Complement factor B inhibitors, pharmaceutical compositions and uses thereof

Abstract

The present invention relates to complement factor B inhibitors of formula (I), pharmaceutical compositions thereof and uses thereof. [Formula 1] TIFF2026502231000352.tif47167

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 202211737515.0, filed December 31, 2022, and Chinese Patent Application No. 202310699631.6, filed June 13, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to novel complement factor B (FB) inhibitors, their pharmaceutical compositions and uses. [Background technology]

[0003] The complement system, an important part of the innate immune system, consists of over 40 proteins, including innate complement components C1–C9, various regulatory factors, and complement receptors. The complement system is activated through three pathways: the classical pathway (CP), mediated by complement components C1, C2, and C4; the lectin pathway (LP), mediated by the mannose-binding lectin (MLB) complex and serine proteases; and the alternative pathway (AP), mediated by complement factor B (FB) and complement factor D (FD).

[0004] FB is a trypsin-like serine protease that circulates as a zymogen in the blood. It is a key component in AP activation. Upon activation, FB binds to C3b and is cleaved by FD to generate the C3 convertase complex (C3bBb) containing the FB catalytic subunit (Bb). C3bBb further cleaves C3 to generate more C3b, amplifying the activation of the entire complement system. Uncontrolled C3 cycling leads to excessive deposition of active C3b and terminal complement factors in the glomerulus, altering renal structure and function and contributing to complement-mediated kidney diseases. Inhibiting BF activity blocks AP activation without interfering with CP and LP, thereby avoiding increased risk of infection and other diseases due to suppression of the complement system.

[0005] Several drugs targeting the complement system, such as the C5 inhibitors clizumab and ravulizumab and the C3 inhibitor pegcetacoplan, have been approved for indications including atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria (PNH). However, clinical observations have shown that a large number of PNH patients treated with C5 or C3 inhibitors still experience mild to moderate extravascular hemolysis due to incomplete suppression of AP, highlighting an unmet medical need in complement-mediated disorders.

[0006] LNP023 (WO2015009616A1 and WO2019043609A1), developed by Novartis Inc, is the first small molecule FB inhibitor currently in phase III clinical trials for the treatment of PNH, IgA nephropathy (IgAN), C3 glomerulopathy (C3G) and other diseases.

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2015009616A1 [Patent Document 2] WO2019043609A1 Summary of the Invention [Problem to be solved by the invention]

[0009] There remains a pressing need in the field to advance clinical research and develop novel small molecule FB inhibitors to address the treatment of diseases caused by complement abnormalities. [Means for solving the problem]

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

[0011] The novel small molecule FB inhibitors of the present invention demonstrate high affinity for FB and effectively inhibit its catalytic activity, significantly suppressing AP activation. Therefore, the small molecule FB inhibitors of the present invention have the potential to inhibit complement system amplification caused by C3 activation and prevent and treat diseases, disorders, or conditions mediated by complement activation, particularly those driven by AP activation. The compounds of the present invention have excellent properties, such as improved pharmacokinetic properties (e.g., increased bioavailability and metabolic stability, favorable half-life and duration of action), an excellent safety profile (e.g., reduced toxicity, such as lower cardiotoxicity and / or almost no side effects), and a lower tendency to drug resistance.

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

[0013] [ka]

[0014] 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.

[0015] In another aspect, the present invention provides a pharmaceutical composition 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, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] In another aspect, the present invention provides a pharmaceutical composition 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, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and another therapeutically active agent.

[0017] In another aspect, the present invention provides a method of modulating complement pathway activity in an individual, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present application, 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 application; or administering to the individual a therapeutically effective amount of a drug composition according to the present application.

[0018] In another aspect, the present invention provides a method for preventing or treating a disease, disorder or condition mediated by complement activation, particularly those mediated by activation of the alternative complement pathway, in an individual, comprising the step of 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 application, or administering to the individual a therapeutically effective amount of a drug composition according to the present application.

[0019] In another aspect, the present invention provides a compound of formula (I) according to the present application, 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 the present application or pharmaceutical compositions according to the present invention, for use as a medicament.

[0020] In another aspect, the present invention provides the use 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 a drug composition according to the present invention, or a pharmaceutical composition according to the present invention, in the preparation of a medicament for use in the treatment of a disease, disorder or condition mediated by complement activation, in particular one mediated by activation of the alternative complement pathway, in an individual.

[0021] In some embodiments, the disease, disorder, or condition is age-related macular degeneration (AMD), macular map atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, bird's eye choroiditis, sympathetic ophthalmia, cicatricial pemphigoid, pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, diseases caused by inappropriate or unexpected complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2) induced toxicity, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion disease. , myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex 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 (membranous nephropathy (MN) and Escherichia coli (E. coli) coli-induced hemolytic uremic syndrome (HUS), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumoconiosis, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic infectious diseases, pulmonary hemorrhagic nephritic syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity. [Brief explanation of the drawings]

[0022] [Figure 1]FIG. 1 shows 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. [Figure 2] FIG. 10 shows the therapeutic effects of LNP023 and the compound of the present invention on sheep anti-rat FxlA serum-induced passive Heymann nephritis in rats in Experimental Example 8. [Figure 3A] FIG. 1 shows the inhibitory effects of LNP023 and the compounds of the present invention on lipopolysaccharide (LPS)-induced complement activation in rats in Experimental Example 9. [Figure 3B] FIG. 1 shows the inhibitory effects of LNP023 and the compounds of the present invention on lipopolysaccharide (LPS)-induced complement activation in rats in Experimental Example 9. [Figure 3C] FIG. 1 shows the inhibitory effects of LNP023 and the compounds of the present invention on lipopolysaccharide (LPS)-induced complement activation in rats in Experimental Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0023] definition Unless otherwise defined, in the following text, all technical and scientific terms used herein are intended to have the same meaning as those generally understood by those skilled in the art.The technical meaning used herein refers to the techniques generally understood in this field, including modifications or equivalent replacements that are obvious to those skilled in the art.Although the following terms are believed to be easy to understand for those skilled in the art, in order to better explain the present invention, the following definitions are still described in detail.

[0024] As used herein, the terms "including," "comprising," "having," "containing," or "involving," and other variations thereof, are inclusive or open-ended and do not exclude other, non-recited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of").

[0025] As used herein, the term "alkane" refers to a saturated aliphatic hydrocarbon having a straight or branched chain.

[0026] As used herein, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon having a straight or branched chain, which can be viewed as a group obtained by the loss of one hydrogen atom from an alkane. In some embodiments, an alkyl group has 1 to 12 carbon atoms, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6). For example, as used herein, the term "C 1~6 "Alkyl" means "C 2~6 Alkyl," "C 2~5 Alkyl" and "C 1~4 "C" refers to a linear or branched functional group consisting of 1 to 6 carbon atoms, including alkyl. 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 group may be optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as a "halogenated alkyl," such as CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3). The term "C 1~4 "Alkyl" refers to an alkyl group having from 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0027] As used herein, the term "alkylene" refers to a divalent saturated aliphatic hydrocarbon having a straight or branched chain. 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.

[0028] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, where one or more CH groups in the backbone are replaced by heteroatoms, each of said heteroatoms being independently selected from O, S, S(O), S(O), NR', and compositions thereof, where R' is a hydrogen atom or C 1~6 Alkenyl or halo-C 1~6 The term "heteroalkyl" refers to the alkyl group described above, which is an alkyl group. As used herein, the prefix "x-membered" or "x- to y-membered" in combination with heteroalkylene refers to the total number of C atoms and heteroatoms in the heteroalkylene backbone chain. In some embodiments, the heteroalkylene can be, for example, a 2- to 6-membered heteroalkylene, a 2- to 5-membered heteroalkylene, or a 2- to 4-membered heteroalkylene (e.g., -CHOCHCH, -CHN(CH)CHCH). The heteroalkyl group can be connected to the remainder of the molecule via a heteroatom or a carbon atom in the backbone chain.

[0029] As used herein, the term "alkenyl" refers to a monovalent aliphatic hydrocarbon group, whether linear or branched, containing one or more double bonds. In some embodiments, an alkenyl group is an alkyl group having 2 to 6 carbon atoms ("C 2~6Alkenyl groups include, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present application contain an alkenyl group, the compounds can exist in the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof. The term "alkenylene" refers to, for example, "C 2~6 alkenylene," "C 2~4 Specific examples thereof include, but are not limited to, -CH=CH-, -CHCH=CH-, -C(CH)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, and cyclohexenylene.

