(m,1H),4.52-4.49(m,1H),3.86(s,2H),3.39(s,6H),2.76(d,J=5.6Hz 1H),1.82(s,1H).

[0429] Step 2: C032-c (25 g) was slowly added dropwise to chlorosulfonic acid under ice bath. The reaction solution was heated to 100 ° C for 0.5 hours and the reaction was completed by LCMS monitoring. The reaction solution was slowly poured into ice water and the pH was adjusted to 10 with sodium hydroxide solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain C032-d (8 g). LCMS (ESI) m / z: 228.0 [M+H], 1 H NMR (400MHz, DMSO-d6) δ9.51 (s, 1H), 8.76 (d, J = 5.6Hz 1H), 8.04-8.01 (m, 1H), 7.98 (d, J = 6.0Hz 1H), 7.65-7.60 (m, 1H).

[0430] Step 3: Dissolve C032-d (6.0 g, 26.7 mmol, 1 eq.), benzophenone imine (7.2 g, 40 mmol, 1.5 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.4 g, 2.7 mmol, 0.1 eq.), tris(dibenzylideneacetone)dipalladium (2.5 g, 2.7 mmol, 0.1 eq.), and cesium carbonate (25 g, 80 mmol, 3 eq.) in anhydrous 1,4-dioxane. Under nitrogen, heat the reaction mixture to 90°C for 16 hours. Completion of the reaction was monitored by LCMS. Dichloromethane and methanol were added to the mixture, the mixture was filtered, and the filtrate was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was added with a solution of hydrochloric acid in 1,4-dioxane and water, and the reaction was stirred at room temperature for 2 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added to the concentrate until the pH reached 8, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (0-10% methanol / dichloromethane) to afford C032-f (3.5 g). LCMS (ESI) m / z: 163.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 8.47 (d, J = 6.0Hz 1H), 7.69-7.67 (m, 1H), 7.28-7.23 (m, 1H), 6.68-6.65 (m, 1H), 6.13 (s, 2H).

[0431] Step 4: Dissolve C032-f (3.8 g, 23.45 mmol, 1 eq.), C032-g (9.746 g, 35.18 mmol, 1 eq.), tris(dibenzylideneacetone)dipalladium (2.147 g, 2.345 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.714 g, 4.691 mmol, 0.2 eq.), and cesium carbonate (23.12 g, 70.37 mmol, 3 eq.) in 1,4-dioxane, then replace the atmosphere with nitrogen. The reaction mixture was incubated at 90°C for 12 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C032-h (2.2 g). LCMS (ESI) m / z: 312.2 [M+H] + .

[0432] Step 5: C032-h (3.0 g, 9.646 mmol, 1 eq.) was dissolved in acetic acid and then replaced with nitrogen. Liquid bromine (1.618 g, 10.128 mmol, 1.05 eq.) was added at 0°C and the reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (3% methanol / dichloromethane) to obtain C032-i (1.1 g). LCMS (ESI) m / z: 390.0 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.69(d,J=6.0Hz,1H),8.11(s,1H),7.96(d,J=5.6Hz,1H) ,7.90(d,J=9.6Hz,1H),7.55(d,J=8.2Hz,1H),7.26(d,J=8.2Hz,1H),2.11(s,3H),2.04(s,3H).

[0433] Step 6: Dissolve C032-i (509 mg, 7.712 mmol, 2.0 eq.) in N,N-dimethylformamide (50 ml) and replace the atmosphere with nitrogen. Add sodium hydride (308 mg, 7.71 mmol, 2.0 eq.) at 0°C, and incubate the reaction at 0°C for 1 hour. Then, add malononitrile (1.5 g, 3.856 mmol, 1.0 eq.) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (282 mg, 0.385 mmol, 0.1 eq.). The reaction mixture is incubated at 70°C for 12 hours. After completion of the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product is purified by column chromatography (3% methanol / dichloromethane) to obtain compound C032-j (330 mg). LCMS (ESI) m / z: 376.3 [M+H] + .

[0434] Step 7: C032-j (300 mg, 0.80 mmol, 1.0 eq.), di-tert-butyl dicarbonate (350 mg, 1.60 mmol, 2.0 eq.), 4-dimethylaminopyridine (10 mg, 0.08 mmol, 0.1 eq.), and triethylamine (243 mg, 2.40 mmol, 3.0 eq.) were dissolved in tetrahydrofuran, then purged with nitrogen. The reaction mixture was reacted at 50°C for 1 hour. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C032-k (270 mg). LCMS (ESI) m / z: 576.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.6Hz,1H),8.33(d,J=8.4Hz,1H),8.26(s,1H),8.18(d,J= 9.6Hz, 1H), 8.10 (d, J = 5.6Hz, 1H), 7.77 (d, J = 8.4Hz, 1H), 1.98 (d, J = 2.0Hz, 6H), 1.37 (s, 18H).

[0435] Step 8: Dissolve C032-k (285 mg, 0.60 mmol, 1.0 eq), reduced iron powder (168 mg, 3.0 mmol, 5.0 eq), and ammonium chloride (159 g, 3.0 mmol, 5 eq) in ethanol and water and react at 80°C for 1 hour. Filter the reaction solution, add saturated brine to the filtrate, extract with ethyl acetate, and combine the organic phases. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain crude compound C032-1 (250 mg), which is used directly in the next step. LCMS (ESI) m / z: 446.3 [M+1] + .

[0436] Step 9: Dissolve C032-1 (267 mg, 0.6 mmol, 1.0 eq) in anhydrous toluene (20 mL) and glacial acetic acid (1 mL). Add isoamyl nitrite (140 mg, 1.2 mmol, 2.0 eq) dropwise at 0°C and react under nitrogen at 0°C for 1 hour. Add potassium acetate (176 mg, 1.8 mmol, 3.0 eq) and react overnight at room temperature under nitrogen. The reaction solution is quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product is purified by silica gel column chromatography (methanol / dichloromethane = 3%) to obtain C032-m (150 mg). LCMS (ESI) m / z: 457.3 [M+1] + .

[0437] Step 10: Dissolve C032-m (150 mg, 0.33 mmol, 1.0 eq) in anhydrous ethanol (10 mL) and 6 M hydrochloric acid (5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C032-n (120 mg). LCMS (ESI) m / z: 357.1 [M+1] + .

[0438] Step 11: Dissolve C032-n (120 mg, 0.373 mmol, 1.0 eq.) in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and stir at room temperature for 90 minutes. Add methionine (223 mg, 1.49 mmol, 4 eq.) to the reaction solution and react at 40°C for 3 hours. After the reaction is completed, the reaction solution is slowly added dropwise to a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by high-performance liquid chromatography to obtain C032 (45 mg). LCMS (ESI) m / z: 375.1 [M+1] + .

[0439] The product C032 was separated by chirality to obtain products C032A (19.03 mg) and C032B (17.91 mg):

[0440] C032A: LCMS(ESI):m / z=375.1(M+H)+, 1 H NMR (400MHz, CD3OD) δ8.14(d,J=6.0Hz,1H),8.12(d,J=11.6Hz,1H),7.95(s,1H),7.91(d,J= 6.0Hz,1H),7.85(d,J=8.8Hz,1H),7.63(d,J=8.8Hz,1H),7.57(d,J=0.8Hz,1H),2.15(s,3H).

[0441] C032B: LCMS(ESI):m / z=375.2(M+H)+, 1 H NMR (400MHz, CD3OD) δ8.13(m,2H),7.96(s,1H),7.91(d,J=6.0Hz,1H),7.85(d,J=8.8Hz,1H),7.63(d,J=8.4Hz,1H),7.57(s,1H),2.15(s,3H).

[0442] Example 12: Preparation of Compound C033

[0443] Preparation method

[0444] Step 1: Add glycerol (28.8 g, 312.74 mmol, 2.69 eq.) to a 500 mL three-necked flask, then heat to 160°C and stir for 1 hour. Cool naturally to 110°C, then add compound C033-a (20 g, 116.28 mmol, 1 eq.) and potassium iodide (348 mg, 2.096 mmol, 0.007 eq.). Then, heat to 150°C and slowly add concentrated sulfuric acid (14.4 mL). The atmosphere is purged with nitrogen three times. The mixture is reacted at 150°C for 1 hour. After completion of the reaction, the reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The crude product is purified on a silica gel column (5% ethyl acetate / petroleum ether) to yield compound C033-b (6.1 g). LCMS (ESI) m / z: 209.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.20–9.10(m,1H),8.80–8.68(m,1H),8.34(m,1H),8.06–7.98(m,1H),7.94–7.83(m,1H).

[0445] Step 2: C033-b (12.30 g, 59.13 mmol, 1 eq.) and stannous chloride (55.88 g, 295.67 mmol, 5.0 eq.) were dissolved in ethanol (100 ml), and then replaced with nitrogen. The reaction solution was reacted at 80°C for 4 hours. After the reaction was completed, dichloromethane was added to dilute it, and the pH was adjusted to 13 with 2M sodium hydroxide solution. The solution was filtered and the filtrate was extracted three times with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound C033-c (8.0 g). LCMS (ESI) m / z: 179.1 [M+H] + .

[0446] Step 3: Dissolve C033-c (6.328 g, 35.55 mmol, 1 eq.), compound C033-d (8.142 g, 35.55 mmol, 1 eq.), tris(dibenzylideneacetone)dipalladium (3.254 g, 3.555 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (4.114 g, 7.11 mmol, 0.2 eq.), and cesium carbonate (34.75 g, 106.66 mmol, 3 eq.) in 1,4-dioxane (100 ml) and replace the atmosphere with nitrogen. The reaction mixture was reacted at 120°C for 12 hours. After completion of the reaction, water was added to quench the reaction, and the organic phases were extracted with ethyl acetate. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give compound C033-e (1.2 g). LCMS (ESI) m / z: 328.2 [M+H] + .

[0447] Step 4: Dissolve C033-e (1 g, 3.06 mmol, 1 eq.) in acetonitrile (30 ml) and replace the atmosphere with nitrogen. Add N-bromosuccinimide (572 mg, 3.21 mmol, 1.05 eq.) at 0°C and incubate the reaction at 0°C for half an hour. After completion of the reaction, dilute with water and extract with ethyl acetate. The combined organic phases are washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The resulting crude product is purified by silica gel column chromatography to obtain C033-f, which is used directly in the next step.

[0448] Step 5: Dissolve malononitrile in 1,4-dioxane and replace with nitrogen. Add sodium tert-butoxide at 0°C, and let the reaction mixture react at room temperature. Then add C033-f (320 mg, 1.659 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (58 mg, 0.079 mmol, 0.1 eq.). The reaction mixture was reacted at 90°C for 12 hours. After the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (3% methanol / dichloromethane) to obtain compound C033-g (120 mg). LCMS (ESI) m / z: 392.0 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ8.49(d,J=8.4Hz,1H),8.40(d,J=4.0Hz,1H),8.11(d,J=8.4Hz,1H),7.80( s,1H),7.53(d,J=8.4Hz,1H),7.38(dd,J=8.4,4.0Hz,1H),7.06(s,2H),2.00(s,3H),1.90(s,3H).

[0449] Step 6: Dissolve C033-g (277 mg, 0.708 mmol, 1.0 eq.), di-tert-butyl dicarbonate (232 mg, 1.063 mmol, 1.5 eq.), 4-dimethylaminopyridine (9 mg, 0.0708 mmol, 0.1 eq.), and triethylamine (215 mg, 2.125 mmol, 3.0 eq.) in tetrahydrofuran, then replace the atmosphere with nitrogen. The reaction mixture was incubated at 50°C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain C033-h (240 mg). LCMS (ESI) m / z: 492.1 [M+H] + .

[0450] Step 7: Dissolve C033-h (160 mg, 0.326 mmol, 1.0 eq), iron powder (91 mg, 1.629 mmol, 5.0 eq), and ammonium chloride (86.4 mg, 1.629 mmol, 5 eq) in ethanol (10 mL) and water (2 mL) and react at 80°C for 1 hour. The reaction mixture was hot filtered, the filter cake was washed with ethyl acetate, the filtrate was added to saturated brine, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain crude compound C033-i (130 mg). LCMS (ESI) m / z: 462.2 [M+H] + .

[0451] Step 8: Dissolve C033-i (212 mg, 0.461 mmol, 1.0 eq) in anhydrous toluene (10 mL) and glacial acetic acid (0.5 mL). Slowly add isoamyl nitrite (107 mg, 0.919 mmol, 2.0 eq) dropwise at 0°C and maintain the reaction at 0°C for 1 hour. Then add potassium acetate (135 mg, 1.379 mmol, 3.0 eq) and react overnight at room temperature under nitrogen. The reaction solution is quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The crude product is purified by silica gel column chromatography (3% methanol / dichloromethane) to obtain compound C033-j (128 mg). LCMS (ESI) m / z: 473.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.53(s,1H),8.61(dd,J=8.4,1.6Hz,1H),8.40(dd,J=4.4,1.6Hz,1H),8.14(s, 1H),7.65(d,J=8.4Hz,1H),7.53(dd,J=8.4,4.4Hz,1H),7.42(d,J=8.4Hz,1H),7.33(s,1H),1.93(s,3H),1.30(s,8H).

