Complement factor B inhibitor as well as pharmaceutical composition and application thereof

Abstract

The invention relates to complement factor B inhibitors of formula (I) and pharmaceutical compositions and uses thereof. # imgabs0 #

Description

Complement factor B inhibitor and its pharmaceutical composition and use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application document claims the priority of Chinese invention patent application 202211737515.0 with an application date of December 31, 2022 and Chinese invention patent application 202310699631.6 with an application date of June 13, 2023, and incorporates all their contents into this application as a whole by reference. Technical Field

[0003] The present application relates to a novel complement factor B inhibitor and its pharmaceutical composition and application. Background Art

[0004] The complement system is composed of over 40 proteins, including the intrinsic complement components C1 to C9, various regulatory factors, and complement receptors, and is a crucial component of the innate immune system. The complement system has three activation pathways: the classical pathway (CP), which involves the intrinsic components C1, C2, and C4; the lectin pathway (LP), which involves the mannose-binding lectin complex (MBL) and serine proteases; and the alternative pathway (AP), which involves complement factor B (FB) and complement factor D (FD).

[0005] FB is a trypsin-like serine protease that circulates in a zymogen form. FB is the primary component of the AP pathway. Upon activation, it binds to C3b, which is then cleaved by FD to produce a C3 convertase complex (C3bBb) containing the FB catalytic subunit (Bb). C3bBb then cleaves C3 to produce more C3b, thereby amplifying the activation of the entire complement system. Uncontrolled circulation of C3 leads to the deposition of large amounts of active C3b and terminal complement factors in the glomeruli, causing alterations in glomerular structure and function, and further triggering renal diseases associated with complement system involvement. Inhibiting FB activity can prevent AP pathway activation without interfering with the CP and LP pathways, thereby avoiding the increased risk of infection and other infections caused by complement system inhibition.

[0006] Currently, several drugs targeting the complement system have been approved for marketing, such as the C5 inhibitors Culizumab and Ravulizumab, and the C3 inhibitor Pegcetacoplan, with indications for atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria (PNH). However, clinical findings show that most PNH patients treated with C5 or C3 inhibitors fail to completely block AP activation and still experience mild to moderate extravascular hemolysis. There is still a significant unmet clinical need for complement-related diseases.

[0007] LNP023 (WO2015009616A1 and WO2019043609A1) is the first small molecule FB inhibitor developed by Novartis. It is currently in Phase III clinical trials for the treatment of diseases such as PNH, immunoglobulin A nephropathy (IgAN), and C3 glomerulopathy (C3G).

[0008] There is still an urgent need in this field to develop novel small molecule inhibitors of the complement system FB to increase clinical research and meet the treatment of various diseases or conditions caused by complement abnormalities.

[0009] Summary of the Invention

[0010] The present invention provides compounds that modulate, and preferably inhibit, complement alternative pathway activation.In some embodiments, the present invention provides compounds that modulate, and preferably inhibit, complement factor B (FB) activity and / or FB-mediated complement pathway activation.

[0011] The novel FB small molecule inhibitors of the present invention have high affinity for FB, can inhibit the catalytic activity of FB, and have a significant inhibitory effect on activation of the alternative complement pathway. Therefore, they have the potential to inhibit complement system expansion caused by C3 activation and prevent and treat diseases, disorders, or conditions mediated by complement activation, particularly those mediated by activation of the alternative complement pathway. The compounds of the present invention have further superior properties, such as 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.

[0012] In one aspect, the present invention provides a compound of formula (I) as defined below:

[0013] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0015] In another aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, and another therapeutically active agent.

[0016] In another aspect, the present invention provides a method for modulating complement alternative pathway activity in a subject, wherein the method comprises: administering to the subject a therapeutically effective amount of a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; or administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the present invention; or administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present invention.

[0017] In another aspect, the present invention provides a method for preventing or treating a disease, disorder or condition mediated by complement activation in an individual, particularly a disease, disorder or condition mediated by activation of the alternative complement pathway, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present invention.

[0018] In another aspect, the present invention provides a compound of formula (I) according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, or a pharmaceutical combination according to the present invention, for use as a medicament.

[0019] In another aspect, the present invention provides a compound of formula (I) according to the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition according to the present invention, or a pharmaceutical combination according to the present invention for the preparation of a medicament for treating a disease, disorder or condition mediated by complement activation in an individual, in particular a disease, disorder or condition mediated by activation of the complement alternative pathway.

[0020] In some embodiments, the disease, disorder or condition is selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian eye retinochoroiditis, sympathetic eye, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple sclerosis, Stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions resulting from inappropriate or undesirable complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2)-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia Blood, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or other renal diseases with evidence of glomerular C3 deposition (such as membranous nephropathy (MN) and Escherichia coli-induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity. DETAILED DESCRIPTION

[0021] definition

[0022] 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.

[0023] 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").

[0024] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0025] 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 6 (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 2-6 Alkyl", "C 2-5 Alkyl" and "C 1-4 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).

[0026] 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 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0027] As used herein, the term "heteroalkyl" means an alkyl group as defined herein, wherein one or more CH2 in the backbone is replaced by a heteroatom, each of which is independently selected from O, S, S(O), S(O)2, NR', and combinations thereof, wherein R' is a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 Alkyl. As used herein, the prefix "x yuan" or "x to y yuan" in combination with heteroalkyl represents the total number of C atoms and heteroatom members in the heteroalkyl backbone chain. In some embodiments, heteroalkylene can be, for example, 2 to 6 membered heteroalkylenes, 2 to 5 membered heteroalkylenes, or 2 to 4 membered heteroalkylenes (e.g., -CH2OCH2CH3, -CH2N(CH3)CH2CH3). Heteroalkylene can be connected to the rest of the molecule by heteroatoms or carbon atoms in the backbone chain.

[0028] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-6 carbon atoms ("C 2-6 The 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 compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0029] 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. The term "alkynylene" is a corresponding divalent group, including, for example, "C 2-6 Alkynylidene", "C 2-4 Examples include, but are not limited to, The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0030] 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 rings having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. It includes but is not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (ylidene) cyclohexyl (ring), (ylidene) cycloheptyl (ring), (ylidene) cyclooctyl (ring), (ylidene) cyclononyl (ring), (ylidene) cyclobutenyl (ring), (ylidene) cyclopentenyl (ring), (ylidene) cyclohexenyl (ring), (ylidene) cycloheptenyl (ring), (ylidene) cyclooctenyl (ring), (ylidene) cyclononenyl (ring) and the like.

[0031] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[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 term "bridged cycloalkyl" refers to a cyclic structure formed by two cycloalkyl groups as defined above, which share two ring carbon atoms connected via a carbon chain of 1 or more (e.g., 2) carbon atoms, and the cyclic structure can be saturated (i.e., "bridged cycloalkyl") or partially unsaturated (i.e., having one or more double bonds (i.e., "bridged cycloalkenyl") and / or triple bonds within the ring). In some embodiments, the "bridged cycloalkyl" group has, for example, 5-10 ring carbon atoms (C 5-10 ), for example 6 (C6), 7 (C7), 8 (C8) or 9 (C9) ring carbon atoms. The bridged cyclic hydrocarbon group is optionally substituted with one or more (such as 1 to 3) suitable substituents (such as halogen, methyl, methoxy, CN, NH2, methylamino). Examples that can be cited include: bicyclo[1.1.1]pentyl, for example Bicyclo[2.1.1]hexyl, for example Bicyclo[2.2.1]heptyl, for example Bicyclo[3.2.1]octyl; bicyclo[5.2.0]nonyl;

[0035] As used herein, the term "monospirocycloalkyl" refers to a cyclic structure formed by two cycloalkyl groups as defined above sharing one ring carbon atom, which ring structure can be saturated (i.e., "monospirocycloalkyl") or partially unsaturated (i.e., having one or more double bonds (i.e., "monospirocycloalkenyl") and / or triple bonds within the ring). In some embodiments, the "monospirocycloalkyl" has, for example, 5-11 ring carbon atoms (C 5-11 ), such as 6 (C6), 7 (C7), 8 (C8), 9 (C9) or 10 (C 10 ) ring carbon atoms.Monospirocyclic hydrocarbon groups include but are not limited to 5-11 membered monospirocyclic alkyls, 6-10 membered monospirocyclic alkyls, 7-10 membered monospirocyclic alkyls, 6-10 membered nitrogen-containing monospirocyclic alkyls, 6-10 membered oxygen-containing monospirocyclic alkyls, 6-10 membered sulfur-containing monospirocyclic alkyls; and 5-11 membered monospirocyclic alkenyls, 6-10 membered monospirocyclic alkenyls, 7-10 membered monospirocyclic alkenyls, 6-10 membered nitrogen-containing monospirocyclic alkenyls, 6-10 membered oxygen-containing monospirocyclic alkenyls, 6-10 membered sulfur-containing monospirocyclic alkenyls.Monospirocyclic hydrocarbon groups can include, for example, 3 yuan / 5 membered ring systems, 4 yuan / 4 membered ring systems, 4 yuan / 5 membered ring systems, 4 yuan / 6 membered ring systems, 5 yuan / 5 membered ring systems, 5 yuan / 6 membered ring systems and 6 yuan / 6 membered ring systems, wherein the count of each ring includes spiral atoms. The monospirocyclic hydrocarbon group is optionally substituted by one or more (such as one to three) suitable substituents (such as halogen, methyl, methoxy or ethoxy). Examples that can be cited include, for example

[0036] 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' in the ring, wherein R ’ As defined above. 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 (such as 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, aziridinyl, 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.

[0037] As used herein, the term "heterocyclyl" encompasses fused ring structures, and the connection point of the fused ring structure to the other groups can be on any ring in the fused ring structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0038] As used herein, the term "bridged heterocyclyl" refers to a cyclic structure formed by one cycloalkyl as defined herein and one heterocyclyl as defined herein, or by two heterocyclyls as defined herein, by sharing two ring atoms that are not directly connected, which has 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' in the ring, wherein R ’ As defined above. The bridged heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, a 5-10 membered bridged heterocyclic group is a group having 5-10 carbon atoms and heteroatoms in the ring. "Bridged heterocyclic group" can be saturated (i.e., "bridged heterocyclic alkyl") or partially unsaturated (e.g., having one or more double bonds in the ring (i.e., "bridged heterocyclic alkenyl")). In some embodiments, bridged heterocyclic groups include but are not limited to 6-10 membered bridged heterocyclic groups, 7-10 membered bridged heterocyclic groups, 8-10 membered bridged heterocyclic groups, and 9-10 membered bridged heterocyclic groups. The bridged heterocyclic group includes nitrogen-containing bridged heterocyclic groups, oxygen-containing bridged heterocyclic groups, and sulfur-containing bridged heterocyclic groups. The bridged heterocyclic group is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., methyl, ethyl, or oxo). Examples that can be cited include but are not limited to The “nitrogen-containing bridged heterocyclic group”, “oxygen-containing bridged heterocyclic group” and “sulfur-containing bridged heterocyclic group” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

[0039] As used herein, the term "monospiro heterocyclyl" refers to a cyclic structure formed by one cycloalkyl as defined herein and one heterocyclyl as defined herein, or two heterocyclyl groups as defined herein, which share one ring atom and have 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' in the ring, wherein R ’As defined above.The monospiro heterocyclic radical can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present).Especially, 5-11 yuan monospiro heterocyclic radical is a group with 5-11 carbon atoms and heteroatoms in the ring, including but not limited to 6-11 yuan monospiro heterocyclic radical, 7-9 yuan monospiro heterocyclic radical or 8-10 yuan monospiro heterocyclic radical.Monospiro heterocyclic radical can be saturated (that is, "monospiro heterocycloalkyl") or partially unsaturated (for example, having one or more double bonds (that is, "monospiro heterocycloalkenyl") in the ring). Monospiro heterocyclyl includes but is not limited to 5-11 membered monospiro heterocycloalkyl, 6-10 membered monospiro heterocycloalkyl, 7-10 membered monospiro heterocycloalkyl, 6-10 membered nitrogen-containing monospiro heterocycloalkyl, 6-10 membered oxygen-containing monospiro heterocycloalkyl, 6-10 membered sulfur-containing monospiro heterocycloalkyl; and 5-11 membered monospiro heterocycloalkenyl, 6-10 membered monospiro heterocycloalkenyl, 7-10 membered monospiro heterocycloalkenyl, 6-10 membered nitrogen-containing monospiro heterocycloalkenyl, 6-10 membered oxygen-containing monospiro heterocycloalkenyl, 6-10 membered sulfur-containing monospiro heterocycloalkenyl. Monospiro heterocyclyl can include, for example, 3 / 5 membered ring system, 4 / 4 membered ring system, 4 / 5 membered ring system, 4 / 6 membered ring system, 5 / 5 membered ring system, 5 / 6 membered ring system and 6 / 6 membered ring system, wherein the count of each ring includes spiro atom. The monospiro heterocyclic group is optionally substituted by one or more (such as one to three) suitable substituents (such as methyl, ethyl or oxo). Examples include but are not limited to The "nitrogen-containing monospiro heterocyclic group", "oxygen-containing monospiro heterocyclic group" and "sulfur-containing monospiro heterocyclic group" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "5-11 membered nitrogen-containing monospiro heterocyclic group" refers to a monospiro heterocyclic group containing a total of 5-11 ring atoms, at least one of which is a nitrogen atom.

[0040] 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.

[0041] 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.

[0042] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0043] As used herein, the term "guanidino" is

[0044] 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 valency in the present context is not exceeded 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.

[0045] If a group is described as being "optionally substituted by" or "optionally substituted", the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as being optionally substituted by one or more of the listed substituents, then one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, by independently selected optional substituents. If a nitrogen of a group is described as being optionally substituted by one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced by an independently selected optional substituent. Optional substituents may be selected from: halogen, OH, SH, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -SC 1-6 Alkyl, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -CN, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-NH(C 1-6 Alkyl), -C 1-6 Alkylene-N(C 1-6 Alkyl)2, -C 1-6 Alkyl-OC 1- 6-alkyl, -C 0-6 Alkylene-C(O)OH, -C 0-6 Alkylene-C(O)OC 1-6 Alkyl, -C 0-6 Alkylene-C(O)NH2, -C 0-6 Alkylene-C(O)NH(C 1-6 Alkyl), -C 0-6 Alkylene-C(O)N(C 1-6 Alkyl)2, -C 0-6 Alkylene-S(O)2C 1-6 Alkyl, -C 0-6 Alkylene-S(O)2NH2, -C 0-6 Alkylene-S(O)2NH(C 1-6 Alkyl), -C 0-6 Alkylene-S(O)2N(C 1-6 Alkyl)2, -NH-C(O)C1-6 Alkyl, -N(C 1-6 alkyl)-C(O)C 1-6 Alkyl, -NH-C(=O)OH, -NH-C(=O)OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl, -NH-C(O)NH2, -NH-C(O)NH(C 1-6 alkyl), -NH-C(O)N(C 1-6 Alkyl)2, -NH-S(O)2-C 1-6 Alkyl, -N(C 1-6 alkyl)-S(O)2-C 1-6 Alkyl, -C 0-6 Alkylene-C 3-10 Cycloalkyl, -C 0-6 Alkylene-(3-10 membered heterocyclic group), -C 0-6 Alkylene-phenyl and -C 0-6 Alkylene-(5-10 membered heteroaryl).

[0046] 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.

[0047] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0048] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0049] 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 ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0050] 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. 13C 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 and 13 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.

[0051] 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.

[0052] The term "diastereoisomer" refers 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 reactivity. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0053] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0054] 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.

[0055] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0056] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0057] 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.

[0058] In this article, solid lines can be used Solid wedge or virtual wedge Depict chemical bonds of the compounds of the present 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 stereoisomers shown are present. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. 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, conformational isomers, 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 diastereomeric pairs). When a compound contains two chiral centers, a thick solid line may be used. and thick dashed line The chemical bonds in the compounds are drawn to show the relative relationship of the two chiral centers and are not intended to imply any absolute stereochemistry. For example, Indicates that the bond connecting Ra and the bond connecting Rb on the ring are cis to each other, and Covered Two enantiomers.

[0059] 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.

[0060] 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.

[0061] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0067] 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.

[0068] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0069] The term "N-oxide" is also known as amine oxide, which is a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0070] 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.

[0071] 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)).

[0072] 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. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0073] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0074] Compound

[0075] In one aspect, the present invention provides compounds of formula (I):

[0076] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0077] in:

[0078] R 1 -L 2 -R L ,

[0079] in:

[0080] L 2 C is a direct bond, straight chain or branched chain 1-6 Alkylene, or linear or branched C 2-6 alkenylene,

[0081] Optionally, the C 1-6 Alkylene or C 2-6 An available C atom in an alkenylene group is substituted with two substituents, whereby the two substituents together with the C atom form an optionally substituted C 3-6 Cycloalkylene or optionally substituted 3 to 6 membered heterocycloalkylene; or optionally, the C 1-6 Alkylene or C 2-6 The two adjacent carbon atoms in the alkenylene group are connected by a straight chain C 1-4 Alkylene groups are linked to form optionally substituted C 3-6 cycloalkylene, or connected through -S-, -O-, -NH-, or a linear 2- to 4-membered heteroalkylene to form an optionally substituted 3- to 6-membered heterocycloalkylene; and

[0082] wherein the C 1-6 Alkylene or C 2-6 The alkenylene group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl; and

[0083] wherein the L 2 -R L The portion of CH2 (if present) attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e replace;

[0084] R L Selected from: R 9 、R 10 、-OR 10 、-SR 10 and -NR 1e -R 10 ,and

[0085] R 10 Selected from: H, R 11 、Halogen、OH、SH、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2- 6-alkenyl, -OC 2-6 Alkynyl, guanidinyl and -C 1-6 Alkylene-guanidinium, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl and -OC 2-6 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2;

[0086] R 9 and R 11 Each independently selected from -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -3-10 membered heterocyclic group, -(CH2) 0-6 -C 5-10 Bridged cyclic hydrocarbon group, -(CH2) 0-6 -5-10 membered bridged heterocyclic group, -(CH2) 0-6 -C 5-11 Monospirocyclic hydrocarbon group, -(CH2) 0-6 -5-11 membered monospiro heterocyclic group, -(CH2) 0-6 -C 6-10 Aryl and -(CH2) 0-6- 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups:

[0087] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , Cy, -(optionally substituted C 1-6 Alkylene)-Cy, -NR 1a -Cy and -CR 1c R 1d -C(O)-NR 1a R 1b ;

[0088] Cy is selected from optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl and optionally substituted 5-10 membered heteroaryl; and

[0089] R 2 H, halogen, OH, SH, CN, C 1-6 Alkyl, -C1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and -NR 2a -S(O)2-R 2b ,

[0090] R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 2a and R 2b independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1- 6-alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -NH2 and -C 1-6 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl;

[0091] or

[0092] R 1 、R 2 Together with the carbon atom indicated by the symbol "#" to which both of them are commonly attached, they form a moiety represented by the following formula:

[0093] in:

[0094] Ring D is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-10 Bridged cycloalkyl or 5-10 membered bridged heterocycloalkyl;

[0095] R 6 Selected from:

[0096] H, halogen, OH, SH, CN, N(R 7a )2,

[0097] C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl,

[0098] -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-O-halogenated C 1-6 alkyl,

[0099] C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl and -C(O)-C 3-10 Cycloalkyl, wherein the C 3-10 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of the haloalkoxy group, and

[0100] 3-10 membered heterocycloalkyl and -C 1-6 Alkylene-3-10 membered heterocycloalkyl, wherein said 3-10 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents;

[0101] R 7a Each independently selected from: H, C 1-6 Alkyl, -(CH2) q -C 3-10 Cycloalkyl, -(CH2) q -3-10 membered heterocycloalkyl, q is selected from an integer from 0 to 6, and said C 1-6 Alkyl, -(CH2) q -C3-10 Cycloalkyl, -(CH2) q -3-10 membered heterocycloalkyl groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6 alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is substituted; and

[0102] n is 1, 2, or 3;

[0103] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0104] Each R 3 Independently selected from: halogen, OH, SH, CN, -NR 3a R 3b 、-C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1- 6-alkylene-C(O)OR 3a 、-C 1-6 Alkylene-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R 3b and a 5- or 6-membered heteroaryl group having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms,

[0105] R 3a and R 3b independently selected at each occurrence from H and C 1-6 alkyl, and

[0106] p is 1, 2, or 3;

[0107] L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond marked with * is attached to the phenyl ring B;

[0108] R 4a and R 4b Each independently selected from H, deuterium, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0109] R 4c Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0110] R is

[0111] in:

[0112] R 4 Selected from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-NR 6aR 6b 、-C 1-6 Alkylene-NR 6a -C(O)R 6b 、-OC 1-6 Alkylene C(O)OR 6a 、-OC 1-6 Alkylene C(O)NR 6a R 6b 、C 3-10 Cycloalkyl and -OC 1-6 Alkylene-C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-NR 6a R 6b 、-C 1-6 Alkylene-NR 6a -C(O)R 6b 、-OC 1-6 Alkylene C(O)OR 6a 、-OC 1-6 Alkylene C(O)NR 6a R 6b 、C 3-10 Cycloalkyl and -OC 1-6 Alkylene-C 3-10 The cycloalkyl groups are each optionally substituted with one or more deuterium (D);

[0113] R 5 Selected from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6Alkylene -SH and C 3-10 cycloalkyl; and

[0114] R 5a 、R 5b 、R 6a and R 6b independently selected at each occurrence from H and C 1-6 alkyl;

[0115] X is selected from CR 7 、C(R 7 )2 and N;

[0116] Y is selected from CR 8 、C(R 8 )2 and N;

[0117] Z is selected from O, S and NH;

[0118] R 7 and R 8 Each occurrence is independently selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-6 Alkyl), -N(C 1- 6 alkyl)2, C 1-6 Alkyl and C 3-10 Cycloalkyl;

[0119] Indicates a single bond or a double bond.

[0120] In some embodiments, the present invention provides a compound of formula (I) as described above, wherein:

[0121] Cy is selected from optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl and optionally substituted 5-10 membered heteroaryl; and

[0122] R 6 Selected from: H, halogen, OH, SH, CN, N(R 7a )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkyl-C 3-10 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2- 6 alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of haloalkoxy is substituted with C3-10 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 3-10 membered heterocycloalkyl substituted by a haloalkoxy substituent; and

[0123] R 4 Selected from: halogen, OH, SH, CN, -NR 6a R 6b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-NR 6a R 6b 、-C 1-6 Alkylene-NR 6a -C(O)R 6b 、-OC 1-6 Alkylene C(O)OR 6a 、-OC 1-6 Alkylene C(O)NR 6a R 6b 、C 3-10 Cycloalkyl and -OC 1-6 Alkylene-C 3-10 Cyclic hydrocarbon group.

[0124] In some embodiments, the present invention provides a compound of formula (I) as described above, wherein:

[0125] R 10 Selected from: H, R 11 、Halogen、OH、SH、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC2- 6-alkenyl, -OC 2-6 Alkynyl and guanidinyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl and -OC 2-6 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2;

[0126] R 9 and R 11 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0127] Halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a-S(O)2-R 1b , Cy, -(optionally substituted C 1-6 Alkylene)-Cy and -CR 1c R 1d -C(O)-NR 1a R 1b ;

[0128] R 2 H, halogen, OH, SH, C 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and -NR 2a -S(O)2-R 2b ;

[0129] R 6 Selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -CN, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -OC 1- 6-alkyl-C 3-10 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from halogen, OH, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituent of haloalkyl is substituted with C 3-10 cycloalkyl; and

[0130] R 4a and R 4b Each independently selected from H, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R5b ;as well as

[0131] R 5 Selected from: halogen, OH, SH, CN, -NR 6a R 6b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH and C 3-10 Cyclic hydrocarbon group.

[0132] In some embodiments, L 2 and said -(optionally substituted C 1-6 Alkylene)-Cy is optionally linked to R 9 or R 11 Two adjacent or non-adjacent (e.g., meta or para) ring members.

[0133] In some embodiments, the present invention provides a compound of formula (I) according to the present invention, wherein:

[0134] R 1 -L 2 -R L ;

[0135] L 2 is a direct key; and

[0136] R L R 9 .

[0137] In some embodiments, R 9 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5- 11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0138] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkenyl, C 2- 6-alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-10 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 3-10 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b .

[0139] In some preferred embodiments, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 monospirocycloalkenyl, 5-11 membered monospiro heterocycloalkyl, 5-11 membered monospiro heterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups: deuterium, halogen, -OR 1a、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl optionally substituted by 1, 2 or more halogen, -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 3-10 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a 、R 1b 、R 1c and R 1d independently selected at each occurrence from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c 、R 1dTogether with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0140] In some more preferred embodiments, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 Monospirocyclic alkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the group consisting of F, Cl, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a 、C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , 3-6 membered heterocycloalkyl optionally substituted by 1, 2 or more halogens, -NR 1a -(optionally substituted C 3-10 Cycloalkenyl) and -NR 1a -(optionally substituted 3-10 membered heterocyclyl), wherein R 1a and R 1b independently selected at each occurrence from H and C 1-4 alkyl.

[0141] In some more preferred embodiments, R 9 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]heptanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl, C5, C6 or C7 bridged cycloalkyl (e.g. ), C5, C6 or C7 bridged cycloalkenyl, 6, 7, 8 or 9 membered bridged heterocycloalkyl, C 5-11 monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl, each of which is optionally substituted with 1, 2 or more groups independently selected from the group consisting of F, Cl, OH, SH, CN, NH2, CH3, CH2CH3, CH 2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2CH2OCH2CH3, -CH2-NH-C(O)CH3, =O, =CH2, -OCH3, -OCH2CH3, -O-CH2-cyclopropyl, phenoxy, -NHCH3, -NHCH2CH3, -N(CH3)2, -NH-C(O)CH3, -NH-C(O)NH2, -NH-S(O)2CH3,

[0142] In other embodiments, R 9 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0143] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6-alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-10 Cycloalkyl), -NR 1a -(optionally substituted 3-10 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b .

[0144] In some preferred embodiments, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 Monospirocycloalkenyl, 5-11 membered monospiroheterocycloalkyl, 5-11 membered monospiroheterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0145] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R1a , =NH, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-6 Cycloalkyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ;and

[0146] R 1a 、R 1b 、R 1c and R 1d independently selected at each occurrence from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0147] In some more preferred embodiments, R 9Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 Monospirocyclic alkenyl, phenyl and 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0148] F, Cl, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a 、C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(O)NR 1a R 1b and -NR 1a -S(O)2-R 1b , where R 1a and R 1b independently selected at each occurrence from H and C 1-4 alkyl.

[0149] In some more preferred embodiments, R 9Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl, C5, C6 or C7 bridged cycloalkyl, C5, C6 or C7 bridged cycloalkenyl, 6, 7, 8 or 9 membered bridged heterocycloalkyl, C 5-11 monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl; each of which is optionally substituted by 1, 2 or more groups independently selected from the group consisting of F, Cl, OH, SH, CN, NH2, CH3, CH2CH3, CH2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2CH2OCH2CH3, -CH2-NH-C(O)CH3, =O, =CH2, -OCH3, -OCH2CH3, -O-CH2-cyclopropyl, phenoxy, -NHCH3, -NH-C(O)CH3, -NH-C(O)NH2, and -NH-S(O)2CH3.

[0150] In yet other embodiments, R 9 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0151] Halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b .

[0152] In some preferred embodiments, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 monospirocycloalkenyl, 5-11 membered monospiro heterocycloalkyl, 5-11 membered monospiro heterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups: halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b ;and

[0153] R 1a 、R 1b 、R 1c and R 1d independently selected at each occurrence from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0154] In some preferred embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl; dihydropyrrolyl, dihydroimidazolyl; azooctenyl; C5, C6 or C7 bridged cycloalkyl; C5, C6 or C7 bridged cycloalkenyl; 6, 7, 8 or 9 membered bridged heterocycloalkyl; C 5-11monospirocycloalkyl; 5-11 membered monospiroheterocycloalkyl; phenyl; pyrrolyl, furyl, thienyl, pyrazolyl, pyridyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl; each of which is optionally substituted by 1, 2 or more groups independently selected from the following: F, Cl, OH, SH, CN, NH2, CH3, CH2CH3, C H2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2CH2OCH2CH3, -CH2-NH-C(O)CH3, =O, =CH2, -OCH3, -OCH2CH3, -O-CH2-cyclopropyl, phenoxy, -NHCH3, -NH-C(O)CH3, -NH-C(O)NH2 and -NH-S(O)2CH3.

[0155] In some embodiments, the present invention provides a compound of formula (I) according to the present invention, wherein:

[0156] R 1 -L 2 -R L ;

[0157] L 2 is the straight or branched C 1-6 Alkylene, or linear or branched C 2-6 alkenylene,

[0158] Optionally, the C 1-6 Alkylene or C 2-6 An available C atom in an alkenylene group is substituted with two substituents, whereby the two substituents together with the C atom form an optionally substituted C 3-6 Cycloalkylene or optionally substituted 3 to 6 membered heterocycloalkylene; or optionally, the C 1-6 Alkylene or C 2-6 The two adjacent carbon atoms in the alkenylene group are connected by a straight chain C 1-4 Alkylene groups are linked to form optionally substituted C 3-6 cycloalkylene, or connected through -S-, -O-, -NH-, or a linear 2- to 4-membered heteroalkylene to form an optionally substituted 3- to 6-membered heterocycloalkylene; and

[0159] wherein the C 1-6 Alkylene or C 2-6 The alkenylene group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R1b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl; and

[0160] wherein the L 2 -R L The portion of CH2 (if present) attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e instead; and

[0161] R L Selected from: R 10 、-OR 10 、-SR 10 and -NR 1e -R 10 .

[0162] In some embodiments, the C 3-6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0163] In some embodiments, the 3- to 6-membered heterocycloalkylene group is a 4- to 6-membered heterocycloalkylene group, preferably an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or thiomorpholinyl group.

[0164] In some embodiments, the L 2 Straight or branched chain C 1-6 Alkylene, or linear or branched C 2-6 Optional substituents of alkenylene include: F, Cl, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1- 4 alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, preferably CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, cyclopropyl and azetidinyl.