[0030] As used herein, the term "alkynyl" refers to a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, an alkynyl group is an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms ("C"), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. 2~6 The alkynyl group is optionally substituted with one or more (e.g., 1 to 3) of the same or different substituents. The term "alkynylene group" refers to, for example, "C 2~6 alkynylene group," "C 2~4 The term "alkynylene group" refers to a corresponding divalent functional group, including, but not limited to,

[0031] [ka]

[0032] The alkynylene groups are optionally substituted with one or more (eg, 1 to 3) of the same or different substituents.

[0033] As used herein, the terms "cyclic hydrocarbon group," "hydrocarbon ring," and "cyclohydrocarbylene" refer to, for example, saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., containing one or more double bonds ("cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic fused carbon atoms having 3 to 10 ring carbon atoms (preferably 3 to 8, more preferably 3 to 7, 3 to 6, 4 to 6, or 5 to 6). It refers to a hydrogen ring, including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclobutenyl(ene)(ring), cyclopentenyl(ene)(ring), cyclohexenyl(ene)(ring), cycloheptenyl(ene)(ring), cyclooctenyl(ene)(ring), cyclononenyl(ene)(ring), and the like.

[0034] As used herein, the term "fused" refers to two or more cyclic structures that share two adjacent atoms.

[0035] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to saturated monocyclic or polycyclic (including bicyclic) fused hydrocarbon rings, including monocyclic or cyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like.

[0036] [ka]

[0037] The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, with a preferred range of 3 to 8, such as 3 to 7, 3 to 6, 4 to 6, or 5 to 6. The cycloalkyl and "cyclohexene" groups can be optionally substituted with one or more (such as 1 to 3) suitable substituents (such as methyl or halogen), such as methyl-substituted cyclopropyl.

[0038] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to a monocyclic or polycyclic (e.g., bicyclic) fused hydrocarbon ring having one or more double bonds within the ring (e.g., monocyclic or bicyclic cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclooctenyl, cyclononenyl, etc.). The cycloalkenyl and "cycloalkenylene" groups have 3 to 10 carbon atoms, with a preferred range of 3 to 8, such as 3 to 7, 3 to 6, 4 to 6, or 5 to 6. The cycloalkenyl and cycloalkenylene groups may be optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopentenyl.

[0039] As used herein, the term "bridged cyclic hydrocarbon" refers to a cyclic structure formed by two cyclic hydrocarbon groups, as defined above, that share two ring carbon atoms connected by a carbon chain of one or more (e.g., two) carbon atoms. The cyclic structure can be saturated (i.e., a "bridged cycloalkyl") or partially unsaturated (i.e., having one or more double bonds (i.e., a "bridged cycloalkenyl") and / or triple bonds within the ring). In some embodiments, a "bridged cyclic hydrocarbon group" is a cyclic hydrocarbon group having, for example, 5 to 10 ring carbon atoms (C), such as 6 (C), 7 (C), 8 (C), or 9 (C) ring carbon atoms. 5~10The bridged cyclic hydrocarbon group may be optionally substituted with one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, methyl, methoxy, CN, NH2, methylamino). Examples that may be mentioned include bicyclic [1.1.1]pentyl, e.g.

[0040] [ka]

[0041] Bicyclic [2.1.1]hexyl, such as;

[0042] [ka]

[0043] Bicyclic [2.2.1]heptyl; Bicyclic [3.2.1]octyl; Bicyclic [5.2.0]nonyl;

[0044] [ka]

[0045] As used herein, the term "monospirohydrocarbyl" refers to a cyclic structure formed by two hydrocarbyl groups, as defined above, sharing one ring carbon atom. This cyclic structure can be saturated (i.e., a "monospirohydrocarbyl") or partially unsaturated (i.e., containing one or more double bonds (i.e., a "monospirocycloalkenyl") and / or triple bonds within the ring). In some embodiments, a "monospirohydrocarbyl" can have six (C6), seven (C7), eight (C8), nine (C9), or ten (C10) carbon atoms. 10 5 to 11 ring carbon atoms (C 5~11Monospirohydrocarbyl groups include, but are not limited to, 5-11-membered monospirocycloalkyls, 6-10-membered monospirocycloalkyls, 7-10-membered monospirocycloalkyls, 6-10-membered nitrogen-containing monospirocycloalkyls, 6-10-membered oxygen-containing monospirocycloalkyls, and 6-10-membered sulfur-containing monospirocycloalkyls; and 5-11-membered monospirocycloalkenyls, 6-10-membered monospirocycloalkenyls, 7-10-membered monospirocycloalkenyls, 6-10-membered nitrogen-containing monospirocycloalkenyls, 6-10-membered oxygen-containing monospirocycloalkenyls, and 6-10-membered sulfur-containing monospirocycloalkenyls. Monospirohydrocarbyl groups can include, for example, 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, where the spiro atom is included in the calculation of each ring. The monospirohydrocarbon group may be optionally substituted with one or more (e.g., 1 to 3) suitable substituents (such as halogen, methyl, methoxy, or ethoxy). Representative examples are:

[0046] [ka]

[0047] As used herein, the terms "heterocyclyl," "heterocycle," and "heteroclylene" refer to monovalent, monocyclic or bicyclic fused ring structures that are saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., containing one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")). These structures contain 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms within the ring and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O)2, and NR' (R' is as defined above). The heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or, if present, through the nitrogen atom. Specifically, a 3- to 10-membered heterocyclyl group refers to a group containing 3 to 10 (e.g., 3 to 8, 3 to 7, 3 to 6, 4 to 6, or 5 to 6) ring carbon atoms and heteroatoms in the ring. The heterocyclyl group may have one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, OH, NH, oxo (=O), C 1~6 Alkyl or C 1~6 Representative examples include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, and azocinyl.

[0048] As used herein, the term "heterocyclyl" encompasses fused ring structures, and points of attachment to other groups may occur on any ring of the fused structure. Thus, heterocyclyl groups of the present application also include, but are not limited to, heterocyclyl-fused heterocyclyl, heterocyclyl-fused cycloalkyl, monocyclic heterocyclyl-fused monocyclic heterocyclyl, and monocyclic heterocyclyl-fused monocyclic cycloalkyl. Examples include, but are not limited to, 3- to 7-membered (monocyclic) heterocyclyl-fused 3- to 7-membered (monocyclic) heterocyclyl, 3- to 7-membered (monocyclic) heterocyclyl-fused (monocyclic) cycloalkyl, and 3- to 7-membered (monocyclic) heterocyclyl-fused C4-6 (monocyclic) cycloalkyl. Illustrative examples include, but are not limited to, pyrrolidinyl-fused cyclopropyl, cyclopentyl-fused aziridinyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, pyrrolidinyl-fused piperazinyl, piperidinyl-fused morpholinyl,

[0049] [ka]

[0050] As used herein, the term "bridged heterocyclyl" refers to a cyclic structure formed by the sharing of two non-adjacent ring atoms, either one hydrocarbon ring as defined herein and one heterocyclic ring as defined herein, or two heterocyclic rings as defined herein. The structure contains 3, 4, 5, 6, 7, 8, or 9 carbon atoms within the ring, and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O)2, and NR' (where R' is as defined above). The bridged heterocyclyl may be attached to the remainder of the molecule through any of the carbon atoms or through a nitrogen atom, if present. Specifically, a 5- to 10-membered bridged heterocyclyl refers to a group containing 5 to 10 ring carbon atoms and heteroatoms. A "bridged heterocyclyl" may be saturated (i.e., a "bridged heterocycloalkyl") or partially unsaturated (e.g., containing one or more double bonds within the ring, i.e., a "bridged heterocycloalkenyl"). In some embodiments, bridged heterocyclyls include, but are not limited to, 6-10 membered bridged heterocyclyls, 7-10 membered bridged heterocyclyls, 8-10 membered bridged heterocyclyls, and 9-10 membered bridged heterocyclyls. Said bridged heterocyclyls include nitrogen-containing bridged heterocyclyls, oxygen-containing bridged heterocyclyls, and sulfur-containing bridged heterocyclyls. Said bridged heterocyclyls may be optionally substituted with one or more (e.g., 1-3) suitable substituents, such as methyl, ethyl, or oxo. Representative examples include, but are not limited to:

[0051] [ka]

[0052] etc. A "nitrogen-containing bridged heterocyclyl," "oxygen-containing bridged heterocyclyl," and "sulfur-containing bridged heterocyclyl" may optionally contain one or more additional heteroatoms selected from oxygen, nitrogen, and sulfur.