[0452] Step 9: Dissolve C033-j (100 mg, 0.212 mmol, 1.0 eq) in anhydrous ethanol (5 mL) and 6 M hydrochloric acid (2.5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C033-k (90 mg), which was used directly in the next reaction. LCMS (ESI) m / z: 373.2 [M+H] + .

[0453] Step 10: Dissolve C033-k (80 mg, 0.211 mmol, 1.0 eq.) in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water in 12 mL of methanesulfonic acid) and stir at room temperature for 90 minutes. Add methionine (127 mg, 0.847 mmol, 4 eq.) to the reaction mixture and allow to react at 40°C for 12 hours. After completion of the reaction, monitored by LCMS, slowly add the reaction mixture dropwise to 5N aqueous sodium hydroxide solution and extract with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The residue is purified by HPLC to yield C033 (50 mg).

[0454] Step 11: Purification by SFC separation (chromatographic column: DAICEL CHIRALCEL OJ (250*25mm 10μm); mobile phase A (CO2) and B (methanol containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 45%) to obtain products C033A (9.16 mg) and C033B (15.53 mg):

[0455] C033A:LCMS(ESI):m / z=391.2(M+H) + .,T=9.338min, 1 H NMR(400MHz,CD3OD)δ8.49(dd,J=8.4,1.6Hz,1H),8.21(s,1H),8.17(dd,J=4.0,1.6Hz,1H),7.6 6(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.44(s,1H),7.20(dd,J=8.4,4.0Hz,1H),2.08(s,3H).

[0456] C033B: LCMS (ESI): m / z=391.2(M+H)+, T=9.336min, 1 H NMR(400MHz,CD3OD)δ8.49(dd,J=8.4,1.6Hz,1H),8.21(s,1H),8.17(dd,J=4.0,1.6Hz,1H),7.6 6(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.44(s,1H),7.20(dd,J=8.4,4.0Hz,1H),2.08(s,3H).

[0457] Example 13: Preparation of Compound C034

[0458] Preparation method

[0459] Step 1: Dissolve compound C034-a (20 g, 128.11 mmol, 1.0 eq) in N,N-dimethylformamide (300 mL). Add N-chlorosuccinimide (25.7 g, 192.16 mmol, 1.5 eq) at 0°C and react overnight at room temperature. Add water to the reaction solution, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified on a silica gel column (10% ethyl acetate / petroleum ether) to afford compound C034-b (8.2 g). 1H NMR (400MHz, CDCl3) δ7.29 (dd, J=9.2, 7.2Hz, 1H), 6.56 (dd, J=9.2, 2.0Hz, 1H), 5.59 (s, 2H).

[0460] Step 2: C034-b (8.5 g, 44.61 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (80 mL), and N-bromosuccinimide (9.53 g, 53.53 mmol, 1.2 eq) was added portionwise. The mixture was reacted at 100°C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (10% ethyl acetate / petroleum ether) to afford compound C034-c (12.0 g).

[0461] Step 3: Dissolve C034-c (2 g, 7.42 mmol, 1.0 eq) and potassium iodide (4.93 g, 29.69 mmol, 4.0 eq) in acetonitrile (24 mL), sulfuric acid (6 mL), and water (22 mL). Add sodium nitrite (1.02 g, 14.85 mmol, 2.0 eq) in water (16 mL) at 0°C. React at 0°C for 0.5 h, then warm to room temperature and allow to react overnight. The reaction mixture is quenched with saturated aqueous sodium sulfite solution and extracted with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified on a silica gel column (100% petroleum ether) to afford compound C034-d (1.35 g). 1 H NMR (400MHz, CDCl3) δ7.87 (d, J=6.8Hz, 1H).

[0462] Step 4: Dissolve C034-d (4.1 g, 10.78 mmol, 1.0 eq) in methylamine in tetrahydrofuran (2 M, 40 mL) and allow to react at room temperature for 2 hours. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to obtain crude compound C034-e (4.65 g). The crude product was used directly in the next step without purification. LCMS (ESI) m / z: 391.0 [M+H] + .

[0463] Step 5: Dissolve C034-e (4.65 g, 11.88 mmol, 1.0 eq) in ethanol (100 mL), add iron powder (6.64 g, 118.81 mmol, 10.0 eq), ammonium chloride (6.36 g, 118.81 mmol, 10.0 eq), and water (20 mL), and react at 60°C for 0.5 h. The reaction mixture was hot filtered, the filtrate diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified on a silica gel column (6% ethyl acetate / petroleum ether) to afford compound C034-f (2.71 g). LCMS (ESI) m / z: 361.0 [M+H] + .

[0464] Step 6: Dissolve C034-f (2.71 g, 7.50 mmol, 1.0 eq) in trimethyl orthoformate (30 mL), add p-toluenesulfonic acid monohydrate (143 mg, 0.75 mmol, 0.1 eq), and react at 85°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified on a silica gel column (5% methanol / dichloromethane) to obtain compound C034-g (2.65 g). LCMS (ESI) m / z: 371.0 [M+H] + .

[0465] Step 7: Dissolve C034-g (2.65 g, 7.14 mmol, 1.0 eq) in anhydrous 1,4-dioxane (35 mL), add compound C034-h (1.19 g, 7.14 mmol, 1.0 eq), tris(dibenzylideneacetone)dipalladium (653 mg, 0.71 mmol, 0.1 eq), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (826 mg, 1.43 mmol, 0.2 eq), and cesium carbonate (4.65 g, 14.27 mmol, 2.0 eq), and react at 120°C under nitrogen for 2 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (20% ethyl acetate / petroleum ether) to afford compound C034-i (1.25 g). LCMS (ESI) m / z: 409.2 & 411.2 [M+H] + .

[0466] Step 8: Dissolve malononitrile (1.87 g, 28.27 mmol, 6.0 eq) in anhydrous 1,4-dioxane (100 mL). Add sodium tert-butoxide (2.72 g, 28.27 mmol, 6.0 eq) at 0°C and react at room temperature under nitrogen for 0.5 hour. Then add C034-i (1.93 g, 4.71 mmol, 1.0 eq) and Pd(dppf)Cl2 (345 mg, 0.47 mmol, 0.1 eq). React at room temperature under nitrogen for 10 minutes, then raise the temperature to 110°C and react overnight under nitrogen. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified on a silica gel column (60% ethyl acetate / petroleum ether) to afford compound C034-j (1.18 g). LCMS (ESI) m / z: 395.0 [M+H] + .

[0467] Step 9: Dissolve C034-j (1.13 g, 2.86 mmol, 1.0 eq) in tetrahydrofuran (25 mL), add triethylamine (869 mg, 8.59 mmol, 3.0 eq) and trifluoroacetic anhydride (1.20 g, 5.72 mmol, 2.0 eq), and react at room temperature for 2 hours. The reaction solution is diluted with water, extracted with ethyl acetate, and the organic phases are combined. Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is purified on a silica gel column (2%-6% methanol / dichloromethane) to obtain compound C034-k (580 mg). LCMS (ESI) m / z: 491.3 [M+H] + .

[0468] Step 10: Dissolve C034-k (530 mg, 1.08 mmol, 1.0 eq) in ethanol (5 mL), add iron powder (603 mg, 10.80 mmol, 10.0 eq), ammonium chloride (578 mg, 10.80 mmol, 10.0 eq), and water, and react at 60°C for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL x 2). The filtrate was diluted with water and extracted with ethyl acetate. The organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified on a silica gel column (3% methanol / dichloromethane) to afford C034-l (310 mg). LCMS (ESI) m / z: 461.3 [M+H] + .

[0469] Step 11: Dissolve C034-1 (560 mg, 1.22 mmol, 1.0 eq) in anhydrous toluene (19 mL) and glacial acetic acid (1 mL). Add isoamyl nitrite (285 mg, 2.43 mmol, 2.0 eq) dropwise at 0°C and react under nitrogen at 0°C for 1 hour. Add potassium acetate (358 mg, 3.65 mmol, 3.0 eq) and react overnight at room temperature under nitrogen. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified on a silica gel column (0-6% methanol / dichloromethane) to afford compound C034-m (240 mg). LCMS (ESI) m / z: 472.3 [M+H] + .

[0470] Step 12: Dissolve C034-m (220 mg, 0.47 mmol, 1.0 eq) in a mixture of methanesulfonic acid:sulfuric acid:water (86:13:1) (8 mL) and allow to react at room temperature for 1 hour. Add DL-methionine (278 mg, 1.87 mmol, 4.0 eq) and allow to react overnight at 60°C. After completion of the reaction, monitored by LCMS, the reaction solution was slowly added dropwise to a 5N aqueous sodium hydroxide solution. Extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (46%-56% acetonitrile / formic acid solution) to obtain compound C034 (30 mg). LCMS (ESI) m / z: 394.2 [M+H] + .

[0471] Step 13: Compound C034 (30 mg, 0.08 mmol, 1.0 eq) was subjected to chiral separation (chromatographic column: AD-30 (250*30mm 10μm); mobile phase A (CO2) and B (ethanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 55%), to obtain compounds C034A (6.41 mg) and C034B (11.82 mg):

[0472] C034A:LCMS(ESI)m / z:394.2[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ13.20(s,1H),7.73(s,1H),7.69(s,1H),7.65–7.60(m,1H), 7.44–7.40(m,1H),7.39(s,1H),6.77(s,2H),6.44(s,2H),3.99(s,3H),2.00(s,3H).

[0473] C034B:LCMS(ESI)m / z:394.1[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ13.20(s,1H),7.73(s,1H),7.69(s,1H),7.65–7.61(m,1H), 7.44–7.40(m,1H),7.39(s,1H),6.77(s,2H),6.44(s,2H),3.99(s,3H),2.00(s,3H).

[0474] Example 14: Preparation of Compound C035

[0475] Preparation method

[0476] Step 1: Dissolve C035-a (25.0 g, 187.70 mmol, 1 eq.) in N,N-dimethylformamide (250 ml), then slowly add N-chlorosuccinimide (27.64 g, 206.47 mmol, 1.1 eq.) to the reaction flask and react at room temperature for 23 hours. After completion of the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C035-b (9.0 g). LCMS (ESI) m / z: 168.1 [M+H] + , 1 H NMR (400 MHz, acetone-d6) δ 6.86 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.48 (s, 2H), 2.88–2.84 (m, 2H), 2.79–2.77 (m, 2H), 2.06–2.04 (m, 2H).

[0477] Step 2: Dissolve C035-b (2.0 g, 11.93 mmol, 1 eq.), compound C035-c (3.96 g, 14.32 mmol, 1.2 eq.), tris(dibenzylideneacetone)dipalladium (1.09 g, 1.19 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (1.38 g, 2.39 mmol, 0.2 eq.), and cesium carbonate (11.67 g, 35.79 mmol, 3.0 eq.) in ultra-dry 1,4-dioxane, then replace the atmosphere with nitrogen three times. The reaction mixture was incubated at 90°C for 12 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to afford compound C035-d (1.2 g). LCMS (ESI) m / z: 358.3 [M+H+ACN] + , 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.12(s,1H),6.89(d,J=8.4H z,1H),5.76(d,J=8.4Hz,1H),2.89(t,J=7.6Hz,4H),2.23(s,3H),2.20(s,3H),2.15–2.03(m,2H).

[0478] Step 3: Dissolve compound C035-d (1.2 g, 3.79 mmol, 1.0 eq.) in ultra-dry tetrahydrofuran (15 mL). The reaction mixture was cooled to -78°C, and N-bromosuccinimide (742 mg, 4.17 mmol, 1.1 eq.) was added portionwise. The reaction mixture was allowed to react at -78°C for half an hour. After the reaction, the mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to obtain compound C035-e (900 mg). LCMS (ESI) m / z: 395.2 & 397.2 [M+H] + .

[0479] Step 4: Dissolve malononitrile (450 mg, 6.81 mmol, 3.0 eq.) in ultra-dry 1,4-dioxane (20 ml). The reaction mixture was cooled to 0°C, and then sodium tert-butoxide (763 mg, 7.95 mmol, 3.5 eq.) was added. The reaction mixture was allowed to react at room temperature for 1 hour. Then, C035-e (900 mg, 2.27 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (166 mg, 0.23 mmol, 0.1 eq.) were added. The reaction mixture was allowed to react at 110°C for 3 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to obtain compound C035-f (400 mg). LCMS (ESI) m / z: 381.0 [M+H] + .

[0480] Step 5: C035-f (400 mg, 1.05 mmol, 1.0 eq.), di-tert-butyl dicarbonate (275 mg, 1.26 mmol, 1.2 eq.), and triethylamine (318 mg, 3.15 mmol, 3.0 eq.) were dissolved in ultra-dry tetrahydrofuran (15 ml), and 4-dimethylaminopyridine (13 mg, 0.10 mmol, 0.1 eq.) was slowly added to the reaction solution. The reaction solution was reacted at room temperature for 4 hours. After completion of the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound C035-g (500 mg, crude product). LCMS (ESI) m / z: 481.2 [M+H] + .