[0165] In other embodiments, R 1 For: -CR al R bl -(CR cl R dl ) m -R 10 、-CR al R bl -(CR cl R dl ) m-OR 10 、-CR al R bl -(CR cl R dl ) m -SR 10 、-CR al R bl -(CR cl R dl ) m -NR 1e -R 10 、-O-(CR cl R dl ) m -R 10 、-S-(CR cl R dl ) m -R 10 , or -NR 1e -(CR cl R dl ) m -R 10 ;

[0166] R al 、R bl 、R cl and R dl Each occurrence is independently selected from: H, halogen, OH, SH, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0167] Where: Optionally, R al and R bl , or 1 CR cl R dl R in cl and R dl , together with the carbon atoms to which they are commonly connected, form =CH2, =CH(C 1-4 Alkyl), C 3-6 cycloalkylene or 3 to 6 membered heterocycloalkylene; or optionally, CR al R bl -(CR cl R dl ) m or (CR cl R dl ) mThe two adjacent carbon atoms in the straight chain carbon chain are connected by the straight chain C 1-4 Alkylene groups are linked to form C 3-6 Cycloalkylene, or connected through -S-, -O-, -NH-, or a linear 2- to 4-membered heteroalkylene to form a 3- to 6-membered heterocycloalkylene;

[0168] R 1a and R 1b independently selected at each occurrence from H and C 1-6 alkyl;

[0169] R 1e independently selected at each occurrence from H and C 1-4 Alkyl; and

[0170] m is 0, 1, 2, 3, 4 or 5.

[0171] In some such embodiments, the C 3-6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0172] In some such embodiments, the 3- to 6-membered heterocycloalkylene is a 4- to 6-membered heterocycloalkylene, preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or thiomorpholinyl.

[0173] In some such embodiments, R al 、R bl 、R cl and R dl Each occurrence is independently selected from: H, F, Cl, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, preferably H, CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, cyclopropyl and azetidinyl.

[0174] In some such embodiments, R al and R bl , or 1 CR cl R dl R in cl and R dl , together with the carbon atoms to which they are connected, form =CH2, C 3-6 cycloalkylene or 3- to 6-membered heterocycloalkylene.

[0175] In some such embodiments, m is 0, 1, or 2.

[0176] In some such embodiments, the compound of Formula (I) has the structure of Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4), Formula (I-5), Formula (I-6), or Formula (I-7):

[0177] In some preferred embodiments, m is 0, 1 or 2.

[0178] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-7), wherein R 10 Selected from: H, R 11 、F、Cl、OH、SH、CN、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 2-4 Alkenyl, -OC 2-4 Alkynyl, guanidinyl and -C 1-4 Alkylene-guanidinium, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-6 Alkyl, -OC 2-4 Alkenyl and -OC 2-4 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2. 10 Selected from: H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, CF3, -CH2CF3, -OCH3, -OCH2CH3, guanidinyl and -CH2CH2guanidinyl. In some preferred embodiments, R 10 Selected from: H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, -OCH3, -OCH2CH3, guanidinyl and -CH2CH2guanidinyl.

[0179] In some embodiments, R 10 Selected from: H, R 11 、F、Cl、OH、SH、CN、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 2-4Alkenyl, -OC 2-4 Alkynyl and guanidinyl, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-6 Alkyl, -OC 2-4 Alkenyl and -OC 2-4 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2. 10 Selected from: H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, -OCH3, -OCH2CH3 and guanidinyl.

[0180] In some embodiments, R 11 Selected from -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -3-10 membered heterocyclic group, -(CH2) 0-6 -C 5-10 Bridged cyclic hydrocarbon group, -(CH2) 0-6 -5-10 membered bridged heterocyclic group, -(CH2) 0-6 -C 5-11 Monospirocyclic hydrocarbon group, -(CH2) 0-6 -5-11 membered monospiro heterocyclic group, -(CH2) 0- 6-C 6-10 Aryl and -(CH2) 0-6 - 5-10 membered heteroaryl groups, each of which is optionally substituted by 1, 2 or more substituents independently selected from the groups listed in Group A1:

[0181] (Group A1) Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-C 3-10Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(optionally substituted C 1-6 Alkylene)-C 3-6 Cycloalkyl, -(optionally substituted C 1-6 Alkylene)-(3-6 membered heterocycloalkyl), -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted 4-7 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b In some embodiments, the group A1 further comprises -NR 1a -(optionally substituted C 3-10 cycloalkenyl), wherein R 1a As defined above.

[0182] In some preferred embodiments, R 11 Selected from: -(CH2) 0-3 -C 3-10 Cycloalkyl, -(CH2) 0-3 -C 3-10 Cycloalkenyl, -(CH2) 0-3 -3-10 membered heterocycloalkyl, -(CH2) 0-3 -3-10 membered heterocycloalkenyl, -(CH2) 0-3 -C 5-10 Bridged cycloalkyl, -(CH2) 0-3 -C 5-10 Bridged cycloalkenyl, -(CH2) 0- 3-5-10 membered bridged heterocycloalkyl, -(CH2) 0-3 -5-10 membered bridged heterocycloalkenyl, -(CH2) 0-3 -C 5-11 Monospirocycloalkyl, -(CH2) 0-3 -C5-11 Monospirocycloalkenyl, -(CH2) 0-3 -5-11 membered monospiro heterocycloalkyl, -(CH2) 0-3 -5-11 membered monospiro heterocycloalkenyl, -(CH2) 0-3 -phenyl and -(CH2) 0-3 - 5- or 6-membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the groups listed in Group A2:

[0183] (Group A2) Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a - C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted 4-7 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a 、R 1b 、R 1cand R 1d independently selected at each occurrence from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 In some embodiments, the group A2 further includes -NR 1a -(optionally substituted C 3-10 cycloalkenyl), wherein R 1a As defined above.

[0184] In some more preferred embodiments, R 11 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-11 Monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, -(CH2) 0-3 -phenyl, and -(CH2) 0-3 - 5- or 6-membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the groups listed in Group A3:

[0185] (Group A3) Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=NH、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -NR 1a -(optionally substituted C 3-6 Cycloalkyl) and -CR 1c R1d -C(O)-NR 1a R 1b ; and R 1a 、R 1b 、R 1c and R 1d independently selected at each occurrence from H and C 1-4 Alkyl, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 In some embodiments, the group A3 further comprises -NR 1a -(optionally substituted C 3-10 Cycloalkenyl) and -NR 1a -(optionally substituted 4-7 membered heterocyclyl), wherein R 1a As defined above.

[0186] In some preferred embodiments, R 11 A group selected from the group listed in Group B:

[0187] (Group B) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydroimidazolyl, azacyclooctenyl, 5-11 membered monospiro heterocycloalkyl, phenyl, -CH2-phenyl, pyrrolyl, -CH2-pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, -CH2-pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl.

[0188] In some embodiments, the group B further comprises an imidazole group and / or

[0189] Each of the groups of Group B described above is optionally substituted by 1, 2 or more groups independently selected from the group consisting of F, Cl, OH, SH, CN, =O, =NH, NH2, -NHCH3, CH3, CH2CH3, vinyl, ethynyl, CH2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -OCH3, -OCH2CH3, -NHC(O)CH3, cyclopropyl, azetidinyl, pyridyl, and-CR 1c R 1d-C(O)NH2, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they form a cyclopropyl group.

[0190] In some embodiments, R 11 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the group consisting of halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(optionally substituted C 1-6 Alkylene)-C 3-6 Cycloalkyl, -(optionally substituted C 1-6 alkylene)-(3-6 membered heterocycloalkyl) and -CR 1c R 1d-C(O)-NR 1a R 1b .

[0191] In some preferred embodiments, R 11 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 Monospirocycloalkenyl, 5-11 membered monospiroheterocycloalkyl, 5-11 membered monospiroheterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0192] Halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR1a R 1b ;and

[0193] R 1a 、R 1b 、R 1c and R 1d In each occurrence, independently selected from H, C1-4 alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0194] In some more preferred embodiments, R 11 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-11 Monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups: halogen, -OR 1a 、-SR 1a 、CN、=O、=NH、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a 、-C 1-4 Alkylene-SR 1a 、-C 1-4 Alkylene-NR 1a R 1b 、-NR 1a R 1b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a 、R 1b 、R 1c and R 1d independently selected at each occurrence from H and C 1-4 Alkyl, where R 1c 、R 1dTogether with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl.

[0195] In some preferred embodiments, R 11 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydroimidazolyl, azocinyl; 5-11 membered monospiro heterocycloalkyl; phenyl; pyrrolyl, furyl, thienyl, pyrazolyl, pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl; each of which is optionally substituted with 1, 2 or more groups independently selected from the group consisting of F, Cl, OH, SH, CN, =O, =NH, NH2, -NHCH3, CH3, CH2CH3, vinyl, ethynyl, CH2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -OCH3, -OCH2CH3, cyclopropyl, azetidinyl, and -CR 1c R 1d -C(O)NH2, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they form a cyclopropyl group.

[0196] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-7), wherein:

[0197] R 2 H, halogen, OH, SH, CN, C 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and -NR 2a -S(O)2-R 2b ;and

[0198] R2a and R 2b independently selected at each occurrence from H and C 1-4 alkyl.

[0199] In some preferred embodiments, R 2 It is H, F, Cl, OH, SH, CN, methyl, ethyl, -CH2-OH, -CH2-SH, -NH2, -NH-C(O)CH3, -NH-C(O)OCH3, -NH-C(O)NH2 and -NH-S(O)2CH3.

[0200] In some embodiments, R 2 H, halogen, OH, SH, C 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and -NR 2a -S(O)2-R 2b ;and

[0201] R 2a and R 2b independently selected at each occurrence from H and C 1-4 alkyl.

[0202] In some preferred embodiments, R 2 It is H, F, Cl, OH, SH, methyl, ethyl, -CH2-OH, -CH2-SH, -NH2, -NH-C(O)CH3, -NH-C(O)OCH3, -NH-C(O)NH2 and -NH-S(O)2CH3.

[0203] In some embodiments, the present invention provides a compound of formula (I) having the structure of formula (I-8):

[0204] In some embodiments, Ring D is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-8 Bridged cycloalkyl or 5-8 membered bridged heterocycloalkyl.

[0205] In some embodiments, R 6 Selected from:

[0206] H, halogen, OH, SH, CN, N(R 7a )2,

[0207] C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl,

[0208] -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-O-halogenated C 1-6 alkyl,

[0209] C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkylene-C 3-6 Cycloalkyl and -C(O)-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of the haloalkoxy group, and

[0210] 4-7 membered heterocycloalkyl and -C 1-6 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is substituted; and

[0211] R 7a Each independently selected from: H, C 1-6 Alkyl, -(CH2) q -C 3-6 Cycloalkyl, -(CH2) q-4-7 membered heterocycloalkyl, q is selected from an integer from 0 to 4, and said C 1-6 Alkyl, the -(CH2) q -C 3-6 C in cycloalkyl 3-6 Cycloalkyl, and the -(CH2) q -4-7 membered heterocycloalkyl in the 4-7 membered heterocycloalkyl group are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituents of the haloalkoxy group are substituted.

[0212] In some preferred embodiments, N(R 7a ) 1 R in 2 7a For H.

[0213] In some preferred embodiments, R 6 Selected from:

[0214] H, F, Cl, OH, SH, CN, NH2,

[0215] -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 cycloalkyl) and -NH(4-7 membered heterocycloalkyl), wherein the -NH(C 1- 4 alkyl) and -N(C 1-4 C in alkyl)2 1-4 Alkyl, the -NH(C 3-6 C in cycloalkyl) 3-6 The 4-7 membered heterocycloalkyl in the cycloalkyl and -NH(4-7 membered heterocycloalkyl) groups are each independently optionally substituted by one, two or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituent of the haloalkyl group is substituted,

[0216] -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Haloalkyl-OH, -C 1-4Alkylene -SH, -C 1-4 Haloalkyl-SH, -C 1-4 Alkylene -CN, -C 1-4 Haloalkyl-CN, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkyl-O-halogenated C 1-4 alkyl,

[0217] C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl and -C(O)-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Substitution of the haloalkoxy group, and

[0218] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 In some more preferred embodiments, R 6 Selected from:

[0219] H, OH, SH,

[0220] -NH(C 1-4 Alkyl), -NH(C 3-6 partially unsaturated cyclic hydrocarbon group) and -NH(4-6 membered heterocycloalkyl), the -NH(C 1-4 C in alkyl) 1-4 Alkyl, the -NH(C 3-6 C in partially unsaturated cyclic hydrocarbon group 3-6The partially unsaturated cyclic hydrocarbon group and the 4-6 membered heterocycloalkyl in the -NH(4-6 membered heterocycloalkyl) are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of the haloalkyl group is substituted,

[0221] -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -C 1- 4-alkylene-OC 1-4 Alkyl, -C 1-4 Alkyl-O-halogenated C 1-4 alkyl,

[0222] C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1- 4 alkyl, C 1-4 Haloalkyl and C 1-4 Substitution of the haloalkoxy group, and

[0223] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituents of the haloalkyl group are substituted.

[0224] In other embodiments, R 6 Selected from: H, halogen, OH, SH, CN, N(R 7a )2、C 1-6 Alkyl, -OC 1-6 Alkyl, -OC1-6 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of haloalkoxy is substituted with C 3-6 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is a 4- to 7-membered heterocycloalkyl group substituted with a halogenated alkoxy group.

[0225] In some preferred embodiments, R 6 Selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH(C 3-10 Cycloalkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -CN, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -OC 1-6 Alkyl-C 3-10 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1- 6 haloalkyl and C 1-6 The substituent of haloalkoxy is substituted with C 3-10 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C1-6 3-10 membered heterocycloalkyl substituted by a haloalkoxy substituent; the -NH(C 1-6 Alkyl), -N(C 1-6 C in alkyl)2 1-6 Alkyl, and the -NH(C 3-10 C in cycloalkyl) 3-10 The cycloalkyl groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 The substituents of the haloalkoxy group are substituted.

[0226] In some preferred embodiments, R 6 Selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 Cycloalkyl), -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1- 4-7 membered heterocycloalkyl substituted with 4 haloalkoxy substituents; said -NH(C 1-4 Alkyl), -N(C 1-4 C in alkyl)21-4 Alkyl, and the -NH(C 3-6 C in cycloalkyl) 3-6 The cycloalkyl groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted.

[0227] In some preferred embodiments, R 6 Selected from: H, OH, SH, -NH(C 1-4 Alkyl), -NH(C 3-6 Partially unsaturated cyclic hydrocarbon group), -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 4-7 membered heterocycloalkyl substituted by a haloalkyl substituent; the -NH(C 1-4 C in alkyl) 1-4 Alkyl, and the -NH(C 3-6 C in partially unsaturated cyclic hydrocarbon group 3-6 The partially unsaturated cyclic hydrocarbon groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1- 4 alkyl and C 1-4 The substituents of the haloalkyl group are substituted.

[0228] In some more preferred embodiments, R 6 A group selected from the group listed in Group C:

[0229] (Group C) H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, difluorocyclopropyl, amino, -NHCH3, -N(CH3) 2、 -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl, -NH-cyclobutane, and -O-CH2-cyclopropyl.

[0230] In some embodiments, the group C further includes the following groups:

[0231] Cyclopropyl,

[0232] In other embodiments, R 6 Selected from H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, Cyclopropyl, difluorocyclopropyl, Amino, -NHCH3, -N(CH3) 2、 -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl, -NH-cyclobutane, -O-CH2-cyclopropyl and

[0233] In other embodiments, R 6 Selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN, -OC 1-4 Alkyl, -O-halogenated C1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl.

[0234] In some preferred embodiments, R 6 Selected from: H, OH, SH, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl.

[0235] In some preferred embodiments, R 6 Selected from: H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, difluorocyclopropyl and -O-CH2-cyclopropyl.

[0236] In some preferred embodiments, n is 1.

[0237] In some preferred embodiments, Ring D is C 4-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 5-8 Bridged cycloalkyl or 5-8 membered bridged heterocycloalkyl.

[0238] In some preferred embodiments, Ring D is C 4-6 Cycloalkyl or 5-8 membered bridged heterocycloalkyl.

[0239] In some preferred embodiments, ring D is cyclohexane or Among them, $ A is the connection point with ring A, $ L1 For L 1 connection point.

[0240] In some more preferred embodiments, Part of Among them, $ A is the connection point with ring A, $ L1 For L1 connection point.

[0241] In some embodiments, R 6 Selected from:

[0242] H, F, Cl, OH, SH, CN, NH2,

[0243] -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 Cycloalkyl), -NH(4-7 membered heterocycloalkyl), wherein said -NH(C 1-4 Alkyl) and -N(C 1-4 C in alkyl)2 1-4 Alkyl, the -NH(C 3-6 C in cycloalkyl) 3-6 The 4-7 membered heterocycloalkyl in the cycloalkyl and -NH(4-7 membered heterocycloalkyl) groups are each independently optionally substituted by one, two or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituent of the haloalkyl group is substituted,

[0244] -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 alkyl,

[0245] C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and -OC 1-4 Alkyl-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Substitution of the haloalkoxy group, and

[0246] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1- 4 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 The substituents of the haloalkoxy group are substituted.

[0247] In some preferred embodiments, R 6 Selected from:

[0248] C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl,

[0249] C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1- 4 haloalkoxy substituents,

[0250] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Substitution of the haloalkoxy group, and

[0251] -NH(4-7 membered heterocycloalkyl), wherein the 4-7 membered heterocycloalkyl is each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted.

[0252] In some more preferred embodiments, R 6 Selected from:

[0253] C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -NH(4-6 membered heterocycloalkyl),

[0254] C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, C 1-4 Haloalkyl and C 1-4 Substitution of the haloalkoxy group, and

[0255] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN and C 1-4 The alkyl group is substituted with a substituent.

[0256] In other embodiments, R 6 Selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 Cycloalkyl), -NH(C 1-4 alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -OC 1-4 Alkyl-C 3-6 Cycloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 4-7 membered heterocycloalkyl substituted by a haloalkoxy substituent; the -NH(C 1-4 Alkyl), -N(C 1-4 C in alkyl)2 1-4 Alkyl, and the -NH(C 3-6 C in cycloalkyl) 3-6 The cycloalkyl groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted.

[0257] In some preferred embodiments, R 6 Selected from: C 1-4 Alkyl, C 1-4 haloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 The substituent of the haloalkoxy group is a 4- to 7-membered heterocycloalkyl group substituted with a halogenated alkoxy group.

[0258] In some preferred embodiments, Ring D is C 4-6 Cycloalkyl, R 6 Selected from C 1-4 Alkyl, C 1-4 haloalkyl, and optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of haloalkyl is substituted with C 3-6 Cycloalkyl, optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 The substituent of the haloalkoxy group is a 4- to 7-membered heterocycloalkyl group substituted with a halogenated alkoxy group.

[0259] In some preferred embodiments, Ring D is C 4-6 Cycloalkyl, R 6 Selected from 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituent of the haloalkyl group is a 4-7 membered heterocycloalkyl group substituted by a haloalkyl group; more preferably, ring D is cyclohexane.

[0260] In some preferred embodiments, ring D is a 5-8 membered bridged heterocycloalkyl group, R 6 Selected from C 1-4 Alkyl, C 1-4 haloalkyl, and C3-6 cycloalkyl optionally substituted by 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl and C1-4 haloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2 or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl and C1-4 haloalkyl; more preferably, Part of Among them, $ A is the connection point with ring A, $ L1 For L 1 connection point.

[0261] In some embodiments, R 1 -L 2 -R L ,in:

[0262] L 2 C is a direct bond, straight chain or branched chain 1-6 Alkylene, or linear or branched C 2-6 alkenylene,

[0263] Optionally, the C 1-6 Alkylene or C 2-6 An available C atom in an alkenylene group is substituted with two substituents, whereby the two substituents together with the C atom form an optionally substituted C 3-6 Cycloalkylene or optionally substituted 3 to 6 membered heterocycloalkylene; or optionally, the C 1-6 Alkylene or C 2-6 The two adjacent carbon atoms in the alkenylene group are connected by a straight chain C 1-4 Alkylene groups are linked to form optionally substituted C3-6 cycloalkylene, or connected through -S-, -O-, -NH-, or a linear 2- to 4-membered heteroalkylene to form an optionally substituted 3- to 6-membered heterocycloalkylene; and

[0264] wherein the C 1-6 Alkylene or C 2-6 The alkenylene group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 aryl and 5-10 membered heteroaryl; and

[0265] wherein the L 2 -R L The portion of CH2 (if present) attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e replace;

[0266] R L Selected from: R 9 、R 10 、-OR 10 、-SR 10 and -NR 1e -R 10 ,and

[0267] R 10 Selected from: H, R 11 、Halogen、OH、SH、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2- 6-alkenyl, -OC 2-6 Alkynyl, guanidinyl and -C 1-6 Alkylene-guanidinium, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl and -OC 2-6 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2;

[0268] R 9 and R 11 Each independently selected from -(CH2)0-3 -C 3-10 Cycloalkyl, -(CH2) 0-3 -3-10 membered heterocyclic group, -(CH2) 0-3 -C 5-10 Bridged cyclic hydrocarbon group, -(CH2) 0-3 -5-10 membered bridged heterocyclic group, -(CH2) 0-3 -C 5-11 Monospirocyclic hydrocarbon group, -(CH2) 0-3 -5-11 membered monospiro heterocyclic group, -(CH2) 0-3 -C 6-10 Aryl and -(CH2) 0-3 - 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups:

[0269] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , Cy, -(optionally substituted C 1-6 Alkylene)-Cy, -NR 1a -Cy and -CR 1c R1d -C(O)-NR 1a R 1b ;

[0270] Cy is selected from optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl and optionally substituted 5-10 membered heteroaryl; and

[0271] R 2 H, halogen, OH, SH, CN, C 1-6 Alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and -NR 2a -S(O)2-R 2b ,

[0272] R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 2a and R 2b independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1- 6-alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -NH2 and -C 1-6 Alkylene-CN, where R 1c 、R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0273] In some preferred embodiments, -L 2 -R L , L 2 For direct keys, R L Selected from R 9 , R 9 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups:

[0274] Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 1-6 Alkylene-OR 1a 、-C 1-6 Alkylene-SR 1a 、-C 1-6 Alkylene-NR 1a R 1b 、-C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , Cy, -(optionally substituted C 1-6 Alkylene)-Cy, -NR 1a -Cy and -CR 1c R 1d -C(O)-NR 1a R 1b ;

[0275] Cy is selected from optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 10-membered heteroaryl.

[0276] In some preferred embodiments, R1 -L 2 -R L , L 2 C is a straight chain or branched chain 1-6 Alkylene, R L Selected from R 9 More preferably, R 2 For H.

[0277] In some preferred embodiments, R 1 -L 2 -R L , L 2 For direct keys, R L Selected from: -OR 10 、-SR 10 and -NR 1e -R 10 , R 10 Selected from R 11 More preferably, R 2 For H.

[0278] In some embodiments, Ring A is C 6-10 Aryl or 5 or 6 membered heteroaryl, preferably phenyl (more preferably ), naphthyl, benzopyridinyl (preferably quinolinyl, more preferably ), pyridyl or thiazolyl.

[0279] In some embodiments, Ring A is C 6-10 Aryl or 5- or 6-membered heteroaryl, preferably phenyl, naphthyl, pyridyl or thiazolyl.

[0280] In some embodiments, R 3 Selected from: halogen, OH, SH, CN, -NR 3a R 3b 、-C 1-4 Alkyl-OH, -C 1-4 Alkyl-SH, -C 1-4 Alkylene-C(O)OR 3a 、-C 1-4 Alkylene-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R3b and 5-membered heteroaryl groups having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms.

[0281] In some preferred embodiments, R 3 Selected from: F, Cl, OH, CN, -NH2, -CH2-OH, -CH2-SH, -CH2-C(O)OR 3a 、-CH2-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R 3b and 5-membered heteroaryl groups having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms.

[0282] In some preferred embodiments, R 3a and R 3b independently selected at each occurrence from H and C 1-4 alkyl.

[0283] In some preferred embodiments, R 3 Selected from: F, Cl, OH, CN, -NH2, -CH2-OH, -CH2-SH, -CH2-C(O)OH, -CH2-C(O)OCH3, -CH2-C(O)-NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2, -C(O)-NH-S(O)2-CH3, -S(O)2-CH3, -S(O)2-NH2, -S(O)2-NH-C(O)CH3 and 5-membered heteroaryl having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms.

[0284] In some preferred embodiments, R 3 Selected from: F, Cl, -CH2-C(O)OH, -C(O)OH, -C(O)-NH2, -S(O)2-CH3, -S(O)2-NH2, -S(O)2-NH-C(O)CH3, tetrazolyl and pyrazolyl.

[0285] In some preferred embodiments, p is 1 or 2.

[0286] In some more preferred embodiments, Selected from: Each of them is optionally replaced by another independent R 3 Replacement, R 3 is independently as defined above at each occurrence.

[0287] In some embodiments, Selected from: Each of them is optionally replaced by another independent R 3 Replacement, R 3 is independently as defined above at each occurrence.

[0288] In some preferred embodiments, for In some more preferred embodiments,

[0289] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 In other embodiments, X is C(R 7 ) 2. In other embodiments, X is N.

[0290] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein Y is CR 8 In other embodiments, Y is C(R 8 ) 2. In other embodiments, Y is N.

[0291] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein Z is O. In other embodiments, Z is S. In other embodiments, Z is NH.

[0292] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 , Y is CR 8 , and Z is NH.

[0293] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 , Y is CR 8 , and Z is O.

[0294] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 , Y is CR 8 , and Z is S.

[0295] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is CR 7 , Y is N, and Z is NH.

[0296] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is N, Y is CR 8 , and Z is NH.

[0297] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein X is C(R 7 )2, Y is C(R 8 )2, and Z is NH.

[0298] In some preferred embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein R is:

[0299] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-8), wherein the compound has a structure of formula (I-9):

[0300] where R 1 、R 2 、R 4 、R 5 、R 7 、R 8 and L 1 Each is as defined in the embodiments described above.

[0301] In some preferred embodiments, the compound of formula (I) has the structure of formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17) or formula (I-18):

[0302] where R 2 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R al 、R bl 、R cl 、R dl 、R 1e , L 1 , Ring D, m and n are each as defined in the embodiments described above.

[0303] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), wherein:

[0304] R 4 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b 、-C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b 、C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b 、-C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b 、C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 The cycloalkyl groups are each optionally substituted with one or more D, and

[0305] R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b 、-C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a、-OC 1-4 Alkylene C(O)NR 6a R 6b 、C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl.

[0306] In some preferred embodiments, R 4 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with one or more D, and

[0307] R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl.

[0308] In other embodiments, R 4 and R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b 、-C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b 、C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 In some preferred embodiments, R 4 and R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl.

[0309] In other embodiments, R 4 and R 5 is independently selected at each occurrence from: halogen, OH, SH, CN, -NR 6a R 6b 、C 1- 4 alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1- 4-alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C1- 4-alkylene-NR 6a R 6b 、-C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b 、C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 In some preferred embodiments, R 4 and R 5 is independently selected at each occurrence from: halogen, OH, SH, CN, -NR 6a R 6b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl.

[0310] In some preferred embodiments, R 6a and R 6b independently selected at each occurrence from H and C 1-4 alkyl.

[0311] In some preferred embodiments, R 4 is independently selected at each occurrence from the group consisting of: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -O-CD3, -S-CH3, -S-CD3, and cyclopropyl, and R 5 is independently selected at each occurrence from the group consisting of: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropyl. In some more preferred embodiments, R 4 For-OC 1-4 Alkyl, -O-deuterated C 1-4 alkyl, or cyclopropyl, and R 5 H or C 1-4 In some more preferred embodiments, R 4 is -O-CH3, -O-CD3, or cyclopropyl, and / or R 5It is a methyl group.

[0312] In some preferred embodiments, R 4 and R 5 In some other embodiments, R is independently selected from the group consisting of H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropane. 4 and R 5 is independently selected at each occurrence from the group consisting of: F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropane.

[0313] In other embodiments, R 4 In some preferred embodiments, R 5 In some preferred embodiments, R 5 It is a methyl group.

[0314] In yet other embodiments, R 4 For-OC 1-4 Alkyl, and R 5 is hydrogen or C 1-4 In some preferred embodiments, R 4 is -O-CH3, and R 5 It is a methyl group.

[0315] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), wherein R 7 and R 8 Each occurrence is independently selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0316] In some preferred embodiments, R 7 and R 8 Each occurrence is independently selected from the group consisting of: H, F, Cl, OH, SH, CN, NH2, -NH(CH3), -N(CH3)2, methyl, ethyl and cyclopropyl, preferably H, F, Cl, methyl, ethyl and cyclopropyl.

[0317] In some embodiments, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), wherein:

[0318] L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond identified by * is attached to the phenyl ring B; and

[0319] R 4a and R 4b Each independently selected from H, deuterium, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl.

[0320] In some preferred embodiments, L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond identified by * is attached to the phenyl ring B; and R 4a and R 4bEach independently selected from: H, deuterium, F, Cl, OH, SH, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b , preferably H, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl.

[0321] In other embodiments, L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -, *-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond identified by * is attached to the phenyl ring B; and

[0322] R 4a and R 4b Each independently selected from H, deuterium, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl.

[0323] In some preferred embodiments, L 1 Selected from: *-CR 4aR 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond identified by * is attached to the phenyl ring B; and

[0324] R 4a and R 4b Each independently selected from H, deuterium, F, Cl, OH, SH, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl.

[0325] In other embodiments, L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-、*-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond identified by * is attached to the phenyl ring B; and R 4a and R 4b Each independently selected from: H, F, Cl, OH, SH, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R5b , preferably H, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b .

[0326] In some preferred embodiments, R 5a and R 5b independently selected at each occurrence from H and C 1-4 alkyl.

[0327] In some preferred embodiments, R 4a and R 4b Each independently selected from H, deuterium, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b In some preferred embodiments, R 4a and R 4b are each independently selected from H, deuterium, F, Cl, OH, SH, CN, -NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2 and -C(O)-NCH3. In some preferred embodiments, R 4a and R 4b Together with the carbon atom to which they are both attached, they form a cyclopropane group.