[0053] As used herein, the term "monospiroheterocyclyl" refers to a cyclic structure formed by the sharing of one ring atom between one hydrocarbon ring, as defined herein, and one heterocyclic ring, as defined herein, or two heterocyclic rings, as defined herein. This structure contains 3, 4, 5, 6, 7, 8, or 9 carbon atoms within the ring, and one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(=O), S(=O)2, and NR' (where R' is as defined above). The monospiroheterocyclyl may be attached to the remainder of the molecule through any of the carbon atoms or through the nitrogen atom, if present. Specifically, "5-11-membered monospiroheterocyclyl" refers to a group containing 5-11 carbon atoms and heteroatoms, including, but not limited to, a 6-11-membered monospiroheterocyclyl, a 7-9-membered monospiroheterocyclyl, or an 8-10-membered monospiroheterocyclyl. The monospiroheterocyclyl may be saturated (i.e., a "monospiroheterocyclyl") or partially unsaturated (e.g., containing one or more double bonds within the ring, i.e., a "monospiroheterocycloalkenyl"). Monospiroheterocyclyl includes, but is not limited to, 5-11-membered monospiroheterocycloalkyl, 6-10-membered monospiroheterocycloalkyl, 7-10-membered monospiroheterocycloalkyl, 6-10-membered nitrogen-containing monospiroheterocycloalkyl, 6-10-membered oxygen-containing monospiroheterocycloalkyl, 6-10-membered sulfur-containing monospiroheterocycloalkyl, as well as 5-11 monospiroheterocycloalkenyl, 6-10 monospiroheterocycloalkenyl, 7-10 monospiroheterocycloalkenyl, 6-10 nitrogen-containing monospiroheterocycloalkenyl, 6-10 oxygen-containing monospiroheterocycloalkenyl, and 6-10 sulfur-containing monospiroheterocycloalkenyl. Monospiroheterocyclyl can include, for example, 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, where the spiro atom is included in the calculation of each ring.The monospiroheterocyclyl may be optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as methyl, ethyl, or oxo. Representative examples include, but are not limited to, the following:

[0054] [ka]

[0055] The "nitrogen-containing monospiroheterocyclyl," "oxygen-containing monospiroheterocyclyl," and "sulfur-containing monospiroheterocyclyl" may optionally contain one or more additional heteroatoms selected from oxygen, nitrogen, and sulfur. The term "5-11-membered nitrogen-containing monospiroheterocyclyl" refers to a monospiroheterocycle containing a total of 5 to 11 ring atoms, at least one of which is nitrogen.

[0056] As used herein, the term "aryl" refers to an all-carbon monocyclic aromatic group or a fused polycyclic aromatic group having a conjugated π electron system. For example, the term "C 6~14 "Aryl" refers to an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. An aryl group is an aromatic group containing halogen, -OH, -CN, -NO, C 1~6 It may be optionally substituted with one or more (eg, 1 to 3) suitable substituents such as alkyl.

[0057] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system containing 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), particularly 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)2. One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). The heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzofuryl, benzothienyl, and the like. Heteroaryl groups include aryl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like. Heteroaryl groups can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0058] As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

[0059] As used herein, the term "guanidyl" refers to the following group:

[0060] [ka]

[0061] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with substituents selected from the indicated group, provided that such substitutions do not exceed the normal valence of the designated atom and result in a stable compound. Configurations of substituents and / or variables are permissible only if they result in the formation of stable compounds.

[0062] When a group is described as "optionally substituted with..." or "optionally substituted," it can be (1) unsubstituted or (2) substituted. When a carbon of a group is described as being optionally substituted with one or more substituents from a list of substituents, one or more hydrogens on that carbon (to the extent any hydrogens are present) can be individually and / or together replaced by any independently selected substituents. When a nitrogen of a group is described as being optionally substituted with one or more substituents from a list of substituents, one or more hydrogens on that nitrogen (to the extent any hydrogens are present) can each be independently replaced by any substituent. Optional substituents include halogen, OH, SH, CN, NO, C, and the like. 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -O-halo-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 1~6alkyl), -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, -C0~6 alkylene-S(O)2C 1~6 Alkyl, -C 0~6 Alkylene-S(O)2NH2, -C 0~6 Alkylene-S(O)NH(C 1~6 alkyl), -C 0~6 Alkylene-S(O)N(C 1~6 alkyl)2, -NH-C(O)C 1~6 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 heterocyclyl), -C 0~6 Alkylene-phenyl and -C 0~6 It may be selected from alkylene-(5-10 membered heteroaryl).

[0063] When substituents are described as being "independently selected from" a group, each substituent is selected independently of the others, and thus each substituent may be the same as or different from another (other) substituent.

[0064] As used herein, "one or more" means one or more, for example, two, three, four, five or ten, under appropriate conditions.

[0065] Unless otherwise specified, the site of attachment of a substituent in this description may be at any suitable position on the substituent.

[0066] When a substituent bond is depicted as crossing a ring bond and connecting two atoms (a "dangling bond"), that substituent may be attached to any substitutable ring atom unless otherwise stated. If a substitutable hydrogen is present on a ring member and a dangling bond is connected to the ring member, the substitutable hydrogen is substantially replaced (i.e., absent).

[0067] The present invention includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms have been replaced by an atom having the same atomic number but a different mass number or a mass number other than the atom predominantly occurring in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes (e.g., 2 H / D and 3 H / T), carbon isotopes (e.g., 11 C. 13 C and 14 C), chlorine isotopes (e.g., 36 Cl), fluorine isotopes (e.g., 18 F), iodine isotopes (e.g., 123 I and 125 I), nitrogen isotopes (e.g., 13 N and 15 N), oxygen isotopes (e.g., 15 O. 17 O and 18O), phosphorus isotopes (e.g., 32 P) and sulfur isotopes (e.g., 35 The compounds of the present invention labeled with certain isotopes (e.g., doped with a radioactive isotope) can be used 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 detect. 11 C. 18 F, 15 O and 13 Substitution with methyl groups (e.g., N) can be used in positron emission tomography (PET) studies to examine receptor occupancy of substrates. Isotopically labeled compounds of the present application can be prepared using the accompanying routes and / or methods similar to those described in the embodiments and preparations by replacing the previously used unlabeled reagent with the appropriate radiolabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the solvent of crystallization can be isotopically substituted, such as DO, acetone-d6, or DMSO-d6. In some embodiments, isotopically labeled compounds of the present application are deuterated compounds.

[0068] The term "stereoisomer" refers to isomers formed by at least one asymmetric center that have the same chemical composition but differ in the spatial arrangement of atoms or functional groups. Compounds with one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist in rapid equilibrium as mixtures of two or more structurally distinct forms (commonly referred to as tautomers). Representative examples of tautomers include ketone-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% and 99%).

[0069] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of one another. Diastereomers exhibit different physical properties, including melting points, boiling points, spectroscopic characteristics, and reactivities. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

[0070] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0071] The term "chiral" refers to molecules that are not superimposable on their mirror image, while "achiral" refers to molecules that are superimposable on their mirror image.

[0072] The compounds of the invention may be prepared in racemic form. Alternatively, single enantiomers may be obtained by enantiomeric synthesis or resolution techniques.

[0073] The terms "racemate," "racemic compound," or "racemic mixture" refer to an equimolar mixture of two enantiomers, a mixture devoid of optical activity.

[0074] As used herein, the term "cis / trans isomers" or "geometric isomers" refers to isomers that arise from double bonds or single bonds at cyclic carbon atoms that cannot freely rotate. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures.

[0075] In the present invention, the chemical bonds of the compounds of the present invention are illustrated by solid lines (

[0076] [ka]

[0077] ), solid wedge (

[0078] [ka]

[0079] ) or dashed wedge (

[0080] [ka]

[0081] ) may be used. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to represent all possible stereoisomers (e.g., a specific enantiomer, a racemic mixture, etc.) in which that carbon atom is included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the shown stereoisomer exists. When the solid and dashed wedges are present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist in stereoisomeric forms, including cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, geometric isomers, rotamers, stereoisomers, anti-rotamers, and mixtures thereof. The compounds of the present invention can exhibit more than one type of isomerism and consist of mixtures thereof (such as racemic mixtures and diastereomeric pairs). If the compound contains two chiral centers, a thick solid line (

[0082] [ka]

[0083] ) and thin dashed lines (

[0084] [ka]

[0085] ) can be used to depict chemical bonds in the compound and indicates the relative relationship between two chiral centers, but does not imply any absolute stereochemistry. For example,

[0086] [ka]

[0087] the bond connecting Ra to the ring and the bond connecting Rb to the ring are in a cis relationship with each other;

[0088] [ka]

[0089] represents both of the corresponding isomers, i.e.,

[0090] [ka]

[0091] It should be understood that certain compounds of the present invention may exist for therapeutic purposes in free form or, where appropriate, in their pharmaceutically acceptable derivative form. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, when administered to a patient in need thereof, can directly or indirectly yield the compounds of the present invention, or their metabolites or residues. Thus, when referring to "compounds of the present application" herein, it is also intended to encompass various derivative forms of the compounds specified above.