[0481] Step 6: Dissolve compound C035-g (500 mg, 1.04 mmol, 1.0 eq), iron powder (582 mg, 10.39 mmol, 10.0 eq), and ammonium chloride (556 mg, 10.39 mmol, 10.0 eq) in ethanol (20 mL) and water and react at 80°C for 1 hour. The reaction mixture was filtered while hot, and the filtrate was added to saturated brine and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (60% ethyl acetate / petroleum ether) to obtain compound C035-h (300 mg). LCMS (ESI) m / z: 451.3 [M+H] + .

[0482] Step 7: Compound C035-h (400 mg, 0.887 mmol, 1.0 eq) was dissolved in anhydrous toluene (20 mL) and glacial acetic acid (1 mL). The reaction mixture was cooled to 0°C, and then isoamyl nitrite (208 mg, 1.77 mmol, 2.0 eq) was added. The reaction was maintained at 0°C for 1 hour. Potassium acetate (304 mg, 3.10 mmol, 3.5 eq) was then added, and the reaction was continued at room temperature for 16 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove excess solvent. The residue was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to obtain compound C035-i (200 mg). LCMS (ESI) m / z: 462.3 [M+H] + .

[0483] Step 8: Dissolve compound C035-i (200 mg, 0.43 mmol, 1.0 eq) in anhydrous ethanol (10 mL) and hydrochloric acid (5 mL, 6 N) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C035-j (200 mg). LCMS (ESI) m / z: 362.0 [M+H] + .

[0484] Step 9: Compound C035-j (200 mg, 0.554 mmol, 1.0 eq.) was dissolved in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and allowed to react at 40°C for 16 hours. After completion of the reaction, monitored by LCMS, the reaction solution was slowly added dropwise to a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to afford racemate C035 (60 mg).

[0485] Step 10: Chiral preparative separation (chromatographic column: OJ-30 (250*25mm 10mm); mobile phase: A (CO2) and B (methanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 40%), purification, to give C035A (23.44 mg) and C035B (17.23 mg):

[0486] C035A:LCMS(ESI)m / z:380.2[M+H] + , 1H NMR (400MHz, CD3OD) δ7.70(d,J=8.4Hz,1H),7.57(s,1H),7.52–7.43(m,2H),2.89–2.78(m,2H),2.16–2.06(m,4H),1.85–1.69(m,3H).

[0487] C035B:LCMS(ESI)m / z:380.2[M+H] + , 1 H NMR (400MHz, CD3OD) δ7.69(d,J=8.4Hz,1H),7.57(s,1H),7.52–7.42(m,2H),2.91–2.74(m,2H),2.19–2.01(m,4H),1.88–1.68(m,3H).

[0488] Example 15: Preparation of Compound C036

[0489] Preparation method

[0490] Step 1: Dissolve compound C046-c (800 mg, 4.371 mmol, 1 eq.), compound 1 (1.224 g, 4.371 mmol, 1 eq.), tris(dibenzylideneacetone)dipalladium (400 mg, 0.457 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (506 mg, 0.874 mmol, 0.2 eq.), and cesium carbonate (4.262 g, 13.11 mmol, 3 eq.) in 1,4-dioxane (20 ml), then replace the atmosphere with nitrogen. The reaction mixture was incubated at 90°C for 12 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the resulting crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C036-a (600 mg). LCMS (ESI) m / z: 326.2 [M+H] + .

[0491] Step 2: Dissolve C036-a (700 mg, 2.089 mmol, 1 eq.) in acetonitrile (30 ml), then replace the atmosphere with nitrogen. Add N-bromosuccinimide (390 mg, 2.194 mmol, 1.05 eq.) in portions at 0°C, and incubate the reaction mixture at 0°C for half an hour. After the reaction is complete, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The resulting crude product is purified by column chromatography (3% methanol / dichloromethane) to obtain compound C036-b (370 mg). LCMS (ESI) m / z: 412.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ7.54(s,1H),6.92(d,J=12.0Hz,1H),6.52(s,1H),4.11(s, 2H),3.80–3.76(m,2H),3.73(d,J=0.8Hz,3H),2.65(t,J=6.0Hz,2H),1.94(s,6H).

[0492] Step 3: Dissolve malononitrile (335 mg, 5.084 mmol, 5.0 eq.) in 1,4-dioxane (35 mL) and replace the atmosphere with nitrogen. Add sodium tert-butoxide (488 mg, 5.084 mmol, 5.0 eq.) at 0°C, and let the reaction stand at room temperature for 1 hour. Then, add C036-b (420 mg, 1.016 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (74 mg, 0.102 mmol, 0.1 eq.). Let the reaction stand at 90°C for 16 hours. After completion of the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. Wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo. The resulting crude product is purified by silica gel column chromatography (3% methanol / dichloromethane) to yield compound C036-c (108 mg). LCMS (ESI) m / z: 400.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ7.25(d,J=12.0Hz,1H),7.20(s,1H),6.81(s,2H),4.44(s,2H),3.8 6(s,3H),3.84(s,2H),3.76(t,J=5.6Hz,2H),2.70(t,J=5.6Hz,2H),1.83(d,J=3.2Hz,6H).

[0493] Step 4: Dissolve C036-c (108 mg, 0.271 mmol, 1.0 eq.) in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water in 12 mL of methanesulfonic acid) and stir at room temperature for 90 min. Add methionine (161 mg, 1.083 mmol, 4 eq.) to the reaction mixture and react at 60°C for 16 h. After completion of the reaction, monitored by LCMS, slowly add the reaction mixture dropwise to 5N sodium hydroxide solution and extract with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The residue is purified by HPLC to yield C036 (20 mg).

[0494] Step 5: Purification by SFC separation (chromatographic column: DAICEL CHIRALPAK IC (250*25mm 10μm); mobile phase A (CO2) and B (methanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 35%) to obtain products C036A (5.46 mg) and C036B (4.69 mg):

[0495] C036A: LCMS (ESI): m / z=404.2(M+H)+, T=9.710min, 1 H NMR (400MHz, CD3OD) δ7.60(s,1H),7.02(d,J=11.2Hz,1H),4.01(s,2H),3.82(t,J=6.0Hz,2H),2.82(t,J=5.6Hz,2H),1.89(s,3H),1.88(s,3H).

[0496] C036B: LCMS (ESI): m / z=404.2(M+H)+, T=9.701min, 1 H NMR (400MHz, CD3OD) δ7.60(s,1H),7.02(d,J=11.2Hz,1H),4.01(s,2H),3.82(t,J=6.0Hz,2H),2.82(t,J=5.6Hz,2H),1.89(s,3H),1.88(s,3H).

[0497] Example 16: Preparation of Compound C037

[0498] Preparation method

[0499] Step 1: Compound C024 (130 mg, 0.333 mmol, 1 eq.), cyclopropylboronic acid (57 mg, 0.666 mmol, 2.0 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (28 mg, 0.0333 mmol, 0.1 eq.), and cesium carbonate (325 mg, 0.999 mmol, 3.0 eq.) were dissolved in toluene and water, and the atmosphere was replaced with nitrogen three times. The reaction mixture was reacted at 80°C for 16 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by high-performance liquid chromatography to obtain C037 (20.11 mg). LCMS (ESI) m / z: 397.2 [M+1] + .

[0500] Step 2: The product C037 was separated by chirality to obtain products C037A (4.78 mg) and C037B (5.59 mg):

[0501] C037A: LCMS(ESI):m / z=397.2(M+H)+, 1 H NMR (400MHz, CD3OD) δ8.31(d,J=5.6Hz,1H),8.14(d,J=5.6Hz,1H),8.09(d,J=0.8Hz,1H),8.00(s,1H),7.84(d,J=8. 8Hz,1H),7.62(d,J=8.8Hz,1H),7.55(s,1H),2.42–2.32(m,1H),2.14(s,3H),1.17–1.13(m,2H),0.91–0.86(m,2H).

[0502] C037B: LCMS(ESI):m / z=397.3(M+H)+, 1 H NMR (400MHz, CD3OD) δ8.29(d,J=5.6Hz,1H),8.13(d,J=6.0Hz,1H),8.08(d,J=0.8Hz,1H),8.00(s,1H),7.83(d,J=8. 8Hz,1H),7.62(d,J=8.4Hz,1H),7.54(s,1H),2.42–2.33(m,1H),2.14(s,3H),1.17–1.11(m,2H),0.92–0.84(m,2H).

[0503] Example 17: Preparation of Compound C038

[0504] Preparation method

[0505] Step 1: Dissolve compound C027 (150 mg, 0.38 mmol, 1.0 eq) in toluene (5 mL), add cyclopropylboronic acid (65 mg, 0.75 mmol, 2.0 eq), Ruphos.Pd.G3 (31 mg, 0.04 mmol, 0.1 eq), cesium carbonate (368 mg, 1.13 mmol, 3.0 eq), and water, and react at 100°C under nitrogen overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was concentrated, and the crude product was purified by preparative HPLC (15%-25% acetonitrile / formic acid in water) to obtain compound C038 (100 mg). LCMS (ESI) m / z: 405.3 [M+1] + .

[0506] Step 2: Compound C038 (100 mg, 0.25 mmol, 1.0 eq) was subjected to chiral separation to prepare compounds C038A (25.52 mg) and C038B (29.04 mg):

[0507] C038A:LCMS(ESI)m / z:405.2[M+1] + , 1 H NMR(400MHz, DMSO-d6)δ9.88(s,1H),8.27(d,J=6.0Hz,1H),8.18–8.12(m,2H),7.93(s,1H),7.30(d,J=11.6Hz,1 H),6.94(s,2H),6.59(s,2H),2.36–2.28(m,1H),1.78(s,3H),1.73(s,3H),1.08–1.00(m,2H),0.92–0.85(m,2H).

[0508] C038B:LCMS(ESI)m / z:405.3[M+1] + , 1 H NMR(400MHz, DMSO-d6)δ9.90(s,1H),8.27(d,J=6.0Hz,1H),8.18–8.13(m,2H),7.93(s,1H),7.30(d,J=11.6Hz,1 H),6.95(s,2H),6.59(s,2H),2.36–2.28(m,1H),1.78(s,3H),1.73(s,3H),1.07–1.00(m,2H),0.92–0.85(m,2H).

[0509] Example 18: Preparation of Compound C039

[0510] Preparation method

[0511] Step 1: Compound C024 (300 mg, 0.77 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and compound 1 (199 mg, 1.54 mmol, 2.0 eq), t-BuXphos.Pd.G3 (61 mg, 0.08 mmol, 0.1 eq), and sodium tert-butoxide (295 mg, 3.07 mmol, 4.0 eq) were added. The mixture was reacted at 100°C under nitrogen overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC (15%-25% acetonitrile / formic acid solution) to obtain compound C039 (60 mg). LCMS (ESI) m / z: 448.2 [M+1] + .

[0512] Step 2: Compound C039 (60 mg, 0.13 mmol, 1.0 eq) was subjected to chiral separation to prepare compounds C039A (11.55 mg) and C039B (11.23 mg):

[0513] C039A:LCMS(ESI)m / z:448.3[M+1] + , 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=6.0Hz,1H),7.89(s,1H),7.82(d,J=8.4Hz,1H),7.69(d,J=6.0Hz,1H),7.5 6(d,J=8.4Hz,1H),7.49(s,1H),7.46(s,1H),7.02(s,2H),6.58(s,2H),4.57(t,J=12.4Hz,4H),2.03(s,3H).

[0514] C039B:LCMS(ESI)m / z:448.3[M+1] + , 1 H NMR (400MHz, DMSO-d6) δ13.46(s,1H),8.07(d,J=6.0Hz,1H),7.88(s,1H),7.81(d,J=8.4Hz,1H),7.69(d,J=6.0Hz,1 H),7.57(d,J=8.4Hz,1H),7.49(s,1H),7.46(s,1H),7.02(s,2H),6.59(s,2H),4.57(t,J=12.4Hz,4H),2.04(s,3H).

[0515] Example 19: Preparation of Compound C040A

[0516] Preparation method

[0517] Step 1: Compound C027A (50 mg, 0.13 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (0.5 mL). Propylene solution (1 M in DMF) (0.75 mL, 0.75 mmol, 6.0 eq), Xphos.Pd.G3 (11 mg, 0.01 mmol, 0.1 eq), and cesium carbonate (123 mg, 0.38 mmol, 3.0 eq) were added. The mixture was reacted at 120°C under nitrogen for 6 hours. LCMS monitored the reaction completion. The reaction solution was filtered and directly purified by HPLC (18%-28% acetonitrile / formic acid in water) to obtain compound C040A (17.10 mg). LCMS (ESI) m / z: 403.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),8.43(s,1H),8.30(d,J=5.6Hz,1H),8.14(s,1H),8.03(d,J=5. 6Hz,1H),7.31(d,J=11.2Hz,1H),6.98(s,2H),6.73(s,2H),2.22(s,3H),1.78(s,3H),1.74(s,3H).