[0328] In other embodiments, R 4a and R 4b Each is independently selected from H, F, Cl, OH, SH, CN, -NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2 and -C(O)-NCH3.

[0329] In some preferred embodiments, R 4c Selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0330] In some preferred embodiments, R 4c Selected from H, methyl, ethyl, -CH2F, -CHF2 and -CF3.

[0331] In some preferred embodiments, L 1Selected from: *-CH2-NH-, *-CF2-NH-, *-CD2-NH-, *-CH(CF3)-NH-, *-C(CH3)2-NH-, *-CH2-N(CH3)-, *-CH2-N(CH2CH3)-, *-CH2 -N(CH2F)-, *-C(O)-NH-, *-C(S)-NH-, *-S(O)2-NH-, *-NH-CH2-, *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O)2-, The bond marked with * is connected to the phenyl ring B.

[0332] In other embodiments, L 1 Selected from: *-CH2-NH-, *-CF2-NH-, *-CH(CF3)-NH-, *-CH2-N(CH3)-, *-CH2-N(CH2CH3)-, *-CH2-N(CH2F)-, *-C(O)-NH-, *-C(S)-NH-, *-S(O)2-NH-, *-NH-CH2-, *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O)2-, More preferred are *-CH2-NH- and *-C(O)-NH-, wherein the bond indicated by * is attached to the phenyl ring B.

[0333] In some more preferred embodiments, L 1 Selected from: *-CH2-NH-, *-CD2-NH-, *-C(CH3)2-NH-, *-C(O)-NH- and The bond marked with * is connected to the phenyl ring B.

[0334] In some preferred embodiments, the present invention provides a compound of formula (I) according to the present invention, which has the structure of formula (I-19):

[0335] In some embodiments of the compound according to formula (I-19), L 1 Selected from *-CR 4a R 4b -NR 4c - and *-C(O)-NR 4c -, wherein the bond marked with * is connected to the phenyl ring B;

[0336] R 4a and R 4b are each independently selected from H and deuterium;

[0337] R4c is H;

[0338] R 4 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-6 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with 1, 2, 3 or more D;

[0339] R 5 Selected from C 1-6 alkyl;

[0340] Ring D is C 4-6 Cycloalkyl or 5-8 membered bridged heterocycloalkyl;

[0341] R 6 Selected from:

[0342] C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl,

[0343] -C 1-6 Alkylene-O-halogenated C 1-6 alkyl,

[0344] C 3-6 Cycloalkyl and -C 1-6 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is substituted,

[0345] 4-7 membered heterocycloalkyl and -C 1-6 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group, and

[0346] -NH(4-7 membered heterocycloalkyl); and

[0347] n is 1.

[0348] In some such embodiments, Ring D is preferably cyclohexane or where $A is the connection point with ring A, $ L1 For L 1 More preferably, Part of Among them, $ A is the connection point with ring A, $ L1 For L 1 connection point.

[0349] In some preferred embodiments, L 1 Selected from *-CH2-NH-, *-CD2-NH- and *-C(O)-NH-, wherein the bond marked with * is attached to the phenyl ring B.

[0350] In some preferred embodiments, R 4 Selected from -OC 1-4 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2, 3 or more D. More preferably, R 4 Selected from -OC 1-2 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-2 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2, 3 or more D groups.

[0351] In some preferred embodiments, R 5 Selected from C 1-4 Alkyl, more preferably C 1-2 alkyl.

[0352] In some more preferred embodiments, R 4 is -O-CH3, -O-CD3, or cyclopropyl, and R 5 It is a methyl group.

[0353] In some preferred embodiments, R 6 Selected from:

[0354] C optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2 and CN 1-6 Alkyl, C 2-4 Alkenyl and each C 2-4 Alkynyl,

[0355] -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl),

[0356] C3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 The substituent of the haloalkoxy group is substituted,

[0357] 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein said 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituents of the haloalkyl group are substituted.

[0358] In some more preferred embodiments, R 6 Selected from:

[0359] C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH and CN 1- 6 alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl,

[0360] -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl),

[0361] C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen and C 1-4 The substituent of the haloalkyl group is substituted,

[0362] 4-6 membered heterocycloalkyl and -C 1-4 Alkylene-4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, CN and C 1-4 The alkyl group is substituted with a substituent, and

[0363] wherein the above halo or halogen is independently selected from F and Cl at each occurrence.

[0364] In some more preferred embodiments, R 6 Selected from:

[0365] C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl),

[0366] C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, C 1-4 Haloalkyl and C 1-4 The substituent of the haloalkoxy group is substituted,

[0367] 4-6 membered heterocycloalkyl and -C 1-4 Alkylene-4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, CN and C 1-4 The alkyl group is substituted with a substituent, and

[0368] wherein the above halo or halogen is independently selected from F and Cl at each occurrence.

[0369] In some more preferred embodiments, R 6 Selected from:

[0370] C 1-4 Alkyl, C 1-6 Fluoroalkyl, -C 1-4 Fluoroalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -NH (4-6 membered heterocycloalkyl having 1 O or S heteroatom),

[0371] C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from F, C 1-4 Fluoroalkyl and C 1-4 Substitution of the fluoroalkoxy group, and

[0372] 4-6 membered heterocycloalkyl and -C 1-4Alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl at each occurrence is independently a 4-6 membered heterocycloalkyl having 1 N heteroatom and is optionally substituted by 1, 2 or more independently selected from deuterium, F, CN and C 1-4 The alkyl group is substituted with a substituent.

[0373] In some more preferred embodiments, R 6 Selected from methyl, ethyl,

[0374] In some more preferred embodiments, the compound of formula (I-19) has a structure of one of formulas (I-20)-(I-27):

[0375] Preferred More preferred

[0376] In some preferred embodiments, Part of where $ A is the connection point with ring A, $ L1 For L 1 connection point.

[0377] In some such embodiments, preferably, R 4 is -O-CH3 or cyclopropyl, and R 5 In some embodiments, R 6 substituted with 1, 2, 3, 4 or more substituents independently selected from halogen and OH 1-4 In some preferred embodiments, R 6 selected from C substituted by 1, 2, 3, 4 or more substituents independently selected from F, Cl and OH 1-6 In some preferred embodiments, R 6 substituted with 1, 2, 3, 4 or more substituents independently selected from F and OH 1-6 In some preferred embodiments, R 6 Selected from C substituted with 1, 2, 3 or more F and 0 or 1 OH 1-6 In some preferred embodiments, R 6 Selected from C substituted with 1, 2, 3 or more F and 0 or 1 OH 3-6 In some more preferred embodiments, R 6 Selected from

[0378] In some embodiments, the compound of formula (I-19) has a structure having one of formulas (I-28)-(I-31):

[0379] In some such embodiments, preferably, R 4 is -O-CH3 or cyclopropyl, and R 5 In some embodiments, R 6 Selected from N(R 7a )2, or 4-7 membered heterocycloalkyl. In some embodiments, R 6 Selected from: -NH(4-6 membered heterocycloalkyl), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule via the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl and C 1-4 In some preferred embodiments, R 6 is selected from -NH(4-6 membered heterocycloalkyl), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule through the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, F, Cl, CN and C 1-4 In some preferred embodiments, R 6 is selected from -NH(4-6 membered heterocycloalkyl with 1 O or S heteroatom), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule through the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, F, CN and C 1-4 In some more preferred embodiments, R 6 Selected from

[0380] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0381] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0382] Pharmaceutical compositions and uses

[0383] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a semisolid preparation.

[0384] In another aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts thereof, and another therapeutically active agent.

[0385] In another aspect, the present invention provides a compound of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to the present invention, or the pharmaceutical combination according to the present invention, which is used as a drug.

[0386] In another aspect, the present invention provides a method for modulating complement alternative pathway activity in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of the pharmaceutical combination according to the present invention.

[0387] In some embodiments, the compounds, pharmaceutical compositions, or pharmaceutical combinations according to the present invention are used to prevent or treat diseases, disorders, or conditions mediated by complement activation, particularly diseases, disorders, or conditions mediated by activation of the alternative complement pathway.

[0388] In another aspect, the present invention provides a method for preventing or treating a disease, disorder or condition mediated by complement activation in an individual, particularly a disease, disorder or condition mediated by activation of the complement alternative pathway, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of the pharmaceutical combination according to the present invention.

[0389] In another aspect, the present invention provides compounds of formula (I) according to the present invention, including compounds of formula (I-1) to formula (I-18), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to the present invention, or the pharmaceutical combination according to the present invention for the preparation of a medicament for treating a disease, disorder or condition mediated by complement activation in an individual, in particular a disease, disorder or condition mediated by activation of the complement alternative pathway.

[0390] In some embodiments, the disease, disorder or condition is selected from age-related macular degeneration, geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian eye retinochoroiditis, sympathetic eye, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions caused by inappropriate or undesirable complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2)-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia , mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or other renal diseases with evidence of glomerular C3 deposition (such as membranous nephropathy (MN) and Escherichia coli-induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (a HUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

[0391] In some embodiments, the disease, disorder or condition is selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian retinochoroiditis, sympathetic eye, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple sclerosis, induction of inflammatory bowel disease, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions resulting from inappropriate or undesirable complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2)-induced toxicity during IL-2 therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or other renal diseases with evidence of glomerular C3 deposition (such as membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (a HUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

[0392] 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.

[0393] As used herein, unless otherwise indicated, the terms "treat," ...

[0394] 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.).

[0395] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0396] FIG1 is a graph showing the inhibitory effects of the positive control compound LNP023 and the compounds of the present invention on lipopolysaccharide (LPS)-induced complement activation in mice in Experimental Example 7.

[0397] FIG2 is a graph showing the therapeutic effects of LNP023 and the compound of the present invention on passive Heymann nephritis in rats induced by sheep anti-rat Fx1A serum in Experimental Example 8.

[0398] 3A , 3B and 3C are graphs showing the inhibitory effects of LNP023 and the compound of the present invention on lipopolysaccharide (LPS)-induced complement activation in rats in Experimental Example 9.

[0399] Example

[0400] 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.

[0401] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0402] MS was determined using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B). Liquid chromatography-mass spectrometry (LCMS) conditions were as follows: Agilent (Agilent 1260infinityⅡ-G6125B), column: Waters CORTECS C18+, 2.7 μm, 4.6 mm × 30 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 0-95% over 0-2 minutes, flow rate: 2 mL / min, UV detection at 220 and 254 nm.

[0403] High-performance liquid chromatography (HPLC) conditions: Agilent 1260 infinity II, chromatographic column: Agilent EC-C18, 2.7 μm, 4.6 × 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow over 10 min, flow rate: 1.2 mL / min, UV detection bands at 220 and 254 nm.

[0404] High-performance liquid chromatography (HPLC) conditions II: Agilent 1260 infinity II, chromatographic column: Agilent EC-C18, 2.7 μm, 4.6 × 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow over 5 minutes, flow rate: 1.2 mL / min, UV detection bands at 220 and 254 nm.

[0405] High-performance liquid chromatography (HPLC) assay conditions three: Shimadzu high-pressure liquid chromatograph (Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector), chromatographic column: Kinetex C18, 2.1×50 mm, 1.7 μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-30% gradient flow over 7 min, flow rate: 1.2 mL / min, UV detection band at 220 and 254 nm.

[0406] High-performance liquid chromatography (HPLC) conditions IV: Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector, Kinetex C18 column, 2.1 × 50 mm, 1.7 μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-60% over 7 min, flow rate: 1.2 mL / min, UV detection at 220 and 254 nm.

[0407] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0408] Thin layer chromatography separation and purification was performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF254 produced in Yantai).

[0409] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0410] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0411] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0412] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0413] In conventional synthesis methods and synthesis examples of compounds and intermediates of the present invention, the meanings of the abbreviations are as follows.

[0414] Synthesis Example

[0415] Example 1: Preparation of Compounds 1, 1-P1, and 1-P2

[0416] Step 1: Compound 1-1 (2.5 g, 10.10 mmol) and imidazole (1.03 g, 15.15 mmol) were dissolved in N,N-dimethylformamide (35 mL), triethylamine (3.06 g, 30.30 mmol) was added, and the mixture was heated to 120°C and stirred for 5 hours. The reaction was monitored by LCMS and TLC. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×70 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 5%-10% methanol / dichloromethane gradient to obtain compound 1-2. MS m / z (ESI): = 279.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.05-7.95(m,2H),7.87-7.79(m,2H),7.73(t,J=1.1Hz,1H),7. 28(t,J=1.3Hz,1H), 6.93(d,J=1.1Hz,1H), 4.39(t,J=6.8Hz,2H), 3.67(t,J=6.8Hz,2H).

[0417] Step 2: Compound 1-2 (600 mg, 2.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (350.79 mg, 0.43 mmol), and N,N-diisopropylethylamine (693.20 mg, 5.37 mmol) were dissolved in methanol (5 mL) and N,N-dimethylformamide (10 mL). The mixture was heated to 100°C and stirred for 24 hours under the protection of carbon monoxide. The reaction was monitored by LCMS and TLC. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 5%-10% methanol / dichloromethane gradient to obtain compound 1-3. MS m / z (ESI): = 259.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.14-8.05(m,4H),7.67(d,J=1.2Hz,1H),7.22(t,J=1.3Hz,1 H), 6.87 (d, J = 1.1Hz, 1H), 4.34 (t, J = 6.8Hz, 2H), 3.89 (s, 3H), 3.66 (t, J = 6.8Hz, 2H).

[0418] Step 3: Dissolve compound 1-3 (160 mg, 0.59 mmol), hydroxylamine hydrochloride (61 mg, 0.88 mmol), and sodium acetate (145 mg, 1.77 mmol) in ethanol (6 mL), heat to 90°C, and stir for 2 hours. Monitor the reaction by LCMS and TLC. The reaction solution is filtered, the filtrate is concentrated, and the crude product is purified by normal phase silica gel column chromatography: 5%-10% methanol / dichloromethane gradient to obtain compound 1-4. MS m / z (ESI): =274.1 [M+H] + .

[0419] Step 4: Compound 1-4 (124 mg, 0.45 mmol) was dissolved in ethyl acetate (8 mL), and palladium / carbon (10%, 120 mg, 1.13 mmol) was added. The mixture was stirred at room temperature for 16 hours under hydrogen protection. The reaction was monitored by LCMS and TLC. Filtered through celite, the filtrate was concentrated to give compound 1-5. MS m / z (ESI): = 260.0 [M+H] + .

[0420] Step 5: Compound 1-6 (117 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (218.42 mg, 0.57 mmol) and N,N-diisopropylethylamine (123.58 mg, 0.96 mmol) were added. After stirring at room temperature for 5 minutes, 1-5 (99.37 mg, 0.38 mmol) was added and stirring continued for 2 hours. The reaction was monitored by LCMS. The reaction solution was purified by reverse phase chromatography: 12%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient to obtain compound 1-7. MS m / z (ESI): = 547.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=8.4Hz,1H),8.36(s,1H),7.97(d,J=8.3Hz,2H),7.64(d,J=3.8Hz,1H),7.58-7.50(m,3H),7.35(s,1H),6. 99(s,1H),6.53(d,J=3.7Hz,1H),5.04(s,1H),4.23(t,J=6.9Hz,2H),3 .91(s,3H),3.86(s,3H),2.58(s,3H),2.33-2.24(m,2H),1.59(s,9H).

[0421] Step 6: Compound 1-7 (15 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (12.6 mg, 0.30 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 1. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.67(d,J=8.4Hz,1H),8.29(s,1H),7.9 2(d,J=8.0Hz,2H),7.62(s,1H),7.47(d,J=8.0Hz,2H),7.33(t,J=2.8Hz,1H), 7.23(s,1H),6.93(s,1H),6.83(s,1H),6.46(t,J=2.5Hz,1H),5.02(q,J=7.9H z, 1H), 4.10 (t, J = 6.9Hz, 2H), 3.87 (s, 3H), 2.50 (s, 3H), 2.23 (d, J = 7.2Hz, 2H).

[0422] Step 7: Compound 1-7 (100 mg, 0.18 mmol) was subjected to chiral separation (chromatographic column: AD-H 100 mm × 4.6 mm, 5 μm; mobile phase: A: carbon dioxide, B: [7.0 N ammonia-methanol]; gradient: B%: 30%) to obtain compound 1-7-P1 and compound 1-7-P2.

[0423] SFC analysis and detection method: chromatographic column: AD-H 4.6×100 mm, 5 μm; mobile phase: A: carbon dioxide, B: methanol (0.2% ammonia), gradient: B%: 30%, gradient flow: 6.0 min, flow rate: 3.0 mL / min, resolution wavelength 220 nm.

[0424] Compound 1-7-P1: retention time: 1.993 minutes, MS m / z (ESI): =547.2 [M+H] + .

[0425] Compound 1-7-P2: retention time: 3.060 minutes, MS m / z (ESI): =547.2 [M+H] + .

[0426] Step 8: Compound 1-7-P1 (30 mg, 0.054 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (26 mg, 0.60 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 1-P1. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.68(d,J=8.3Hz,1H),7.93(d,J=8.1Hz,2H),7.62(s,1H),7.49(d,J=8.0Hz,2H),7.34(t,J=2.8Hz,1H), 7.23(s,1H),6.93(s,1H),6.83(s,1H),6.46(t,J=2.5Hz,1H),5.02(q,J =7.8Hz,1H),4.10(t,J=6.9Hz,2H),3.88(s,3H),2.23(q,J=7.1Hz,2H).

[0427] Compound 1-P2 was obtained from compound 1-7-P2 according to the method for preparing 1-P1 from 1-7-P1. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.69(d,J=8.4Hz,1H),7.97-7.90(m,2H),7.72(s,1H),7.51(d,J=8.3Hz,2H),7.34(t,J=2.8Hz,1H),7.27 (s,1H),6.98(s,1H),6.83(s,1H),6.46(dd,J=3.0,2.0Hz,1H),5.03(q,J=7.7Hz,1H),4.12(t,J=6.8Hz,2H),3.88(s,3H),2.24(q,J=7.2Hz,2H).

[0428] Example 2: Preparation of Compounds 2-P1 and 2-P2

[0429] Step 1: Dissolve 2-1 (4.5 g, 37.45 mmol) and tert-butylsulfenamide (5 g, 36.44 mmol) in dichloromethane (100 mL) at room temperature. Add tetraisopropyl titanate (12.47 g, 54.66 mmol) at 0°C and stir at room temperature for 16 hours. After the reaction is complete, water is added to the reaction solution, which is extracted with ethyl acetate (3 × 70 mL). The combined organic phases are washed with saturated brine (100 mL), dried, and concentrated. The crude product is purified by silica gel column chromatography using a gradient of 5%-10% ethyl acetate / petroleum ether to obtain compound 2-2.

[0430] Step 2: 2-2 (5.5 g, 23.17 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature under nitrogen. A solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (46.00 mL, 1 M) was slowly added dropwise to the reaction mixture at -78°C. The reaction was stirred at -78°C for 2 hours. After the reaction was complete, water was added to the reaction solution, which was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 10% to 50% ethyl acetate / petroleum ether to afford compound 2-3. MS m / z (ESI): = 346.2 [M+H] + .

[0431] Step 3: Dissolve 2-3 (1.0 g, 2.89 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen. Add sodium hydride (0.23 g, 2.30 mmol) at 0°C and stir at room temperature for 0.5 hour. Then add benzyl bromide (0.50 g, 2.89 mmol) and react at room temperature for 2 hours. Add water to the reaction solution, extract with ethyl acetate (3 × 20 mL), wash the combined organic phases with saturated brine (30 mL), dry, and concentrate. The crude product is purified by silica gel column chromatography: 5%-20% ethyl acetate / petroleum ether gradient to obtain compound 2-4.

[0432] Step 4: To 2-4 (6.5 g, 14.92 mmol) was added a solution of hydrogen chloride in ethyl acetate (30 mL, 2 M) and stirred at room temperature for 0.5 h. Upon completion of the reaction, the organic solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 25% to 50% ethyl acetate / petroleum ether to afford compound 2-5. MS m / z (ESI): = 332.2 [M+H] + .

[0433] Step 5: Dissolve 2-5 (2.5 g, 7.54 mmol) in dichloromethane (30 mL), add boron tribromide (1.45 mL, 15.08 mmol) at -30°C, and stir at room temperature for 0.5 hour. After the reaction is complete, quench the reaction with water at -30°C, adjust the pH to 8-9 with aqueous ammonia, and extract with ethyl acetate (3 x 100 mL). The combined organic phases are washed with saturated brine (200 mL), dried, and concentrated. The crude product is purified by silica gel column chromatography using a gradient of 50% to 100% ethyl acetate / petroleum ether to provide compound 2-6. MS m / z (ESI): = 318.2 [M+H] + .

[0434] Step 6: Dissolve 2-6 (1.6 g, 5.04 mmol) and N,N-diisopropylethylamine (1.95 g, 15.12 mmol) in dichloromethane (30 mL) at room temperature. Add N-phenylbis(trifluoromethylsulfonyl)imide (2.34 g, 6.55 mmol) at 0°C and stir at room temperature for 3 hours. After the reaction is complete, water is added to the reaction solution, which is extracted with ethyl acetate (3 x 100 mL). The combined organic phases are washed with saturated brine (200 mL), dried, and concentrated. The crude product is purified by silica gel column chromatography using a gradient of 5% to 50% ethyl acetate / petroleum ether to afford compound 2-7. MS m / z (ESI): = 450.2 [M+H] + .

[0435] Step 7: Compound 2-7 (2.1 g, 4.67 mmol) was dissolved in dimethyl sulfoxide (10 mL) and methanol (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.38 g, 0.47 mmol) and triethylamine (0.94 g, 9.34 mmol) were then added. The carbon monoxide atmosphere was replaced three times. The mixture was stirred at 80°C for 16 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (200 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5% to 50% ethyl acetate / petroleum ether to obtain compound 2-8. MS m / z (ESI): = 360.2 [M+H] + .

[0436] Step 8: Dissolve compound 2-8 (500 mg, 1.39 mmol) in methanol (10 mL), then add palladium / carbon (50 mg). Replace the mixture with hydrogen three times and stir at room temperature for 16 hours. After the reaction is complete, filter and concentrate to obtain compound 2-9. MS m / z (ESI): = 270.2 [M+H] + .

[0437] Step 9: Compounds 2-9 (220 mg, 0.82 mmol) and 1-6 (274.34 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (465.88 mg, 1.23 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.63 mmol) were added, respectively. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0% to 5% methanol / dichloromethane to obtain compound 2-10. MS m / z (ESI): = 557.3 [M+H] + .

[0438] Step 10: Dissolve 2-10 (100 mg, 0.18 mmol) in water (1 mL), methanol (2 mL), and tetrahydrofuran (2 mL). Then add lithium hydroxide (75.38 mg, 1.80 mmol) and stir at 50°C for 16 hours. Once the reaction is complete, adjust the pH to 5-6. Concentrate. The crude product is purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile in a buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 2. MS m / z (ESI): = 443.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),11.05(s,1H),8.62(d,J=8.2Hz,1H),8.03-7.8 5(m,2H),7.53(d,J=8.1Hz,2H),7.36-7.21(m,5H),7.24-7.15(m,1H),6.83(s,1H),6. 53(dd,J=3.0,1.9Hz,1H),5.10(td,J=8.9,5.1Hz,1H),3.88(s,3H),2.78(ddd,J=14.3 ,9.5,5.2Hz,1H),2.66(ddd,J=13.9,9.2,7.0Hz,1H),2.50(s,3H),2.19-1.97(m,2H).

[0439] Step 11: Compound 2-10 (500 mg, 0.90 mmol) was further subjected to chiral separation (chromatographic column: AD-H 4.6×100 mm, 5 μm; mobile phase: A: carbon dioxide, B: [7.0 N ammonia-methanol]; gradient: B%: 35%) to obtain compound 2-10-P1 and compound 2-10-P2.

[0440] SFC analysis and detection method: chromatographic column: AD-H 4.6×100 mm, 5 μm, mobile phase: A: carbon dioxide, B: methanol (0.2% ammonia), gradient: B%: 35%, gradient flow 5.0 min, flow rate: 3.0 mL / min, resolution wavelength 220 nm.

[0441] Compound 2-10-P1: retention time: 1.512 min, MS m / z (ESI): =557.3 [M+H] + , 1 H NMR (400 MHz, methanol-d4) δ 8.08-7.99 (m, 2H), 7.61 (d, J = 3.8 Hz, 1H), 7.57-7.51 (m, 2H), 7.30-7.15 (m, 5H), 6.96 (s, 1H), 6.70 (d, J = 3.8 Hz, 1H), 5.17 (dd, J = 9.4, 5.4 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 2.91-2.75 (m, 2H), 2.47 (s, 3H), 2.24-2.10 (m, 2H), 1.65 (s, 9H).

[0442] Compound 2-10-P2: retention time: 2.668 min. MS m / z (ESI): = 557.2 [M+H] + , 1 H NMR (400MHz, methanol-d4) δ8.02-7.94(m,2H),7.57(d,J=3.8Hz,1H),7.53-7.45(m,2H),7.30-7.20(m,4H),7.20-7.12(m,1H),6.91(s,1H),6.6 8(d,J=3.8Hz,1H),5.14(dd,J=9.4,5.4Hz,1H),3.95(s,3H),3.88(s,3H),2.89-2.67(m,2H),2.62(s,3H),2.24-2.06(m,2H),1.62(s,9H).

[0443] Step 12: Compound 2-10-P1 (30 mg, 0.05 mmol) was dissolved in tetrahydrofuran (0.6 mL), methanol (0.6 mL), and water (0.6 mL). Lithium hydroxide (30 mg) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH using dilute hydrochloric acid (1 N), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L formic acid in water) to obtain compound 2-P1. MS m / z (ESI): = 443.6 [M+H] + .1 H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 8.2 Hz, 1H), 8.06-8.01 (m, 2H), 7.57-7.51 (m, 2H), 7.33-7.24 (m, 5H), 7.22-7.16 (m, 1H), 6.86 (s, 1H), 6.74 (d, J = 3.1 Hz, 1H), 5.28-5.14 (m, 2H), 3.98 (s, 3H), 2.94-2.81 (m, 1H), 2.82-2.71 (m, 1H), 2.57 (s, 3H), 2.29-2.12 (m, 2H).

[0444] Compound 2-P2 was obtained from compound 2-10-P2 according to the method for preparing 2-P1 from 2-10-P1. MS m / z (ESI): = 443.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),11.07(s,1H),8.64(d,J=8.1Hz,1H),7.93(d,J=8.0Hz,2H ),7.53(d,J=8.1Hz,2H),7.33(t,J=2.8Hz,1H),7.32-7.27(m,2H),7.26-7.22(m,2H),7.22-7.1 7(m,1H),6.83(s,1H),6.52(t,J=2.4Hz,1H),5.10(td,J=9.0,5.3Hz,1H),3.88(s,3H),2.78(dd d,J=14.3,9.5,5.2Hz,1H),2.66(ddd,J=13.7,9.0,6.9Hz,1H),2.50(s,3H),2.17-1.97(m,2H).

[0445] Example 3: Preparation of Compounds 3, 3-P1, and 3-P2

[0446] Step 1: To a solution of compound 3-1 (1.6 g, 9.75 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise a solution of phenylmagnesium bromide in tetrahydrofuran (8.77 mL, 1 M, 8.77 mmol) at 0 ° C. The reaction was stirred at 30 ° C for 2 hours. The reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2×30 mL). Washed with saturated brine (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel chromatography: 5%-15% ethyl acetate / petroleum ether gradient to give compound 3-2.

[0447] Step 2: Compound 3-2 (1.4 g, 5.78 mmol) was dissolved in dichloromethane (5 mL), and manganese dioxide (5.02 g, 57.79 mmol) was added. The mixture was stirred at 20°C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain compound 3-3. MS m / z (ESI): = 241.1 [M+H] + .

[0448] Step 3: Compound 3-3 (950 mg, 3.95 mmol) was dissolved in methanol (10 mL) solution, hydroxylamine hydrochloride (548.97 mg, 7.90 mmol) and sodium acetate (648.04 mg, 7.90 mmol) were added, and the reaction was stirred at 70 ° C for 18 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2×30 mL). Washed with saturated brine (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography: 5%-15% ethyl acetate / petroleum ether gradient to obtain compound 3-4. MS m / z (ESI): =256.1[M+H] + .

[0449] Step 4: Compound 3-4 (1.05 g, 4.11 mmol) was dissolved in ethanol (10 mL) solution, acetic acid amine (0.32 g, 4.11 mmol) and zinc powder (1.34 g, 20.57 mmol) were added, and the reaction was stirred at 80 ° C for 18 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2×30 mL). Washed with saturated brine (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography: 5%-20% methanol / dichloromethane gradient to obtain compound 3-5.

[0450] Step 5: Compound 3-6 (1.15 g, 3.97 mmol) was dissolved in 1,2-dichloroethane (10 mL) and compound 3-5 (800 mg, 3.32 mmol) was added. The reaction was stirred at 25 ° C for 30 min, and then sodium triacetoxyborohydride (1.40 g, 6.62 mmol) was added. Under a nitrogen atmosphere, the reaction was stirred at 25 ° C for 18 hours and the reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2x30 mL). Washed with saturated brine (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography: 0%-10% ethyl acetate / petroleum ether gradient to obtain compound 3-7. MS m / z (ESI): =515.3 [M+H] + .

[0451] Step 6: Compound 3-7 (500 mg, 0.97 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (122.3 mg, 2.91 mmol) was added. The reaction was stirred at 50°C under a nitrogen atmosphere for 18 hours and monitored by LCMS. Dilute hydrochloric acid (1 M) was added to the reaction, the pH of the reaction solution was adjusted to 5-6, and the solid was filtered out to obtain a crude product. The crude product was purified by reverse phase preparative HPLC at a flow rate of 25 mL / min and a gradient of 14%-95% acetonitrile / buffer (0.1 mol / L formic acid aqueous solution) to obtain compound 3. MS m / z (ESI): =401.5 [M+H] + , HPLC:95.07%, 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.9Hz,1H),8.17(d,J=1.8Hz,1H),7.87(d,J=8.1Hz,2H),7.54(d,J=8.2Hz,2H),7.42-7.38(m,2H) ,7.32-7.26(m,3H),7.24-7.18(m,1H),6.72(s,1H),6.19(dd,J=3.1,1.8Hz,1H),4.91(s,1H),3.83(s,2H),3.72(s,3H),2.45(s,3H).