[0092] The term "pharmaceutically acceptable" refers to a substance or composition that must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated with the formulation.

[0093] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0094] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, hydrogensulfate / sulfate, fumarate, gluconate, glucuronide, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate, niacin, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0095] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, glucosamine salts, potassium salts and other similar salts.

[0096] A review of suitable salts can be found in Stahl and Wermuth's "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.

[0097] As used herein, the term "ester" refers to esters derived from various compounds of the general formula in the present application, including physiologically hydrolyzable esters (compounds of the present application that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the present application may also themselves be esters.

[0098] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0099] The compounds of the present invention can exist in the form of solvates (preferably hydrates), and contain polar solvents, such as water, methanol or ethanol, as structural elements of the lattice of the compounds. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

[0100] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires an available lone electron pair to oxidize to an oxide. Those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for N-oxides used in the preparation of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines using peracids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tertbutyl hydroperoxide, sodium perborate, and dioxolanes such as dimethylbis(oxyethane). These methods for preparing N-oxides have been widely described and reviewed in the literature, see, for example, T. L. Gilchrist, Comprehensive Organic Synthesis, Vol. 7, pp. 748-750; A. R. Katrittzky and A. J. Boulton (eds.), Academic Press; as well as G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, Vol. 22, pp. 390-392, A. R. Katrittzky and A. J. Boulton (eds.), Academic Press.

[0101] The term "N-oxides," also known as amine oxides, is a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0102] The scope of the present invention also includes metabolites of the compounds of the present invention, which are substances formed in the body upon administration of a compound of the present invention. Such substances may be produced by oxidation, reduction, hydrolysis, amidation, deamination, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound. Thus, the present application includes metabolites of the compounds of the present application, including compounds prepared by contacting a compound of the present application with a mammal for a time sufficient to produce a metabolic product thereof.

[0103] The present invention further includes prodrugs of the compounds of the present invention. Prodrugs are certain derivatives of the compounds of the present invention that may themselves have relatively low or no pharmacological activity, and can be converted to the compounds of the present application having the desired activity, for example, by hydrolysis, when administered to the body or on the surface of the body. Typically, such prodrugs are functional derivatives of the compounds, which are easily converted to the desired therapeutically active compound in vivo. Additional information regarding the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, 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 "promoieties" (such as those described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0104] The present invention also encompasses the compounds of the present invention that contain protecting groups.In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming a chemically protected form of the compounds of the present invention.This can be achieved by conventional protecting groups, such as those mentioned in Protective Groups in Organic Chemistry, J.F.W. McCoy (ed.), Plenum Press, 1973; and T.W. Greene & P.G.W. Buts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference.Protective groups can be removed at a later stage as appropriate using methods known in the art.

[0105] As used herein, the term "approximately" refers to within ±10%, preferably within ±5%, and more preferably within ±2% of the numerical value. chemical compound

[0106] In one aspect, the present application provides a compound of formula (I):

[0107] [ka]

[0108] 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 (In the formula, R 1 -L 2 -R L and L 2 is a direct bond, linear or branched C 1~6 Alkylene or linear or branched C 2~6 is alkenylene, Optionally, C 1~6 Alkylene or C 2~6 One available carbon atom in an alkenylene may be substituted with two substituents, whereby the two substituents together with the carbon atom form an optionally substituted C 3~6 cycloalkylene or optionally substituted 3- to 6-membered heterocycloalkylene, or alternatively, 1~6 Alkylene or C 2~6 The two adjacent carbon atoms in an alkenylene are linear C 1~4 Optionally substituted C linked via alkylene 3~6 may form a cycloalkylene, or may be linked via -S-, -O-, -NH- or a linear 2-4 membered heteroalkylene to form an optionally substituted 3-6 membered heterocycloalkylene; Said C 1~6 Alkylene or C 2~6 Alkenylene is a group containing halogen, OH, SH, CN, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -NR 1a R 1b , C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 optionally substituted with one, two, three or more substituents independently selected from aryl and 5- to 10-membered heteroaryl; The L connected to the carbon atom indicated by the symbol "#" 2 -R L The CH2 moiety (if present) is O, S, or NR 1e and optionally replaced by R L is R 9 , R 10 , -O-R10, -SR 10 and -NR 1e -R 10 is selected from R 10 H, R 11 , halogens, OH, SH, CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkynyl, guanidyl and -C 1~6 alkylene-guanidyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC 2~6 Alkenyl and -OC 2~6 each alkynyl is optionally substituted with one, two or more substituents independently selected from halogen, OH, SH and NH; R 9 and R 11 is -(CH2) 0~6 -C 3~10 Cyclic hydrocarbon group, -(CH2) 0~6 -3 to 10-membered heterocyclyl, -(CH2) 0~6 -C 5~10 Bridged cyclic hydrocarbon group, -(CH2) 0~6 -5-10 membered bridged heterocyclyl, -(CH2) 0~6 -C 5~11 Spirocyclic hydrocarbon group, -(CH2) 0~6 -5 to 11-membered spiroheterocyclyl, -(CH2) 0~6 -C 6~10 Aryl and -(CH2) 0~6 -5 to 10-membered heteroaryl, each of which is independently selected from: 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 R1b , -C 1~6 Alkylene-OC 1~6 Alkyl, -OC 1~6 Alkylene-C 3~10 Cyclic hydrocarbon group, -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 and optionally substituted with one, two or more substituents independently selected from Cy is an 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; 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 or -NR2a -S(O)2-R 2b and R 1a , R 1b , R 1c , R 1d , R 1e , R 2a and R 2b are each independently, if present, 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; R 1c and R 1d together with the carbon atoms to which they are attached, are optionally substituted C 3~6 optionally forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl, or R 1 and R 2 together with the carbon atoms to which they are attached, marked by the symbol "#", form the following formula:

[0109] [ka]

[0110] forming a portion represented by During the ceremony, Ring D is C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 5~10 selected from a bridged cycloalkyl or a 5- to 10-membered bridged heterocycloalkyl; R 6 teeth, H, halogen, OH, SH, CN, N(R 7a )2, C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH and CN; -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -C 1~6 Alkylene-OC 1~6 Alkyl, -C 1~6 Alkylene-OC 1~6 haloalkyl, C 3~10 Cyclic hydrocarbon group, -C 1~6 Alkylene-C 3~10 Cyclic hydrocarbon group, -OC 1~6 Alkylene-C 3~10 Cyclic hydrocarbon group or -C(O)-C 3~10 Cyclic hydrocarbon groups (C 3~10 Cyclic hydrocarbons are deuterium, halogens, 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 haloalkoxy), and 3-10 membered heterocycloalkyl or -C 1~6 Alkylene-3 to 10-membered heterocycloalkyl (heterocycloalkyl is a 3-membered heterocycloalkyl group, which is a heterocycloalkyl group, and is substituted with deuterium, halogen, OH, SH, NH, 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 and optionally substituted with one, two or more substituents independently selected from haloalkoxy. is selected from R 7a is H, C 1~6 Alkyl, -(CH2) q -C 3~10 Cyclic hydrocarbon group or -(CH2)q - 3 to 10-membered heterocycloalkyl (q is an integer selected from 0 to 6); C 1~6 Alkyl, -(CH2) q -C 3~10 Cyclic hydrocarbon group or -(CH2) q -3 to 10-membered heterocycloalkyl are each selected from deuterium, halogen, OH, SH, NH2, CN, oxo, and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 optionally substituted independently with one, two or more substituents independently selected from haloalkoxy; n is 1, 2 or 3; Ring A is C 6~10 aryl or 5-10 membered heteroaryl; R 3 are halogen, OH, SH, CN, and -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 or a 5-6 membered heteroaryl containing 1-4 N heteroatoms and 0-1 O or S heteroatoms; R 3a / R 3b is, if present, independently H or C 1~6is alkyl, p is 1, 2 or 3; L 1 teeth, * -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 -or-NR 4c -C(S)-, * is connected to the phenyl ring B, R 4a and R 4b H, deuterium, halogen, OH, SH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b or R 4a and R 4b together with the common carbon atom to which they are attached, C 3~6 forming a cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 4c is H, C 1~6 Alkyl or C 1~6 haloalkyl; R is

[0111] [ka]

[0112] and During the ceremony, R 4 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 Haloalkyl, -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 Cyclic hydrocarbon groups and -OC 1~6 Alkylene-C 3~10 cyclic hydrocarbon groups, and 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -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-NR6a 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 Cyclic hydrocarbon groups and -OC 1~6 Alkylene-C 3~10 the cyclic hydrocarbon groups are each optionally substituted with one or more deuterium atoms (D); R 5 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 or C 3~10 carbocyclyl, R 5a , R 5b , R 6a and R 6b If present, H and C 1~6 independently selected from alkyl, X is CR 7 , C(R 7 )2 and N; Y is CR 8 , C(R 8 )2 and N; Z is selected from O, S and NH; R 7 and R 8 If present, H, halogen, OH, SH, CN, NH, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 1~6 Alkyl and C 3~10 independently selected from carbocyclyl,

[0113] [ka]

[0114] represents a double or single bond) to provide.