[0518] Example 20: Preparation of Compound C041

[0519] Preparation method

[0520] Step 1: Dissolve C024-b (22.0 g, 105.77 mmol, 1.0 eq.) in glacial acetic acid (100 mL). Cool the reaction mixture to 0°C, then slowly add sodium borohydride (6.4 g, 169.23 mmol, 1.6 eq.) to the reaction mixture. Gradually raise the reaction mixture temperature to room temperature for reaction. After the reaction is complete, slowly pour the reaction mixture into ice water and adjust the pH to greater than 10 with aqueous ammonia. A large amount of solid precipitates, which is filtered, washed with ice water, and dried to obtain compound C041-a (25.0 g, crude product), which is used directly in the next reaction. LCMS (ESI) m / z: 213.1 [M+H] + .

[0521] Step 2: C041-a (25.0 g, crude product) was dissolved in ultra-dry dichloromethane (300 mL), and then di-tert-butyl dicarbonate (34.59 g, 158.65 mmol, 1.5 eq.) and triethylamine (32.05 g, 317.31 mmol, 3.0 eq.) were added. The reaction solution was reacted at room temperature. After the reaction was completed, the reaction solution was diluted with dichloromethane and washed with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / petroleum ether) to obtain compound C041-b (15.0 g). 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=8.8Hz,1H),7.67(d,J=8.8Hz,1H),4.81(s,2H),3.65(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.41(s,9H).

[0522] Step 3: C041-b (15.0 g, 47.96 mmol, 1.0 eq.), iron powder (16.11 g, 287.76 mmol, 6.0 eq.), and ammonium chloride (15.40 g, 287.76 mmol, 6.0 eq.) were dissolved in anhydrous ethanol (200 mL) and water (20 mL). The reaction mixture was incubated at 80°C for 1 hour. After completion of the reaction, the reaction mixture was filtered while hot, the filter cake was washed with ethyl acetate, and the filtrate was added with saturated brine and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to yield compound C041-c (12.5 g). LCMS (ESI) m / z: 227.1 [M+H-56] + , 1 H NMR(400MHz,DMSO-d6)δ6.99(d,J=8.4Hz,1H),6.54(d,J=8.4Hz,1H),5.07(s ,2H),4.22(s,2H),3.54(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),1.43(s,9H).

[0523] Step 4: C041-c (10.0 g, 35.36 mmol, 1.0 eq.), compound C041-d (12.20 g, 53.05 mmol, 1.5 eq.), tris(dibenzylideneacetone)dipalladium (3.24 g, 3.54 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.09 g, 7.07 mmol, 0.2 eq.), and cesium carbonate (34.58 g, 106.08 mmol, 3.0 eq.) were dissolved in ultra-dry 1,4-dioxane (100 ml). The atmosphere was then purged with nitrogen three times, and the reaction mixture was reacted at 90°C for 16 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C041-e (8.0 g). LCMS (ESI) m / z: 376.2 [M+H-56] + , 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.4Hz,1H),7.02(d,J=8.4Hz,1H),6.84(d,J=8.0Hz,1H),6.68(d,J=8.0Hz,1H) ,4.98(s,1H),4.45(s,2H),3.67(t,J=6.0Hz,2H),2.88(t,J=6.0Hz,2H),2.25(s,3H),2.13(s,3H),1.47(s,9H).

[0524] Step 5: C041-e (10.0 g, 23.15 mmol, 1.0 eq.) was dissolved in glacial acetic acid (100 mL). The reaction solution was cooled to 0°C, and then liquid bromine (7.4 g, 46.30 mmol, 2.0 eq.) was slowly added dropwise to the reaction solution. The reaction solution was gradually warmed to room temperature and reacted for 3 hours. After the reaction was completed, the reaction solution was slowly added to a saturated sodium thiosulfate solution to quench the reaction. The pH was then adjusted to a weak base with sodium hydroxide solution (5 N), and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound C041-f (15.0 g). LCMS (ESI) m / z: 410.1 & 412.1 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.78(s,1H),7.16(s,1H),6.97(d,J=8.4Hz,1H),6.05(d,J=8.4Hz,1H),4.02 (d,J=16.8Hz,1H),3.49(d,J=16.4Hz,1H),3.02(t,J=6.0Hz,2H),2.69(t,J=5.6Hz,2H),2.15(s,3H),2.09(s,3H).

[0525] Step 6: C041-f (15.0 g, crude product) was dissolved in ultra-dry dichloromethane (200 mL), followed by the addition of di-tert-butyl dicarbonate (10.09 g, 46.30 mmol, 2.0 eq.) and triethylamine (7.01 g, 69.45 mmol, 3.0 eq.). The reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / petroleum ether) to afford compound C041-g (5.5 g). LCMS (ESI) m / z: 454.2 [M+H-56] + , 1 H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 6.90 (d, J = 8.4Hz, 1H), 6.23 (s, 1H), 5.19 (s, 1H), 4.93–4. 32(m,1H),4.10–3.20(m,3H),2.84(t,J=6.0Hz,2H),2.27(s,3H),2.21(s,3H),1.40(s,9H).

[0526] Step 7: Dissolve malononitrile (3.49 g, 52.84 mmol, 5.0 eq.) in ultra-dry 1,4-dioxane (200 ml). The reaction mixture was cooled to 0°C, and then sodium tert-butoxide (5.58 g, 58.12 mmol, 5.5 eq.) was added. The reaction mixture was allowed to react at room temperature for 1 hour. Then, C041-g (5.4 g, 10.57 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (772 mg, 1.06 mmol, 0.1 eq.) were added. The reaction mixture was allowed to react at 90°C for 16 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to obtain compound C041-h (4.2 g). LCMS (ESI) m / z: 496.4 [M+H] + ,1 H NMR (400MHz, DMSO-d6) δ7.65(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.21(s,1H),6.89(s,2H),3.96(d,J=16.4Hz,1H), 3.67(d,J=16.8Hz,1H),3.59–3.50(m,1H),3.44–3.36(m,1H),2.81–2.64(m,2H),2.37(s,3H),1.88(s,3H),1.29(s,9H).

[0527] Step 8: Dissolve C041-h (1.2 g, 2.42 mmol, 1.0 eq.), di-tert-butyl dicarbonate (633 mg, 2.90 mmol, 1.2 eq.), and triethylamine (733 mg, 7.26 mmol, 3.0 eq.) in ultra-dry tetrahydrofuran (15 ml), then slowly add 4-dimethylaminopyridine (30 mg, 0.24 mmol, 0.1 eq.) to the reaction mixture. The reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, it was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product which was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to afford C041-i (1.1 g). LCMS (ESI) m / z: 596.5 [M+H] + .

[0528] Step 9: C041-i (800 mg, 1.34 mmol, 1.0 eq), iron powder (750 mg, 13.40 mmol, 10.0 eq) and ammonium chloride (717 mg, 13.40 mmol, 10.0 eq) were dissolved in ethanol (20 mL) and water (4 mL) and reacted at 80°C for 1 hour. The reaction solution was filtered while hot, the filtrate was added with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain C041-j (600 mg). LCMS (ESI) m / z: 566.5 [M+H] + .

[0529] Step 10: Dissolve C041-j (600 mg, 1.06 mmol, 1.0 eq) in anhydrous toluene (20 mL) and glacial acetic acid (1 mL). The reaction mixture was cooled to 0°C, and then isoamyl nitrite (248 mg, 2.12 mmol, 2.0 eq) was added. The reaction was maintained at 0°C for 1 hour. Potassium acetate (364 mg, 3.71 mmol, 3.5 eq) was then added, and the reaction was allowed to proceed at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove excess solvent. The residue was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (40% ethyl acetate / petroleum ether) to yield compound C041-k (400 mg). LCMS (ESI) m / z: 577.5 [M+H] + , 1 H NMR (400MHz, CD3OD) δ7.67(s,1H),7.62(s,1H),7.35(d,J=7.6Hz,1H),7.21(d,J=7.2Hz,1H) ,4.27–4.05(m,1H),3.87–3.52(m,3H),2.97–2.81(m,2H),2.70(s,3H),1.40–1.25(m,18H).

[0530] Step 11: C041-k (400 mg, 0.43 mmol, 1.0 eq) was dissolved in anhydrous ethanol (10 mL) and hydrochloric acid (5 mL, 6 N) and reacted at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo, and the resulting residue was purified by reverse preparative purification to obtain the intermediate compound, which was then subjected to chiral preparative separation (chromatographic column: IG-30 (250*25mm 10mm); mobile phase: A (CO2) and B (isopropanol containing 0.1% 7 mol / L ammonia methanol solution); gradient: B% = 35%), to obtain compound C041-1 (20 mg). LCMS (ESI) m / z: 377.7 [M+H] + .

[0531] Step 12: Compound C041-1 (20 mg, 0.053 mmol, 1.0 eq.) was dissolved in 2 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and allowed to react at 60°C for 16 hours. After completion of the reaction, the reaction solution was slowly added dropwise to a 5N aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to yield C041 (9.73 mg). LCMS (ESI) m / z: 395.2 [M+H] + , 1H NMR (400MHz, CD3OD) δ8.49(s,1H),7.77(s,1H),7.71(s,1H),7.40(d,J=7.2Hz,1H),7.23(d,J=7.2Hz,1H ),3.77(d,J=15.6Hz,1H),3.25(t,J=6.4Hz,2H),3.19(d,J=15.6Hz,1H),3.10–2.99(m,2H),2.70(s,3H).

[0532] Example 21: Preparation of Compounds C042 and C043

[0533] Preparation method

[0534] Step 1: Compound C024 (400 mg, 1.025 mmol, 1 eq.), isopropenylboronic acid pinacol ester (344 mg, 2.051 mmol, 2.0 eq.), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) methanesulfonate (86 mg, 0.1025 mmol, 0.1 eq.), and potassium phosphate (653 mg, 3.077 mmol, 3.0 eq.) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was then purged with nitrogen and reacted at 80°C for 16 h. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted three times with ethyl acetate (15 mL). The organic phases were combined. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%) to obtain compound C042-b (300 mg). LCMS (ESI) m / z: 397.5 [M+H] + .

[0535] Step 2: Compound C042-b (300 mg, 0.757 mmol, 1.0 eq) and 10% palladium on carbon (300 mg) were dissolved in methanol (10 mL), then the atmosphere was replaced with hydrogen and the reaction was carried out at 25°C for 8 hours. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by HPLC to afford C042 (60 mg, 20% yield) and C043 (30 mg, 10% yield).

[0536] Step 3: Separate by SFC, chromatographic column: DAICEL CHIRALPAK IG (250*25mm 10μm); mobile phase A (CO2) and B (ethanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 30%, and purify to obtain products C042A (7.59 mg) and C042B (9.63 mg), as well as C043A (2.57 mg) and C043B (3.15 mg).

[0537] C042A: LCMS(ESI):m / z=399.2(M+H) + ,T=6.341min, 1 H NMR(400MHz,CD3OD)δ8.19(s,1H),8.10(d,J=6.0Hz,1H),8.07–8.00(m,2H),7.83(d,J=8.4Hz,1H ),7.62(d,J=8.8Hz,1H),7.56(s,1H),3.83–3.73(m,1H),2.15(s,3H),1.51(s,3H),1.50(s,3H).

[0538] C042B: LCMS(ESI):m / z=399.2(M+H) + ,T=6.348min, 1 H NMR(400MHz,CD3OD)δ8.19(s,1H),8.10(d,J=6.0Hz,1H),8.06–8.00(m,2H),7.83(d,J=8.4Hz,1H ),7.62(d,J=8.8Hz,1H),7.56(s,1H),3.84–3.73(m,1H),2.15(s,3H),1.51(s,3H),1.50(s,3H).

[0539] C043A: LCMS(ESI):m / z=399.3(M+H) + ,T=6.428min, 1 H NMR (400MHz, CD3OD) δ8.47(s,1H),8.16(s,1H),8.09(d,J=6.0Hz,1H),8.03(s,1H),7.91(d,J=6.0Hz,1H),7.83(d,J=8. 4Hz,1H),7.62(d,J=8.4Hz,1H),7.56(s,1H),3.18–3.10(m,2H),2.15(s,3H),1.89–1.75(m,2H),1.09(t,J=7.2Hz,3H).

[0540] C043B: LCMS(ESI):m / z=399.2(M+H) + ,T=6.432min, 1 H NMR (400MHz, CD3OD) δ8.17(s,1H),8.09(d,J=6.0Hz,1H),8.03(s,1H),7.91(d,J=6.0Hz,1H),7.83(d,J=8. 4Hz,1H),7.62(d,J=8.8Hz,1H),7.56(s,1H),3.18–3.11(m,2H),1.88–1.76(m,2H),1.09(t,J=7.2Hz,3H).