[0452] Step 7: Compound 3 (180 mg, 0.01 mmol) was subjected to chiral separation (chromatographic column: DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 30%) to obtain compound 3-P1 and compound 3-P2.

[0453] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 150mm×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), gradient: B%: 30%, gradient flow for 5 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0454] Compound 3-P1: retention time: 1.900 minutes, MS m / z (ESI): = 401.5 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.18(d,J=2.3Hz,1H),7.87(d,J=8.3Hz,2H),7.55-7.51(m,2H),7.40(d,J=7.3Hz,2H),7.3 1-7.26(m,3H),7.22-7.18(m,1H),6.71(s,1H),6.19(dd,J=3.1,1.9Hz,1H),4.90(s,1H),3.82(s,2H),3.72(s,3H),2.45(s,3H).

[0455] Compound 3-P2: retention time: 2.774 minutes, MS m / z (ESI): =401.5 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.16(s,1H),7.89-7.86(m,2H),7.54(d,J=8.2Hz,2H),7.40(d,J=7.2Hz,2H),7.32 -7.26(m,3H),7.21(t,J=7.3Hz,1H),6.71(s,1H),6.20-6.18(m,1H),4.91(s,1H),3.83(s,2H),3.72(s,3H),2.45(s,3H).

[0456] Example 4: Preparation of Compounds 4, 4-P1, and 4-P2

[0457] Step 1: To a solution of compound 3-5 (220 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (410.96 mg, 1.08 mmol), compound 1-6 (173.86 mg, 0.72 mmol) and triethylamine (145.82 mg, 1.44 mmol) were added and stirred at 30 ° C for 18 hours. The reaction was monitored by LCMS. Water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (2x30 mL). Washed with saturated brine (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography: 5%-15% ethyl acetate / petroleum ether gradient to obtain compound 4-1. MS m / z (ESI): =529.1 [M+H] + .

[0458] Step 2: Compound 4-1 (370 mg, 0.70 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (40.80 mg, 0.97 mmol) was added. The reaction was stirred at 50°C under a nitrogen atmosphere for 18 hours, and the reaction was monitored by LCMS. Dilute hydrochloric acid (1N) was added to the reaction, the pH of the reaction solution was adjusted to 5-6, and the solid was filtered out to obtain a crude product. The crude product was purified by reverse phase chromatography at a flow rate of 25 mL / min with a gradient of 38%-68% acetonitrile / buffer (0.1 mol / L formic acid aqueous solution) to obtain compound 4. MS m / z (ESI): =415.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),11.15(s,1H),9.11(d,J=8.3Hz,1H),7.99(d,J=8.3Hz,2H),7.59(d,J=8.1Hz,2H),7.49-7.43(m,3 H),7.40(t,J=2.8Hz,1H),7.36-7.32(m,1H),6.90(s,1H),6.73(dd,J=3.0,2.0Hz,1H),6.52(d,J=8.3Hz,1H),3.93(s,3H),2.56(s,3H).

[0459] Step 3: Compound 4 (200 mg, 0.48 mmol) was subjected to chiral separation (chromatographic column: DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 15%) to obtain compound 4-P1 and compound 4-P2.

[0460] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 150mm×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), gradient: B%: 40%, gradient flow 5 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0461] Compound 4-P1: retention time: 2.175 minutes, MS m / z (ESI): =415.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),11.09(s,1H),9.04(d,J=8.3Hz,1H),7.93(d,J=8.3Hz,2H),7.53(d,J=8.2Hz,2H),7.41(t,J=8.0Hz,3H) ,7.34(dd,J=5.8,3.0Hz,2H),7.28(t,J=7.1Hz,1H),6.84(s,1H),6.68(dd,J=3.1,2.0Hz,1H),6.46(d,J=8.3Hz,1H),3.87(s,3H),2.50(s,3H).

[0462] Compound 4-P2: retention time: 2.316 minutes, MS m / z (ESI): =415.1 [M+H] + , 1 H NMR(400MHz,DMSO- d6)δ12.91(s,1H),11.09(s,1H),9.04(d,J=8.3Hz,1H),7.95-7.91(m,2H),7.53(d,J=8.1Hz,2H),7.44-7.41(m,2H),7.37(t,J=7.5Hz,2H ),7.34(t,J=2.8Hz,1H),7.29(d,J=7.1Hz,1H),6.84(s,1H),6.68(dd,J=3.0,1.9Hz,1H),6.46(d,J=8.4Hz,1H),3.87(s,3H),2.50(s,3H).

[0463] Example 5: Preparation of Compounds 5, 5-P1, and 5-P2

[0464] Step 1: Compound 5-1 (2 g, 7.24 mmol) was dissolved in tetrahydrofuran (20 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (6.44 mL, 1.3 M) was added at -40°C. After stirring for 50 minutes, cuprous iodide (0.41 g, 2.17 mmol) was added. The mixture was then stirred at 0°C for 10 minutes. Cyclobutyric acid chloride (1.29 g, 10.87 mmol) dissolved in THF (20 mL) was added at -40°C. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water was added to the reaction solution, which was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5% to 8% ethyl acetate / petroleum ether to obtain compound 5-2.

[0465] Step 2: Compound 5-2 (200 mg, 0.92 mmol), ammonium acetate (851 mg, 11.04 mmol), and sodium cyanoborohydride (232 mg, 3.68 mmol) were dissolved in methanol (15 mL) and stirred at 60°C under argon for 16 hours. The reaction was monitored by LCMS and TLC. After completion of the reaction, the solid was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using a 5%-10% methanol / dichloromethane gradient to afford compound 5-3. MS m / z (ESI): = 220.1 [M+H] + .

[0466] Step 3: Compound 5-3 (255 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (476.34 mg, 1.25 mmol) was added under ice-cooling. A solution of N,N-diisopropylethylamine (0.42 mL, 2.51 mmol) in N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 15 minutes. A solution of 1-6 (220 mg, 1.00 mmol) in N,N-dimethylformamide (2 mL) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 2%-5% methanol / dichloromethane gradient to obtain compound 5-4. MS m / z (ESI): = 507.2 [M+H] + . 1H NMR (400MHz, methanol-d4) δ8.67(d,J=8.0Hz,1H),8.01-7.95(m,2H),7.57(d,J=3.8Hz,1H),7.52-7.47(m,2H),6.91(s,1H),6.72(dd,J=3.8,1. 5Hz,1H),3.93(s,3H),3.89(s,3H),2.83-2.69(m,1H),2.61(s,3H),2.22-2.11(m,1H),2.04-1.97(m,2H),1.96-1.82(m,4H),1.62(s,9H).

[0467] Step 4: Compound 5-4 (190 mg, 0.38 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide (157 mg) was added. The mixture was heated to 50°C and stirred for 5 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH using dilute hydrochloric acid (1 N), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to give compound 5. MS m / z (ESI): = 393.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.49(d,J=8.1Hz,1H),7.95-7.85(m,2H),7.56-7.44(m,2H),7.32(t,J=2.8Hz,1H),6.8 1(s,1H),6.59(dd,J=3.0,1.9Hz,1H),5.06(t,J=8.8Hz,1H),3.86(s,3H),2.75-2.67(m,1H),2.49(s,3H),2.05-1.72(m,6H).

[0468] Step 5: Compound 5 (70 mg, 0.18 mmol) was further subjected to chiral separation (chromatographic column: ChiralPak AS, 150×4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 5-P1 and compound 5-P2.

[0469] SFC analysis and detection method: chromatographic column: ChiralPak AD, 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), gradient: B%: 5%-40% gradient flow for 5 minutes, 40% hold for 5 minutes, 5% hold for 2.5 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0470] Compound 5-P1: retention time: 3.201 min, MS m / z (ESI): =393.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.48(d,J=8.1Hz,1H),7.89(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),7.31(d,J= 2.8Hz,1H),6.81(s,1H),6.64-6.53(m,1H),5.05(s,1H),3.85(s,3H),2.74-2.66(m,1H),2.49(s,3H),2.08-1.73(m,6H).

[0471] Compound 5-P2: retention time: 3.736 min, MS m / z (ESI): =393.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.48(d,J=8.2Hz,1H),7.99-7.81(m,2H),7.47(d,J=8.1Hz,2H),7.31(t,J=2.8Hz,1H),6 .81(s,1H),6.59(dd,J=3.0,2.0Hz,1H),5.05(t,J=8.7Hz,1H),3.85(s,3H),2.74-2.66(m,1H),2.49(s,3H),2.05-1.73(m,6H).

[0472] Example 6: Preparation of Compounds 6, 6-P1, and 6-P2

[0473] Step 1: Compound 5-3 (42 mg, 0.19 mmol), 3-6 (49 mg, 0.17 mmol), acetic acid (0.01 mL, 0.17 mmol), and sodium cyanoborohydride (36 mg, 0.57 mmol) were dissolved in methanol (4 mL) and stirred at 40°C for 16 hours. The reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction solution was purified by reverse phase chromatography using a 12%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) gradient to afford compound 6-1. MS m / z (ESI): = 493.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=7.9Hz,2H),7.57(s,1H),7.44(d,J=7.9Hz,2H),6.83(s,1H),6.36(d,J=3.6Hz,1H),3.86(s,3H),3.77(s,3H ),3.71-3.63(m,1H),3.60-3.54(m,1H),3.48-3.45(m,1H),2.51(s,3H) ,2.38-2.30(m,1H),2.11-1.91(m,2H),1.59(s,9H),1.50-1.43(m,1H).

[0474] Step 2: Compound 6-1 (60 mg, 0.12 mmol) was dissolved in tetrahydrofuran (1.5 mL), methanol (1.5 mL), and water (1.5 mL). Lithium hydroxide (40.89 mg, 0.97 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 12% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 6. MS m / z (ESI): = 379.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.91(d,J=8.1Hz,2H),7.43(d,J=8.0 Hz,2H),7.26(t,J=2.8Hz,1H),6.70(s,1H),6.13(t,J=2.5Hz,1H),3.73(s,3 H),3.69(d,J=12.3Hz,1H),3.57(d,J=12.3Hz,1H),3.50(d,J=9.2Hz,1H),2 .45(s,3H),2.37-2.31(m,1H),1.95(s,1H),1.74-1.56(m,4H),1.48(s,1H).

[0475] Step 3: Compound 6-1 (330 mg, 0.67 mmol) was further subjected to chiral separation (chromatographic column: IG 100 mm × 4.6 mm, 5 μm; mobile phase: A: carbon dioxide, B: 0.2% ammonia-methanol); gradient: B%: 25% to obtain compound 6-1-P1 and compound 6-1-P2.

[0476] SFC analysis and detection method: chromatographic column: IG 4.6×100 mm, 5 μm, mobile phase: A: carbon dioxide, B: ethanol (1% NH3 (7N in MeOH), gradient: B%: 25% gradient flow over 5.0 minutes, flow rate: 5.0 mL / min, resolution wavelength 220 nm.

[0477] Retention time of compound 6-1-P1: 1.212 min, retention time of compound 6-1-P2: 1.550 min. MS m / z (ESI): = 493.1 [M+H] + .

[0478] Step 4: Compound 6-1-P1 (115 mg, 0.23 mmol) was dissolved in tetrahydrofuran (1.5 mL), methanol (1.5 mL), and water (1.5 mL). Lithium hydroxide (27 mg, 0.97 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 6-P1. MS m / z (ESI): = 379.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.91(d,J=8.0Hz,2H),7.44(d,J=8.0H z,2H),7.26(t,J=2.8Hz,1H),6.70(s,1H),6.13(s,1H),3.73(s,3H),3.69(d ,J=12.3Hz,1H),3.58(d,J=12.3Hz,1H),3.51(d,J=9.1Hz,1H),2.45(s,3H), 2.36-2.31(m,1H),2.00-1.87(m,1H),1.71-1.59(m,4H),1.53-1.45(m,1H).

[0479] Compound 6-P2 was obtained from compound 6-1-P2 according to the method for preparing 6-P1 from 6-1-P1. MS m / z (ESI): = 379.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.91(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H), 7.26(t,J=2.9Hz,1H),6.70(s,1H),6.14(t,J=2.5Hz,1H),3.73(s,3H),3.69(d,J=1 2.3Hz,1H),3.58(d,J=12.3Hz,1H),3.52(d,J=9.1Hz,1H),2.45(s,3H),2.36-2.29( m,1H),1.99-1.92(m,1H),1.74-1.66(m,1H),1.66-1.56(m,3H),1.54-1.47(m,1H).

[0480] Example 7: Preparation of Compound 7

[0481] Step 1: Dissolve compound 7-1 (1.52 mL, 20.81 mmol) and compound 7-2 (9.59 mL, 62.44 mmol) in methanol (30 mL). Add piperidine to the reaction mixture, and stir at 85°C for 12 hours. Monitor the reaction by LCMS. Concentrate the reaction mixture, and purify the crude product by silica gel column chromatography: 5%-20% ethyl acetate / petroleum ether gradient to obtain compound 7-3. MS m / z (ESI): =257.0 [M+H] + .

[0482] Step 2: To a methanol solution (10 mL) of compound 7-3 (500 mg, 1.95 mmol) was added ammonium acetate (751.97 mg, 9.76 mmol) and sodium cyanoborohydride (613 mg, 9.76 mmol). The reaction mixture was stirred at 80°C for 12 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography: 3%-10% methanol / dichloromethane gradient to obtain compound 7-4. MS m / z (ESI): =260.2 [M+H] + .

[0483] Step 3: Dissolve compound 7-4 (70 mg, 0.27 mmol) and compound 1-6 (82.42 mg, 0.27 mmol) in N,N-dimethylformamide (5 ml). Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (112.91 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.68 mmol). Stir at room temperature for 12 hours. Monitor the reaction by LCMS. Pour the reaction solution into water (150 ml) and extract with ethyl acetate (2 × 150 ml). The combined organic phases are washed with water (2 × 150 ml) and saturated brine (150 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel chromatography using a 0% to 5% methanol / dichloromethane gradient to afford compound 7-5. MS m / z (ESI): =547.4 [M+H] + .

[0484] Step 4: To a solution of compound 7-5 (100 mg, 0.16 mmol) in methanol (2 mL) was added water (2 mL) and lithium hydroxide (0.02 mL, 0.62 mmol), heated to 60°C and stirred for 12 hours. The reaction was monitored by LCMS. The pH of the reaction solution was adjusted to 5 with 1N dilute hydrochloric acid and then concentrated. The crude product was purified by reverse phase preparative HPLC at a flow rate of 25 mL / min and a gradient of 28%-38% acetonitrile / buffer (0.01 mol / L formic acid in water) to give compound 7. MS m / z (ESI): =433.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.97-12.27(m,1H),11.04(s,1H),8.60(d,J=8.2Hz, 1H),7.98-7.86(m,2H),7.53(d,J=8.1Hz,2H),7.51-7.43(m,1H),7.32(t,J=2. 8Hz,1H),6.81(s,1H),6.54(dd,J=3.0,2.0Hz,1H),6.07(d,J=1.9Hz,1H),5.20 -5.10(m,1H),3.86(s,3H),2.75-2.61(m,2H),2.51(s,3H),2.16-2.04(m,2H).

[0485] Example 8: Preparation of Compounds 8, 8-P1, and 8-P2

[0486] Step 1: Compound 8-1 (4 g, 41.6 mmol) was dissolved in methanol (40 mL), potassium hydroxide (1.9 g, 33.82 mmol) and methyl 4-acetylbenzoate (7.4 g, 10.64 mmol) were added at room temperature, and the reaction solution was stirred at 50 ° C for 16 hours. The reaction was monitored by LCMS. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The reaction solution was concentrated and the crude product was purified by silica gel chromatography: 4%-8% petroleum ether / ethyl acetate gradient to obtain compound 8-2. MS m / z (ESI): =257.1 [M+H] + .

[0487] Step 2: Dissolve compound 8-2 (783 mg, 3.05 mmol) and palladium / carbon (700 mg, 6.60 mmol) in ethyl acetate (250 mL) and stir at room temperature under a hydrogen atmosphere (15 psi) for 16 hours. Monitor the reaction by LCMS. Filter through celite and concentrate the filtrate to obtain compound 8-3. MS m / z (ESI): = 261.2 [M+H] + .

[0488] Step 3: Compound 8-3 (856 mg, 3.92 mmol) was dissolved in dichloromethane (100 mL), Dess-Martin reagent (1.8 g, 4.28 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Saturated sodium carbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL) were added to the reaction solution, the reaction solution was stirred at room temperature for 30 minutes, and extracted with dichloromethane (3×50 mL). The combined organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography: 3%-10% dichloromethane / methanol gradient to obtain compound 8-4. MS m / z (ESI): =259.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.12-8.06 (m, 4H), 7.52 (s, 1H), 6.80 (s, 1H), 3.90 (s, 3H), 3.41 (d, J = 7.5Hz, 2H), 2.86 (t, J = 7.3Hz, 2H).

[0489] Step 4: Compound 8-4 (643 mg, 2.49 mmol) was dissolved in methanol (10 ml), and ammonium acetate (2.3 g, 29.90 mmol) and sodium cyanoborohydride (628 mg, 6.83 mmol) were added. The mixture was heated to 60° C. and stirred for 3 days under argon protection. The reaction was monitored by LCMS. The reaction solution was cooled to room temperature, quenched with dilute hydrochloric acid, and extracted with dichloromethane (3×50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 0%-10% dichloromethane / methanol gradient to obtain compound 8-5. MS m / z (ESI): =260.1 [M+H] + .

[0490] Step 5: Compound 8-5 (407 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (759 mg, 2.00 mmol) and N,N-diisopropylethylamine (516 mg, 4.00 mmol) were added. The mixture was stirred for 5 minutes, and then compound 1-6 (345 mg, 1.33 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5% to 12% dichloromethane / methanol to obtain compound 8-6. MS m / z (ESI): = 547.4 [M+H] + .

[0491] Step 6: Compound 8-6 (105 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (40 mg) was added and the mixture was heated to 50°C with stirring for 10 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L formic acid in water) to afford compound 8. MS m / z (ESI): = 433.2 [M+H] + . 1H NMR (400MHz, methanol-d4) δ8.17(d,J=1.3Hz,1H),8.06-8.00(m,2H),7.54(d,J=8.1Hz,2H),7.30(d,J=3.1Hz,1H),7.10(d,J=1.2Hz,1H),6 .85(s,1H),6.76(d,J=3.1Hz,1H),5.25(t,J=7.4Hz,1H),3.96(s,3H),2.84(hept,J=7.8Hz,2H),2.56(s,3H),2.26(q,J=7.5Hz,2H).

[0492] Step 7: Compound 8 (40 mg, 0.092 mmol) was further subjected to chiral separation (chromatographic column: ChiralPak IG, 250 mm × 30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 40%) to obtain compound 8-P1 and compound 8-P2.

[0493] SFC analysis and detection method: chromatographic column: ChiralPak IG, 100mm×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), gradient: B%: 40%, gradient flow for 5 minutes, 40% for 5 minutes, 5% for 2.5 minutes, flow rate: 2.5mL / min, separation wavelength 220nm.

[0494] Compound 8-P1: retention time: 2.062 min, MS m / z (ESI): =433.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),11.04(s,1H),8.59(d,J=8.1Hz,1H),7.93(d,J=8.0Hz,2H),7.69(s,1H),7.53(d,J=8.1Hz,2H),7.32(t,J= 2.8Hz,1H),6.82(d,J=10.5Hz,2H),6.55(t,J=2.5Hz,1H),5.12(q,J=7.7 Hz,1H),3.86(s,3H),2.72-2.61(m,2H),2.49(s,3H),2.18-2.01(m,2H).

[0495] Compound 8-P2: retention time: 3.459 min, MS m / z (ESI): =433.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.20(s,1H),11.04(s,1H),8.59(d,J=8.2Hz,1H),7.93(d,J=8.1Hz,2H),7.63(s,1H),7.53(d,J=8.0Hz,2H),7.32(t,J=2. 8Hz,1H),6.81(s,2H),6.55(d,J=2.5Hz,1H),5.12(q,J=7.7Hz,1H),3.86 (s, 3H), 2.62 (dd, J = 16.0, 8.0 Hz, 2H), 2.50 ( s, 3H), 2.08 ( d, J = 8.0 Hz, 2H).

[0496] Example 9: Preparation of Compounds 9, 9-P1, and 9-P2

[0497] Step 1: Compound 7-2 (500 mg, 2.81 mmol) was dissolved in ethanol (5 mL), and methylamine hydrochloride (208.41 mg, 3.09 mmol), paraformaldehyde (101.12 mg, 3.37 mmol), and concentrated hydrochloric acid (2.34 μL, 0.03 mmol) were added. The mixture was stirred in a microwave reactor at 110°C for 18 hours. The reaction was monitored by LCMS. The reaction solution was directly concentrated to give compound 9-1, which was used directly in the next step. MS m / z (ESI): =222.1 [M+H] + .

[0498] Step 2: Compound 9-1 (620 mg, 2.80 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.16 mL, 8.40 mmol) was added, and di-tert-butyl dicarbonate (1.20 mL, 5.60 mmol) was slowly added. The reaction solution was stirred at 20 ° C for 3 hours. The reaction was monitored by LCMS. The reaction solution was diluted with water (30 mL) and dichloromethane (30 mL), the aqueous phase was extracted with dichloromethane (2x30 ml), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography: 80%-90% ethyl acetate / petroleum ether gradient to obtain compound 9-2. MS m / z (ESI): =322.16 [M+H] + .

[0499] Step 3: Compound 9-2 (160 mg, 0.50 mmol) was dissolved in ethanol (10 mL), sodium acetate (205.08 mg, 2.50 mmol) and hydroxylamine hydrochloride (173.72 mg, 2.50 mmol) were added, and the reaction was stirred at 100 ° C for 3 hours. The reaction was monitored by LCMS. The reaction solution was concentrated, diluted with water (30 mL) and dichloromethane (30 mL), and the aqueous phase was extracted with dichloromethane (2x30 ml). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 9-3. MS m / z (ESI): =337.17 [M+H] + .

[0500] Step 4: Compound 9-3 (167 mg, 0.50 mmol) was dissolved in ethanol (10 mL) and Raney nickel (50 mg, 0.85 mmol) was added. The reaction mixture was stirred at 20°C under a hydrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, and the filter cake was rinsed with methanol. The filtrate was dried to give compound 9-4. MS m / z (ESI): = 323.19 [M+H] + .

[0501] Step 5: Compound 9-4 (160 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, and compound 1-6 (151.53 mg, 0.50 mmol), N,N-diisopropylethylamine (0.25 mL, 1.49 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (283.06 mg, 0.74 mmol) were added. The reaction solution was stirred at 20 ° C for 18 hours. Monitored by LCMS. The reaction solution was diluted with water (30 mL) and ethyl acetate (30 mL), the aqueous phase was extracted with ethyl acetate (2x30 ml), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography: 50%-80% ethyl acetate / petroleum ether gradient to obtain compound 9-5, MS m / z (ESI): = 610.31 [M+H] + .

[0502] Step 6: Dissolve compound 9-5 (200 mg, 0.33 mmol) in a solution of hydrogen chloride in dioxane (10 mL, 4 M). Stir the mixture at 20°C for 30 minutes. Monitor by LCMS. The reaction mixture is directly concentrated to give compound 9-6. MS m / z (ESI): = 510.25 [M+H] + .

[0503] Step 7: Compound 9-6 (160 mg, 0.31 mmol) was dissolved in methanol (5 mL), and a solution of lithium hydroxide (30.08 mg, 1.26 mmol) in water (1 mL) was added. The reaction mixture was stirred at 60°C for 18 hours. LCMS monitoring was performed. The reaction mixture was directly concentrated, and the crude product was purified by reverse phase chromatography at a flow rate of 30 mL / min using a gradient of 22% to 100% acetonitrile / buffer (0.225% formic acid in water) to obtain compound 9. MS m / z (ESI): = 396.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.70(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,2H),7.48(d,J=7.9Hz,2H),7.32(t,J=2.8Hz,1H),6.81( s,1H),6.58(d,J=2.5Hz,1H),5.23(q,J=7.9,7.4Hz,1H),3.90-3.84(m,3H),3.40(s,3H),2.73-2.62(m,2H),2.39(s,3H),2.00(s,2H).

[0504] Step 8: Compound 9 (100 mg, 0.25 mmol) was subjected to chiral separation (chromatographic column: ChiralPak IG, 250 mm × 30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-methanol]; gradient: B%: 30%) to obtain compound 9-P1 and compound 9-P2.

[0505] SFC analysis and detection method: chromatographic column: ChiralPak IG, 100mm×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine), gradient: B%: 5%-40% gradient flow for 5 minutes, 40% hold for 5 minutes, 5% hold for 2.5 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0506] Compound 9-P1: Retention time: 1.253 min. MS m / z (ESI): = 396.2 [M+H] + . 1H NMR (400MHz, methanol-d4) δ8.49(s,1H),8.03(d,J=8.0Hz,2H),7.53(d,J=7.9Hz,2H),7.31(d,J=3.0Hz,1H),6.83(d,J=2.4Hz,2H ), 5.37 (t, J = 7.5Hz, 1H), 3.91 (s, 3H), 3.14 (ddt, J = 28.0, 12.6, 7.2Hz, 2H), 2.76 (s, 3H), 2.54 (s, 3H), 2.29 (q, J = 7.2Hz, 2H).

[0507] Compound 9-P2: Retention time: 2.784 min. MS m / z (ESI): = 396.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.00(s,2H),7.50(d,J=6.9Hz,2H),7.31(d,J=3.0Hz,1H),6.84(d,J=3.2Hz,2H) ,5.35(t,J=7.6Hz,1H),3.90(s,3H),3.17-3.07(m,2H),2.75(s,3H),2.54(s,3H),2.33-2.24(m,2H).

[0508] Example 10: Preparation of Compounds 10, 10-P1, and 10-P2

[0509] Step 1: Dissolve triphenylphosphine (22.4 g, 85.60 mmol) in toluene (400 mL) and stir until uniform. Add compound 10-1 (20.0 g, 77.82 mmol) and stir at 80°C under nitrogen for 16 hours. Monitor the reaction by LCMS and TLC. After the reaction, a precipitate was filtered and the filter cake was rinsed with toluene to obtain compound 10-2. MS m / z (ESI): = 440.0 [M-Br+H] + .

[0510] Step 2: Dissolve compound 10-2 (38.0 g, 73.20 mmol) in dichloromethane (40 mL), add sodium carbonate solution (200 mL, 10%), and stir at room temperature for 16 hours. Add water (20 mL) to the reaction solution, and extract with dichloromethane (3 x 200 mL). The combined organic phases are washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to yield compound 10-3. MS m / z (ESI): = 439.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.00 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.73-7.66 (m, 9H), 7.59 (m, J = 7.6, 5.7, 3.3 Hz, 5H), 3.87 (s, 3H).

[0511] Step 3: Compound 10-3 (1.9 g, 4.42 mmol) was dissolved in dichloromethane (10 mL), 4,4,4-trifluorobutyraldehyde (558 mg, 4.42 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated. The concentrated crude product was purified by silica gel chromatography: 0%-25% ethyl acetate / petroleum ether gradient to obtain compound 10-4. MS m / z (ESI): =287.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 4H), 7.25 (d, J = 15.4Hz, 1H), 7.02 (dd, J = 13.5, 7.5Hz, 1H), 3.90 (s, 3H), 2.63-2.55 (m, 4H).

[0512] Step 4: Compound 10-4 (472 mg, 1.65 mmol) was dissolved in 1,4-dioxane (30 mL), tert-butylsulfenamide (599 mg, 4.95 mmol) and tetraethoxytitanium (1.8 g, 8.25 mmol) were added, and the mixture was heated to 100 ° C and stirred for 16 hours. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 0%-25% ethyl acetate / petroleum ether gradient to obtain compound 10-5. MS m / z (ESI): =404.1 [M+H] + .

[0513] Step 5: Dissolve compound 10-5 (181 mg, 0.45 mmol) in methanol (3 mL), add sodium borohydride (51 mg, 1.35 mmol), and react at room temperature for 1 hour. Monitor the reaction by LCMS. Add water (20 mL) to the reaction solution, and extract with ethyl acetate (3×20 mL). The combined organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 10-6. MS m / z (ESI): =405.9 [M+H]+ .

[0514] Step 6: Dissolve compound 10-6 (160 mg, 0.39 mmol) in ethyl acetate (2 mL), add hydrogen chloride in ethyl acetate (3 mL), and react at room temperature for 0.5 hours. Monitor the reaction by LCMS. Concentrate the reaction solution to obtain compound 10-7. MS m / z (ESI): = 302.0 [M+H] + .

[0515] Step 7: Compound 10-7 (100 mg, 0.33 mmol) was dissolved in ethanol (2 mL), and palladium / carbon (5%, 20 mg, 0.19 mmol) was added. The mixture was reacted at room temperature under a hydrogen atmosphere (15 psi) for 16 hours. The reaction was monitored by LCMS. The filtrate was filtered and concentrated to afford compound 10-8. MS m / z (ESI): = 304.1 [M+H] + .

[0516] Step 8: Compound 10-8 (92 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 1-6 (100 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were added to the reaction solution and stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and concentrated to give compound 10-9. MS m / z (ESI): =591.3 [M+H] + .

[0517] Step 9: Compound 10-9 (71 mg, 0.12 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and lithium hydroxide (50 mg, 1.2 mmol) was added. The mixture was heated to 50°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH using dilute hydrochloric acid (1 N), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to give compound 10. MS m / z (ESI): = 463.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.51(d,J=8.2Hz,1H),7.91(d,J=8.1Hz,2H),7.52(d,J=8.0Hz,2H),7.32(t,J=2.9Hz,1H),6.81 (s,1H),6.55(t,J=2.5Hz,1H),5.13-5.07(m,1H),3.85(s,3H),2.48(s,3H),2.28-2.19(m,2H),1.84-1.74(m,2H),1.58-1.42(m,4H).

[0518] Step 10: Compound 10 (48 mg, 0.10 mmol) was further subjected to chiral separation (chromatographic column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 10-P1 and compound 10-P2.