[0115] In some embodiments, the present invention provides compounds of formula (I) above, wherein: Cy is an optionally substituted C 3~10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6~10 aryl or optionally substituted 5-10 membered heteroaryl; R 6 is H, halogen, OH, SH, CN, N(R 7a )2, C 1~6 Alkyl, -OC 1~6 Alkyl, -OC 1~6 Alkyl-C 3~10 Cyclic hydrocarbon groups, and C 3~10 Cyclic hydrocarbon groups (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 3-10 membered heterocycloalkyl groups (deuterium, halogen, OH, SH, NH, 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 optionally substituted with one, two or more substituents independently selected from haloalkoxy; R 4 are halogens, OH, SH, CN, -NR 6a R6b , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -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 Carbocyclyl and -OC 1~6 Alkylene-C 3~10 The cyclic hydrocarbon group is selected from the group consisting of:

[0116] In some embodiments, the present invention provides compounds of formula (I) above, wherein: R 10 H, R 11 , halogens, 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 and guanidinyl, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC 2~6 Alkenyl and -OC 2~6alkynyl is optionally substituted by one, two or more substituents independently selected from halogen, OH, SH and NH; R 9 and R 11 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 5~10 Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5-10 membered heteroaryl, each of which is independently selected from the following group: 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 Cyclic hydrocarbon group, -OC 6~10 Aryl, -C 1~6 Alkylene-NR 1a COR 1b , -NR 1a R 1b , -NR1a-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)-NR1a R 1b and optionally substituted with one, two or more substituents independently selected from 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 and R 6 is 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-halo-C 1~6 Alkyl, -OC 1~6 Alkyl-C 3~10 Cyclic hydrocarbon groups and C 3~10 selected from cyclic hydrocarbon groups, C 3~10 Cyclic hydrocarbon groups include halogens, OH, SH, NH2, CN, and C 1~6 Alkyl and C 1~6 optionally substituted by one, two or more substituents independently selected from haloalkyl; R 4a and R 4b H, halogen, OH, SH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 5a R 5b , -C(O)OR 5aand -C(O)-NR 5a R 5b are each independently selected from R 5 are halogens, 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 The cyclic hydrocarbon group is selected from the group consisting of:

[0117] In some embodiments, L 2 and the -(optionally substituted C 1~6 alkylene)-Cy is R 9 or R 11 is optionally linked to two adjacent or non-adjacent (eg, meta or para) ring members of

[0118] In some embodiments, there is provided a compound of formula (I) according to the present application, wherein: R 1 -L 2 -R L and L 2 is a direct bond, R L is R 9 is.

[0119] In some embodiments, R 9 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 5~10 Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5-10 membered heteroaryl, each of which is selected from the following: 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 Cyclic hydrocarbon group, -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- to 10-membered heterocycloalkyl, -NR 1a -(Optionally substituted C 3~10 cycloalkyl), -NR 1a -(Optionally substituted C 3~10 Cycloalkenyl), -NR 1a -(optionally substituted 3- to 10-membered heterocyclic group) and -CR 1c R 1d -C(O)-NR 1a R 1b and optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0120] In some preferred embodiments, R 9 is C3~10 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 Monospirocyclic alkyl, C 5~11 monospirocyclic alkenyl, 5- to 11-membered monospiroheterocycloalkyl, 5- to 11-membered monospiroheterocyclo-alkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which may be selected from 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 with one, two or more halogens), -NR 1a -(Optionally substituted C 3~6cycloalkyl), -NR 1a -(Optionally substituted C 3~10 Cycloalkenyl), -NR 1a -(optionally substituted 3- to 10-membered heterocyclic group) and -CR 1c R 1d -C(O)-NR 1a R 1b and R is optionally substituted with one, two or more substituents independently selected from the group consisting of 1a , R 1b , R 1c and R 1d If present, 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; R 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl.

[0121] In some more preferred embodiments, R 9 is 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 Monospirocyclic alkyl, C 5~11 and selected from monospirocyclic alkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from F, Cl, -OR 1a , -SR 1a , CN, =O, =CH-R 1a , C 1~4 Alkyl, C 1~4Haloalkyl, -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 with one, two or more halogens), —NR 1a -(Optionally substituted C 3~10 -cycloalkenyl) and -NR 1a -(optionally substituted 3- to 10-membered heterocyclic group), and R 1a and R 1b If present, H and C 1~4 alkyl.

[0122] In some more preferred embodiments, R 9is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]heptanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azocinyl, C5, C6 or C7 bridged cycloalkyl (e.g.,

[0123] [ka]

[0124] ), C5, C6 or C7 bridged cycloalkenyl, 6-, 7-, 8- or 9-membered bridged heterocycloalkyl, C 5~11 and selected from monospirocycloalkyl, 5- to 11-membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and pyrimidinonyl, each of which is selected from F, Cl, OH, SH, C. N, 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, -NHCH2CH3, -N(CH3)2, -NH-C(O)CH3, -NH-C(O)NH2,

[0125] [ka]

[0126] -NH-S(O)2CH3,

[0127] [ka]

[0128] and optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0129] In other embodiments, R 9 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 5~10 Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5-10 membered heteroaryl, each of which is selected from the following: 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 Cyclic hydrocarbon group, -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- to 10-membered heterocyclic group) and -CR 1c R 1d -C(O)-NR 1a R 1b and optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0130] In some preferred embodiments, R 9 is 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 monospirocyclo-alkenyl, 5- to 11-membered monospiroheterocycloalkyl, 5- to 11-membered monospiroheterocyclo-alkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from the following: Deuterium, halogen, -OR 1a , -SR 1a , CN, =O, =CH-R 1a , =NH,C 1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkylene-OR1a, -C 1~4 Alkylene-SR 1a , -C 1~4 Alkylene-NR 1a R1b, -C 1~4 Alkylene-OC 1~4 Alkyl, -OC 1~4Alkylene-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 optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0131] R 1a , R 1b , R 1c and R 1d If present, 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; R 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl.

[0132] In some even more preferred embodiments, R 9 is C 3~10 Cycloalkyl, C 3~10Cycloalkenyl, 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 and selected from monospirocycloalkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from the following: 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 (R 1a and R 1b If present, H and C 1~4 alkyl) and optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0133] In some even more preferred embodiments, R 9is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azocinyl, C5, C6 or C7 bridged cycloalkyl, C5, C6 or C7 bridged cycloalkenyl, 6-, 7-, 8- or 9-membered bridged heterocycloalkyl, C 5~11 and selected from monospirocycloalkyl, 5-11 membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and pyrimidinonyl, which are selected from F, Cl, OH, SH, CN, NH, CH, CHCH, CHCl, CF, -CHCF, -CH-OH, -CH-SH, -CH-NH, -CHCHOCHCH, -CH-NH-C(O)CH, =O, =CH, -OCH, -OCHCH, -O-CH-cyclopropyl, phenoxy, -NHCH, -NH-C(O)CH, -NH-C(O)NH,

[0134] [ka]

[0135] and -NH-S(O)2CH3.

[0136] Further, in some embodiments, R 9 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 5~10Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5-10 membered heteroaryl, each of which is selected from the following: 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 Cyclic hydrocarbon group, -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- to 10-membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b and optionally substituted with one, two or more substituents independently selected from the group consisting of:

[0137] In some preferred embodiments, R 9 is C3~10 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 and selected from monospirocycloalkenyl, 5- to 11-membered monospiroheterocycloalkyl, 5- to 11-membered monospiroheterocycloalkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from 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- to 10-membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1band optionally substituted with one, two or more substituents independently selected from the group consisting of: R 1a , R 1b , R 1c and R 1d If present, 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; R 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl.

[0138] In some preferred embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl, azocanyl; dihydropyrrolyl, dihydroimidazolyl; azocinyl; 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, furanyl, thienyl, pyrazolyl, pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and pyrimidinonyl, which are selected from F, Cl, OH, SH, CN, NH2, CH3, CH2CH3, CH2Cl, Optionally substituted by one, two or more substituents independently selected from 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.