[0541] Example 22: Preparation of Compound C044A

[0542] Preparation method

[0543] Compound C024A (50 mg, 0.128 mmol, 1 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (11 mg, 0.0128 mmol, 0.1 eq.), and cesium carbonate (125 mg, 0.384 mmol, 3.0 eq.) were dissolved in tetrahydrofuran (1 mL) and propyne in N,N-dimethylformamide (1.28 mL, 1.28 mmol, 10 eq.), and the atmosphere was purged with nitrogen. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by high-performance liquid chromatography to yield C044A (10.09 mg). LCMS (ESI): m / z = 395.2 (M+H) + .,T=6.279min, 1 H NMR(400MHz,CD3OD)δ8.42(s,1H),8.15(q,J=6.0Hz,2H),7.98(s,1H),7.85(d ,J=8.8Hz,1H),7.63(d,J=8.8Hz,1H),7.58(s,1H),2.22(s,3H),2.15(s,3H).

[0544] Example 23: Preparation of Compound C045

[0545] Preparation method

[0546] Step 1: Compound C027A (50 mg, 0.13 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1 mL). t-BuXphos.Pd.G3 (20 mg, 0.03 mmol, 0.2 eq), t-BuXphos (11 mg, 0.03 mmol, 0.2 eq), sodium tert-butoxide (24 mg, 0.25 mmol, 2.0 eq), and methanol (20 mg, 0.63 mmol, 5.0 eq) were added. The mixture was reacted at 50°C under nitrogen overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was purified by preparative purification (12%-22% acetonitrile / formic acid in water) to obtain compound C045A (18.09 mg). LCMS (ESI) m / z: 395.2 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.19(d,J=5.6Hz,1H),8.07(s,1H),7.89(d,J=5.6Hz,1H),7.6 3(s,1H),7.29(d,J=11.6Hz,1H),6.98(s,2H),6.60(s,2H),4.07(s,3H),1.79(s,3H),1.74(s,3H).

[0547] Example 24: Preparation of Compound C046

[0548] Preparation method

[0549] Step 1: Dissolve compound C046-a (4 g, 21.74 mmol, 1 eq.) and pyridine (17.195 g, 217.39 mmol, 10 eq.) in dichloromethane (50 ml), replace the atmosphere with nitrogen, and then add trifluoromethanesulfonic anhydride (12.26 g, 43.47 mmol, 2 eq.) at 0°C. React at 0°C for 3 h. After completion of the reaction, pour the reaction mixture into ice water and extract three times with ethyl acetate. The organic phases are combined, washed with 10% citric acid solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain crude compound C046-b (6.5 g). 1 H NMR (400MHz, CDCl3) δ7.34(d,J=8.8Hz,1H),7.11(d,J=8.8Hz,1H),4.80(d,J=4.0Hz,3H),4.00(t,J=6.0Hz,3H),2.86(t,J=6.0Hz,2H).

[0550] Step 2: Dissolve C046-b (6.848 g, 21.74 mmol, 1 eq.), tert-butyl carbamate (5.096 g, 43.48 mmol, 2 eq.), Pd2(dba)3 (1.990 g, 2.174 mmol, 0.1 eq.), xantphos (2.516 g, 4.348 mmol, 0.2 eq.), and Cs2CO3 (21.196 g, 65.22 mmol, 3 eq.) in 1,4-dioxane (100 ml) and replace the atmosphere with nitrogen. The reaction mixture was incubated at 90°C for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to afford C046-c (757 mg). LCMS (ESI) m / z: 184.1 [M+H] + .

[0551] Step 3: C046-c (1.0 g, 5.46 mmol, 1 eq.), C046-d (1.250 g, 5.46 mmol, 1 eq.), Pd2(dba)3 (500 mg, 0.546 mmol, 0.1 eq.), xantphos (630 mg, 1.09 mmol, 0.2 eq.), and Cs2CO3 (5.320 g, 16.39 mmol, 3 eq.) were dissolved in 1,4-dioxane (30 ml) and the atmosphere was replaced with nitrogen. The reaction mixture was incubated at 70°C for 24 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (40% ethyl acetate / petroleum ether) to obtain compound C046-e (550 mg). LCMS (ESI) m / z: 332.3 [M+H] + .

[0552] Step 4: Dissolve C046-e (570 mg, 1.716 mmol, 1 eq.) in acetonitrile (15 ml) and replace the atmosphere with nitrogen. Add NBS (321 mg, 1.803 mmol, 1.05 eq.) at 0°C, and incubate the reaction at 0°C for 0.5 h. After completion of the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product is purified by column chromatography (3% methanol / dichloromethane) to obtain compound C046-f (310 mg). LCMS (ESI) m / z: 412.2 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ7.81(s,1H),7.12(s,1H),6.97(d,J=8.4Hz,1H),6.07(d,J=8.4Hz ,1H),3.87(t,J=5.6Hz,2H),3.33(s,2H),2.73(t,J=5.6Hz,2H),2.13(s,3H),2.09(s,3H).

[0553] Step 5: Dissolve C046-f (742 mg, 11.24 mmol, 5.0 eq.) in 1,4-dioxane (100 ml) and replace the atmosphere with nitrogen. Add sodium tert-butoxide (1079 mg, 11.24 mmol, 5.0 eq.) at 0°C, and let the reaction sit at room temperature for 1 hour. Then, add malononitrile (922 mg, 2.248 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (164 mg, 0.2248 mmol, 0.1 eq.). Let the reaction sit at 90°C for 12 hours. After completion of the reaction, dilute with water, extract with ethyl acetate, and combine the organic phases. Wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. The resulting crude product is purified by column chromatography (3% methanol / dichloromethane) to yield C046-g (180 mg). LCMS (ESI) m / z: 397.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ7.64(d,J=8.0Hz,1H),7.52(d,J=8.0Hz,1H),7.21(s,1H),6.92(s,2H),3.97(d,J= 14.8Hz,1H),3.77(d,J=4.0Hz,1H),3.75(d,J=5.6Hz,2H),2.70(t,J=5.6Hz,2H),2.38(s,3H),1.84(s,3H).

[0554] Step 6: Dissolve C046-g (485 mg, 1.22 mmol, 1.0 eq.), di-tert-butyl dicarbonate (534 mg, 2.45 mmol, 2.0 eq.), 4-dimethylaminopyridine (15 mg, 0.122 mmol, 0.1 eq.), and triethylamine (371 mg, 3.674 mmol, 3.0 eq.) in tetrahydrofuran, then replace the atmosphere with nitrogen. The reaction mixture was incubated at 50°C for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to obtain compound C046-h (350 mg). LCMS (ESI) m / z: 497.2 [M+H]+ .

[0555] Step 7: Dissolve C046-h (463 mg, 0.777 mmol, 1.0 eq), iron powder (218 mg, 3.884 mmol, 5.0 eq), and ammonium chloride (206 mg, 3.884 mmol, 5 eq) in ethanol and water and react at 80°C for 1 hour. Filter the reaction mixture, add saturated brine to the filtrate, extract with ethyl acetate, and combine the organic phases. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain crude compound C046-i (310 mg). LCMS (ESI) m / z: 467.2 [M+1] + .

[0556] Step 8: Compound C046-i (384 mg, 0.824 mmol, 1.0 eq) was dissolved in anhydrous toluene and glacial acetic acid. Isoamyl nitrite (193 mg, 1.648 mmol, 2.0 eq) was added dropwise at 0°C and reacted under nitrogen at 0°C for 1 hour. Potassium acetate (243 mg, 2.472 mmol, 3.0 eq) was then added and the reaction was allowed to proceed overnight at room temperature under nitrogen. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a silica gel column (methanol / dichloromethane = 3%) to yield compound C046-j (150 mg). LCMS (ESI) m / z: 478.2 [M+1] + .

[0557] Step 9: Dissolve C046-j (150 mg, 0.31 mmol, 1.0 eq) in anhydrous ethanol (10 mL) and 6 M hydrochloric acid (5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C046-k (140 mg). LCMS (ESI) m / z: 378.1 [M+1] + .

[0558] Step 10: Dissolve C046-k (140 mg, 0.37 mmol, 1.0 eq.) in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water in 12 mL of methanesulfonic acid) and stir at room temperature for 90 min. Add methionine (221 mg, 1.48 mmol, 4 eq.) to the reaction mixture and react at 60°C for 12 h. After completion of the reaction, monitored by LCMS, the reaction mixture was slowly added dropwise to a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a silica gel column (methanol / dichloromethane = 6%) to yield compound C046-1 (100 mg). LCMS (ESI) m / z: 396.2 [M+1]+ .

[0559] Step 11: C046-1 (120 mg, 0.304 mmol, 1 eq.), potassium cyclopropyltrifluoroborate (450 mg, 3.04 mmol, 10 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (127 mg, 0.152 mmol, 0.5 eq.), and cesium carbonate (987 mg, 3.04 mmol, 10 eq.) were dissolved in toluene and water, then the atmosphere was replaced with nitrogen and the reaction was carried out at 110°C for 16 h. After completion of the reaction, the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by high-performance liquid chromatography to obtain C046 (15 mg).

[0560] Step 12: C046 was separated and purified by SFC (chromatographic column: DAICEL CHIRALPAK OD (250*25mm 10μm); mobile phase A (CO2) and B (methanol, containing 0.1% 7mol / L ammonia methanol solution); gradient: B% = 35%) to obtain products C046-A (3.45 mg) and C046-B (1.53 mg).

[0561] C046-A: LCMS (ESI): m / z=402.2(M+H)+, T=9.247min, 1 H NMR (400MHz, CD3OD) δ7.62(s,1H),7.36(d,J=7.2Hz,1H),7.24(s,1H),7.16(d,J=7.2Hz,1H),4.21(d,J=15.2Hz,1H),3.84–3.7 0(m,2H),3.65(d,J=14.8Hz,1H),2.92(t,J=6.0Hz,2H),2.70(s,3H),1.92–1.80(m,1H),0.94–0.89(m,2H),0.73–0.68(m,2H).

[0562] C046-B: LCMS (ESI): m / z=402.2(M+H)+, T=9.239min, 1H NMR (400MHz, CD3OD) δ7.62(s,1H),7.36(d,J=7.2Hz,1H),7.24(s,1H),7.16(d,J=7.2Hz,1H),4.21(d,J=14.8Hz,1H),3.83–3.7 3(m,2H),3.65(d,J=14.8Hz,1H),2.93(t,J=6.0Hz,2H),2.70(s,3H),1.91–1.83(m,1H),0.95–0.91(m,2H),0.73–0.67(m,2H).

[0563] Example 25: Preparation of Compound C047

[0564] Preparation method

[0565] Step 1: Compound C047-a (20 g, 63.12 mmol, 1.0 eq.), methylboronic acid (37.78 g, 631.15 mmol, 10 eq.), palladium acetate (4.289 g, 18.93 mmol, 0.3 eq.), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (18.05 g, 37.86 mmol, 0.6 eq.), and potassium phosphate (66.98 g, 315.57 mmol, 5.0 eq.) were dissolved in 1,4-dioxane and the atmosphere was purged with nitrogen. The reaction mixture was incubated at 90°C for 12 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with petroleum ether. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (100% petroleum ether) to obtain crude compound C047-b (8.1 g). 1 H NMR (400MHz, CDCl3) δ6.93 (t, J = 8.8 Hz, 1H), 2.18 (t, J = 1.6 Hz, 6H).

[0566] Step 2: Dissolve C047-b (8 g, 42.78 mmol, 1 eq.) and 5.4 M sodium methoxide solution (40 mL, 213.90 mmol, 5.0 eq.) in methanol, then replace the atmosphere with nitrogen. The reaction mixture was incubated at 80°C for 2 hours, followed by the addition of 5.4 M sodium methoxide solution (40 mL, 213.90 mmol, 5.0 eq.) and continued at 80°C for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with petroleum ether. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (100% petroleum ether) to afford C047-c (5.5 g). 1H NMR (400MHz, CDCl3) δ6.67 (d, J=11.2Hz, 1H), 3.83 (s, 3H), 2.10 (dd, J=14.6, 1.4Hz, 6H).

[0567] Step 3: Dissolve C047-c (5.5 g, 27.61 mmol, 1.0 eq), iron powder (7.731 g, 138.06 mmol, 5.0 eq), ammonium chloride (14.770 g, 276.13 mmol, 10 eq), and acetic acid (829 mg, 13.80 mmol, 0.5 eq) in ethanol and water and react at 80°C for 1 hour. The reaction mixture was filtered, the filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (7% ethyl acetate / petroleum ether) to afford C047-d (4.2 g). 1 H NMR (400MHz, DMSO-d6) δ6.07(d,J=12.0Hz,1H),4.84(s,2H),3.67(s,3H),1.92(d,J=1.2Hz,3H),1.88(s,3H).

[0568] Step 4: Dissolve C047-d (4.2 g, 24.82 mmol, 1 eq.) in concentrated hydrochloric acid (5.0 mL) and acetone (50 mL), then replace the atmosphere with nitrogen. Add aqueous sodium nitrite (2.055 g, 29.78 mmol, 1.2 eq, dissolved in 84 mL of water) at 0°C. The reaction mixture is incubated at 0°C for 0.5 h. Then, add aqueous potassium iodide (7.4 g, 49.64 mmol, 2.0 eq, dissolved in 8.4 mL of water). The reaction mixture is warmed to 25°C and allowed to react overnight. After completion, the reaction is quenched with saturated sodium sulfite solution, extracted with ethyl acetate, and the organic phases are combined. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography (petroleum ether) to yield compound C047-e (4.5 g). 1 H NMR (400MHz, DMSO-d6) δ6.95 (d, J = 12.0Hz, 1H), 3.77 (s, 3H), 2.28 (s, 3H), 2.26 (d, J = 2.4Hz, 3H).