[0519] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA), gradient: B%: 5%-40% gradient flow for 4 minutes, 40%-5% hold for 0.2 minutes, 5% hold for 1.8 minutes, 5% hold for 2.5 minutes, flow rate: 3.0mL / min, resolution wavelength 220nm.

[0520] Compound 10-P1: retention time: 2.607 minutes, MS m / z (ESI): =463.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),11.05(s,1H),8.51(d,J=8.3Hz,1H),8.02-7.83(m,2H),7.53(d,J=8.3Hz,2H),7.32(t,J=2.8Hz,1H),6.81( s,1H),6.54(dd,J=3.0,1.9Hz,1H),5.24-5.01(m,1H),3.85(s,3H),2.50 (s,3H),2.28-2.15(m,2H),1.81(q,J=8.2,7.6Hz,2H),1.57-1.38(m,4H).

[0521] Compound 10-P2: retention time: 2.915 minutes, MS m / z (ESI): =463.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.79(s,1H),11.04(s,1H),8.51(d,J=8.2Hz,1H),8.00-7.89(m,2H),7.58-7.45(m,2H),7.32(t,J=2.8Hz,1H),6.81( s,1H),6.54(dd,J=3.0,1.9Hz,1H),5.11(q,J=8.2Hz,1H),3.85(s,3H) ,2.50(s,3H),2.30-2.21(m,2H),1.85-1.75(m,2H),1.61-1.43(m,4H).

[0522] Example 11: Preparation of Compounds 11, 11-P1, and 11-P2

[0523] Step 1: To a solution of compound 10-8 (150 mg, 0.52 mmol) in methanol (5 mL) was added 3-6 (150 mg, 0.52 mmol) and sodium cyanoborohydride (81.5 mg, 1.23 mmol), and 2 drops of acetic acid were added dropwise. Under argon protection, the reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with dilute hydrochloric acid (1N, 3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 0%-10% dichloromethane / methanol gradient to obtain compound 11-1. MS m / z (ESI): =577.6 [M+H] + .

[0524] Step 2: Dissolve compound 11-1 (152 mg, 0.27 mmol) in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Add lithium hydroxide (114 mg, 2.7 mmol) and heat to 50°C with stirring for 16 hours. Monitor the reaction by LCMS. Adjust the pH of the reaction mixture to neutral, filter, and concentrate the filtrate. The crude product is purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) and lyophilized to obtain compound 11. MS m / z (ESI): = 449.7 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.92(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),7.25(t,J=2.8Hz,1H),6.68(s,1H),6.19(t,J= 2.4Hz,1H),3.72(s,3H),3.64(d,J=13.7Hz,3H),2.43(s,3H),2.09(td,J=10.9,6.4Hz,2H),1.69-1.45(m,2H),1.39-1.05(m,4H).

[0525] Step 3: Compound 11 (100 mg, 0.22 mmol) was subjected to chiral separation (chromatographic column: ChiralPak AS, 150×4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 11-P1 and compound 11-P2.

[0526] SFC analysis and detection method: chromatographic column: ChiralPak AS, 150×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA), gradient: B%: 5%-40% gradient flow for 5 minutes, 40% hold for 2.5 minutes, 5% hold for 2.5 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0527] Compound 11-P1: retention time: 3.588 min, MS m / z (ESI): =449.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.94-7.91(m,2H),7.46(d,J=8.2Hz,2H),7.25(t,J=2.8Hz,1H),6.68(s,1H),6.19(dd,J=3.0,1. 9Hz,1H),3.72(s,3H),3.65(d,J=14.0Hz,3H),2.43(s,3H),2.13-2.04(m,2H),1.65-1.49(m,2H),1.39-1.26(m,3H),1.15-1.08(m,1H).

[0528] Compound 11-P2: retention time: 4.091 min, MS m / z (ESI): =449.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.93(d,J=8.2Hz,2H),7.47(d,J=8.0Hz,2H),7.25(t,J=2.9Hz,1H),6.68(s,1H),6.20(dd,J=3. 1,1.9Hz,1H),3.72(s,3H),3.67(s,3H),2.43(s,3H),2.15-2.04(m,2H),1.58(d,J=45.7Hz,2H),1.38-1.25(m,3H),1.16-1.07(m,1H).

[0529] Example 12: Preparation of Compounds 12, 12-P1, and 12-P2

[0530] Step 1: Compound 5-1 (5.0 g, 19.08 mmol) was dissolved in tetrahydrofuran (70 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (16.1 mL, 1.3 M) was added at -40°C. After stirring for 50 minutes, cuprous iodide (1.1 g, 5.72 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. A solution of 12-1 (3.8 g, 28.62 mmol) in tetrahydrofuran (20 mL) was then added at -40°C. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 7% petroleum ether / ethyl acetate to obtain compound 12-2. MS m / z (ESI): =233.1 [M+H] + .

[0531] Step 2: Compound 12-2 (500 mg, 2.15 mmol) was dissolved in methanol (10 mL), and ammonium acetate (1.9 g, 25.83 mmol) and sodium cyanoborohydride (405 mg, 6.46 mmol) were added. The mixture was heated to 60°C under argon protection for 5 hours. The reaction was monitored by LCMS. The reaction solution was cooled to room temperature, quenched with dilute hydrochloric acid (1 N), and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrated crude product was purified by silica gel chromatography: 0%-10% dichloromethane / methanol gradient to obtain compound 12-3. MS m / z (ESI): =234.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.2Hz,2H),7.47(d,J=8.2Hz,2H),3.84(s,3H) ,3.63(d,J=8.5Hz,1H),2.05-1.91(m,1H),1.83-1.58(m,4H),1.40-1.01(m,4H).

[0532] Step 3: Compound 12-3 (251 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (586 mg, 1.54 mmol) was added thereto under an ice bath, and a solution of N,N-diisopropylethylamine (0.51 mL, 3.09 mmol) in N,N-dimethylformamide (2 mL) was dropped into the reaction solution. After moving to room temperature and stirring for 15 minutes, a solution of compound 1-6 (240 mg, 1.03 mmol) in N,N-dimethylformamide (2 mL) was dropped into the reaction solution. The reaction was stirred at room temperature for 2 hours and the reaction was monitored by LCMS. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 15% to 30% petroleum ether / ethyl acetate to obtain compound 12-4. MS m / z (ESI): = 521.4 [M+H] + .

[0533] Step 4: Compound 12-4 (100 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide (42 mg) was added. The mixture was heated to 50°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH using dilute hydrochloric acid (1 N), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to give compound 12. MS m / z (ESI): = 407.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.60(d,J=8.3Hz,1H),7.90(d,2H),7.51(d,J=8.3Hz,2H),7.30(t,J=2.8Hz,1H),6.80(s,1H),6.57(dd,J=3. 0,1.9Hz,1H),4.90(t,J=8.8Hz,1H),3.84(s,3H),2.48(s,3H),2.33(q,J =8.4Hz,1H),1.79(t,J=6.2Hz,1H),1.68-1.41(m,5H),1.37-1.19(m,2H).

[0534] Step 5: Compound 12 (100 mg, 0.24 mmol) was subjected to chiral separation (chromatographic column: Chiralpak IG-3 100×4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-methanol]; gradient: B%: 40%) to obtain compound 12-P1 and compound 12-P2.

[0535] SFC analysis and detection method: chromatographic column: Chiralpak IG-3 100×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: methanol (0.05% DEA), gradient: B%: 40% gradient flow for 8 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0536] Compound 12-P1 retention time: 1.945 min, MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.57(d,J=8.4Hz,1H),7.88(d,J=8.0Hz ,2H),7.46(d,J=8.0Hz,2H),7.30(t,J=2.8Hz,1H),6.80(s,1H),6.61-6.55(m ,1H),4.90(t,J=8.8Hz,1H),3.84(s,3H),2.48(s,3H),2.34(d,J=7.8Hz,1H), 1.79(d,J=7.7Hz,1H),1.62(s,3H),1.48(d,J=20.3Hz,3H),1.38-1.32(m,1H).

[0537] Compound 12-P2 retention time: 4.040 min. MS m / z (ESI): = 407.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.82 (s, 1H), 11.04 (s, 1H), 8.60 (d, J = 8.3Hz, 1H), 7.93-7.8 5(m,2H),7.51(d,J=8.3Hz,2H),7.30(t,J=2.8Hz,1H),6.80(s,1H),6.56(dd,J=3.1,2 .0Hz,1H),4.90(t,J=8.8Hz,1H),3.84(s,3H),2.48(s,3H),2.33(q,J=8.3Hz,1H),1.8 3-1.75(m,1H),1.67-1.57(m,2H),1.55-1.39(m,3H),1.41-1.32(m,1H),1.23(s,1H).

[0538] Example 13: Preparation of Compounds 13, 13-P1, and 13-P2

[0539] Step 1: Compound 12-3 (100 mg, 0.43 mmol) was dissolved in methanol (5 mL), 3-6 (99 mg, 0.34 mmol) and sodium cyanoborohydride (67 mg, 1.07 mmol) were added, 2 drops of acetic acid were added, and the reaction was stirred for 16 hours under argon protection. The reaction was monitored by LCMS. The reaction was quenched with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography: 40%-50% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) gradient to give compound 13-1. MS m / z (ESI): =507.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.86(d,J=7.9Hz,2H),7.49(d,J=3.8Hz,1H),7.40(d,J=7.9Hz,2H),6.73(s,1 H),6.32(s,1H),3.77(s,3H),3.68(s,3H),3.64(s,1H),2.49(s,3H),1.48(s,9H),1.42-0.80(m,9H).

[0540] Step 2: Compound 13-1 (190 mg, 0.38 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (126 mg, 1.9 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH using dilute hydrochloric acid (1 N), filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to obtain compound 13. MS m / z (ESI): = 393.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.85(d,J=2.6Hz,1H),7.92(d,J=8.2Hz,2H),7.44(d,J=8.2Hz, 2H),7.25(t,J=2.8Hz,1H),6.69(s,1H),6.11(dd,J=3.1,1.9Hz,1H),3.73(s,3H),3.64(d ,J=12.2Hz,1H),3.55(d,J=12.2Hz,1H),3.35(d,J=8.7Hz,1H),2.44(s,3H),1.95(q,J=8. 3Hz,1H),1.79-1.68(m,1H),1.44(d,J=7.8Hz,3H),1.37-1.28(m,1H),1.21-0.93(m,3H).

[0541] Step 3: Compound 13 (98 mg, 0.25 mmol) was further subjected to chiral separation (chromatographic column: Chiralpak AD-3 50*4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 13-P1 and compound 13-P2.

[0542] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA), gradient: B%: 5%-40% gradient flow for 4 minutes, 40%-5% hold for 0.2 minutes, 5% hold for 1.8 minutes, 5% hold for 2.5 minutes, flow rate: 3.0mL / min, resolution wavelength 220nm.

[0543] Compound 13-P1: retention time: 2.462 min, MS m / z (ESI): =393.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.86(s,1H),7.92(d,J=8.0Hz,2H),7.46(d,J=8.1Hz,2H),7.25(s,1H),6.69(s,1H),6.12(s,1H),3.73(s, 3H),3.67-3.62(m,1H),3.59-3.52(m,1H),3.32-3.28(m,2H),2.44(s,3H),2.01-1.91(m,1H),1.56-1.26(m,5H),1.20-0.98(m,3H).

[0544] Compound 13-P2: retention time: 2.847 min, MS m / z (ESI): =393.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.93(d,J=7.9Hz,2H),7.47(d,J=8.0Hz,2H),7.26(s,1H),6.69(s,1H),6.12(s,1H),3.73(s,3H),3. 65(s,1H),3.59-3.49(m,1H),3.32-3.28(m,2H),2.44(s,3H),2.04-1 .90(m,1H),1.81-1.70(m,1H),1.54-1.31(m,4H),1.22-0.97(m,3H).

[0545] Example 14: Preparation of Compounds 14, 14-P1, and 14-P2

[0546] Step 1: Compound 5-1 (4 g, 15.26 mmol) was dissolved in tetrahydrofuran (8 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (12.88 mL, 1.3 M) was added at -40°C. After stirring for 50 minutes, cuprous iodide (0.87 g, 4.58 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. A solution of cyclohexanoyl chloride (3.36 g, 22.90 mmol) in tetrahydrofuran (4 mL) was then added at -40°C. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 5% ethyl acetate / petroleum ether to obtain compound 14-1. MS m / z (ESI): =247.1 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ8.12(s,4H),3.94(s,3H),3.53-3.44(m,1H),1.89-1.70(m,5H),1.49-1.19(m,5H).

[0547] Step 2: Compound 14-1 (400 mg, 1.62 mmol), ammonium acetate (1.50 g, 19.49 mmol), and sodium cyanoborohydride (402.74 mg, 6.50 mmol) were dissolved in methanol (15 mL) and stirred at 60°C under argon for 16 hours. The reaction was monitored by LCMS and TLC. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using a 0% to 3% methanol / dichloromethane gradient to afford compound 14-2. MS m / z (ESI): = 248.1 [M+H] + .

[0548] Step 3: Compound 14-2 (120 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (224 mg, 0.59 mmol) and N,N-diisopropylethylamine (101 mg, 0.79 mmol) were added. After stirring at room temperature for 5 minutes, 1-6 (97 mg, 0.39 mmol) was added and stirring was continued for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated, and the crude product was purified by reverse phase chromatography: 12%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient to obtain compound 14-3. MS m / z (ESI): = 535.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=8.6Hz,1H),7.97-7.90(m,2H),7.61(d,J =3.7Hz,1H),7.54-7.47(m,2H),6.95(s,1H),6.54(d,J=3.8Hz,1H),4.89(t ,J=8.4Hz,1H),3.86(d,J=3.2Hz,6H),2.56(s,3H),1.87(d,J=12.3Hz,1H), 1.77-1.68(m,2H),1.58(s,11H),1.32(d,J=12.4Hz,1H),1.17-0.90(m,5H).

[0549] Step 4: Compound 14-3 (220 mg, 0.41 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (138 mg, 3.29 mmol) was added and the mixture was heated to 50°C with stirring for 6 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 14. MS m / z (ESI): = 421.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.56(d,J=8.5Hz,1H),7.90(d,J=8.1Hz,2H ),7.45(d,J=8.1Hz,2H),7.31(t,J=2.9Hz,1H),6.82(s,1H),6.61(t,J=2.5Hz,1H) ,4.93(t,J=8.1Hz,1H),3.87(s,3H),2.49(s,3H),1.86(d,J=12.2Hz,1H),1.74(t, J=10.4Hz,2H),1.62(d,J=16.0Hz,2H),1.39(d,J=12.5Hz,1H),1.20-0.98(m,5H).

[0550] Step 5: Compound 14 (100 mg, 0.24 mmol) was subjected to chiral separation (chromatographic column: ChiralPak AD, 50×4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5%-40%) to obtain compound 14-P1 and compound 14-P2.

[0551] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA), gradient: B%: 5%-40% gradient flow for 4 minutes, 40%-5% hold for 0.2 minutes, 5% hold for 1.8 minutes, flow rate: 3.0mL / min, resolution wavelength 220nm.

[0552] Compound 14-P1: retention time: 2.986 min, MS m / z (ESI): =421.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.56(d,J=8.5Hz,1H),7.93-7.87(m,2H),7.50-7.43(m,2H),7.30(t,J=2.8Hz,1H),6.81(s,1H),6. 59(dd,J=3.0,2.0Hz,1H),4.93(t,J=8.1Hz,1H),3.87(s,3H),2.49-2.47(m,3H),1.73(m,5H),1.38(d,J=12.4Hz,1H),1.21-0.95(m,5H).

[0553] Compound 14-P2: Retention time: 3.523 min. MS m / z (ESI): = 421.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.81 (s, 1H), 11.04 (s, 1H), 8.56 (d, J = 8.5Hz, 1H), 7.9 3-7.87(m,2H),7.49-7.43(m,2H),7.30(t,J=2.8Hz,1H),6.81(s,1H),6.59(dd, J=3.0,2.0Hz,1H),4.93(t,J=8.1Hz,1H),3.87(s,3H),2.49-2.47(m,3H),1.85( d,J=12.3Hz,1H),1.79-1.56(m,4H),1.38(d,J=12.6Hz,1H),1.21-0.97(m,5H).

[0554] Example 15: Preparation of Compounds 15, 15-P1, and 15-P2

[0555] Step 1: Dissolve compound 14-2 (3.0 g, 12.01 mmol) in methanol (30 mL), add compound 3-6 (3.5 g, 12.11 mmol), sodium cyanoborohydride (2.3 g, 35.44 mmol) and 1 drop of acetic acid, and stir at room temperature for 16 hours. Monitor the reaction by LCMS. Pour the reaction solution into water (200 mL) and extract with ethyl acetate (3×200 mL). The combined organic phase is washed with saturated brine (150 mL), dried over anhydrous sodium sulfate and concentrated. The crude product is purified by silica gel chromatography: 5%-10% methanol / dichloromethane gradient to obtain compound 15-1. MS m / z (ESI): =521.4 [M+H] + .

[0556] Step 2: Compound 15-1 (1.1 g, 2.05 mmol) was dissolved in tetrahydrofuran (3.5 mL), methanol (3.5 mL), and water (3.5 mL). Lithium hydroxide (444 mg, 10.25 mmol) was added and the mixture was heated to 50°C with stirring for 10 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) and lyophilized to obtain compound 15. MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.91(d,J=8.2Hz,2H),7.40(d,J=8.0Hz,2H),7.25 (t,J=2.9Hz,1H),6.68(s,1H),6.14(dd,J=3.1,1.9Hz,1H),3.72(s,3H),3.66(d,J=12.1H z,1H),3.56(d,J=12.1Hz,1H),3.42(d,J=6.6Hz,1H),2.43(s,3H),1.76(d,J=12.7Hz,1H ), 1.58 (m, 4H), 1.29 (d, J = 12.7Hz, 1H), 1.16-0.91 (m, 3H), 0.80 (dt, J = 25.2, 11.4Hz, 2H).

[0557] Step 3: Compound 15 (453.80 mg, 1.12 mmol) was subjected to chiral separation (chromatographic column: Chiralpak AD-3 150*4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-methanol]; gradient: B%: 30%) to obtain compound 15-P1 and compound 15-P2.

[0558] SFC analysis and detection method: chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA), gradient: B%: 30% gradient flow for 9 minutes, flow rate: 2.5mL / min, resolution wavelength 220nm.

[0559] Compound 15-P1: retention time: 1.892 min, MS m / z (ESI): =407.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),11.08(s,1H),9.00(s,1H),7.99(d,J=7.8Hz,2H),7.5 3(d,J=8.0Hz,2H),7.36(s,1H),6.75(s,1H),6.28(s,1H),4.20(m,2H),4.12-4.01(m,1H),3. 75(t,J=1.7Hz,3H),2.48(s,3H),2.17-2.07(m,1H),1.97-1.87(m,1H),1.75-1.66(m,1H),1. 64-1.48(m,3H),1.26-1.16(m,1H),1.14-1.04(m,1H),1.02-0.91(m,1H),0.85-0.64(m,2H).

[0560] Compound 15-P2: Retention time: 2.273 min. MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),11.08(s,1H),8.92(d,J=74.1Hz,2H),7.99(d,J=7.8 Hz,2H),7.53(d,J=8.1Hz,2H),7.36(d,J=3.1Hz,1H),6.75(s,1H),6.28(s,1H),4.20(m,2H ),4.10-4.01(m,1H),3.75(s,3H),2.48(s,3H),2.17-2.08(m,1H),1.95-1.88(m,1H),1.74 -1.66(m,1H),1.64-1.52(m,3H),1.25-1.07(m,2H),1.03-0.94(m,1H),0.83-0.63(m,2H).

[0561] Example 16: Preparation of Compounds 16-P1 and 16-P2

[0562] Step 1: Dissolve compound 16-1 (2.5 g, 10.90 mmol) in tetrahydrofuran (20 mL). Add a solution of borane in tetrahydrofuran (24 mL, 24 mmol, 1.0 M) at 0°C and stir at room temperature for 3 hours. Monitor the reaction by LCMS and TLC. Add a 10% aqueous sodium hydroxide solution (10 mL) at 0°C, and extract with ethyl acetate (3 × 20 mL). The combined organic phases are washed with saturated brine (10 mL), dried, and concentrated to afford compound 16-2. 1H NMR (400MHz, CDCl3) δ4.41 (s, 1H), 4.15 (s, 1H), 3.56 (d, J = 12.0Hz, 2H), 3.32-3.26 (m, 2 H),1.85(dq,J=6.6,4.0,3.4Hz,3H),1.71-1.67(m,2H),1.46(s,9H),1.39-1.21(m,1H).

[0563] Step 2: Dissolve compound 16-2 (2.42 g, 11.24 mmol) in dichloromethane (50 mL) and add Dess-Martin reagent (5.72 g, 13.49 mmol) at 0°C. Stir at room temperature for 2 hours. Monitor the reaction by LCMS and TLC. The reaction mixture is filtered, the filtrate is concentrated, and the crude product is purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate / petroleum ether to obtain compound 16-3. 1 H NMR (400MHz, CDCl3) δ9.77(s,1H),4.25(s,1H),3.34(s,2H),2.90(s,1H),2.47(dd ,J=15.9,7.2Hz,1H),2.09(s,1H),1.86(q,J=7.0Hz,2H),1.64(s,1H),1.45(s,9H).

[0564] Step 3: Compound 5-1 (2.4 g, 9.16 mmol) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection, a tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (7.75 mL, 10.08 mmol, 1.3 M) was added at -40°C. After stirring for 50 minutes, a tetrahydrofuran solution of compound 16-3 (1.95 g, 9.16 mmol) was added at -40°C. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. An aqueous ammonium chloride solution (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 0%-20% ethyl acetate / petroleum ether gradient to obtain compound 16-4. MS m / z (ESI): =350.2 [M+H] + .

[0565] Step 4: Dissolve compound 16-4 (2.42 g, 6.93 mmol) in dichloromethane (20 mL) and add Dess-Martin reagent (3.82 g, 9.00 mmol) at 0°C. Stir at room temperature for 2 hours. Monitor the reaction by LCMS and TLC. The reaction mixture is filtered, the filtrate is concentrated, and the crude product is purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate / petroleum ether to obtain compound 16-5. MS m / z (ESI): = 348.1 [M+H] + .

[0566] Step 5: Compound 16-5 (1 g, 2.88 mmol), ammonium acetate (1.11 g, 14.39 mmol), and sodium cyanoborohydride (0.9 g, 14.39 mmol) were dissolved in methanol (15 mL) and stirred at 80°C under argon for 16 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using a 0% to 3% methanol / dichloromethane gradient to obtain compound 16-6. MS m / z (ESI): = 349.6 [M+H] + .

[0567] Step 6: Compound 1-6 (508 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (759 mg, 2 mmol) and N,N-diisopropylethylamine (430 mg, 3.33 mmol) were added. After stirring at room temperature for 5 minutes, 16-6 (580 mg, 1.66 mmol) was added and stirring was continued for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography: 0%-17% ethyl acetate / petroleum ether gradient to obtain compound 16-7-P1 (MS m / z (ESI): =636.4 [M+H] + , retention time: 1.467 min) and 16-7-P2 (MS m / z (ESI): = 636.4 [M+H] + , retention time: 1.367 min).

[0568] Step 7: Dissolve compound 16-7-P1 (460 mg, 0.72 mmol) in a hydrochloric acid-dioxane solution (5 mL, 4 M) and stir at 25°C for 0.5 h. Monitor the reaction by LCMS. After completion of the reaction, the reaction solution is concentrated to yield compound 16-8-P1. MS m / z (ESI): = 536.4 [M+H] + Compound 16-8-P2 was obtained from compound 16-7-P2 according to the method for preparing 16-8-P1 from 16-7-P1. MS m / z (ESI): = 536.4 [M+H]+ .

[0569] Step 8: Compound 16-8-P1 (415 mg, 0.72 mmol) was dissolved in methanol (6 mL). A solution of lithium hydroxide (90.7 mg, 2.16 mmol) in water (1 mL) was added at 25°C and stirred for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the pH of the reaction solution was adjusted to neutral, filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 16-P1. MS m / z (ESI): = 422.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 8.66 (m, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.39 ( d,J=8.1Hz,2H),7.31(t,J=2.7Hz,1H),6.79(s,1H),6.65-6.61(m,1H),5.18(dd, J=14.7,7.6Hz,1H),3.83(s,3H),3.13(m,5H),2.48(s,3H),2.30-2.20(m,1H),2. 11-2.08(m,1H),2.05-2.01(m,1H),1.91(m,1H),1.76(m,1H),1.65-1.51(m,1H).

[0570] Compound 16-P2 was obtained from compound 16-8-P2 according to the method for preparing 16-P1 from 16-8-P1. MS m / z (ESI): = 422.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 8.66 (M, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.39 ( d,J=8.1Hz,2H),7.31(t,J=2.7Hz,1H),6.79(s,1H),6.65-6.61(m,1H),5.18(dd, J=14.7,7.6Hz,1H),3.83(s,3H),3.13(m,5H),2.48(s,3H),2.30-2.20(m,1H),2. 11-2.08(m,1H),2.05-2.01(m,1H),1.91(m,1H),1.76(m,1H),1.65-1.51(m,1H).

[0571] Example 17: Preparation of Compounds 17, 17-P1, and 17-P2

[0572] Step 1: 4-Iodocyanobenzene (5.01 g, 21.86 mmol) was dissolved in tetrahydrofuran (50 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (12.93 mL, 16.81 mmol, 1.3 M) was added at -50°C. After stirring for 1 hour, a solution of 17-1 (1.65 g, 16.81 mmol) in tetrahydrofuran (10 mL) was added. After 5 minutes, the mixture was warmed to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The mixture was quenched by adding saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 15%-20% ethyl acetate / petroleum ether gradient to give compound 17-2. MS m / z (ESI): =202.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.80-7.73(m,2H),7.55-7.48(m,2H),5.38(d,J=4.7Hz,1H), 4.40(dd,J=7.3,4.6Hz,1H),2.13-2.00(m,1H),1.62-1.40(m,6H),1.33-1.19(m,2H).

[0573] Step 2: Compound 17-2 (2.0 g, 9.94 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (6.32 g, 14.91 mmol) was added at 0°C and stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. Water (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (3×30 mL). The combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 15%-20% ethyl acetate / petroleum ether gradient to obtain compound 17-3. MS m / z (ESI): =200.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.16-8.08(m,2H),8.04-7.97(m,2H),3.91-3.80(m,1H),1.97-1.85(m,2H),1.79-1.67(m,2H),1.65-1.55(m,4H).

[0574] Step 3: Compound 17-3 (500 mg, 2.51 mmol) was dissolved in methanol (10 mL), and ammonium acetate (2.32 g, 30.11 mmol) and sodium cyanoborohydride (630.77 mg, 10.04 mmol) were added. The reaction system was stirred at 60 ° C for 16 hours under nitrogen protection. The reaction was monitored by LCMS and TLC. It was quenched with hydrochloric acid (1N) and extracted with ethyl acetate (3x30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 3%-5% methanol / dichloromethane gradient to obtain compound 17-4. MS m / z (ESI): =201.0 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),3.80(d,J=9.5Hz,1H) ,2.25-2.13(m,1H),1.98-1.90(m,1H),1.73-1.49(m,4H),1.41-1.30(m,2H),1.10-1.00(m,1H).

[0575] Step 4: Dissolve compound 1-6 (571.69 mg, 1.87 mmol) in N,N-dimethylformamide (6 mL). Add a solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.07 mg, 2.81 mmol) and N,N-diisopropylethylamine (0.93 mL, 5.62 mmol) in N,N-dimethylformamide (1 mL) at 0°C. Warm to room temperature, stir for 15 minutes, and then add a solution of 17-4 (450 mg, 2.25 mmol) in N,N-dimethylformamide (2 mL) dropwise. Stir for 2 hours. Monitor the reaction by LCMS. Quench with water (20 mL) and extract with ethyl acetate (3 x 50 mL). Wash the combined organic phases with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate. The crude product was purified by silica gel column chromatography: 20%-25% ethyl acetate / petroleum ether gradient to obtain compound 17-5. MS m / z (ESI): = 488.2 [M+H] + .

[0576] Step 5: Compound 17-5 (260 mg, 0.53 mmol) was dissolved in toluene (5 mL), and Lawesson's reagent (646.99 mg, 1.60 mmol) was added. The system was heated to 110°C and stirred for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 20%-25% ethyl acetate / petroleum ether gradient to obtain compound 17-6. MS m / z (ESI): =504.2 [M+H] + .

[0577] Step 6: Compound 17-6 (300 mg, 0.60 mmol) was dissolved in isopropanol (1.5 mL) and water (4.5 mL), and barium hydroxide (408.23 mg, 2.38 mmol) was added. The mixture was heated to 100°C and stirred for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, the mixture was filtered, and the mixture was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L formic acid in water) to afford compound 17. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),10.95(s,1H),10.60(d,J=8.4Hz,1H),7.95-7.88(m,2H),7.58-7.52(m,2H),7.25(t,J=2.8Hz,1H) ,6.72(s,1H),6.13(dd,J=3.0,1.9Hz,1H),5.61(dd,J=10.5,8.4Hz,1H),3.68(s,3H),2.46(s,3H),1.87-1.80(m,1H),1.68-1.17(m,8H).

[0578] Step 7: Compound 17 (100 mg, 0.24 mmol) was further subjected to chiral separation (chromatographic column: ChiralCel OJ, 250×30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.05% diethylamine-methanol]; gradient: B%: 30%-40%) to obtain compound 17-P1 and compound 17-P2.

[0579] SFC analysis and detection method: Chromatographic column: ChiralCel OJ, 150×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine), gradient: B%: 5%-40% gradient flow for 5 minutes, 40% for 5 minutes, 5% for 2.5 minutes, flow rate: 150mL / min, resolution wavelength 220nm.

[0580] Retention time of compound 17-P1: 2.501 min. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.04-7.97(m,3H),7.59-7.53(m,3H),7.17(d,J=3.0Hz,1H),6.72(s,1H),6.31(d,J=3.1Hz,1H),5.65(d,J=10.6Hz,1H ),3.73(s,3H),2.53(d,J=8.2Hz,1H),2.48(s,3H),2.02-1.90(m,1H), 1.77-1.59(m,4H),1.55(s,1H),1.47-1.40(m,1H),1.36-1.24(m,1H).