[0139] In some embodiments, there is provided a compound of formula (I) according to the present application, wherein: R 1 -L 2 -R L and L 2 is a linear or branched C 1~6 Alkylene or linear or branched C 2~6 is alkenylene, Optionally, said C 1~6 Alkylene or C 2~6 One available C atom in an alkenylene is substituted by two substituents, and thus the two substituents together with the C atom form an optionally substituted C 3~6 cycloalkylene or an optionally substituted 3- to 6-membered heterocycloalkylene, or optionally, C 1~6 Alkylene or C 2~6 The two adjacent carbon atoms in an alkenylene are linear C 1~4 C linked by alkylene and optionally substituted 3~6form a cycloalkylene, or are joined by -S-, -O-, -NH- or a linear 2-4 membered heteroalkylene to form an optionally substituted 3-6 membered heterocycloalkylene; Said C 1~6 Alkylene or C 2~6 Alkenylene is a group containing halogen, OH, SH, CN, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -NR 1a R 1b , C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 6~10 optionally substituted with one, two, three or more substituents independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; L attached to the carbon atom marked by the symbol "#" 2 -R L The CH2 moiety (if present) is O, S, or NR 1e and optionally replaced by R L is R 10 , -OR 10 , -SR 10 and -NR 1e -R 10 is selected from.

[0140] In some embodiments, the C 3~6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0141] In some embodiments, the 3- to 6-membered heterocycloalkylene is a 4- to 6-membered heterocycloalkylene, preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or thiomorpholinyl.

[0142] In some embodiments, L 2 Linear or branched C 1~6 Alkylene or linear or branched C2~6 Optional substituents on 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.

[0143] In other embodiments, R 1 -CR al R bl -(CRclR 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 and R al , R bl , R cl and R dl If present, H, halogen, OH, SH, CN, C 1~4 Alkyl, C1~4 Haloalkyl, -OC 1~4 Alkyl, -NR 1a R 1b , C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl and 5- to 10-membered heteroaryl; Optionally, one CR cl R dl R in al and R bl or R cl and R dl together with the carbon atoms to which they are both attached, =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 ) m Two adjacent carbon atoms in a linear carbon chain are linear C 1~4 Linked by alkylene, C 3~6 form a cycloalkylene, or are linked by -S-, -O-, -NH- or a linear 2- to 4-membered heteroalkylene to form a 3- to 6-membered heterocycloalkylene; R 1a and R 1b If present, H and C 1~6 are each independently selected from alkyl, R 1e If present, H and C 1~4 are each independently selected from alkyl, m is 0, 1, 2, 3, 4 or 5.

[0144] In some such embodiments, the C 3~6 Cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0145] In some such embodiments, the 3- to 6-membered heterocycloalkylene is a 4- to 6-membered heterocycloalkylene, preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, or thiomorpholinyl.

[0146] In some such embodiments, R al , R bl , R cl and R dl are H, F, Cl, OH, SH, CN, and C, respectively, if present. 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 independently selected from H, CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, cyclopropyl and azetidinyl.

[0147] In some such embodiments, one CR cl R dl R in al and R bl or R cl and R dl Together with the carbon atoms to which they are both attached, =CH2, C 3~6 It forms a cycloalkylene or a 3- to 6-membered heterocycloalkylene.

[0148] In some such embodiments, m is 0, 1, or 2.

[0149] In some such embodiments, the compound of Formula (I) has the structure of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7):

[0150] [ka]

[0151] In some preferred embodiments, m is 0, 1, or 2.

[0152] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-7), wherein R is 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-guanidinyl; 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 is optionally substituted with one, two or more substituents independently selected from halogen, OH, SH and NH. In some preferred embodiments, R 10 H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, CF, —CHCF, —OCH, —OCHCH, guanidinyl, and —CHCH-guanidinyl. 10 H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, -OCH3, -OCH2CH3, guanidinyl and -CH2CH2-guanidinyl.

[0153] In some embodiments, R 10 H, R 11 , F, Cl, OH, SH, CN, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, -OC 1~4Alkyl, -OC 2~4 Alkenyl, -OC 2~4 alkynyl and guanidinyl, 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 is optionally substituted with one, two or more substituents independently selected from halogen, OH, SH and NH. In some preferred embodiments, R 10 H, R 11 , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, -OCH3, -OCH2CH3 and guanidinyl.

[0154] In some embodiments, R 11 is -(CH2) 0~6 -C 3~10 Cyclic hydrocarbon group, -(CH2) 0~6 -3 to 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 monospiroheterocyclic group, -(CH2) 0~6 -C 6~10 Aryl and -(CH2) 0~6 - 5 to 10 membered heteroaryl, each of which is selected from group A1: (Group A1) 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-SR1a , -C 1~6 Alkylene-NR 1a R 1b , -C 1~6 Alkylene-OC 1~6 Alkyl, -OC 1~6 Alkylene-C 3~10 Cyclic hydrocarbon group, -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- to 6-membered heterocycloalkyl), -NR 1a -(Optionally substituted C 3~6 cycloalkyl), -NR 1a -(optionally substituted 4- to 7-membered heterocyclic group) and -CR 1c R 1d -C(O)-NR 1a R 1b In some embodiments, Group A1 is optionally substituted with one, two or more substituents independently selected from: 1a -(Optionally substituted C 3~10 cycloalkenyl), and R 1a is as defined above.

[0155] In some preferred embodiments, R 11 is -(CH2) 0~3 -C 3~10 Cycloalkyl, -(CH2) 0~3 -C3~10 Cycloalkenyl, -(CH2) 0~3 -3 to 10-membered heterocycloalkyl, -(CH2) 0~3 -3 to 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 -C 5~11 Monospiro-cycloalkenyl, -(CH2) 0~3 -5 to 11-membered monospiroheterocycloalkyl, -(CH2) 0~3 -5- to 11-membered monospiroheterocycloalkenyl, -(CH2)0-3-phenyl and -(CH2) 0~3 - 5- or 6-membered heteroaryl, which are each selected from group A2: (Group A2) 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 , -NR1a -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- to 7-membered heterocyclic group) and -CR 1c R 1d -C(O)-NR 1a R 1b and R 1a , R 1b , R 1c and R 1d If present, 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; R 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 In some embodiments, group A2 is -NR 1a -(Optionally substituted C 3~10 cycloalkenyl), and R 1a is as defined above.

[0156] In some more preferred embodiments, R 11 is C 3~10 Cycloalkyl, C 3~10Cycloalkenyl, 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, which are each selected from group A3: (Group A3) 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- to 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -NR 1a -(Optionally substituted C 3~6 cycloalkyl) and -CR 1c R 1d -C(O)-NR 1a R 1b and R 1a , R 1b , R 1c and R 1d If present, H and C 1~4 alkyl; 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 In some embodiments, the group A3 is -NR 1a -(Optionally substituted C3~10 -cycloalkenyl) and -NR 1a -(optionally substituted 4- to 7-membered heterocyclic group), and R 1a is as defined above.

[0157] In some preferred embodiments, R 11 Group B: (Group B) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl,

[0158] [ka]

[0159] Dihydropyrrolyl, dihydroimidazolyl, azocinyl, 5-11 membered monospiroheterocycloalkyl, phenyl, -CH2-phenyl, pyrrolyl, -CH2-pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, -CH2-pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidinonyl is selected from.

[0160] In some embodiments, Group B is imidazolyl and / or

[0161] [ka]

[0162] The groups listed in Group B above are 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, and pyridinyl.

[0163] [ka]

[0164] and -CR 1c R 1d optionally substituted with one, two or more substituents independently selected from —C(O)NH; 1c and R 1d taken together with the carbon atom to which they are both attached form cyclopropyl.

[0165] In some embodiments, R 11 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 5~10 Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5- to 10-membered heteroaryl, each of which is selected from 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-OC1~6 Alkyl, -OC 1~6 Alkylene-C 3~10 Cyclic hydrocarbon group, -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- to 6-membered heterocycloalkyl) and -CR 1c R 1d -C(O)-NR 1a R 1b and optionally substituted with one, two or more substituents independently selected from:

[0166] In some preferred embodiments, R 11 is 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 and selected from monospirocycloalkenyl, 5- to 11-membered monospiroheterocycloalkyl, 5- to 11-membered monospiroheterocycloalkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from the following: Halogen, -OR 1a , -SR1a , 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- to 6-membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b and optionally substituted with one, two or more substituents independently selected from R 1a , R 1b , R 1c and R 1d If present, 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; R 1cand R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl.