[0569] Step 5: Compound C024-c (688 mg, 3.867 mmol, 1 eq.), C047-e (1.3 g, 4.640 mmol, 1.2 eq.), tris(dibenzylideneacetone)dipalladium (354 mg, 0.386 mmol, 0.1 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (447 mg, 0.773 mmol, 0.2 eq.), and cesium carbonate (3.778 g, 11.59 mmol, 3 eq.) were dissolved in 1,4-dioxane, and the atmosphere was replaced with nitrogen. The reaction mixture was reacted at 90°C for 16 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (30% ethyl acetate / petroleum ether) to afford C047-f (550 mg). LCMS (ESI) m / z: 331.2 [M+H] + .

[0570] Step 6: C047-f (500 mg, 1.520 mmol, 1 eq.) was dissolved in acetonitrile (20 mL), and then the atmosphere was replaced with nitrogen. N-bromosuccinimide (283 mg, 1.59 mmol, 1.05 eq.) was added at 0°C, and the reaction mixture was reacted at 0°C for half an hour. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (3% methanol / dichloromethane) to obtain C047-g (420 mg). LCMS (ESI) m / z: 411.0 [M+H] + , 1 HNMR(400MHz,DMSO-d6)δ9.42(s,1H),8.66(d,J=6.0Hz,1H),8.04(s,1H),8.01(s,1H),7.9 2(d,J=5.6Hz,1H),6.72(d,J=12.0Hz,1H),3.77(s,3H),1.85(d,J=2.0Hz,3H),1.82(s,3H).

[0571] Step 7: Dissolve malononitrile (413 mg, 6.26 mmol, 5 eq.) in 1,4-dioxane (50 ml) and replace the atmosphere with nitrogen. Add sodium tert-butoxide (601 mg, 6.26 mmol, 5 eq.) at 0°C, and let the reaction react at room temperature for 1 hour. Then, add C047-g (511 mg, 1.252 mmol, 1.0 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (92 mg, 0.125 mmol, 0.1 eq.). The reaction mixture is allowed to react at 110°C for 6 hours. After the reaction is complete, dilute with water, extract with ethyl acetate, and combine the organic phases. The organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product is purified by column chromatography (3% methanol / dichloromethane) to yield C047-h (110 mg). LCMS (ESI) m / z: 395.1 [M+H] + .

[0572] Step 8: C047-h (110 mg, 0.279 mmol, 1.0 eq.) was dissolved in 4 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and stirred at 60°C for 1 hour. Methionine (166 mg, 1.117 mmol, 4 eq.) was added to the reaction solution and reacted at 60°C for 12 hours. After completion of the reaction, the reaction solution was slowly added dropwise to a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (6% methanol / dichloromethane) to obtain C047-i (50 mg). LCMS (ESI) m / z: 405.2 [M+H] + .

[0573] Step 9: C047-i (50 mg, 0.125 mmol, 1 eq.), cyclopropylboronic acid (33 mg, 0.376 mmol, 3.0 eq.), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.0125 mmol, 0.1 eq.), and cesium carbonate (122 mg, 0.376 mmol, 3.0 eq.) were dissolved in toluene and water, then the atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by high performance liquid chromatography to obtain C047 (30 mg, 59.10%).

[0574] Step 10: Product C047 was subjected to chiral separation to obtain products C047A (5.03 mg) and C047B (4.41 mg).

[0575] C047A: LCMS (ESI): m / z=405.2.2(M+H)+, T=6.703min, 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),8.33(d,J=6.0Hz,1H),8.29(s,1H),8.23(d,J=6.0Hz,1H),8.04(s,1H) ,6.89(d,J=10.8Hz,1H),2.44–2.28(m,1H),1.77(d,J=2.4Hz,6H),1.17–1.08(m,2H),0.92–0.83(m,2H).

[0576] C047-P2: LCMS (ESI): m / z=405.4(M+H)+, T=6.703min, 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),8.33(d,J=6.0Hz,1H),8.29(s,1H),8.23(d,J=6.0Hz,1H),8.04(d,J=0.8Hz ,1H),6.89(d,J=10.8Hz,1H),2.44–2.30(m,1H),1.77(d,J=2.4Hz,6H),1.17–1.09(m,2H),0.93–0.83(m,2H).

[0577] Example 26: Preparation of Compound C048

[0578] Preparation method

[0579] Step 1: Compound INT1 (600 mg 0.92 mmol, 1.0 eq) and tricyclohexylphosphine (78.4 mg, 0.15 mmol, 0.3 eq) were dissolved in toluene (10 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (164 mg, 0.18 mmol, 0.2 eq) and tributyl(1-ethoxyethylene)tin (1.33 g, 3.68 mmol, 4 eq). The reaction mixture was purged with nitrogen three times and stirred at 100°C for 16 hours. After completion of the reaction, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound C048-a (500 mg, crude product), which was used directly in the next step. LCMS (ESI) m / z: 693.1 [M+H] + .

[0580] Step 2: Dissolve C048-a (500 mg, 0.73 mmol, 1.0 eq) in anhydrous ethanol (10 mL) and 6 M hydrochloric acid (5 mL) and react at 80°C under nitrogen for 1 hour. The reaction solution was concentrated in vacuo to obtain crude compound C048-b (270 mg), which was used directly in the next step. LCMS (ESI) m / z: 381.1 [M+1] + .

[0581] Step 3: Dissolve C048-b (270 mg, 0.71 mmol, 1.0 eq.) in 8 mL of a mixed acid solution (2 mL of concentrated sulfuric acid and 0.2 mL of water dissolved in 12 mL of methanesulfonic acid) and react at 60°C for 16 hours. After completion of the reaction, monitored by LCMS, the reaction solution was slowly added dropwise to a 5N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound C048-c (150 mg), which was used directly in the next step. LCMS (ESI) m / z: 405.2 [M+H] + .

[0582] Step 4: Dissolve C048-c (150 mg, 0.38 mmol, 1.0 eq.) in tetrahydrofuran (3 mL). Cool the system to -78°C using a dry ice acetone bath, then slowly add a solution of methylmagnesium bromide in tetrahydrofuran (1.14 ml, 1.14 mmol, 3.0 eq.) dropwise. Maintain the reaction at -78°C for 5 hours. After completion of the reaction, monitor the reaction by LCMS. After completion, quench the reaction with saturated ammonium chloride (20 mL), extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by HPLC to yield C048 (1.37 mg). LCMS (ESI) m / z: 415.3 [M+H] + , 1 H NMR(400MHz,CD3OD)δ8.73–8.64(m,1H),8.38(s,1H),8.08(d,J=18.2Hz,2H),7.8 3(d,J=8.6Hz,1H),7.62(d,J=8.6Hz,1H),7.54(s,1H),2.140(s,3H),1.90(s,6H).

[0583] Example 27: Preparation of Compound C050

[0584] Compound C049 (30 mg, 0.0753 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1 mL), and t-BuXphos.Pd.G3 (12 mg, 0.0151 mmol, 0.2 eq), t-BuXphos (7 mg, 0.0151 mmol, 0.2 eq), sodium tert-butoxide (15 mg, 0.0151 mmol, 2.0 eq), and methanol (24 mg, 0.753 mmol, 10.0 eq) were added. The mixture was reacted at 50°C under nitrogen overnight. The reaction solution was concentrated, and the crude product was purified by HPLC to afford C050 (6.2 mg, 20.87% yield) as a white solid.

[0585] LCMS (ESI) m / z: 395.2 [M+H] + .

[0586] 1 H NMR (400MHz, CD3OD) δ8.20(s,1H),8.15(d,J=6.0Hz,1H),8.08(d,J=6.0Hz,1H),7.65(s,1H),6.88(d,J=10.8Hz,1H),4.14(s,3H),1.79(m,6H).

[0587] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

[0588] Biological tests

[0589] Experimental Example 1: PKMYT1 Enzyme Assay (ADP-GLO)

[0590] A.Main Materials

[0591] 1. Reagents: Human MYT1 protein (05-176, Carna), Inactive CDK1 (C22-14G, Signalchem), DTT (DTT-TO, Sigma), ADP-Glo ​​(V9101, Promega)

[0592] 2. Consumables: 96-well polypropylene microplate (249944, Nunc), 384-well microplate (Optiplate 384, Perkin),

[0593] 3. Instruments: 665SYSTEM (665, LABCYTE), microplate low-speed centrifuge (TDZ5-WS, Xiangyi), HTS high-throughput drug screening multifunctional microplate reader (PHERAstar FSX, BMG)

[0594] B. Test Method

[0595] Determination of IC of PKMYT1 inhibitor compounds using the ADP-GLO assay 50 . Serially dilute the test compound 3-fold with DMSO in a 384-well dilution plate, with a final starting concentration of 1 μM. Transfer 100 nL of the diluted compound to a 384-well reaction plate using an ECHO aspirator, ensuring the DMSO content is 1%. Transfer 5 μL of 2X MYT1 enzyme solution to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes. Transfer 5 μL of 2X ATP and Inactive CDK1 solution to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 180 minutes. Transfer 5 μL of ADP-Glo ​​reagent to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 10 μL of ADP-Glo ​​Detection reagent to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. The RLU (Relative luminescence unit) signal was read using a BMG microplate reader. IC was calculated using the nonlinear fitting formula of XFit 5.5.0. 50 :

[0596] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×HillSlope)),

[0597] Where X is the log value of compound concentration, and Y is the inhibition rate (inhibition %).

[0598] Table 1. IC of inhibition of PKMYT1 kinase activity 50 (nM)

[0599] Experimental Example 2: Cell Viability Test (CCK8)

[0600] Reagents: SNU601 cells (CBP60507, Nanjing Kebai), RMPI1640 medium (Cellmax, CGM112.05), trypsin (Cellmax, CPT101.02), serum (GEMINI, 900-108), CCK8 (Bimake, B34304), 96-well cell culture plates (3599, Corning), 96-well dilution plates (651101, Greiner Bio-One)

[0601] Instruments: CO2 incubator (MX-M, ESCO), centrifuge (TD5, Shanghai Lu Xiangyi), cell counter (IC1000, Countstar), multifunctional microplate reader (Spark, Tecan)

[0602] Test Method

[0603] SNU601 cells (CCNE1-overexpressing gastric cancer cells) in the logarithmic proliferation phase were collected and counted, and resuspended in RMPI1640 medium. The cell suspension was inoculated into a 96-well cell culture plate with 100 μL per well and a seeding density of 6000 cells / well. Two replicates were set up and then cultured overnight at 37°C to allow the cells to adhere. The diluted compound was transferred to a 96-well cell culture plate with a maximum concentration of 10 μM and a 3-fold dilution. After the compound and cells were incubated for 72 hours, the culture medium was removed and the prepared CCK8 solution was added at 50 μL / well (CCK8: culture medium = 1:10, v:v). The culture plate was placed in an incubator and incubated at 37°C for another 2 hours. After the reaction was completed, the optical density signal of the analysis plate was read using a multifunctional microplate reader. The signal intensity indicated the degree of cell viability. The IC was obtained by curve fitting using Prism software (GraphPad7.0). 50 value.

[0604] Table 2. Cell viability test results (IC 50 , nM)

[0605] Experimental Example 3: Pharmacokinetic (PK) experiment in mice

[0606] Male C57BL / 6N mice (weighing 18-22 g) were fasted overnight before the experiment. The test compound was dissolved in the vehicle. The intravenous (iv) group (n=3) was administered 2 mg / kg intravenously, and the oral (po) group (n=3) was administered 10 mg / kg by oral gavage. Blood was collected from the orbital venous plexus 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. Approximately 0.08 mL of blood was collected at each time point and placed in a 1.5 mL centrifuge tube containing EDTA-2K anticoagulant. Blood samples were centrifuged within 2 hours (3200 g, 10 minutes, 4°C) to obtain plasma samples, which were frozen in a -70°C to -80°C ultra-low temperature freezer until processing. The plasma samples were taken out of the refrigerator and thawed at room temperature. 20 μL of plasma sample was added to each well of a 96-well plate, and then 120 μL of acetonitrile containing an internal standard was added to precipitate the protein. After vortex mixing, the samples were centrifuged at 4°C and 4950 g for 15 min. The supernatant was collected and mixed with an equal volume of 0.1% formic acid aqueous solution for LC-MS / MS analysis.

[0607] Table 3. PK experimental test results

[0608] The results showed that the test compounds exhibited good PK properties.