[0581] Compound 17-P2 retention time: 2.498 min. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ10.43(s,1H),8.00(d,J=8.1Hz,2H),7.56(d,J=8.1Hz, 2H),7.17(t,J=2.3Hz,1H),6.72(s,1H),6.31(d,J=2.9Hz,1H),5.65(d,J=10. 6Hz,1H),3.73(s,3H),2.55-2.49(m,1H),2.48(s,3H),2.01-1.91(m,1H),1.7 0(m,4H),1.59-1.51(m,1H),1.47-1.40(m,1H),1.31(td,J=12.5,6.7Hz,2H).

[0582] Example 18: Preparation of Compounds 18-P1, 18-P2, 18-P3, and 18-P4

[0583] Step 1: Dissolve compound 18-1 (6.8 g, 29.66 mmol) in tetrahydrofuran (30 mL). Add a solution of borane in tetrahydrofuran (29.66 mL, 2 M) at 0°C and stir at 0°C for 4 hours. Monitor the reaction by LCMS and TLC. Concentrate directly to obtain compound 18-2. MS m / z (ESI): =160 [M-55] + .

[0584] Step 2: Compound 18-2 (7 g) was dissolved in dichloromethane (140 mL), and Dess-Martin periodinane (20.68 g, 48.77 mmol) was added in portions at 0°C and stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution to quench the mixture, which was then extracted with dichloromethane (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 0%-15% ethyl acetate / petroleum ether gradient to obtain compound 18-3. MS m / z (ESI): =158 [M-55] + .

[0585] Step 3: Compound 5-1 (3 g, 14.07 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen at -40°C, a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (14.07 mL, 1.3 M) was slowly added dropwise. After stirring for 1 hour, a solution of 18-3 (3 g, 14.07 mmol) in tetrahydrofuran (15 mL) was added dropwise and stirring was continued at -40°C for 3 hours. The reaction was monitored by LCMS and TLC. Saturated ammonium chloride solution (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 0%-20% ethyl acetate / petroleum ether gradient to obtain compound 18-4. MS m / z (ESI): =372 [M+Na] + .

[0586] Step 4: Compound 18-4 (2.3 g, 6.58 mmol) was dissolved in dichloromethane (80 mL) and Dess-Martin periodinane (4.2 g, 9.87 mmol) was added in portions at 0°C and stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution to quench the mixture, which was then extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to obtain compound 18-5. MS m / z (ESI): = 292 [M-55] + .

[0587] Step 5: Compound 18-5 (800 mg, 2.30 mmol) and ammonium acetate (709.99 mg, 9.21 mmol) were dissolved in methanol (15 mL), sodium cyanoborohydride (725.37 mg, 11.51 mmol) was added, and the mixture was stirred at reflux at 80°C for 16 hours. The reaction was monitored by LCMS. The mixture was concentrated directly, and the crude product was purified by silica gel column chromatography: 0%-50% ethyl acetate / petroleum ether gradient to obtain compound 18-6. MS m / z (ESI): =349 [M+H] + .

[0588] Step 6: Compound 1-6 (547 mg, 1.79 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.02 g, 2.69 mmol), and triethylamine (543.49 mg, 5.38 mmol) were dissolved in N,N-dimethylformamide (10 mL), and compound 18-6 (625 mg, 1.79 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. Water (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 0%-50% ethyl acetate / petroleum ether gradient to obtain compound 18-7. MS m / z (ESI): =636 [M+H] + .

[0589] Step 7: Dissolve compound 18-7 (600 mg, 0.94 mmol) in dioxane (8 mL), add hydrochloric acid (4.0 mL, 8.00 mmol, 2 M), and stir at room temperature for 2 hours. Monitor the reaction by LCMS. Concentrate directly to obtain compound 18-8. MS m / z (ESI): =536 [M+H] + .

[0590] Step 8: Compound 18-8 (500 mg) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (67.07 mg, 2.80 mmol) was added. The mixture was stirred at 50°C for 3 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 M) was added to adjust the pH to approximately 4 and the mixture was concentrated directly. The crude product was purified by silica gel chromatography: 30% methanol / dichloromethane, and then by reverse phase chromatography: 15%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient purification to obtain compound 18-P1. MS m / z (ESI): =422 [M+H] + HPLC (determination condition 1) retention time: 2.233 min. 1H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 8.60 (d, J = 8.3 Hz,1H),7.91(d,J=8.1Hz,2H),7.51(d,J=7.9Hz,2H),7.31(s,1H),6.80(s,1H),6.52(s,1H),4.98(t,J=9.1Hz,1H),3.84(s,3H) ,3.66-3.54(m,1H),2.54(s,3H),2.07-1.99(m,1H),1.95-1.88(m,1H),1.82-1.73(m,1H),1.56-1.44(m,2H),1.38-1.19(m,2H).

[0591] Compound 18-P2 was obtained. MS m / z (ESI): = 422 [M+H] + HPLC (determination condition 1) retention time: 2.291 min. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.65(d,J=8.4Hz,1H),7.81(d,J=7.9Hz,2H),7 .35(d,J=7.9Hz,2H),7.29(t,J=2.8Hz,1H),6.78(s,1H),6.60-6.53(m,1H),5.00(t, J=8.5Hz,1H),3.84(s,3H),3.44-3.37(m,1H),2.48(s,3H),2.41(d,J=8.5Hz,1H),2. 17-2.09(m,1H),1.83-1.74(m,1H),1.54(dd,J=14.9,8.9Hz,2H),1.45-1.30(m,2H).

[0592] Compound 18-P3 was obtained. MS m / z (ESI): = 422 [M+H] + HPLC (determination condition 1) retention time: 2.278 min. 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.54(d,J=8.6Hz,1H),7.75(d,J=7.9Hz,2H),7.37-7.28(m,3H),6.78(s,1H),6.64-6.57(m,1H),4.91 (t,J=9.0Hz,1H),3.84(s,3H),3.62-3.53(m,1H),2.77-2.65(m,1H),2.48(s,3H),2.10-2.00(m,1H),1.99-1.89(m,1H),1.70-1.42(m,4H).

[0593] Compound 18-P4 was obtained. MS m / z (ESI): = 422 [M+H] + HPLC (determination condition 1) retention time: 2.316 min. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.60(d,J=8.3Hz,1H),7.82(s,2H),7.39(s,2H),7.30(d,J=3.4Hz,1H),6.79(s,1H),6.54(d,J=3.0Hz,1H ),5.00-4.85(m,1H),3.83(s,3H),3.41-3.39(m,1H),2.48(s,3H),2.41 -2.36(m,1H),1.95-1.74(m,3H),1.74-1.53(m,3H),1.37-1.03(m,2H).

[0594] Example 19: Preparation of Compounds 19-P1, 19-P2, 19-P3, and 19-P4

[0595] Step 1: Compound 18-8 (300 mg, 0.56 mmol) and 3-oxetanone (80.7 mg, 1.12 mmol) were dissolved in methanol (5 mL), sodium cyanoborohydride (130.0 mg, 2.07 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. Water (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 0%-5% methanol / dichloromethane gradient to obtain compound 19-1. MS m / z (ESI): =592.3 [M+H] + .

[0596] Step 2: Dissolve compound 19-1 (300 mg, 0.51 mmol) in methanol (1 mL) and water (3 mL), add lithium hydroxide (63.8 mg, 2.66 mmol), and heat to 50°C with stirring for 16 hours. Monitor the reaction by LCMS. After completion of the reaction, adjust the pH to neutral, filter, and concentrate the filtrate. The crude product is purified by reverse phase chromatography using a gradient of 20% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 19-P1. MS m / z (ESI): = 478.3 [M+H] + HPLC (determination condition three) retention time: 2.337 min. 1 H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 3.1 Hz, 1H), 6.81 (s, 1H), 6.71 (d, J = 3.1 Hz, 1H), 5.00 (d, J = 9.6 Hz, 1H), 4.81 (q, J = 6.7 Hz, 2H), 4.57 (t, J = 6.5Hz,2H),4.19(t,J=6.6Hz,1H),3.91(s,3H),3.39-3.33(m,1H),2.66(q,J=8.3Hz,1H),2 .52(s,3H),2.07-1.91(m,2H),1.83-1.73(m,1H),1.57(q,J=7.5Hz,1H),1.47-1.28(m,2H).

[0597] Compound 19-P2 was obtained. MS m / z (ESI): = 478.3 [M+H] + HPLC (determination condition three) retention time: 2.517 min. 1 H NMR (400 MHz, methanol-d4) δ 8.03-7.93 (m, 2H), 7.53-7.44 (m, 2H), 7.26 (d, J = 3.1 Hz, 1H), 6.81 (s, 1H), 6.68 (d, J = 3.1 Hz, 1H), 5.06 (d, J = 9.0 Hz, 1H), 4.74 (dt, J = 12.1, 7.0 Hz, 2H), 4.48 (dt, J = 13.6, 6.5 Hz ,2H),4.15(p,J=6.6Hz,1H),3.91(s,3H),3.29-3.11(m,2H),2.60-2.45(m,4H),2.18(dt,J=13.5 ,7.0Hz,1H),1.90(q,J=9.0,7.2Hz,1H),1.57(p,J=5.4,4.5Hz,3H),1.43(dt,J=13.0,8.6Hz,1H).

[0598] Compound 19-P3 was obtained. MS m / z (ESI): = 478.3 [M+H] + HPLC (determination condition three) retention time: 2.573 min. 1 H NMR (400MHz, methanol-d4) δ7.96(d,J=8.2Hz,2H),7.47(d,J=8.3Hz,2H),7.25(d,J=3.1Hz,1H),6.80 (s,1H),6.72(d,J=3.1Hz,1H),5.03(d,J=9.4Hz,1H),4.76(dt,J=9.9,7.0Hz,2H),4.53(dt,J= 8.2,6.5Hz,2H),4.17-4.10(m,1H),3.90(s,3H),3.38-3.32(m,1H),2.69(q,J=8.3Hz,1H),2.5 4-2.48(m,3H),2.06(dt,J=19.3,7.2Hz,2H),1.71(dt,J=13.7,8.1Hz,1H),1.60-1.42(m,3H).

[0599] Compound 19-P4 was obtained. MS m / z (ESI): = 478.3 [M+H] + HPLC (determination condition three) retention time: 2.787 min. 1 H NMR (400MHz, methanol-d4) δ7.97(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H),7.26(d,J=3.1Hz,1H),6.81(s,1H),6. 70(d,J=3.1Hz,1H),5.04(d,J=8.9Hz,1H),4.73(t,J=7.0Hz,1H),4.60(t,J=7.0Hz,1H),4.48(t,J=6.4Hz ,1H),4.40(t,J=6.5Hz,1H),4.06(t,J=6.6Hz,1H),3.92(s,3H),3.19-3.09(m,1H),2.52(s,4H),1.88(dq ,J=21.2,7.9,7.4Hz,2H),1.83-1.66(m,2H),1.59(dt,J=12.2,6.4Hz,1H),1.25(dt,J=12.2,9.3Hz,1H).

[0600] Example 20: Preparation of Compounds 20-P1, 20-P2, 20-P3, and 20-P4

[0601] Step 1: Dissolve compound 18-1 (5 g, 21.81 mmol) in tetrahydrofuran (100 mL). Add lithium aluminum tetrahydride in tetrahydrofuran (98.13 mL, 98.13 mmol, 1 M) at 0°C. Stir for 1 hour, then warm to 65°C overnight. Monitor the reaction by LCMS and TLC. Slowly add excess sodium sulfate decahydrate at 0°C to quench the reaction. Filter and concentrate to obtain compound 20-1. MS m / z (ESI): =130 [M+H] + .

[0602] Step 2: Compound 20-1 (2.3 g) was dissolved in dichloromethane (50 mL), triethylamine (5.39 g, 53.41 mmol) was added, and di-tert-butyl dicarbonate (4.27 g, 19.58 mmol) was added dropwise at 0°C and stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 0%-15% ethyl acetate / petroleum ether gradient to obtain compound 20-2. MS m / z (ESI): =230 [M+H] + .

[0603] Step 3: Compound 20-2 (2.7 g, 11.77 mmol) was dissolved in dichloromethane (50 mL), and pyridinium chlorochromate (3.81 g, 17.66 mmol) was slowly added at 0°C and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 0%-15% ethyl acetate / petroleum ether gradient to obtain compound 20-3. MS m / z (ESI): =172 [M-55] + .

[0604] Step 4: Compound 5-1 (732.08 mg, 2.79 mmol) was dissolved in tetrahydrofuran (15 mL). Under nitrogen at -40°C, a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (2.79 mL, 1.3 M) was slowly added dropwise. After stirring for 1 hour, a solution of compound 20-3 (635 mg, 2.79 mmol) in tetrahydrofuran (5 mL) was added and stirring was continued for 3 hours. The reaction was monitored by LCMS and TLC. A saturated solution of ammonium chloride (100 mL) was added to the reaction solution to quench the mixture, which was then extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 0%-20% ethyl acetate / petroleum ether gradient to obtain compound 20-4. MS m / z (ESI): =386 [M+Na] + .

[0605] Step 5: Compound 20-4 (1.6 g, 4.40 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin periodinane (2.80 g, 6.60 mmol) was added in portions at 0°C and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction solution to quench the mixture, which was then extracted with dichloromethane (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 0%-20% ethyl acetate / petroleum ether gradient to give compound 20-5. MS m / z (ESI): =362 [M+H] + .

[0606] Step 6: Dissolve compound 20-5 (700 mg, 1.94 mmol) and ammonium acetate (149.28 mg, 1.94 mmol) in methanol (20 mL), add sodium cyanoborohydride (122.01 mg, 1.94 mmol), and stir under reflux at 80°C for 16 hours. Monitor the reaction by LCMS. Concentrate directly, and the crude product is purified by silica gel column chromatography: 0%-50% ethyl acetate / petroleum ether gradient to obtain compound 20-6. MS m / z (ESI): =363 [M+H] + .

[0607] Step 7: Compound 1-6 (496.99 mg, 1.63 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (804.09 mg, 2.12 mmol), and N,N-diisopropylethylamine (629.93 mg, 4.88 mmol) were dissolved in N,N-dimethylformamide (15 mL), and compound 20-6 (590 mg, 1.63 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The reaction solution was quenched by adding water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 0%-50% ethyl acetate / petroleum ether gradient to obtain compound 20-7. MS m / z (ESI): =650 [M+H] + .

[0608] Step 8: Dissolve compound 20-7 (570 mg, 0.88 mmol) in dioxane (5 mL), add hydrochloric acid (5 mL, 2 M), and stir at room temperature for 2 hours. Monitor the reaction by LCMS. Concentrate directly to obtain compound 20-8. MS m / z (ESI): =550 [M+H] + .

[0609] Step 9: Compound 20-8 (482 mg) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL). Lithium hydroxide (84.01 mg, 3.51 mmol) was added and stirred at 50°C for 3 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 M) was added to adjust the pH of the system to approximately 4, and the mixture was concentrated directly. The crude product was purified by silica gel chromatography: 30% methanol / dichloromethane, and then by reverse phase chromatography: 15%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient purification to obtain compound 20-P1. MS m / z (ESI): =436 [M+H] + HPLC (determination condition three) retention time: 2.396 min. 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.64(d,J=8.6Hz,1H),7.79(d,J=8.0Hz,2H),7.3 9-7.24(m,3H),6.81(s,1H),6.65(dd,J=3.0,1.9Hz,1H),4.90(t,J=8.8Hz,1H),3.91(s, 3H),3.33(s,1H),2.80-2.63(m,1H),2.52(d,J=1.8Hz,1H),2.49(s,3H),2.43(s,3H),1. 94(s,2H),1.82-1.67(m,1H),1.58(d,J=8.3Hz,1H),1.38(s,1H),1.28(d,J=9.8Hz,1H).

[0610] Compound 20-P2 was obtained. MS m / z (ESI): = 436 [M+H] + HPLC (determination condition three) retention time: 2.545 min. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.74(d,J=8.2Hz,1H),7.83(d,J=7.9Hz,2H),7.3 8(d,J=8.0Hz,2H),7.28(t,J=2.7Hz,1H),6.78(s,1H),6.62-6.46(m,1H),4.98(t,J=8. 3Hz,1H),3.84(s,3H),3.19-3.11(m,1H),2.48(s,3H),2.42(t,J=8.7Hz,2H),2.35(s,3 H), 2.14-2.01 (m, 1H), 1.75 (d, J = 7.5Hz, 1H), 1.60 (d, J = 5.4Hz, 1H), 1.53-1.31 (m, 3H).

[0611] Compound 20-P3 was obtained. MS m / z (ESI): = 436 [M+H] + HPLC (determination condition three) retention time: 2.582 min. 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.55(d,J=8.6Hz,1H),7.76(d,J=7.9 Hz,2H),7.44-7.25(m,3H),6.77(s,1H),6.59(d,J=2.7Hz,1H),4.92(t,J=8 .9Hz,1H),3.82(s,3H),3.39(s,1H),2.73-2.64(m,1H),2.52(d,J=3.5Hz,1 H),2.47(s,3H),2.42(s,3H),2.05(s,1H),1.91(s,1H),1.67-1.41(m,4H).

[0612] Compound 20-P4 was obtained. MS m / z (ESI): = 436 [M+H] + HPLC (determination condition three) retention time: 2.755 min. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.61(d,J=8.3Hz,1H),7.75(d,J=8.0Hz,2 H),7.40-7.24(m,3H),6.78(s,1H),6.56(dd,J=3.0,2.0Hz,1H),4.87(t,J=9.1H z,1H),3.83(s,3H),3.17-3.11(m,1H),2.53-2.51(m,1H),2.48(s,3H),2.40(s, 3H),2.37-2.23(m,1H),1.96-1.77(m,2H),1.75-1.50(m,3H),1.39-1.25(m,1H).

[0613] Example 21: Preparation of Compound 21

[0614] Step 1: Compound 21-1 (5.0 g, 50.44 mmol) was dissolved in dichloromethane (30 mL) and water (30 mL). Benzyl chloroformate (10.33 g, 60.53 mmol) was added at 0°C. After 5 minutes, the mixture was warmed to room temperature and stirred for 16 hours. The reaction was monitored by LCMS and TLC. The mixture was extracted with ethyl acetate (3 x 300 mL), and the combined organic phases were washed with saturated brine (200 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 21-2. MS m / z (ESI): =256.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ7.47-7.25 (m, 5H), 5.12 (s, 2H), 3.70 (t, J = 6.3Hz, 4H), 2.39 (t, J = 6.3Hz, 4H).

[0615] Step 2: Compound 5-1 (1.08 g, 4.12 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (4.46 mL, 1.3 M) was added at -78 ° C. After stirring for 90 minutes, a solution of compound 21-2 (800 mg, 3.43 mmol) in tetrahydrofuran (10 mL) was added at -78 ° C. After 5 minutes, the mixture was heated to 0 ° C and stirred for 1 hour. The reaction was monitored by LCMS and TLC. Saturated ammonium chloride solution (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3x80 mL). The combined organic phases were washed with saturated brine (100 mL), dried and concentrated. The crude product was purified by silica gel chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 21-3. MS m / z (ESI): =392.2 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),7.43-7.31(m,5H),5.32(s,1H),5.10(s, 2H), 4.00-3.91 (m, 2H), 3.84 (s, 3H), 3.29-3.17 (m, 2H), 1.87 (td, J = 13.1, 4.8Hz, 2H), 1.60 (d, J = 13.3Hz, 2H).

[0616] Step 3: Compound 21-3 (430 mg, 1.16 mmol) was dissolved in chloroacetonitrile (8 mL), and acetic acid (0.2 mL) and concentrated sulfuric acid (0.2 mL) were slowly added dropwise at 0 ° C. After stirring for 5 minutes, the mixture was moved to room temperature and stirred for 30 minutes. The reaction was monitored by LCMS and TLC. Saturated sodium bicarbonate solution (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3x40 mL). The combined organic phases were washed with saturated brine (80 mL), dried and concentrated. The crude product was purified by silica gel chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 21-4. MS m / z (ESI): =445.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),7.92-7.88(m,2H),7.53-7.47(m,2H),7.39-7.34(m,5H),5.10(s,2H),4.14 (s,2H),3.95(d,J=13.2Hz,2H),3.84(s,3H),3.16-3.06(m,2H),2.32(d,J=13.1Hz,2H),1.83(dt,J=13.4,6.8Hz,2H).

[0617] Step 4: Compound 21-4 (630 mg, 1.42 mmol) was dissolved in ethanol (10 mL), and thiourea (538.94 mg, 7.08 mmol) and acetic acid (0.2 mL) were added sequentially. The reaction system was heated to 85 ° C and stirred for 16 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the mixture and extracted with ethyl acetate (3x40 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 21-5. MS m / z (ESI): =352.1 [M-NH2] + . 1 H NMR(400MHz,Chloroform-d)δ7.92-7.88(m,2H),7.69-7.65(m,2H),7.39-7.32(m,5H),5.09(s,2H),3.84(s,3H ), 3.82 (d, J = 3.7Hz, 2H), 3.45-3.35 (m, 2H), 2.06 (s, 2H), 1.83 (td, J = 12.8, 4.6Hz, 2H), 1.57 (d, J = 13.0Hz, 2H).

[0618] Step 5: Dissolve compound 1-6 (250 mg, 0.82 mmol) in N,N-dimethylformamide (2 mL). Add 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (467 mg, 1.23 mmol) under ice. Add a solution of N,N-diisopropylethylamine (0.41 mL, 2.46 mmol) in N,N-dimethylformamide (1 mL) dropwise to the reaction mixture. Bring the reaction mixture to room temperature and stir for 15 minutes. Then, add a solution of compound 21-5 (362 mg, 0.98 mmol) in N,N-dimethylformamide (2 mL) dropwise to the reaction mixture. Stir at room temperature for 1 hour. Monitor the reaction by LCMS. Quench the mixture with water (10 mL) and extract with ethyl acetate (3 × 20 mL). Wash the combined organic phases with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate. The crude product was purified by silica gel column chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 21-6. MS m / z (ESI): = 656.7 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.52 (s, 1H), 7.94 (d, J = 8.3Hz, 2H), 7.66-7.61 (m, 3H),7.41-7.33(m,5H),6.97(s,1H),6.45(d,J=3.7Hz,1H),5.11(d,J=7.9H z,2H),4.05-3.99(m,2H),3.89(s,3H),3.85(d,J=6.2Hz,3H),3.28-3.16(m ,2H),2.57(s,3H),2.45(s,2H),1.87(td,J=13.1,4.4Hz,2H),1.58(s,9H).

[0619] Step 6: Dissolve compound 21-6 (500 mg, 0.76 mmol) in ethyl acetate (6 mL) and stir at room temperature under a hydrogen atmosphere for 16 hours. Monitor the reaction by LCMS. Filter the reaction mixture, wash the filter cake with ethyl acetate (20 mL), and concentrate the filtrate to obtain compound 21-7. MS m / z (ESI): =522.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 7.96-7.91 (m, 2H), 7.64-7.60 (m, 3H), 6.98 (s, 1H), 6.55 (d, J = 3.8Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 2.94 (t, J = 12.1Hz, 2H), 2.83 (d, J = 12.5Hz, 2H), 2.57 (s, 3H), 2.33 (d, J = 12.7Hz, 2H), 1.80 (dd, J = 13.4, 9.3Hz, 2H), 1.58 (s, 9H).

[0620] Step 7: Compound 21-7 (50 mg, 0.096 mmol) was dissolved in methanol (2 mL), and acetic acid (2 drops), paraformaldehyde (25.90 mg, 0.29 mmol) and sodium cyanoborohydride (15.06 mg, 0.24 mmol) were added sequentially and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. Water (10 mL) was added to quench the mixture, and the mixture was concentrated and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase chromatography: 20%-30% acetonitrile / water gradient to obtain compound 21-8. MS m / z (ESI): =536.2 [M+H] + .

[0621] Step 8: Compound 21-8 (80 mg, 0.15 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (50 mg, 1.19 mmol) was added and the mixture was heated to 60°C and stirred for 2 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, the mixture was filtered, and the mixture was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 21. MS m / z (ESI): = 422.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.57(s,1H),8.01-7.94(m,2H),7.64-7.53(m,2H),7.34(t,J=2.8Hz,1H),6.86(s,1H),6.35(t,J=2.4Hz, 1H),3.93(s,3H),3.52(d,J=12.3Hz,2H),3.38(s,3H),3.18(q,J=11.9, 11.3Hz, 2H), 2.83 (d, J = 4.4Hz, 2H), 2.73 (d, J = 14.1Hz, 2H), 2.49 (s, 3H).

[0622] Example 22: Preparation of Compound 22

[0623] Step 1: Compound 22-1 (12.9 g, 79.9 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (25.96 g, 111.84 mmol) were dissolved in dichloromethane (100 mL), triethylamine (16.16 g, 159.78 mmol) was added, and the mixture was stirred at 25°C for 18 hours. The reaction was monitored by LCMS. Water (50 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (3 x 60 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated to give compound 22-2. MS m / z (ESI): = 208.2 [M+H] + .

[0624] Step 2: Under nitrogen atmosphere, compound 22-2 (9.4 g, 45.37 mmol), p-toluenesulfonylmethyl isocyanide (13.29 g, 68.05 mmol) and tert-butanol (6.47 mL, 2.17 mmol) were dissolved in ethylene glycol dimethyl ether (80 mL). A solution of potassium tert-butoxide in tetrahydrofuran (90.73 mL, 1 M) was added dropwise at 0°C. After 1 hour, the system was allowed to warm to room temperature and stirred for 24 hours. The reaction was monitored by LCMS. Saturated ammonium chloride solution (50 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (200 mL), dried and concentrated. The crude product was purified by silica gel column chromatography: 5%-10% ethyl acetate / petroleum ether gradient to give compound 22-3. MS m / z (ESI): =219.2 [M+H] + .

[0625] Step 3: Compound 22-3 (5.69 g, 26.07 mmol) and methyl p-fluorobenzoate (8.04 g, 52.15 mmol) were dissolved in tetrahydrofuran (40 mL). Under nitrogen protection, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (52.15 mL, 1 M) was added dropwise at 0°C. The system was then moved to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Saturated ammonium chloride solution (50 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 5%-10% ethyl acetate / petroleum ether gradient to obtain compound 22-4. MS m / z (ESI): =353.2 [M+H] + .

[0626] Step 4: Compound 22-4 (2.0 g, 5.68 mmol) and potassium carbonate (1.57 g, 11.35 mmol) were dissolved in dimethyl sulfoxide (20 mL), and 30% hydrogen peroxide (2.28 mL, 22.70 mmol) was added dropwise at 0°C. The system was then moved to room temperature and stirred for 16 hours. The reaction was monitored by LCMS and TLC. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 30%-50% ethyl acetate / petroleum ether gradient to obtain compound 22-5. MS m / z (ESI): =371.2 [M+H] + .

[0627] Step 5: Compound 22-5 (200 mg, 0.54 mmol) was dissolved in acetonitrile (1.5 mL) and water (1.5 mL), and [bis(trifluoroacetoxy)iodo]benzene (232.2 mg, 0.54 mmol) was added and stirred at room temperature for 3 hours. The reaction was monitored by LCMS. Saturated sodium carbonate solution (5 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (3×5 mL). The combined organic phases were washed with saturated brine (8 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 30%-50% ethyl acetate / petroleum ether gradient to obtain compound 22-6. MS m / z (ESI): =343.2 [M+H] + .

[0628] Step 6: Compound 22-6 (150 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (4 mL), and compound 1-6 (133.78 mg, 0.44 mmol), N,N-diisopropylethylamine (72.60 μL, 0.44 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166.6 mg, 0.44 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 10%-20% ethyl acetate / petroleum ether gradient to obtain compound 22-7. MS m / z (ESI): = 630.4 [M+H] + .

[0629] Step 7: Compound 22-7 (270 mg, 0.43 mmol) was dissolved in methanol (5 mL) and water (2 mL), and lithium hydroxide (20.5 mg, 0.86 mmol) was added. The mixture was heated to 45°C and stirred for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 M) was added to adjust the pH to neutral and the mixture was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate solution) to afford compound 22. MS m / z (ESI): = 516.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.49 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 6.83 (s, 1H), 6.47 (t, J = 2.5 Hz, 1H), 3.91 (s, 3H), 3.33-3.32 (m, 1H), 3.19-3.07 (m, 2H), 2.67 (d, J = 14.2 Hz, 2H), 2.54-2.48 (m, 3H), 2.15 (dd, J = 11.0, 5.5 Hz, 4H), 1.94-1.83 (m, 2H). The relative stereochemistry of compound 22 was confirmed by two-dimensional NOESY experiments (H 14 With H 33 / H 34 NOE related).

[0630] Example 23: Preparation of Compounds 23-P1 and 23-P2

[0631] Step 1: Compound 23-1 (8.0 g, 50.57 mmol) was dissolved in N,N-dimethylformamide (200 mL), and sodium hydride (4.1 g, 101.25 mmol) was added in portions under an ice-water bath. The mixture was warmed to room temperature and stirred for 20 minutes. Subsequently, iodoethane (10.2 g, 65.40 mmol) was added and stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. Water (200 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography: 8%-12% ethyl acetate / petroleum ether gradient to obtain compound 23-2. MS m / z (ESI): =187.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ3.84(s,4H),3.41(q,J=7.0Hz,2H),3.35(dd,J=7.4,3.7Hz,1H),1.77-1.62(m,4H),1.55-1.41(m,4H),1.09(t,J=7.0Hz,3H).

[0632] Step 2: Compound 23-2 (10.0 g, 53.69 mmol) was dissolved in hydrochloric acid (100 mL, 6 M) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS and TLC. Water (200 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 8%-12% ethyl acetate / petroleum ether gradient to obtain compound 23-3. MS m / z (ESI): =143.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ3.72-3.65(m,1H),3.50(q,J=7.0Hz,2H),2.38-2.30(m ,2H),2.26-2.17(m,2H),1.91(s,2H),1.88-1.80(m,2H),1.17(d,J=7.2Hz,3H).