[0167] In some more preferred embodiments, R 11 is C 3~10 Cycloalkyl, C 3~10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 5~11 and selected from monospirocycloalkyl, 5- to 11-membered monospiroheterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from 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 , C 3~6 Cycloalkyl, 3- to 6-membered heterocycloalkyl and -CR 1c R 1d -C(O)-NR 1a R 1b and R 1a , R 1b , R 1c and R 1d If present, H and C 1~4 alkyl; 1c and R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally, a cycloalkyl is formed.

[0168] In some preferred embodiments, R 11 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl,

[0169] [ka]

[0170] dihydropyrrolyl, dihydroimidazolyl, azocinyl; 5-11 membered monospiroheterocycloalkyl; phenyl; pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyridonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, and pyrimidinonyl, which are selected from 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 optionally substituted with one, two or more substituents independently selected from —C(O)NH; 1c and R 1d taken together with the carbon atom to which they are both attached form cyclopropyl.

[0171] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-7), wherein: R 2 H, halogen, OH, SH, CN, C 1~4 Alkyl, -C 1~4Alkylene -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 If present, H and C 1~4 alkyl.

[0172] In some preferred embodiments, R 2 are 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.

[0173] 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 R 2a and R 2b If present, H and C 1~4 alkyl.

[0174] In some preferred embodiments, R 2are 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.

[0175] In some embodiments, the structure of formula (I-8):

[0176] [ka]

[0177] Compounds of formula (I) are provided, having the formula:

[0178] In some embodiments, ring D is C 3~8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5~8 It is selected from a bridged cycloalkyl or a 5- to 8-membered bridged heterocycloalkyl.

[0179] In some embodiments, R 6 is the following: H, halogen, OH, SH, CN, N(R 7a )2, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, SH, NH and CN; -OC 1~6 Alkyl, -O-halo-C 1~6 Alkyl, -C 1~6 Alkylene-OC 1~6 Alkyl, -C 1~6 Alkylene-O-Halo-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6Cycloalkyl and -C(O)-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, if present, may be substituted with deuterium, halogen, OH, SH, NH, 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 haloalkoxy), and 4-7 membered heterocycloalkyl and -C 1~6 alkylene-4 to 7-membered heterocycloalkyl (4 to 7-membered heterocycloalkyl, if present, is substituted with deuterium, halogen, OH, SH, NH, 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 and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from R 7a is H, C 1~6 Alkyl, -(CH2) q -C 3~6 Cycloalkyl, -(CH2) q - 4 to 7-membered heterocycloalkyl (q is an integer selected from 0 to 4), 1~6 Alkyl, the above -(CH2) q -C 3~6 C in cycloalkyl 3~6 Cycloalkyl and the aforementioned -(CH2) q - 4-7 membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C1~6 Haloalkyl and C 1~6 Optionally substituted with one, two or more substituents each independently selected from haloalkoxy.

[0180] In some preferred embodiments, N(R 7a )R in 2 7a One of them is H.

[0181] In some preferred embodiments, R 6 is the following: H, F, Cl, OH, SH, CN, NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NH(C 3~6 cyclic hydrocarbon group) and -NH(4- to 7-membered heterocycloalkyl) (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 cyclic hydrocarbon groups 3~6 The cyclic hydrocarbon group and the 4- to 7-membered heterocycloalkyl in the -NH(4- to 7-membered heterocycloalkyl) are each selected from deuterium, halogen, OH, oxo, SH, NH, CN, C 1~6 Alkyl and C 1~6 haloalkyl), -NH(C 1~4 alkylene)-(C 3~6 cyclic hydrocarbon group), -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, C2~4 Alkynyl, -OC 1~4 Alkyl, -O-halo-C 1~4 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkyl, -C 1~4 Alkyl-O-Halo-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(C 3~6 Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 haloalkoxy), and 4-7 membered heterocycloalkyl and -C 1~4 alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH, CN, oxo, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from.

[0182] In some more preferred embodiments, R 6 is the following: H, OH, SH, -NH(C 1~4 alkyl), -NH(C 3~6 partially unsaturated cyclic hydrocarbon group) and -NH(4- to 6-membered heterocycloalkyl) (the above -NH(C 1~4 C in alkyl1~4 alkyl, the -NH(C 3~6 C in partially unsaturated cyclic hydrocarbon groups 3~6 The 4- to 6-membered heterocycloalkyl in the partially unsaturated cyclic hydrocarbon group and the -NH(4- to 6-membered heterocycloalkyl) is selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH, CN, C 1~4 Alkyl and C 1~4 haloalkyl), -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-halo-C 1~4 Alkyl, -C 1~4 Alkylene-OC 1~4 Alkyl, -C 1~4 Alkyl-O-Halo-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 (C 3~6 Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 haloalkoxy), and 4-7 membered heterocycloalkyl and -C 1~4alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl and C 1~4 haloalkyl) is selected from.

[0183] Further, in some embodiments, R 6 is H, halogen, OH, SH, CN, N(R 7a )2, C 1~6 Alkyl, -OC 1~6 Alkyl, -OC 1~6 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (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 haloalkoxy), and 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, 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 haloalkoxy).

[0184] In some preferred embodiments, R 6 is 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 1~6Haloalkyl, -C 1~6 Alkylene -OH, -C 1~6 Alkylene-SH, -C 1~6 Alkylene -CN, -OC 1~6 Alkyl, -O-haloC 1~6 Alkyl, -OC 1~6 Alkyl-C 3~10 Cycloalkyl and C 3~10 Cyclic hydrocarbon groups (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 haloalkoxy), and 3-10 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, 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 haloalkoxy), and 1~6 alkyl) and -N(C 1~6 C in alkyl)2 1~6 Alkyl, as well as the aforementioned —NH(C 3~10 C in cycloalkyl 3~10 Cyclic hydrocarbon groups include deuterium, halogen, OH, SH, NH2, CN, oxo, and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 Optionally substituted with one, two or more substituents each independently selected from haloalkoxy.

[0185] In some preferred embodiments, R 6are H, F, Cl, OH, SH, CN, NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NH(C 3~6 cyclic hydrocarbon group), -NH(C 1~4 alkylene)-(C 3~6 cyclic hydrocarbon group), -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-haloC 1~4 Alkyl, -OC 1~4 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl) and 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, CN, oxo, C 1~4 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Alkoxy, C 1~4 Haloalkyl and C 1~4 haloalkoxy), and 1~4 alkyl) and -N(C 1~4 C in alkyl)2 1~4 Alkyl, as well as the aforementioned —NH(C 3~6 C in cyclic hydrocarbon groups 3~6 The cyclic hydrocarbon groups are deuterium, halogen, OH, oxo, SH, NH2, CN, and C. 1~6 Alkyl and C 1~6 Optionally substituted independently with one, two or more substituents independently selected from haloalkyl.

[0186] In some preferred embodiments, R 6 are 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-haloC 1~4 Alkyl, -OC 1~4 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl) and 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl and C 1~4 haloalkyl), and 1~4 C in alkyl 1~4 Alkyl and -NH(C 3~6 C in partially unsaturated cyclic hydrocarbon groups 3~6 Partially unsaturated cyclocyclic hydrocarbon groups include deuterium, halogen, OH, oxo, SH, NH2, CN, and C. 1~4 Alkyl and C 1~4 Optionally substituted with one, two or more substituents each independently selected from haloalkyl.

[0187] In some more preferred embodiments, R 6 Group C: (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,

[0188] [ka]

[0189] -NH-cyclobutane,

[0190] [ka]

[0191] and -O-CH2-cyclopropyl The compound is selected from the group listed in

[0192] In some embodiments, Group C is the following group: cyclopropyl,

[0193] [ka]

[0194] In some other embodiments, R 6 are H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2,

[0195] [ka]

[0196] [ka]

[0197] Amino, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl,

[0198] [ka]

[0199] In some other embodiments, R 6 are 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-haloC 1~4 Alkyl, -OC 1~4 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl).

[0200] In some preferred embodiments, R 6 are H, OH, SH, and C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -O-haloC 1~4 Alkyl, -OC 1~4 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl).

[0201] In some preferred embodiments, R 6 is selected from H, OH, SH, methyl, ethyl, isopropyl, —CF3, —CH2CF3, —OCH3, —OCH2CH3, —OCF3, —OCH2CF3, difluorocyclopropyl, and —O—CH2-cyclopropyl.

[0202] In some preferred embodiments, n is 1.

[0203] In some preferred embodiments, ring D is C 4~6 Cycloalkyl, 4-7 membered heterocycloalkyl, C 5~8 It is a bridged cycloalkyl or a 5- to 8-membered bridged heterocycloalkyl.