[0609] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein: Q is N or CR 1a ; X is N or CR 1b ; Y is N or CR 1c ; Z is N or CR 1d ; R 1 is -C(O)NHR 2 、-C(O)R 3 or -S(O)2R 3 ; R 2 is hydrogen, C 1-6 alkyl, -C 1-6 alkylene -C 1-6 alkoxy, -C 1-6 alkylene -C 6-10 aryl, C 6-10 aryl, C 3-6 cycloalkyl, or a 5 - 14 membered heteroaryl; Each R 3 is independently C 1-6 alkyl, C 3-6 cycloalkyl or C 6-10 aryl; R 1a 、R 1b 、R 1c and R 1d Each independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3- 6-ring hydrocarbon group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 1g 、-SR 1g 、-NR 1g R 1h 、-NHC(O)R 7 、-NHS(O)R 7 、-NHS(O)2R 7 、-C(O)R 1g 、-C(O)OR 1g 、-C(O)NR 1g R 1h 、-OC(O)R 1g 、-S(O)R 1g 、-S(O)OR 1g 、-S(O)NR 1g R 1h 、-S(O)2R 1g 、-S(O)2OR 1g 、-S(O)2NR 1g R 1h 、-OS(O)2R 1g 、-NR 1g -C(O)R 1h 、-NR 1g -C(O)OR 1h 、-NR 1g -S(O)2-R 1h 、-NR 1g -C(O)-NR 1g R 1h 、-C 1-6 Alkylene-R 1g 、-C 1-6 Alkylene-OR 1g and -C 1-6 Alkylene-NR 1g R 1h ; Ring A is selected from C 6-10 aryl and 5- to 14-membered heteroaryl; Ring B is selected from C 5-6 cycloalkyl, C 5-6 cycloalkenyl, phenyl, 5- or 6-membered heteroalkyl, 5- or 6-membered heteroalkenyl, and 5- or 6-membered heteroaryl, wherein said heteroalkyl, heteroalkenyl, and heteroaryl have 1 or 2 heteroatoms independently selected from N, O, and S; the common carbon atoms of ring B and ring D are designated as "a" and "b"; m and n are each 0, 1, 2, 3, 4, or 5; R a independently selected from C at each occurrence 1-6 alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC(O)R 7 , -NHS(O)R 7 , -NHS(O)2R 7 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -S-C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, and 5- to 14-membered heteroaryl, Optionally, when m is 2, 3, 4 or 5 and there are two adjacent Rs a then the two Rs a together with the two ring atoms to which they are attached form a ring C, and the ring C is selected from C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl and 5- to 14-membered heteroaryl; R b independently selected from halogen, =O, CN, NO2, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6- 10 aryl, 5- to 10-membered heteroaryl, -C 1-6 alkylene-C 6-10 aryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-(3- to 10-membered heterocyclic group), -C 1-6 alkylene-(5- to 10-membered heteroaryl), -OR 5 、-SR 5 、-NR 5 R 6 、-C 1-6 alkylene-OR 5 、-C 1-6 alkylene-NR 5 R 6 and -O-C 1-6 alkylene-NR 5 R 6 ; R 1g and R 1h each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl, and -C 1-6 alkylene-C 6-10 aryl, and -C 1-6 alkylene-5- to 14-membered heteroaryl; any of the above-mentioned alkyl, alkylene, alkenyl, alkynyl, alkynylene, cycloalkyl, heterocyclic, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl groups are optionally substituted each time they appear, where the term "optionally substituted" means optionally substituted by 1, 2, 3, or more substituents independently selected from the following groups: Halogen, =O, CN, NO2, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl, -C 1- 6-alkylene-C 6-10 aryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-(3- to 10-membered heterocyclic group), -C 1-6 alkylene-(5- to 14-membered heteroaryl), -C(O)R 5 , -OC(O)R 5 , -C(O)OR 5 , -OR 5 , -SR 5 , -S(O)R 5 , -S(O)2R 5 , -S(O)2NR 5 R 6 , -NR 5 R 6 , -C(O)NR 5 R 6 , -NR 5 -C(O)R 6 , -NR 5 -C(O)OR 6 , -NR 5 -S(O)2-R 6 , -NR 5 -C(O)-NR 5 R 6 , -C 1-6 alkylene-OR 5 , -C 1-6 alkylene-NR 5 R 6 and -O-C 1-6 alkylene-NR 5 R 6 , wherein said alkyl, alkylene, cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally further substituted by 1, 2, 3 or more substituents independently selected from the following groups: halogen, OH, =O, -C(O)O-tert-butyl, NH2, CN, NO2, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl and -C 1- 6-alkylene-C 6-12 aralkyl; R 5 and R 6 each independently at each occurrence is selected from H, C 1-6 alkyl, halo-C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 14-membered heteroaryl and -C 1-6 alkylene-C 6-12 aralkyl; and R 7 each independently selected from C 1-6 alkyl and halo C 1-6 alkyl, each time it appears Provided that the compound represented by formula (I) is not:

2. The compound according to claim 1, wherein Y is CR 1c .

3. The compound according to claim 1 or 2, wherein: R 1g and R 1h each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and -C 1-6 alkylene-C 6-10 aryl, and -C 1-6 alkylene-5- to 10-membered heteroaryl; Preferably, R 1g and R 1h are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6- 10 aryl, 5- to 10-membered heteroaryl, and -C 1-4 alkylene-C 6-10 aryl and -C 1-4 alkylene-5- to 10-membered heteroaryl; More preferably, R 1g and R 1h are each independently selected from H and C 1-6 alkyl each time they appear.

4. The compound according to any one of claims 1-3, wherein: (1)R 1a 、R 1b 、R 1c and R 1d Each independently selected from H, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 1g 、-SR 1g 、-NR 1g R 1h 、-NHC(O)R 7 、-NHS(O)R 7 、-NHS(O)2R 7 、-C(O)OR 1g 、-C(O)NR 1g R 1h 、-S(O)OR 1g 、-S(O)2R 1g 、-S(O)2NR 1g R 1h 、-C 1-6 Alkylene-R 1g 、-C 1-6 Alkylene-OR 1g and -C 1-6 Alkylene-NR 1g R 1h , wherein R 1g and R 1h are each independently optionally selected from H and C 1-6 alkyl each time they appear, and Any of the above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups is optionally substituted, each time it appears, with 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, -OR 5 、-SR 5 and -NR 5 R 6 , where R 5 and R 6 are each independently H at each occurrence; or (2)R 1a 、R 1b 、R 1c and R 1d are each independently selected from H, halogen, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl, 5-10 membered heteroaryl, OH, -OC 1-6 alkyl, NH2, -NHC 1-6 alkyl and -N(C 1- 6 alkyl)2, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, phenyl and heteroaryl is optionally substituted, at each occurrence, by 1, 2 or 3 substituents independently selected from halogen, C 1-6 alkyl, OH and NH2; or (3)R 1a 、R 1b 、R 1c and R 1d are each independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, -OC 1-6 alkyl, OH, CN, NO2, NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, and 5-10-membered heteroaryl, wherein the -OC 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl and OH; or (4)R 1b is H or C 1-6 alkyl, preferably H or C 1-4 alkyl, more preferably H or methyl; and / or R 1c is selected from H, halogen, C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo-C 1-6 alkyl, OH, CN, NO2, NH2 and 5- to 6-membered heteroaryl, more preferably H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-4 alkyl, CN, imidazolyl, thiazolyl and oxazolyl; and / or R 1d each independently is selected from H, halogen, OH, CN, NH2, -NHC 1-6 alkyl and -N(C 1-6 alkyl)2.

5. The compound according to any one of claims 1-4, wherein: Q is N; and / or X is CR 1b ; and / or Z is CR 1d ; and / or R 1 is -C(O)NHR 2 ; and / or R 2 is hydrogen or C 1-6 alkyl, preferably H.

6. The compound according to any one of claims 1-5, which has the structure shown by the following formula (I-A):

7. The compound according to any one of claims 1-6, wherein: (1)R 1c selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, OH, CN, NO2, NH2, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, phenyl and 5- to 6-membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, phenyl and heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, OH and NH2; Preferably, R 1c is selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, imidazolyl, thiazolyl and oxazolyl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, imidazolyl, thiazolyl and oxazolyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and OH; More preferably, R 1c is selected from H, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and OH; or (2)R 1c Selected from H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, OH, CN, NO2, NH2 and 5-6 membered heteroaryl, more preferably H, halogen, C 1-4 alkyl, halo C 1-4 alkyl, CN, imidazolyl, thiazolyl and oxazolyl, more preferably H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, CN, and / or (3)R 1d is NH2.

8. The compound according to any one of claims 1-7, wherein: The ring A is selected from C 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, and 8-, 9- or 10-membered bicyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl and the 8-, 9- or 10-membered bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S; Preferably, ring A is selected from phenyl, 5- or 6-membered monocyclic heteroaryl, and 8-, 9-, or 10-membered bicyclic heteroaryl, where the 5- or 6-membered monocyclic heteroaryl and the 8-, 9-, or 10-membered bicyclic heteroaryl each have 0, 1, 2, or 3 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S, and 1 or more ring carbon atoms in the 5- or 6-membered monocyclic heteroaryl or the 8-, 9-, or 10-membered bicyclic heteroaryl are optionally replaced by C(O); More preferably, ring A is phenyl or a 5- or 6-membered monocyclic heteroaryl, where the 5- or 6-membered monocyclic heteroaryl has 0, 1, or 2 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S, and 1 or more ring carbon atoms in the 5- or 6-membered monocyclic heteroaryl are optionally replaced by C(O); Wherein: Preferably, each time it is mentioned, the 5- or 6-membered monocyclic heteroaryl group is independently selected from furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl and pyridazinyl, more preferably 9. The compound according to any one of claims 1-8, wherein said ring A is wherein A 1 、A 2 and A 3 are each independently CH or N, and A 1 、A 2 and A 3 are not all N.

10. The compound according to any one of claims 1-9, which has the structure shown by the following formula (I-B):

11. The compound according to any one of claims 1-10, wherein ring A is selected from 12. The compound according to any one of claims 1-11, wherein: R a independently selected from C at each occurrence 1-6 alkyl, halo-C 1-6 alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC 1- 6alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -O-halo-C 1-6 alkyl, -S-C 1-6 alkyl, -S-halo-C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heteroalkyl, phenyl and 5 or 6 membered heteroaryl; Preferably, R a is independently selected from C 1-4 alkyl, halo C 1-4 alkyl, halogen, OH, SH, CN, NO2, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2 and C 3-6 cycloalkyl; Preferably, R a is independently selected from C 1-3 alkyl, halo C 1-3 alkyl, F, Cl, Br, I, OH, SH, CN, NO2, NH2, and cyclopropyl each time it appears; More preferably, R a is independently selected from methyl, ethyl, isopropyl, CHF2, CH2F, CF3, F, Cl, OH, NH2 and cyclopropyl each time it appears; Alternatively, when m is 2, 3, 4 or 5 and there are two adjacent Rs a then the two Rs a together with the two ring atoms to which they are attached form the ring C.

13. The compound according to any one of claims 1-12, wherein m is 3 or 4.

14. The compound according to any one of claims 1-13, wherein: The compound has a structure represented by the following formula (I-C): wherein R 8a and R 8b each is R a as defined in any one of claims 1 - 13; p is 1 or 2; A 1 、A 2 and A 3 are each independently CH or N, and A 1 、A 2 and A 3 Not all N; and wherein: Optionally, when there is one R a adjacent to R 8a said R a together with said R 8a forms, together with the two ring atoms to which they are attached, ring C as described in any one of claims 1-13; or Optionally, when there is one R a adjacent to R 8b the R a adjacent to R 8b together with the two ring atoms to which they are attached form ring C as described in any one of claims 1-13; or Optionally, when there are two Rs a adjacent to each other, the two Rs a together with the two ring atoms to which they are attached form ring C as described in any one of claims 1-13; Preferably, the compound has a structure represented by formula (I-D), (I-E), (I-F) or (I-x): wherein R 8a , R 8b , R 8c , R 8d and R 8e are each R a , as defined in any one of claims 1 - 13; q is 0, 1, or 2; and Wherein, optionally, R in the (I-D) or (I-F) 8a and R 8c , or R in the (I-E) or (I-F) 8b and R 8d , together with the two ring atoms to which they are attached, form ring C as described in any one of claims 1-13; or Preferably, the compound has the structure shown in formula (I-y): wherein R 8a , R 8b , R 8c and R 8e each is R a , as defined in any one of claims 1-13; q is 0 or 1; and wherein R 8a and R 8c together with the two ring atoms to which they are attached form ring C as described in any one of claims 1-13.

15. The compound according to claim 14, wherein R in the formula (I-C), (I-D), (I-E), (I-F), (I-x) or (I-y) 8a and R 8b are both not OH or SH.

16. A compound according to claim 14 or 15, wherein when the ring C is not formed, at least one R in the formula (I-C) a , R in the formula (I-D) 8c , R in the formula (I-E) 8d , R in the formula (I-F) 8c and R 8d in at least one of them, or R in the formula (I-x) 8e is OH.