[0633] Step 3: Compound 5-1 (30.4 g, 116.04 mmol) was dissolved in tetrahydrofuran (50 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (89.3 mL, 1.3 M, 116.04 mmol) was added at -78°C. After stirring for 1 hour, a solution of compound 23-3 (11 g, 77.36 mmol) in tetrahydrofuran (50 mL) was added at -50°C. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Saturated ammonium chloride solution (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic phases were washed with saturated brine (400 mL), dried, and concentrated. The crude product was purified by silica gel chromatography: 3%-5% methanol / dichloromethane gradient to obtain compound 23-4. MS m / z (ESI): =261.1 [M-17] + .

[0634] Step 4: Compound 23-4 (800 mg, 2.87 mmol) was dissolved in chloroacetonitrile (5 mL), and acetic acid (1 mL) and concentrated sulfuric acid (1 mL) were slowly added dropwise at 0°C, and stirring was continued at 0°C for 30 minutes. The reaction was monitored by LCMS and TLC. Saturated sodium bicarbonate solution (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (50 mL), dried and concentrated. The crude product was purified by silica gel chromatography: 45%-50% ethyl acetate / petroleum ether gradient to give compound 23-5-P1 (MS m / z (ESI): =354.2 [M+H] + , retention time: 1.075 min). 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.97-7.84(m,2H),7.53-7.39(m,2H),4.09(s,2H),3.84(s,3H),3.42(q ,J=7.0Hz,2H),2.08(d,J=13.2Hz,2H),2.00-1.90(m,2H),1.70(dt,J=8.5,3.4Hz,4H),1.12(t,J=7.0Hz,3H).

[0635] Compound 23-5-P2 (MS m / z (ESI): =354.2 [M+H] + , retention time: 1.042 min). 1H NMR (400MHz, DMSO-d6) δ8.31(s,1H),7.94-7.83(m,2H),7.54-7.46(m,2H),4.12(s,2H),3.83(s,3H),3.47(q,J=7.0Hz,2H ), 2.33 (d, J = 12.8Hz, 2H), 1.88-1.80 (m, 2H), 1.72 (dd, J = 13.5, 3.4Hz, 2H), 1.47 (q, J = 12.1Hz, 2H), 1.10 (t, J = 7.0Hz, 3H).

[0636] Step 5: Compound 23-5-P1 (230 mg, 0.65 mmol) was dissolved in 1,4-dioxane (5 mL), thiourea (247 mg, 3.25 mmol) and acetic acid (1 mL) were added, and the system was heated to 85°C and stirred for 6 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the crude product, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (3×100 mL), and the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 0%-30% ethyl acetate / petroleum ether gradient to obtain compound 23-6-P1. MS m / z (ESI): = 278.5 [M+H] + .

[0637] Compound 23-6-P2 was obtained from compound 23-5-P2 according to the method for preparing 23-6-P1 from 23-5-P1. MS m / z (ESI): = 278.5 [M+H] + .

[0638] Step 6: Compound 23-6-P1 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-6 (132.1 mg, 0.43 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (205.6 mg, 0.54 mmol) and N,N-diisopropylethylamine (116.5 mg, 0.9 mmol) were added sequentially. Stir at room temperature for 1 hour. The reaction was monitored by LCMS. Water (20 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography: 30%-40% ethyl acetate / petroleum ether gradient to obtain compound 23-7-P1. MS m / z (ESI): =565.3 [M+H] + .

[0639] Compound 23-7-P2 was obtained from compound 23-6-P2 according to the method for preparing 23-7-P1 from 23-6-P1. MS m / z (ESI): = 565.3 [M+H] + .

[0640] Step 7: Compound 23-7-P1 (90 mg, 0.16 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL) and water (0.5 mL), and lithium hydroxide (33.4 mg, 0.80 mmol) was added. The reaction system was stirred at 50°C for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 M) was added to adjust the pH to neutral, and the mixture was filtered and concentrated. The crude product was purified by reverse phase chromatography: 0%-95% acetonitrile / buffer (0.01 mol / L formic acid in water) gradient to give compound 23-P1. MS m / z (ESI): =451.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),11.02(s,1H),8.27(s,1H),7.97-7.86(m,2H) ,7.64-7.54(m,2H),7.31(t,J=2.8Hz,1H),6.83(s,1H),6.51(dd,J=3.0,2.0Hz,1H) ,3.90(s,3H),3.61(t,J=3.1Hz,1H),3.46(q,J=7.0Hz,2H),2.49(s,3H),2.22(d,J= 12.9Hz, 2H), 2.10-1.96 (m, 2H), 1.82 (q, J = 15.1, 14.3Hz, 4H), 1.15 (t, J = 7.0Hz, 3H).

[0641] Compound 23-P2 was obtained from compound 23-7-P2 according to the method for preparing 23-P1 from 23-7-P1. MS m / z (ESI): = 451.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),11.03(s,1H),8.23(s,1H),7.92-7.80(m,2H) ,7.66-7.52(m,2H),7.32(t,J=2.8Hz,1H),6.84(s,1H),6.54(dd,J=3.0,2.0Hz,1H) ,3.93(s,3H),3.50(q,J=7.0Hz,2H),3.43-3.36(m,1H),2.49(s,3H),2.47-2.43(m, 2H), 1.97-1.86 (m, 2H), 1.84-1.73 (m, 2H), 1.69-1.54 (m, 2H), 1.12 (t, J = 7.0Hz, 3H).

[0642] Example 24: Preparation of Compounds 24-P1 and 24-P2

[0643] Step 1: Compound 5-1 (92.62 g, 353.44 mmol) was dissolved in tetrahydrofuran (600 mL). Under argon protection at -78°C, a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (294.5 mL, 1.3 M) was added. After stirring for 1 hour, a solution of compound 24-1 (46 g, 294.53 mmol) in tetrahydrofuran (200 mL) was added at -50°C under argon protection. After 5 minutes, the mixture was heated to 0°C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction solution was quenched by adding saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×800 mL). The combined organic phases were washed with saturated brine (400 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 3%-5% methanol / dichloromethane gradient to obtain compound 24-2. MS m / z (ESI): =275.1 [M-17] + . 1 H NMR (400MHz, DMSO-d6) δ7.95-7.87(m,2H),7.63-7.55(m,2H),5.10(s,1H),3.89(d,J=2.0Hz,4H),3.84(s,3H),1.95(d,J=8.6Hz,4H),1.60(m,4H).

[0644] Step 2: Compound 24-2 (26 g, 88.94 mmol) was dissolved in chloroacetonitrile (20 mL), and acetic acid (15 mL) and concentrated sulfuric acid (15 mL) were slowly added dropwise at 0°C. Stirring was continued at 0°C for 30 minutes. The reaction was monitored by LCMS and TLC. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (3 x 800 mL). The combined organic phases were washed with saturated brine (200 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography: 45%-50% ethyl acetate / petroleum ether gradient to obtain compound 24-3. MS m / z (ESI): =306.0 [M-17] + . 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 7.94-7.88 (m, 2H), 7.60-7.52 (m, 2H), 4.19 (s, 2H), 3.84 (d, J = 2.1Hz, 3H), 2.61 (m, 4H), 2.22 (t, J = 14.2Hz, 4H).

[0645] Step 3: Compound 24-3 (3 g, 9.27 mmol) was dissolved in 1,4-dioxane (15 mL), thiourea (3.53 g, 46.33 mmol) was added, and acetic acid (30 mL) was then added dropwise. The reaction system was heated to 85°C and stirred for 6 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the crude product, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (3×100 mL), and the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 4%-5% methanol / dichloromethane gradient to obtain compound 24-4. MS m / z (ESI): =248.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.97-7.85(m,2H),7.81-7.70(m,2H),3.84(s,3H),2.90-2.73(m,2H),2.25-2.08(m,4H),1.89(ddt,J=12.7,5.9,3.0Hz,2H).

[0646] Step 4: Compound 1-6 (1.38 g, 4.53 mmol) was dissolved in N,N-dimethylformamide (10 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.58 g, 6.79 mmol) was added under ice-cooling. A solution of N,N-diisopropylethylamine (2.25 mL, 13.59 mmol) in N,N-dimethylformamide (5 mL) was added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 15 minutes. A solution of 24-4 (1.12 g, 4.53 mmol) in N,N-dimethylformamide (10 mL) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction mixture was quenched by the addition of water (80 mL) and extracted with ethyl acetate (3 × 70 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography using a gradient of 30%-40% ethyl acetate / petroleum ether to afford compound 24-5. MS m / z (ESI): = 535.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.99-7.93(m,2H),7.73-7.62(m,3H),6.98(s,1H),6.45( d,J=3.7Hz,1H),3.86(s,6H),2.81-2.68(m,4H),2.58(s,3H),2.32-2.19(m,4H),1.59(s,9H).

[0647] Step 5: Compound 24-5 (3.00 g, 5.61 mmol) was dissolved in N,N-dimethylformamide (30 mL), and acetic acid (5 drops) and 3,3-difluorotrimethyleneimine hydrochloride (2.18 g, 16.9 mmol) were added. After reacting for 30 minutes, sodium acetate borohydride (3.58 g, 16.85 mmol) was added and stirred at room temperature for 16 hours. The reaction was monitored by LCMS. Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The crude product was purified by silica gel column chromatography: 5%-25% ethyl acetate / petroleum ether gradient to obtain compound 24-6-P1 (MS m / z (ESI): =612.3 [M+H] + , retention time: 0.733 min). 1H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.61 (d, J = 2.9Hz, 2H),6.96(s,1H),6.48(d,J=3.7Hz,1H),4.03(q,J=7.1Hz,1H),3.91(s,3H),3. 85(s,3H),3.56(t,J=12.3Hz,4H),2.56(s,3H),2.13(d,J=12.7Hz,2H),2.04( t,J=12.4Hz,2H),1.86(t,J=13.3Hz,2H),1.58(s,9H),1.50(d,J=13.9Hz,2H).

[0648] Compound 24-6-P2 (MS m / z (ESI): = 612.3 [M+H] + , retention time: 0.887 min). 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.92(d,J=8.4Hz,2H),7.63(d,J=3.3Hz,2H),6.96(s,1H),6.53(d,J=3.7Hz,1H),4.31(t,J=12.6Hz,1H),3.94 (s,3H),3.85(s,3H),3.57(t,J=12.2Hz,4H),2.53(s,1H),2.44(s,1H),2. 25(s,1H),1.99(s,2H),1.70(m,5H),1.58(s,9H),1.50(d,J=12.4Hz,1H).

[0649] Step 6: Compound 24-6-P1 (500 mg, 0.82 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and lithium hydroxide (343 mg, 8.18 mmol) was added. The reaction solution was stirred at 50 ° C for 16 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to a neutral pH with hydrochloric acid (1 M), stirred for 30 minutes, concentrated to remove tetrahydrofuran, slurried with methanol, filtered, and the solid was removed. After slurrying with water, it was filtered, and the solid was dissolved in acetonitrile and water and lyophilized to obtain compound 24-P1. MS m / z (ESI): =498.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.24 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 6.83 (s, 1H), 6.53-6.47 (m, 1H), 3.90 (s, 3H), 3.56 (t, J = 12.3 Hz, 4H), 2.53-2.52 (m, 1H), 2.49 (s, 3H), 2.19-2.02 (m, 4H), 1.83 (t, J = 13.1 Hz, 2H), 1.50 (d, J = 13.7 Hz, 2H). The relative stereochemistry of compound 24-P1 was identified as follows: In the hydrogen spectrum, according to H 27a / H 29a Peak shape can be used to determine H 28 In the e bond; NOE, H 14 With H 27a / H 29a There is a correlation, H 14 In the a key, we can judge H 28 With H 14 It is a relative cis configuration, so compound 24-P1 is a relative trans configuration.

[0650] Compound 24-P2 was obtained from compound 24-6-P2 according to the method for preparing 24-P1 from 24-6-P1. MS m / z (ESI): = 498.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.21(s,1H),7.88(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.31(t,J=2.9Hz,1H),6.83(s,1H),6.5 5(t,J=2.4Hz,1H),3.94(s,3H),3.57(t,J=12.3Hz,4H),2.45(s,3H),2.25(t,J=11.3Hz,1H),1.79-1.63(m,4H),1.47(q,J=12.0Hz,2H).

[0651] Example 25: Preparation of Compounds 25-P1 and 25-P2

[0652] Step 1: Dissolve compound 25-1 (30.3 g, 154.64 mmol) in sulfuric acid (120 mL) and nitric acid (8 mL) under ice bath and stir at 0°C for 2 hours. Monitor the reaction by LCMS. Add water (1000 mL) to quench the mixture, add solid sodium carbonate to adjust the pH to neutral, extract with ethyl acetate (3×500 mL), wash the combined organic phases with saturated brine (500 mL), dry over anhydrous sodium sulfate and concentrate. The crude product was purified by silica gel chromatography: 10%-16% ethyl acetate / petroleum ether gradient to obtain compound 25-2. MS m / z (ESI): =241.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.15(s,1H),2.58(s,3H).

[0653] Step 2: Compound 25-2 (1.5 g, 6.25 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at -20 ° C under nitrogen protection, and a solution of vinyl magnesium bromide in tetrahydrofuran (25 mL, 1 M, 25 mmol) was added. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction was monitored by LCMS. Saturated ammonium chloride solution (100 mL) was added to quench the mixture, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 20%-30% ethyl acetate / petroleum ether gradient to obtain compound 25-3. MS m / z (ESI): =235.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 11.96 (s, 1H), 7.69 (t, J = 2.9 Hz, 1H), 7.33 (s, 1H), 6.57 (dd, J = 3.1, 1.8 Hz, 1H), 2.56 (s, 3H).

[0654] Step 3: Compound 25-3 (2.0 g, 8.51 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL). Cesium carbonate (5.6 g, 17.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (625 mg, 0.86 mmol), and cyclopropylboronic acid (1.1 g, 12.81 mmol) were added. The reaction was stirred at 90 °C for 16 hours. The reaction was monitored by TLC. Water (20 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 10%-20% ethyl acetate / petroleum ether gradient to obtain compound 25-4.1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.55(t,J=2.9Hz,1H),6.60(s,1H),6.50 -6.44(m,1H),2.49(s,3H),2.21(m,1H),1.09-1.03(m,2H),0.81-0.76(m,2H).

[0655] Step 4: Compound 25-4 (200 mg, 1.02 mmol) was dissolved in toluene (4 mL) under nitrogen at -78°C. A hexane solution of diisobutylaluminum hydride (1.6 mL, 1 M, 1.60 mmol) was added and the reaction was stirred at -78°C for 1.5 hours. The reaction was monitored by LCMS. Sodium sulfate decahydrate was added to quench the mixture, and the mixture was stirred for 30 minutes before filtration and concentration. The crude product was purified by silica gel chromatography using a gradient of 10% to 20% ethyl acetate / petroleum ether to afford compound 25-5. MS m / z (ESI): = 200.0 [M+H] + .

[0656] Step 5: Compound 25-5 (917 mg, 4.60 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.92 mL, 13.81 mmol), 4-dimethylaminopyridine (112 mg, 0.92 mmol) and di-tert-butyl dicarbonate (1.5 g, 6.90 mmol) were added and stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. Water (10 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (100 mL), dried and concentrated. The crude product was purified by silica gel chromatography: 5%-15% ethyl acetate / petroleum ether gradient to give compound 25-6. MS m / z (ESI): =300.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.80(d,J=3.7Hz,1H),6.94(s,1H),6.70(d,J=3.7H z,1H),2.56(s,3H),2.25-2.15(m,1H),1.60(s,9H),1.06-1.02(m,2H),0.90-0.84(m,2H).

[0657] Step 6: Compound 25-6 (1.35 g, 4.51 mmol) was dissolved in tetrahydrofuran (9 mL) and water (6 mL), and sodium chlorite (1.31 g, 14.43 mmol), sodium dihydrogen phosphate (2.71 g, 22.55 mmol) and 30% hydrogen peroxide solution (153.39 mg, 4.51 mmol) were added and stirred at 0°C for 30 minutes. The reaction was monitored by LCMS. Water (10 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 5%-25% ethyl acetate / petroleum ether gradient to give compound 25-7. MS m / z (ESI): =316.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.65(d,J=3.8Hz,1H),6.74(d,J=3.8Hz,1H),6.70(s,1H), 2.50(s,3H),2.40-2.45(m,1H),1.59(s,9H),0.98-0.88(m,2H),0.73-0.65(m,2H).

[0658] Step 7: Compound 25-7 (127.53 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (230.64 mg, 0.61 mmol) was added at 0°C. A solution of N,N-diisopropylethylamine (0.20 mL, 1.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for 15 minutes. A solution of 24-4 (100 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL) was then added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography: 20%-30% ethyl acetate / petroleum ether gradient to obtain compound 25-8. MS m / z (ESI): =545.3 [M+H] + .

[0659] Step 8: Compound 25-8 (170 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1 drop of acetic acid and 3,3-difluorotrimethyleneimine hydrochloride (121.29 mg, 0.94 mmol) were added. After reacting at room temperature for 1 hour, sodium triacetoxyborohydride (198.46 mg, 0.94 mmol) was added and stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. Water (10 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography: 20%-30% ethyl acetate / petroleum ether gradient to obtain compound 25-9-P1 (MS m / z (ESI): =622.3 [M+H] + , retention time: 1.643 min). 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.99-7.93(m,2H),7.69-7.62(m,3H),6 .64(s,1H),6.26(d,J=3.8Hz,1H),3.86(s,3H),3.53(t,J=12.3Hz,4H),2.48( s,3H),2.29-2.20(m,2H),2.18-2.07(m,2H),1.99-1.94(m,1H),1.86-1.77( m,2H),1.58(s,9H),1.50-1.41(m,2H),0.84-0.79(m,2H),0.72-0.66(m,2H).

[0660] Compound 25-9-P2 (MS m / z (ESI): =622.3 [M+H] + , retention time: 1.615 min). 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.94(d,J=8.5Hz,2H),7.70-7.63(m,3H),6.65(s,1H),6.34(d,J=3.7Hz,1H),3.86(s,3H),3.57(t,J=12.3Hz ,4H),2.68-2.62(m,2H),2.48(s,3H),2.25-2.19(m,1H),1.73-1.65(m,4 H),1.58(s,9H),1.51-1.44(m,2H),0.87-0.83(m,2H),0.73-0.67(m,2H).

[0661] Step 9: Compound 25-9-P1 (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (27.00 mg, 0.64 mmol) was added and the mixture was heated to 50°C and stirred for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, the mixture was filtered, and the mixture was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 0% to 95% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to afford compound 25-P1. MS m / z (ESI): = 508.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.33(s,1H),7.88(d,J=8.1Hz,2H),7.61(d,J=8. 0Hz,2H),7.32(t,J=2.8Hz,1H),6.44(s,1H),6.21(t,J=2.8Hz,1H),3.54(t,J=12.3Hz,4 H),2.73-2.63(m,1H),2.41(s,3H),2.31-2.23(m,2H),2.17-2.06(m,2H),2.06-1.99(m, 1H), 1.92-1.80 (m, 2H), 1.52-1.41 (m, 2H), 0.74 (d, J = 8.9Hz, 2H), 0.61 (d, J = 5.3Hz, 2H).

[0662] Compound 25-P2 was obtained from compound 25-9-P2 according to the method for preparing 25-P1 from 25-9-P1. MS m / z (ESI): = 508 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),11.05(s,1H),8.36(s,1H),7.91(d,J=8.2Hz,2H),7.65 (d,J=8.2Hz,2H),7.32(t,J=2.8Hz,1H),6.44(s,1H),6.20(t,J=2.5Hz,1H),3.54(t,J=12.3H z,4H),2.88-2.75(m,1H),2.41(s,3H),2.34-2.23(m,2H),2.11(t,J=12.3Hz,2H),2.05-1.98 (m,1H),1.87(t,J=13.0Hz,2H),1.51-1.42(m,2H),0.78-0.70(m,2H),0.62(t,J=5.2Hz,2H).

[0663] Example 26: Preparation of Compounds 26-P1 and 26-P2

[0664] Step 1: Compound 24-5 (170 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (1 mL), 3-fluoroazetidine hydrochloride (106 mg, 0.95 mmol) and acetic acid (2 drops) were added, and after stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (200 mg, 0.95 mmol) was added and stirring was continued for 18 hours. The reaction was monitored by LCMS and TLC. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography: 8%-10% methanol / dichloromethane gradient to obtain compound 26-1. MS m / z (ESI): =594.7 [M+H] + .

[0665] Step 2: Compound 26-1 (120 mg, 0.20 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (85 mg, 2.02 mmol) was added and the mixture was heated to 50°C with stirring for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, the mixture was filtered, and the mixture was concentrated. The crude product was purified by reverse phase chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L formic acid in water) to afford compound 26-P1. MS m / z (ESI): = 480.6 [M+H] + HPLC (determination condition 1) retention time: 3.830 min. 1 H NMR(400MHz,DMSO-d6)δ11.04(d,J=2.7Hz,1H),8.22(s,1H),7.92-7.83(m,2H),7.6 2-7.56(m,2H),7.32(t,J=2.8Hz,1H),6.83(s,1H),6.55(dd,J=3.0,2.0Hz,1H),5.29 -5.02(m,1H),3.93(s,3H),3.64-3.53(m,2H),3.12-2.99(m,2H),2.51(s,3H),2.45( d,J=13.0Hz,2H),2.15(d,J=11.6Hz,1H),1.78-1.61(m,4H),1.41(q,J=11.7Hz,2H).

[0666] Compound 26-P2 was obtained. MS m / z (ESI): = 480.6 [M+H] +HPLC (determination condition 1) retention time: 4.088 min. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.24(s,1H),7.89(d,J=8.3Hz,2H),7. 55(d,J=8.3Hz,2H),7.31(t,J=2.8Hz,1H),6.83(s,1H),6.51(t,J=2.4Hz,1H ),5.30-5.05(m,1H),3.90(s,3H),3.65-3.53(m,2H),3.01(m,2H),2.52(s,3 H), 2.40 (s, 1H), 2.07 (m, 4H), 1.79 (t, J = 13.3Hz, 2H), 1.50 (d, J = 13.7Hz, 2H).

[0667] Example 27: Preparation of Compounds 27-P1 and 27-P2

[0668] Step 1: Compound 24-5 (200 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (3 mL), acetic acid (3 drops) and 3-acetonitrile cyclobutylamine hydrochloride (96 mg, 16.84 mmol) were added, and after stirring for 30 minutes, sodium triacetoxyborohydride (238 mg, 1.12 mmol) was added and stirred at room temperature for 16 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography: 5%-25% ethyl acetate / petroleum ether gradient to obtain compound 27-1-P1. MS m / z (ESI): =601.4 [M+H] + HPLC (determination condition 1) retention time: 4.088 min. Compound 27-1-P2 was obtained. MS m / z (ESI): = 601.4 [M+H] + , HPLC (determination condition 1) retention time: 3.938min.

[0669] Step 2: Compound 27-1-P1 (103 mg, 0.17 mmol) was dissolved in anhydrous acetonitrile (2 mL), potassium trimethylsilanol (66 mg, 0.52 mmol) was added, and the reaction system was stirred at 50°C for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH to neutral, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography: 15%-100% acetonitrile / buffer (0.01 mol / L aqueous hydrochloric acid) gradient to give compound 27-P1. MS m / z (ESI): =487.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),11.03(s,1H),8.24(s,1H),7.89(d,J=8. 4Hz,2H),7.56(d,J=8.4Hz,2H),7.31(t,J=2.8Hz,1H),6.83(s,1H),6.52-6.47( m,1H),3.90(s,3H),3.50-3.46(m,3H),3.19(s,2H),2.49(s,3H),2.42-2.37(m, 1H),2.16-2.08(m,2H),2.08-2.00(m,2H),1.75(m,2H),1.47(d,J=13.8Hz,2H).

[0670] Compound 27-P2 was obtained from compound 27-1-P2 according to the method for preparing 27-P1 from 27-1-P1. MS m / z (ESI): = 487.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.06(s,1H),7.73(d,J=7.9Hz,2H),7.36(s,2H),7.31( t,J=2.8Hz,1H),6.83(s,1H),6.56(t,J=2.6Hz,1H),3.93(s,3H),3.45-3.41(m,3H),3.23(s, 2H), 2.43 (s, 1H), 2.16-2.11 (m, 2H), 1.73-1.55 (m, 5H), 1.38 (d, J = 12.6Hz, 2H).

[0671] Example 28: Preparation of Compounds 28-P1 and 28-P2

[0672] Step 1: Compound 24-5 (300 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (3 mL), acetic acid (3 drops) and azetidine (96 mg, 16.84 mmol) were added, and after stirring for 30 minutes, sodium triacetoxyborohydride (357 mg, 1.68 mmol) was added and stirred ...

Claims

1. Compounds of formula (I): or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, in: R 1 For -L 2 -R L , in: L 2 is a direct bond, a straight or branched C1-6 alkylene group, or a straight or branched C 2-6 Alkenylene, Optionally, the C1-6 alkylene or C 2-6 An available C atom in an alkenylene group is substituted with two substituents, whereby the two substituents together with the C atom form an optionally substituted C 3-6 cycloalkylene or optionally substituted 3 to 6 membered heterocycloalkylene; or optionally, the C1-6 alkylene or C 2-6 Two adjacent carbon atoms in the alkenylene group are connected through a straight-chain C1-4 alkylene group to form an optionally substituted C3-6 cycloalkylene group, or through -S-, -O-, -NH-, or a straight-chain 2 to 4-membered heteroalkylene group to form an optionally substituted 3 to 6-membered heterocycloalkylene group; and wherein the C1-6 alkylene or C 2-6 The alkenylene group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl; and Wherein L 2 -R L The CH2 portion (if present) attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e replace; R L Selected from: R 9 , R 10 、-OR 10 、-SR 10 and-NR 1e -R 10 ,and R 10 Selected from: H, R 11 、Halogen、OH、SH、CN、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2- 6-Alkenyl, -OC 2-6 Alkynyl, guanidinyl and -C1-6 alkylene-guanidinyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl and -OC 2-6 Alkynyl is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2; R 9 and R 11 Each independently selected from -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -3-10 membered heterocyclic group, -(CH2) 0-6 -C 5-10 Bridged cyclic hydrocarbon group, -(CH2) 0-6 -5-10 membered heterocyclic group, -(CH2) 0-6 -C 5-11 Monospirocyclic hydrocarbon group, -(CH2) 0-6 -5-11 membered monospiro heterocyclic group, -(CH2) 0-6 -C 6-10 Aryl and -(CH2) 0-6 -5-10 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups: Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2- 6-Alkynyl, -C 1-6 Alkylene-OR 1a , -C 1-6 Alkylene-SR 1a , -C 1-6 Alkylene-NR 1a R 1b , -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , Cy, -(optionally substituted C 1-6 Alkylene)-Cy, -NR 1a -Cy and -CR 1c R 1d -C(O)-NR 1a R 1b ; Cy is selected from optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6-10 aryl and optionally substituted 5-10 membered heteroaryl; and R 2 H, halogen, OH, SH, CN, C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and-NR 2a -S(O)2-R 2b , R 1a , R 1b , R 1c , R 1d , R 1e , R 2a and R 2b independently selected at each occurrence from H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1- 6-alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -NH2 and -C 1-6 Alkylene-CN, where R 1c , R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl; or R 1 , R 2 Together with the carbon atom indicated by the symbol "#" to which both of them are commonly connected, they form a moiety represented by the following formula: in: Ring D is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5-10 Bridged cycloalkyl or 5-10 membered bridged heterocycloalkyl; R 6 Selected from: H, halogen, OH, SH, CN, N(R 7a )2, C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-O-halogenated C 1-6 alkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl and -C(O)-C 3-10 Cycloalkyl, wherein the C 3-10 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substituents of the haloalkoxy group are substituted, and 3-10 membered heterocycloalkyl and -C 1-6 Alkylene-3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents; R 7a Each independently selected from: H, C 1-6 Alkyl, -(CH2) q -C 3-10 Cycloalkyl, -(CH2) q -3-10 membered heterocycloalkyl, q is selected from an integer from 0 to 6, and said C 1-6 Alkyl, -(CH2) q -C 3-10 Cycloalkyl, -(CH2) q -3-10 membered heterocycloalkyl groups are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6 alkoxy, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is substituted; and n is 1, 2 or 3; Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; Each R 3 Independently selected from: halogen, OH, SH, CN, -NR 3a R 3b , -C 1-6 Alkyl-OH, -C 1-6 Alkyl-SH, -C 1-6 Alkylene-C(O)OR 3a , -C 1-6 Alkylene-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R 3b and a 5- or 6-membered heteroaryl group having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms, R 3a and R 3b is independently selected at each occurrence from H and C 1-6 Alkyl, and p is 1, 2, or 3; L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-, *-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond marked with * is attached to the phenyl ring B; R 4a and R 4b Each is independently selected from H, deuterium, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; R 4c Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R is in: R 4 Selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-NR 6a R 6b , -C 1-6 Alkylene-NR 6a -C(O)R 6b 、-OC 1-6 Alkylene C(O)OR 6a 、-OC 1-6 Alkylene C(O)NR 6a R 6b , C 3-10 Cycloalkyl and -OC 1-6 Alkylene-C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-NR 6a R 6b , -C 1-6 Alkylene-NR 6a -C(O)R 6b 、-OC 1-6 Alkylene C(O)OR 6a 、-OC 1-6 Alkylene C(O)NR 6a R 6b , C 3-10 Cycloalkyl and -OC 1-6 Alkylene-C 3-10 The cycloalkyl groups are each optionally substituted with one or more deuterium (D); R 5 Selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -SH and C 3-10 cycloalkyl; and R 5a , R 5b , R 6a and R 6b is independently selected at each occurrence from H and C 1-6 alkyl; X is selected from CR 7 , C(R 7 )2 and N; Y is selected from CR 8 , C(R 8 )2 and N; Z is selected from O, S and NH; R 7 and R 8 Each occurrence is independently selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-6 Alkyl), -N(C 1- 6 alkyl)2, C 1-6 Alkyl and C 3-10 Cycloalkyl; Indicates a single bond or a double bond.

2. The compound according to claim 1, wherein: R 1 For -L 2 -R L ; L 2 is a direct key; and R L For R 9 .

3. The compound according to claim 1 or 2, wherein: R 9 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Bridged hydrocarbon group, 5-10 membered bridged heterocyclic group, C 5-11 Monospirocyclic hydrocarbon group, 5-11 membered monospiro heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2 or more substituents independently selected from the following groups: Deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2- 6-Alkynyl, -C 1-6 Alkylene-OR 1a , -C 1-6 Alkylene-SR 1a , -C 1-6 Alkylene-NR 1a R 1b , -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1- 6-Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-10 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 3-10 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; Preferably, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 monospirocycloalkenyl, 5-11 membered monospiroheterocycloalkyl, 5-11 membered monospiroheterocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups: deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a , -C 1-4 Alkylene-SR 1a , -C 1-4 Alkylene-NR 1a R 1b , -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl optionally substituted by 1, 2 or more halogen, -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 3-10 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a , R 1b , R 1c and R 1d is independently selected at each occurrence from H, C1-4 alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1- 4-alkylene-CN, where R 1c , R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl; More preferably, R 9 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-10 Bridged cycloalkyl, C 5-10 Bridged cycloalkenyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered bridged heterocycloalkenyl, C 5-11 Monospirocycloalkyl, C 5-11 monospirocycloalkenyl, phenyl and 5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the following groups: F, Cl, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OR 1a , -C 1-4 Alkylene-SR 1a , -C 1-4 Alkylene-NR 1a R 1b , -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , 3-6 membered heterocycloalkyl optionally substituted by 1, 2 or more halogens, -NR 1a -(optionally substituted C 3-10 Cycloalkenyl) and -NR 1a -(optionally substituted 3-10 membered heterocyclyl), wherein R 1a and R 1b is independently selected at each occurrence from H and C1-4 alkyl; More preferably, R 9 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]heptanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl, C5, C6 or C7 bridged cycloalkyl (e.g. ), C5, C6 or C7 bridged cycloalkenyl, 6, 7, 8 or 9 membered bridged heterocycloalkyl, C 5-11 Monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridine , -CH2CH3, -CH2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2CH2OCH2CH3, -CH2-NH-C(O)CH3, =O, =CH2, -OCH3, -OCH2CH3, -O-CH2-cyclopropyl, phenoxy, -NHCH3, -NHCH2CH3, -N(CH3)2, -NH-C(O)CH3, -NH-C(O)NH2, -NH-S(O)2CH3、 4. The compound according to claim 1, wherein: R 1 For -L 2 -R L ; L 2 is the straight chain or branched chain C 1-6 Alkylene, or linear or branched C 2-6 Alkenylene, Optionally, the C1-6 alkylene or C 2-6 One available C atom in the alkenylene group is substituted with two substituents, whereby the two substituents together with the C atom form an optionally substituted C3-6 cycloalkylene group or an optionally substituted 3 to 6 membered heterocycloalkylene group; or optionally, the C1-6 alkylene group or C 2-6 Two adjacent carbon atoms in the alkenylene group are connected through a straight-chain C1-4 alkylene group to form an optionally substituted C3-6 cycloalkylene group, or through -S-, -O-, -NH-, or a straight-chain 2 to 4-membered heteroalkylene group to form an optionally substituted 3 to 6-membered heterocycloalkylene group; and wherein the C1-6 alkylene or C 2-6 The alkenylene group is optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of halogen, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl; and Wherein L 2 -R L The CH2 portion (if present) attached to the carbon atom indicated by the symbol "#" is optionally replaced by O, S or NR 1e instead; and R L Selected from: R 10 、-OR 10 、-SR 10 and-NR 1e -R 10 .

5. The compound according to claim 1 or 4, wherein: The C 3-6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or The 3- to 6-membered heterocycloalkylene group is a 4- to 6-membered heterocycloalkylene group, preferably an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or thiomorpholinyl group; and / or The L 2 C 1-6 Alkylene or C 2-6 Optional substituents of alkenylene include: F, Cl, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, preferably CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, cyclopropyl and azetidinyl.

6. The compound according to claim 1 or 4, wherein: R 1 is: -CR al R bl -(CR cl R dl ) m -R 10 、-CR al R bl -(CR cl R dl ) m -O-R 10 、-CR al R bl -(CR cl R dl ) m -S-R 10 、-CR al R bl -(CR cl R dl ) m -NR 1e -R 10 、-O-(CR cl R dl ) m -R 10 、-S-(CR cl R dl ) m -R 10 、 or -NR 1e -(CR cl R dl ) m -R 10 ; R al , R bl , R cl and R dl Each occurrence is independently selected from: H, halogen, OH, SH, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NR 1a R 1b , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; Where: Optionally, R al and R bl , or 1 CR cl R dl R cl and R dl , together with the carbon atom to which they are commonly connected, form =CH2, =CH(C1-4 alkyl), C 3-6 cycloalkylene or 3 to 6 membered heterocycloalkylene; or optionally, CR al R bl -(CR cl R dl ) m or (CR cl R dl ) m Two adjacent carbon atoms in the straight carbon chain are connected by a straight C1-4 alkylene chain to form a C 3-6 Cycloalkylene, or connected through -S-, -O-, -NH-, or a straight-chain 2- to 4-membered heteroalkylene to form a 3- to 6-membered heterocycloalkylene; R 1a and R 1b is independently selected at each occurrence from H and C 1-6 alkyl; R 1e is independently selected at each occurrence from H and C1-4 alkyl; and m is 0, 1, 2, 3, 4 or 5.

7. The compound according to claim 6, wherein: The C 3-6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or The 3- to 6-membered heterocycloalkylene group is a 4- to 6-membered heterocycloalkylene group, preferably an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or thiomorpholinyl group; and / or R al , R bl , R cl and R dl Each occurrence is independently selected from: H, F, Cl, OH, SH, CN, C 1-4 Haloalkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, preferably H, CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, cyclopropyl and azetidinyl; and / or R al and R bl , or 1 CR cl R dl R cl and R dl , together with the carbon atoms to which they are connected, form =CH2, C 3-6 Cycloalkylene or 3- to 6-membered heterocycloalkylene; and / or m is 0, 1 or 2.

8. The compound according to claim 6 or 7, wherein the compound has a structure of formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6) or formula (I-7): wherein m is preferably 0, 1 or 2.

9. A compound according to any one of claims 1 and 4-8, wherein: R 10 Selected from: H, R 11 、F、Cl、OH、SH、CN、C1-4 alkyl、C 2-4 Alkenyl, C 2-4 Alkynyl, -O-C1-4 alkyl, -OC 2-4 Alkenyl, -OC 2-4 Alkynyl, guanidinyl and -C1-4 alkylene-guanidinyl, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1- 6-alkyl, -OC 2-4 Alkenyl and -OC 2-4 The alkynyl group is optionally substituted with 1, 2 or more substituents independently selected from halogen, OH, SH and NH2; preferably, R 10 Selected from: H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, CF3, -CH2CF3, -OCH3, -OCH2CH3, guanidinyl, and -CH2CH2guanidinyl; and / or R 11 Selected from -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -3-10 membered heterocyclic group, -(CH2) 0-6 -C 5-10 Bridged cyclic hydrocarbon group, -(CH2) 0-6 -5-10 membered heterocyclic group, -(CH2) 0-6 -C 5-11 Monospirocyclic hydrocarbon group, -(CH2) 0-6 -5-11 membered monospiro heterocyclic group, -(CH2) 0-6 -C 6-10 Aryl and -(CH2) 0- 6-5-10 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the group consisting of deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene-OR 1a , -C 1-6 Alkylene-SR 1a , -C 1-6 Alkylene-NR 1a R 1b , -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 6-10 Aryl, -C 1-6 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b , -NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -(optionally substituted C 1-6 Alkylene)-C 3-6 Cycloalkyl, -(optionally substituted C 1-6 -(3-6 membered heterocycloalkyl), -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 4-7 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; Preferably, R 11 Selected from: -(CH2) 0-3 -C 3-10 Cycloalkyl, -(CH2) 0-3 -C 3-10 Cycloalkenyl, -(CH2) 0-3 -3-10 membered heterocycloalkyl, -(CH2) 0-3 -3-10 membered heterocycloalkenyl, -(CH2) 0-3 -C 5-10 Bridged cycloalkyl, -(CH2) 0-3 -C 5-10 Bridged cycloalkenyl, -(CH2) 0-3 -5-10 membered heterocycloalkyl, -(CH2) 0-3 -5-10 membered heterocycloheterocyclic group, -(CH2) 0-3 -C 5-11 Monospirocycloalkyl, -(CH2) 0-3 -C 5-11 Monospirocycloalkenyl, -(CH2) 0- 3-5-11-membered monospiroheterocycloalkyl, -(CH2) 0-3 -5-11-membered monospiroheterocycloalkenyl, -(CH2) 0-3 -phenyl and -(CH2) 0-3 -5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the group consisting of deuterium, halogen, -OR 1a 、-SR 1a 、CN、=O、=CH-R 1a , =NH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a , -C 1-4 Alkylene-SR 1a , -C 1-4 Alkylene-NR 1a R 1b , -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -O-phenyl, -C 1-4 Alkylene-NR 1a COR 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b 、-NR 1a -C(=O)OR 1b 、-NR 1a -C(O)NR 1a R 1b 、-NR 1a -S(O)2-R 1b , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 4-7 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a , R 1b , R 1c and R 1d is independently selected at each occurrence from H, C1-4 alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -NH2 and -C 1-4 Alkylene-CN, where R 1c , R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl; More preferably, R 11 Selected from: C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5-11 Monospirocycloalkyl, 5-11-membered monospiroheterocycloalkyl, -(CH2) 0-3 -phenyl, and -(CH2) 0-3 -5 or 6 membered heteroaryl, each of which is optionally substituted by 1, 2 or more substituents independently selected from the group consisting of deuterium, halogen, -OR 1a 、-SR 1a ,CN,=O,=NH,C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-4 Alkylene-OR 1a , -C 1-4 Alkylene-SR 1a , -C 1-4 Alkylene-NR 1a R 1b 、-NR 1a R 1b 、-NR 1a -C(O)R 1b , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, -NR 1a -(optionally substituted C 3-6 Cycloalkyl), -NR 1a -(optionally substituted C 3-10 Cycloalkenyl), -NR 1a -(optionally substituted 4-7 membered heterocyclyl) and -CR 1c R 1d -C(O)-NR 1a R 1b ; and R 1a , R 1b , R 1c and R 1d is independently selected at each occurrence from H and C 1-4 Alkyl, where R 1c , R 1d Together with the carbon atom to which they are both attached, they optionally form an optionally substituted C 3-6 Cycloalkyl; More preferably, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydroimidazolyl, azacyclooctenyl, 5-11 membered monospiro heterocycloalkyl, phenyl, -CH2-phenyl, pyrrolyl, -CH2-pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridyl, -CH2-pyridyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidonyl, each of which is optionally substituted by 1, 2 or more groups independently selected from the following groups: Group substitution: F, Cl, OH, SH, CN, =O, =NH, NH2, -NHCH3, CH3, CH2CH3, vinyl, ethynyl, CH2Cl, CF3, -CH2CF3, -CH2-OH, -CH2-SH, -CH2-NH2, -CH2-NHCH3, -CH2-N(CH3)2, -OCH3, -OCH2CH3, -NHC(O)CH3, cyclopropyl, azetidinyl, pyridinyl, and-CR 1c R 1d -C(O)NH2, where R 1c , R 1d Together with the carbon atom to which they are both attached, they form a cyclopropyl group.

10. A compound according to any one of claims 1 to 9, wherein: R 2 H, halogen, OH, SH, CN, C 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -NR 2a R 2b 、-NR 2a -C(O)R 2b 、-NR 2a -C(O)OR 2b 、-NR 2a -C(O)NR 2a R 2b and-NR 2a -S(O)2-R 2b ; and R 2a and R 2b is independently selected at each occurrence from H and C 1-4 alkyl; Preferably, R 2 It is H, F, Cl, OH, SH, CN, methyl, ethyl, -CH2-OH, -CH2-SH, -NH2, -NH-C(O)CH3, -NH-C(O)OCH3, -NH-C(O)NH2 and -NH-S(O)2CH3.

11. The compound according to claim 1, wherein the compound has the structure of formula (I-8):

12. The compound according to claim 1 or 11, wherein: Ring D is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-8 Bridged cycloalkyl or 5-8 membered bridged heterocycloalkyl; and / or R 6 Selected from: H, halogen, OH, SH, CN, N(R 7a )2, C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-O-halogenated C 1-6 alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkylene-C 3-6 Cycloalkyl and -C(O)-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substituents of the haloalkoxy group are substituted, and 4-7 membered heterocycloalkyl and -C 1-6 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents; R 7a Each independently selected from: H, C 1-6 Alkyl, -(CH2) q -C 3-6 Cycloalkyl, -(CH2) q -4-7 membered heterocycloalkyl, q is selected from an integer from 0 to 4, and said C 1-6 Alkyl, the -(CH2) q -C 3-6 C in cycloalkyl 3-6 Cycloalkyl, and the -(CH2) q The 4-7 membered heterocycloalkyl in the -4-7 membered heterocycloalkyl is each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents; Preferably, N(R 7a ) 1 R in 2 7a is H; Preferably, R 6 Selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 -NH(4-7 membered heterocycloalkyl) 1- 4 alkyl) and -N(C 1-4 Alkyl)2 in C 1-4 Alkyl, the -NH(C 3-6 Cycloalkyl) 3-6 The cycloalkyl group and the 4-7-membered heterocycloalkyl group in the -NH(4-7-membered heterocycloalkyl) are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted, -NH(C 1-4 Alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -SH, -C 1-4 Haloalkyl -SH, -C 1-4 Alkylene -CN, -C 1-4 Haloalkyl-CN, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkyl-O-halogenated C 1-4 alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl and -C(O)-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Substituents of the haloalkoxy group are substituted, and 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substitution of haloalkoxy substituents; Preferably, R 6 Selected from: H, OH, SH, -NH(C 1-4 Alkyl), -NH(C 3-6 partially unsaturated cyclic hydrocarbon group) and -NH(4-6 membered heterocycloalkyl group), the -NH(C 1-4 C in alkyl 1-4 Alkyl, the -NH(C 3-6 Partially unsaturated cyclic hydrocarbon group) 3-6 The partially unsaturated cycloalkyl group and the 4-6-membered heterocycloalkyl group in the -NH(4-6-membered heterocycloalkyl) are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-4 Alkyl and C 1-4 The substituents of the haloalkyl group are substituted, -NH(C 1-4 Alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 Alkyl, -C 1- 4-Alkylene-OC 1-4 Alkyl, -C 1-4 Alkyl-O-halogenated C 1-4 alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1- 4 alkyl, C 1-4 Haloalkyl and C 1-4 Substituents of the haloalkoxy group are substituted, and 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl and C 1-4 Substitution of haloalkyl groups; More preferably, R 6 Selected from: H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN、 <h2 style=";text-align:left;direction:ltr">-OCH3, -OCH2CH3, -OCF3, -OCH2CF3,<h2 style=";text-align:left;direction:ltr"> Cyclopropyl, difluorocyclopropyl, Amino, -NHCH3, -N(CH3) 2、 -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl, -NH-cyclobutane, -O-CH2-cyclopropyl and and / or n is 1.

13. The compound according to claim 1 or 11, wherein: Ring D is C 4-6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 5-8 Bridged cycloalkyl or 5-8 membered bridged heterocycloalkyl; Preferably, ring D is C 4-6 Cycloalkyl or 5-8 membered bridged heterocycloalkyl; More preferably, ring D is cyclohexane or Among them, $ A is the connection point with ring A, $ L1 For L 1 The connection point; More preferably, Part of Among them, $ A is the connection point with ring A, $ L1 For L 1 The connection point; and / or R 6 Selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NH(C 3-6 cycloalkyl), -NH(4-7 membered heterocycloalkyl), wherein the -NH(C 1-4 Alkyl) and -N(C 1-4 Alkyl)2 in C 1-4 Alkyl, the -NH(C 3-6 Cycloalkyl) 3-6 The cycloalkyl group and the 4-7-membered heterocycloalkyl group in the -NH(4-7-membered heterocycloalkyl) are each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 The substituents of the haloalkyl group are substituted, -NH(C 1-4 Alkylene)-(C 3-6 Cycloalkyl), -NH(C 1-4 Alkylene)-CN, C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -O-halogenated C 1-4 alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl and -OC 1-4 Alkyl-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Substituents of the haloalkoxy group are substituted, and 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1- 4 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substitution of haloalkoxy substituents; Preferably, R 6 Selected from: C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1- 4 haloalkoxy substituents, 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of the haloalkoxy group are substituted, and -NH(4-7 membered heterocycloalkyl), wherein the 4-7 membered heterocycloalkyl is each independently optionally substituted by 1, 2 or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; More preferably, R 6 Selected from: C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -NH(4-6 membered heterocycloalkyl), C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, C 1-4 Haloalkyl and C 1-4 Substituents of the haloalkoxy group are substituted, and 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN and C 1-4 The alkyl group is substituted with a substituent.

14. A compound according to any one of claims 1 to 13, wherein: Ring A is C 6-10 Aryl or 5- or 6-membered heteroaryl, preferably phenyl (more preferably ), naphthyl, benzopyridinyl (preferably Quinolyl, more preferably ), pyridyl or thiazolyl; and / or R 3 Selected from: halogen, OH, SH, CN, -NR 3a R 3b , -C 1-4 Alkyl-OH, -C 1-4 Alkyl-SH, -C 1-4 Alkylene-C(O)OR 3a , -C 1-4 Alkylene-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R 3b and a 5-membered heteroaryl group having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms; Preferably, R 3 Selected from: F, Cl, OH, CN, -NH2, -CH2-OH, -CH2-SH, -CH2-C(O)OR 3a 、-CH2-C(O)-NR 3a R 3b 、-C(O)OR 3a 、-C(O)-NR 3a R 3b 、-C(O)-NR 3a -S(O)2-R 3b 、-S(O)2-R 3a 、-S(O)2-NR 3a R 3b 、-S(O)2-NR 3a -C(O)R 3b and a 5-membered heteroaryl group having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms; and / or R 3a and R 3b is independently selected at each occurrence from H and C 1-4 alkyl; More preferably, R 3 Selected from: F, Cl, OH, CN, -NH2, -CH2-OH, -CH2-SH, -CH2-C(O)OH, -CH2-C(O)OCH3, -CH2-C(O)-NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2, -C(O)-NH-S(O)2-CH3, -S(O)2-CH3, -S(O)2-NH2, -S(O)2-NH-C(O)CH3 and a 5-membered heteroaryl group having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms; More preferably, R 3 Selected from: F, Cl, -CH2-C(O)OH, -C(O)OH, -C(O)-NH2, -S(O)2-CH3, -S(O)2-NH2, -S(O)2-NH-C(O)CH3, tetrazolyl and pyrazolyl; and / or p is 1 or 2; Preferably, Selected from: Each of them is optionally replaced by another independent R 3 replace; More preferably, for: More preferred 15. A compound according to any one of claims 1 to 14, wherein: X is CR 7 ; or X is C(R 7 )2; or X is N; and / or Y is CR 8 ; or Y is C(R 8 )2; or Y is N; and / or Z is O; or Z is S; or Z is NH; and / or X is CR 7 , Y is CR 8 , and Z is NH; and / or X is CR 7 , Y is CR 8 , and Z is O; and / or X is CR 7 , Y is CR 8 , and Z is S; and / or X is CR 7 , Y is N, and Z is NH; and / or X is N, Y is CR 8 , and Z is NH; and / or X is C(R 7 )2, Y is C(R 8 )2, and Z is NH; Preferably, R is:

16. A compound according to any one of claims 1 to 15, wherein: The compound has the structure of formula (I-9): Preferably, the compound has a structure of formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17) or formula (I-18):

17. A compound according to any one of claims 1 to 16, wherein: R 4 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b , -C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b , C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b , -C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b , C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 The cycloalkyl groups are each optionally substituted with one or more D, and R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b , -C 1-4 Alkylene-NR 6a -C(O)R 6b 、-OC 1-4 Alkylene C(O)OR 6a 、-OC 1-4 Alkylene C(O)NR 6a R 6b , C 3-6 Cycloalkyl and -OC 1-4 Alkylene-C 3-6 Cycloalkyl; Preferably, R 4 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with one or more D, and R 5 is independently selected at each occurrence from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl and C 3-6 Cycloalkyl; and / or R 6a and R 6b is independently selected at each occurrence from H and C 1-4 alkyl; Preferably, R 4 is independently selected at each occurrence from: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -O-CD3, -S-CH3, -S-CD3, and cyclopropyl, and R 5 is independently selected at each occurrence from: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropyl; More preferably, R 4 For-OC 1-4 Alkyl, -O-deuterated C 1-4 alkyl, or cyclopropyl, and R 5 H or C 1-4 alkyl; More preferably, R 4 is -O-CH3, -O-CD3, or cyclopropyl, and / or R 5 is methyl; and / or R 7 and R 8 Each occurrence is independently selected from: H, halogen, OH, SH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1- 4 alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl; preferably, R 7 and R 8 Each occurrence is independently selected from the group consisting of: H, F, Cl, OH, SH, CN, NH2, -NH(CH3), -N(CH3)2, methyl, ethyl and cyclopropyl, preferably H, F, Cl, methyl, ethyl and cyclopropyl; and / or L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-, *-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond marked with * is attached to the phenyl ring B; and R 4a and R 4b Each is independently selected from H, deuterium, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl; and / or R 5a and R 5b is independently selected at each occurrence from H and C 1-4 alkyl; and / or R 4a and R 4b Each is independently selected from H, deuterium, F, Cl, OH, SH, CN, -NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2 and -C(O)-NCH3; or R 4a and R 4b Together with the carbon atom to which they are both attached, they form a cyclopropane group; and / or R 4c Selected from H, C 1-4 Alkyl and C 1-4 Preferably, R 4c Selected from H, methyl, ethyl, -CH2F, -CHF2 and -CF3; Preferably, L 1 Selected from: *-CR 4a R 4b -NR 4c -、*-C(O)-NR 4c -、*-C(S)-NR 4c -、*-S(O)2-NR 4c -、*-NR 4c -C(O)-, *-NR 4c -S(O)2-, *-NR 4c -CR 4a R 4b - and *-NR 4c -C(S)-, wherein the bond marked with * is attached to the phenyl ring B; and R 4a and R 4b Each independently selected from: H, deuterium, F, Cl, OH, SH, CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b , preferably H, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b 、-C(O)OR 5a and -C(O)-NR 5a R 5b ; or R 4a and R 4b Together with the carbon atoms to which they are connected, they form C 3-4 Cycloalkyl or 4-5 membered heterocycloalkyl; More preferably, L 1 Selected from: *-CH2-NH-, *-CF2-NH-, *-CD2-NH-, *-CH(CF3)-NH-, *-C(CH3)2-NH-, *-CH2-N(CH3)-, *-CH2-N(CH2CH3)-, *-CH2 -N(CH2F)-, *-C(O)-NH-, *-C(S)-NH-, *-S(O)2-NH-, *-NH-CH2-, *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O)2-, More preferably, *-CH2-NH-, *-CD2-NH-, *-C(CH3)2-NH-, *-C(O)-NH- and The bond marked with * is connected to the phenyl ring B.

18. The compound according to claim 1, wherein the compound has the structure of formula (I-19): in: L 1 Selected from*-CR 4a R 4b -NR 4c - and *-C(O)-NR 4c -, wherein the bond marked with * is connected to the phenyl ring B; R 4a and R 4b are each independently selected from H and deuterium; R 4c is H; R 4 Selected from -OC 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-6 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with 1, 2, 3 or more D; R 5 Selected from C 1-6 alkyl; Ring D is C 4-6 Cycloalkyl or 5-8 membered heterocycloalkyl, preferably cyclohexane or Where $ A is the connection point with ring A, $ L1 For L 1 The connection point; R 6 Selected from: C each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2 and CN 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, -C 1-6 Alkylene-O-halogenated C 1-6 alkyl, C 3-6 Cycloalkyl and -C 1-6 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 The substituent of the haloalkoxy group is substituted, 4-7 membered heterocycloalkyl and -C 1-6 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-6 Alkyl and C 1-6 Substituents of the haloalkyl group, and -NH(4-7 membered heterocycloalkyl); and n is 1; Preferably, L 1 Selected from *-CH2-NH-, *-CD2-NH- and *-C(O)-NH-, wherein the bond marked with * is connected to the phenyl ring B; and / or Preferably, Part of Among them, $ A is the connection point with ring A, $ L1 For L 1 connection point; and / or Preferably, R 4 Selected from -OC 1-4 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with 1, 2, 3 or more D; more preferably, R 4 Selected from -OC 1-2 Alkyl and C 3-6 Cycloalkyl, wherein the -OC 1-2 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with 1, 2, 3 or more D; and / or Preferably, R 5 Selected from C 1-4 Alkyl, more preferably C 1-2 Alkyl; and / or More preferably, R 4 is -O-CH3, -O-CD3, or cyclopropyl, and R 5 is methyl; and / or Preferably, R 6 Selected from: C optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2 and CN 1-6 Alkyl, C 2-4 Alkenyl and each C 2-4 Alkynyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl), C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 The substituent of the haloalkoxy group is substituted, 4-7 membered heterocycloalkyl and -C 1-4 Alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl and C 1-4 Substitution of haloalkyl groups; More preferably, R 6 Selected from: each optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH and CN 1- 6 alkyl, C 2-4 Alkenyl and C 2-4 Alkynyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl), C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen and C 1-4 The substituents of the haloalkyl group are substituted, 4-6 membered heterocycloalkyl and -C 1-4 Alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, CN and C 1-4 The alkyl group is substituted with a substituent, and wherein said halo or halogen is independently selected from F and Cl at each occurrence; More preferably, R 6 Selected from: C 1-4 Alkyl, C 1-6 Haloalkyl, -C 1-4 Haloalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -C 1-4 Alkylene-O-halogenated C 1-4 Alkyl, -NH(4-6 membered heterocycloalkyl), C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from halogen, C 1-4 Haloalkyl and C 1-4 The substituent of the haloalkoxy group is substituted, 4-6 membered heterocycloalkyl and -C 1-4 Alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from deuterium, halogen, CN and C 1-4 The alkyl group is substituted with a substituent, and wherein said halo or halogen is independently selected from F and Cl at each occurrence; More preferably, R 6 Selected from: C 1-4 Alkyl, C 1-6 Fluoroalkyl, -C 1-4 Fluoroalkyl-OH, -C 1-4 Alkylene -CN, C 2-4 Alkynyl, -NH(4-6 membered heterocycloalkyl having 1 O or S heteroatom), C 3-6 Cycloalkyl and -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is optionally substituted at each occurrence by 1, 2 or more independently selected from F, C 1-4 Fluoroalkyl and C 1-4 Substitution of the fluoroalkoxy group, and 4-6 membered heterocycloalkyl and -C 1-4 Alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl at each occurrence is independently a 4-6 membered heterocycloalkyl with 1 N heteroatom and is optionally substituted by 1, 2 or more independently selected from deuterium, F, CN and C 1-4 Substitution of alkyl groups; More preferably, R 6 Selected from methyl, ethyl, 19. The compound according to claim 18, wherein the compound has a structure of one of formulas (I-20)-(I-27): Best 20. The compound according to claim 18 or 19, wherein: Part of Where $ A is the connection point with ring A, $ L1 For L 1 connection point; and / or R 4 is -O-CH3 or cyclopropyl, and R 5 is methyl; and / or R 6 is selected from C substituted by 1, 2, 3, 4 or more substituents independently selected from halogen and OH 1-4 alkyl; Preferably, R 6 is selected from C substituted by 1, 2, 3, 4 or more substituents independently selected from F, Cl and OH 1-6 alkyl; More preferably, R 6 is selected from C substituted by 1, 2, 3, 4 or more substituents independently selected from F and OH 1-6 alkyl; More preferably, R 6 is selected from C substituted with 1, 2, 3 or more F and 0 or 1 OH 1-6 alkyl; More preferably, R 6 is selected from C substituted with 1, 2, 3 or more F and 0 or 1 OH 3-6 alkyl; More preferably, R 6 Selected from 21. The compound according to claim 18, wherein the compound has a structure of one of formulas (I-28)-(I-31):

22. The compound according to claim 21, wherein: R 4 is -O-CH3 or cyclopropyl, and R 5 is methyl; and / or R 6 is selected from: -NH(4-6 membered heterocycloalkyl), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule via the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl and C 1-4 Substitution of haloalkyl groups; Preferably, R 6 is selected from -NH(4-6 membered heterocycloalkyl), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule via the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, F, Cl, CN and C 1-4 Substitution of alkyl groups; More preferably, R 6 is selected from -NH(4-6 membered heterocycloalkyl with 1 O or S heteroatom), and 4-6 membered heterocycloalkyl with 1 N heteroatom, wherein the 4-6 membered heterocycloalkyl with 1 N heteroatom is attached to the rest of the molecule via the N heteroatom and is optionally substituted by 1, 2, 3 or more independently selected from deuterium, F, CN and C 1-4 Substitution of alkyl groups; More preferably, R 6 Selected from 23. The compound according to claim 1, wherein the compound is selected from:

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A pharmaceutical combination comprising a compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and another therapeutically active agent.

26. A method of modulating complement alternative pathway activity in a subject, wherein the method comprises: Administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; or administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 24; or administering to the subject a therapeutically effective amount of a pharmaceutical combination according to claim 25.

27. A method for preventing or treating a disease, disorder or condition mediated by complement activation, particularly a disease, disorder or condition mediated by activation of the complement alternative pathway, in a subject, wherein the method comprises: Administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof; or administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 24; or administering to the subject a therapeutically effective amount of a pharmaceutical combination according to claim 25; Preferably, the disease, disorder or condition is selected from the group consisting of age-related macular degeneration (AMD), geographic atrophy of the macula, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian eye retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, middle cerebral artery disease, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, conditions caused by inappropriate or undesirable complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, Renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN), or other renal diseases with evidence of glomerular C3 deposition (such as membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aH US), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

28. A compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, or a pharmaceutical combination according to claim 25, for use as a medicament.

29. A compound according to any one of claims 1 to 23, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, or a pharmaceutical combination according to claim 25, for the preparation of a medicament for treating a disease, disorder or condition mediated by complement activation in an individual, particularly a disease, disorder or condition mediated by activation of the complement alternative pathway.

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