17. The compound according to any one of claims 1-16, wherein: The ring C is selected from optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 3-6 heterocycloalkenyl, optionally substituted phenyl, optionally substituted 5- or 6-membered monocyclic heteroaryl, and optionally substituted 8-, 9- or 10-membered bicyclic heteroaryl, wherein the 3- to 6-membered heterocycloalkyl, the C 3-6 heterocycloalkenyl, the 5- or 6-membered monocyclic heteroaryl and the 8-, 9- or 10-membered bicyclic heteroaryl each have 0, 1, 2, 3 or 4 nitrogen atoms as ring members and 0, 1 or 2 ring members independently selected from O and S; Preferably, ring C is selected from optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 3- to 6-membered heterocycloalkenyl, optionally substituted 5- or 6-membered monocyclic heteroaryl, and optionally substituted 8-, 9-, or 10-membered bicyclic heteroaryl, where the 3- to 6-membered heterocycloalkyl, the 3- to 6-membered heterocycloalkenyl, the 5- or 6-membered monocyclic heteroaryl, and the 8-, 9-, or 10-membered bicyclic heteroaryl each have 0, 1, 2, 3, or 4 nitrogen atoms as ring members and 0, 1, or 2 ring members independently selected from O and S; More preferably, ring C is an optionally substituted 5- or 6-membered heterocycloalkyl, an optionally substituted 5- or 6-membered heterocycloalkenyl or an optionally substituted 5- or 6-membered monocyclic heteroaryl, wherein the 5- or 6-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkenyl or the 5- or 6-membered monocyclic heteroaryl each has 1, 2, 3 or 4 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S; More preferably, ring C is an optionally substituted 5-membered heterocycloalkyl, an optionally substituted 5-membered heterocycloalkenyl or an optionally substituted 5- or 6-membered monocyclic heteroaryl, wherein the 5-membered heterocycloalkyl, the 5-membered heterocycloalkenyl or the 5- or 6-membered monocyclic heteroaryl each has 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S; More preferably, ring C is selected from pyrrolidinyl, 2,3-dihydro-1H-pyrrolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, each of these groups being optionally substituted; More preferably, the ring C is an optionally substituted 5-membered monocyclic heteroaryl having 1, 2 or 3 nitrogen atoms as ring members and 0 or 1 ring member independently selected from O and S, preferably an optionally substituted pyrazolyl or imidazolyl (e.g. ), more preferably optionally substituted pyrazolyl (e.g., )； wherein the "optionally substituted" independently has the meaning as defined in any one of claims 1-16 each time it appears.

18. A compound according to any one of claims 1-17, wherein is part of: Preferably 19. The compound according to claim 14, wherein: The compound of formula (I-D) has the structure shown in formula (I-G): including The compound of formula (I-E) has the structure shown in formula (I-H): including The compound of formula (I-x) has the structure shown in formula (I-x1) as follows: The compound of formula (I-D) has the structure shown in formula (I-J): including The compound of formula (I-F) has the structure shown in formula (I-K): including The compound of formula (I-y) has the structure shown in formula (I-y1) as follows:

20. The compound according to any one of claims 14-19, wherein: R 8a and R 8b are each independently methyl, ethyl, CHF2, CH2F, CF3, F or Cl, preferably methyl; More preferably, Part is: (including )、 (including )、 (including )、 (including )、 Or More preferably, Part is:

21. The compound according to any one of claims 1-20, wherein: The ring B is selected from C 5-6 cycloalkenyl, 5- or 6-membered heteroalkenyl, phenyl, and 5- or 6-membered heteroaryl, wherein the heteroalkenyl and heteroaryl have 1 or 2 heteroatoms independently selected from N, O, and S; Preferably, the ring B is selected from C 5-6 cycloalkenyl, 5- or 6-membered heteroalkenyl, and 5- or 6-membered heteroaryl, wherein the heteroalkenyl and heteroaryl have 1 or 2 heteroatoms independently selected from N, O, and S; More preferably, ring B is selected from cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, dihydrothiopyranyl, phenyl, pyrrolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, More preferably, ring B is selected from Alternatively, the ring B is selected from wherein the common carbon atoms of ring B and ring D are designated as "a" and "b".

22. The compound according to any one of claims 1-21, wherein n is 0, 1 or 2; and / or R b independently selected from halogen, =O, CN, NO2, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6- 10 aryl, 5- to 10-membered heteroaryl, -C 1-4 alkylene-C 6-10 aryl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-(3- to 10-membered heterocyclic group), -C 1-4 alkylene-(5- to 10-membered heteroaryl), -OR 5 , -SR 5 , -NR 5 R 6 , -C 1-4 alkylene-OR 5 , -C 1-4 alkylene-NR 5 R 6 and -O-C 1-4 alkylene-NR 5 R 6 , where the alkyl, alkylene, cycloalkyl, heterocyclic group, aryl, heteroaryl and each is optionally substituted by 1, 2, 3 or more substituents independently selected from halogen, OH, =O, -C(=O)O-tert-butyl, NH2, CN, NO2, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl and -C 1-6 alkylene-C 6-10 aryl, and where R 5 and R 6 are each independently selected from H, C 1-6 alkyl, halo-C 1-6 alkyl and 3- to 10-membered heterocycloalkyl; Preferably, R b is independently selected from halogen, CN, NO2, OH, C 1-4 alkyl, halo-C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl, 5-6 membered heteroaryl, -OC 1-4 alkyl, -O-halo-C 1-4 alkyl, -SC 1-4 alkyl, -S-halo-C 1-4 alkyl, -NR 5 R 6 , -C 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-O-halo-C 1-4 alkyl, -C 1-4 alkylene-NR 5 R 6 and -O-C 1-4 alkylene-NR 5 R 6 , where R 5 and R 6 are each independently selected from H and C 1-4 alkyl at each occurrence; or Preferably, R b is independently selected, at each occurrence, from halogen, CN, NO2, OH, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -OC 1-4 alkyl, -O-halo C 1-4 alkyl, -SC 1-4 alkyl, -S-halo C 1-4 alkyl, -NR 5 R 6 , -C 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-O-halo C 1-4 alkyl, -C 1-4 alkylene-NR 5 R 6 and -O-C 1-4 alkylene-NR 5 R 6 , where R 5 and R 6 are each independently selected, at each occurrence, from H and C 1-4 alkyl, and where said heterocyclic group and heteroaryl each have 1 or 2 heteroatoms independently selected from N, O, and S; More preferably, R b is independently selected, at each occurrence, from halogen, CN, NO2, OH, C 1-4 alkyl, halo-C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, 5- to 6-membered heteroaryl, -OC 1-4 alkyl, -O-halo-C 1-4 alkyl, -SC 1-4 alkyl, -S-halo-C 1-4 alkyl, -NR 5 R 6 , -C 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-O-halo-C 1-4 alkyl, -C 1-4 alkylene-NR 5 R 6 and -O-C 1- 4-alkylene-NR 5 R 6 , where R 5 and R 6 are each independently selected, at each occurrence, from H and C 1-4 alkyl, and where the heteroalkyl and heteroaryl each have 1 or 2 heteroatoms independently selected from N, O, and S; Further more preferably, R b is independently selected from F, Cl, Br, CN, NO2, OH, C 1-4 alkyl, halo C 1- 4 alkyl, -OC 1-4 alkyl, -O-halo C 1-4 alkyl and -NR 5 R 6 , where R 5 and R 6 are each independently selected from H and C 1-4 alkyl each time they appear, or R b is independently selected from each time it appears Even more preferably, R b is independently selected from F, Cl, Br, CN, NO2, OH, methyl, ethyl, -OCH3, -O CH2CH3, -NH2, at each occurrence 23. The compound according to any one of claims 1-22, wherein said moiety is selected from: or The Partially selected from: wherein the common carbon atoms of ring B and ring D are designated as "a" and "b".

24. The compound according to claim 1, wherein: (1) The compound is represented by formula (II) or (III): wherein ring B is, independently each time it appears, Preferably and wherein the phenyl carbon atom indicated by "#" is not substituted with R a substituted; Preferably represented by formula (II-A), (II-B) or (III-A): The phenyl carbon atom indicated by "#" is not substituted by R a substituted; More preferably, it is represented by formula (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2) or (III-3): or (2) The compound is represented by formula (IV), (V) or (VI): wherein each occurrence of ring B is independently Preferably represented by formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (V-1) or (VI-1): wherein: R a each independently at each occurrence is C 1-4 alkyl or halogen, preferably methyl, F or Cl, more preferably methyl or F; s is independently 0, 1, 2 or 3 each time it appears; t is independently 0, 1 or 2 each time it appears; R 8a and R 8b each independently at each occurrence is C 1-4 alkyl, preferably methyl; R 8d and R 8e each independently at each occurrence is halogen, preferably F or Cl, more preferably F; and R b each independently being H or C at each occurrence 1-4 alkyl, preferably H or methyl; n is independently 0 or 1 each time it appears; R 1c Each independently selected from at each occurrence: Halogen, OH, CN, NO2, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, phenyl and 5- to 6-membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, phenyl and heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, OH and NH2; Preferably halogen, OH, CN, NO2, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl and 5-6 membered heteroaryl, wherein any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, phenyl and heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen and OH; More preferably, halogen, OH, CN, NO2, NH2, C 1-4 alkyl, halo C 1-4 alkyl, -C 1-4 alkylene-OH, C 2-4 alkenyl, C 2- 4-alkenyl, -OC 1-4 alkyl, -O-halo C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein any of the above cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and OH; Still more preferably, F, Cl, Br, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 25. The compound according to claim 24, wherein: (1) In the formula (II), (III), (IV), (V) or (VI), Partially selected from: Preferably or In the formula (II-1), (II-2), (II-3), (II-5), (III-1), (III-2), (III-3), (IV-1), (V-1) or (VI-1), Part is or In the formula (II-4), Part is or In the formula (IV-2), Part is or In the formula (IV-3) Part is or In the formula (IV-4), Part is or In the formula (IV-5) Part is and / or (2) in the formula (II), (II-A) or (II-B) Part is (including )、 or In the formula (II-1), Part is or In the formula (II-2), Part is or In the formula (II-3) or (II-4), The part includes For example, it is (including )； or In the formula (II-5), Part is or In the formula (III) Part is (including )； or In the formula (III-1), Part is or In the formula (III-2), Part is or In the formula (III-3), The part includes For example, it is (including )； or in the formula (IV), (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5) The part includes For example, it is (including ) or or In the formula (V) or (V-1), Part is or In the formula (VI) or (VI-1), Part is and / or (3) Among the compounds represented by the formulas (II), (III), (II-A), (II-B), (III-A), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1), (III-2), or (III-3), R 1c is independently, each time it appears, F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, CHF2, CH2F, CF3, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy or difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and / or In the compounds represented by the formulas (IV), (V), (VI), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (V-1) or (VI-1), R 1c is independently, each time it appears, F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, -C(CH3)2OH, ethynyl, prop-1-yn-1-yl, propargyl, butynyl, methoxy or difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 26. The compound according to claim 24 or 25, wherein: (1) The compound is represented by formula (II-3A): wherein R 1c is halogen, OH, NH2, -OC 1-4 alkyl or C 3-6 cycloalkyl, preferably halogen, -OC 1-4 alkyl or C 3-6 cycloalkyl, more preferably F, Cl, methoxy, ethoxy, cyclopropyl or cyclobutyl, even more preferably Cl, methoxy or cyclopropyl; R 8a and R 8b are each independently C 1-4 alkyl, preferably methyl; and R 8e is halogen, preferably F or Cl, more preferably F; preferably, The portion includes For example, it is (including )； or (2) The compound is represented by the formula (IV-1A). wherein R 1c is halogen, OH, NH2, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, preferably halogen or C 2-4 alkynyl, more preferably F, Cl, ethynyl, prop-1-yn-1-yl, propargyl or butynyl, even more preferably Cl or prop-1-yn-1-yl; and R 8b is C 1-4 alkyl, preferably methyl or ethyl, more preferably methyl; Preferably, The part includes For example, it is (including )。 27. The compound according to claim 1, wherein the compound is selected from:

28. A pharmaceutical composition comprising the compound according to any one of claims 1-27 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

29. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, for use as a medicament, preferably as a membrane-associated tyrosine / threonine-protein kinase 1 (PKMYT1) inhibitor.

30. Use of a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, in the preparation of a medicament, preferably a PKMYT1 inhibitor.

31. A method for preventing or treating a PKMYT1-related disease, disorder or condition in an individual, wherein the method comprises: Administering to the individual a therapeutically effective amount of a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition according to claim 28, wherein the disease, disorder or condition is preferably cancer, more preferably uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer or endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, cholangiocarcinoma, pancreatic cancer and prostate cancer.

32. Use of a compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, metabolite, isotopically labeled compound or prodrug thereof, or the pharmaceutical composition according to claim 28, in the preparation of a medicament for preventing or treating a PKMYT1-mediated disease, disorder or condition in an individual, wherein the disease, disorder or condition is preferably cancer, more preferably uterine cancer, ovarian cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, colorectal cancer, lung cancer, endometrial cancer, liver cancer, head and neck cancer, esophageal cancer, cholangiocarcinoma, pancreatic cancer and prostate cancer.

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