[0204] In some preferred embodiments, ring D is C 4~6 It is a cycloalkyl or a 5- to 8-membered bridged heterocycloalkyl.

[0205] In some preferred embodiments, ring D is cyclohexane or

[0206] [ka]

[0207] In some more preferred embodiments, the moiety

[0208] [ka]

[0209] In some embodiments, R 6 is the following: H, F, Cl, OH, SH, CN, NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NH(C 3~6cyclic hydrocarbon group), -NH(4- to 7-membered heterocycloalkyl) (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 cyclic hydrocarbon groups 3~6 The cyclic hydrocarbon group and the 4- to 7-membered heterocycloalkyl in the -NH(4- to 7-membered heterocycloalkyl) are deuterium, halogen, OH, oxo, SH, NH, CN, C 1~6 Alkyl and C 1~6 haloalkyl), -NH(C 1~4 alkylene)-(C 3~6 cyclic hydrocarbon group), -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-haloC 1~4 Alkyl, C 3~6 Cycloalkyl, -C 1~4 Alkylene-C 3~6 Cycloalkyl and -OC 1~4 Alkyl-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 haloalkoxy), and 4-7 membered heterocycloalkyl and -C 1~4alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH, 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 and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from.

[0210] In some preferred embodiments, R 6 is the following: 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 (C 3~6 Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 optionally substituted independently with one, two or more substituents independently selected from haloalkoxy; 4-7 membered heterocycloalkyl and -C 1~4 alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH, 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 haloalkoxy), and -NH(4- to 7-membered heterocycloalkyl) (The 4- to 7-membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH, CN, C 1~6 Alkyl and C 1~6 and optionally substituted with one, two or more substituents independently selected from haloalkyl. is selected from.

[0211] In some more preferred embodiments, R 6 is the following: 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 (C 3~6 Cycloalkyl, when present, is substituted with halogen, C 1~4 Haloalkyl and C 1~4 haloalkoxy), and 4-7 membered heterocycloalkyl and -C 1~4 alkylene-4 to 7-membered heterocycloalkyl, wherein the 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, NH, CN, and C 1~4 and optionally substituted independently with one, two or more substituents independently selected from alkyl. is selected from.

[0212] In some other embodiments, R 6 are H, F, Cl, OH, SH, CN, NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NH(C 3~6 cyclic hydrocarbon group), -NH(C 1~4alkylene)-(C 3~6 cyclic hydrocarbon group), -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-haloC 1~4 Alkyl, -OC 1~4 Alkyl-C 3~6 Cycloalkyl and C 3~6 Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl), 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, 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 haloalkoxy), and 1~4 alkyl) and -N(C 1~4 C in alkyl)2 1~4 Alkyl, as well as the aforementioned —NH(C 3~6 C in cyclic hydrocarbon groups 3~6 Cyclic hydrocarbon groups include deuterium, halogen, OH, oxo, SH, NH2, CN, and C 1~6 Alkyl and C 1~6 Optionally substituted with one, two or more substituents each independently selected from haloalkyl.

[0213] In some preferred embodiments, R 6 is C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl), 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, 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 haloalkoxy).

[0214] In some preferred embodiments, ring D is C 4~6 is cycloalkyl, and R 6 is C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl), 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, 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 haloalkoxy).

[0215] In some preferred embodiments, ring D is C 4~6 is cycloalkyl, and R 6 is a 4- to 7-membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl and C 1~4substituted by one, two or more substituents independently selected from haloalkyl), more preferably Ring D is cyclohexane.

[0216] In some preferred embodiments, Ring D is a 5-8 membered bridged heterocycloalkyl, and R 6 is C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 Cycloalkyl (deuterium, halogen, OH, SH, NH2, CN, C 1~4 Alkyl and C 1~4 haloalkyl), 4-7 membered heterocycloalkyl (deuterium, halogen, OH, SH, NH, CN, C 1~4 Alkyl and C 1~4 haloalkyl), more preferably the moiety

[0217] [ka]

[0218] In some embodiments, R 1 -L 2 -R L and L 2 is a direct bond, linear or branched C 1~6 Alkylene or linear or branched C 2~6 is alkenylene, Optionally, said C 1~6 Alkylene or C 2~6 One available C atom in an alkenylene is substituted by two substituents, so that 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, 1~6 Alkylene or C 2~6The two adjacent carbon atoms in an alkenylene are linear C 1~4 C linked by alkylene and optionally substituted 3~6 form a cycloalkylene, or are joined by -S-, -O-, -NH- or a linear 2-4 membered heteroalkylene to form an optionally substituted 3-6 membered heterocycloalkylene; Said C 1~6 Alkylene or C 2~6 Alkenylene is a group containing halogen, OH, SH, CN, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -NR 1a R 1b , C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C 6~10 optionally substituted with one, two, three or more substituents independently selected from aryl and 5- to 10-membered heteroaryl; Said L 2 -R L The CH2 attached to the carbon atom designated by the symbol "#" in the moiety (if present) may be O, S, or NR 1e and optionally replaced by R L is R 9 , R 10 , -OR 10 , -SR 10 and -NR 1e -R 10 is selected from R 10 H, R 11 , halogens, 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, guanidyl and -C 1~6 alkylene-guanidyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OC 1~6 Alkyl, -OC2~6 Alkenyl and -OC 2~6 alkynyl is optionally substituted by one, two or more substituents independently selected from halogen, OH, SH and NH; R 9 and R 11 is -(CH2) 0~3 -C 3~10 Cyclic hydrocarbon group, -(CH2) 0~3 -3 to 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 monospiroheterocyclic group, -(CH2) 0~3 -C 6~10 Aryl and -(CH2) 0~3 - 5 to 10 membered heteroaryl, each of which is independently selected from the following: 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 Cyclic hydrocarbon group, -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 and optionally substituted with one, two or more substituents independently selected from

[0219] Cy is an 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; 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 and R 1a , R 1b , R 1c , R 1d , R 1e , R 2a and R 2b are each independently, if present, H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene -OH, -C 1~6Alkylene-SH, -C 1~6 Alkylene -NH2 and -C 1~6 alkylene-CN; R 1c , R 1d together with the carbon atom to which they are both attached, form an optionally substituted C 3~6 Optionally forms a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl.

[0220] In some preferred embodiments, R 1 -L 2 -R L and L 2 is a direct bond, and R L is R 9 wherein R is selected from 9 is C 3~10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic hydrocarbon groups, C 5~10 Bridged cyclic hydrocarbon groups, 5- to 10-membered bridged heterocyclic hydrocarbon groups, C 5~11 Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C 6~10 aryl and 5-10 membered heteroaryl, each of which is selected from the following: 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 Cyclic hydrocarbon group, -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 and optionally substituted with one, two or more substituents independently selected from Cy is an optionally substituted C 3~10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C 6~10 It is selected from aryl and optionally substituted 5-10 membered heteroaryl.

[0221] In some preferred embodiments, R 1 -L 2 -R L and L 2 is a linear or branched C 1~6 alkylene, and R L is R 9 More preferably, R 2 is H.

[0222] In some preferred embodiments, R 1 -L 2 -R L and L 2 is a direct bond, and R L -OR 10 , -SR 10 and -NR 1e -R 10 Selected from R 10 is R 11 More preferably, R2 is H.

[0223] In some embodiments, ring A is C 6~10 Aryl or 5- or 6-membered heteroaryl, preferably phenyl (more preferably

[0224] [ka]

[0225] [ka]

[0226] ), pyridyl or thiazolyl.

[0227] In some embodiments, ring A is C 6~10 Aryl or 5- or 6-membered heteroaryl, preferably phenyl, naphthyl, pyridyl or thiazolyl.

[0228] In some embodiments, R 3 are halogens, OH, SH, CN, -NR 3a R 3b , -C 1~4 Alkylene -OH, -C 1~4 Alkylene-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 3band 5-membered heteroaryl having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms.

[0229] In some preferred embodiments, R 3 is 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 having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms.

[0230] In some preferred embodiments, R 3a and R 3b If present, H and C 1~4 alkyl.

[0231] In some preferred embodiments, R 3 is selected from F, Cl, OH, CN, -NH, -CH-OH, -CH-SH, -CH-C(O)OH, -CH-C(O)OCH, -CH-C(O)-NH, -C(O)OH, -C(O)OCH, -C(O)-NH, -C(O)-NH-S(O)-CH, -S(O)-CH, -S(O)-NH, -S(O)-NH-C(O)CH, and 5-membered heteroaryl having 1 to 4 nitrogen heteroatoms and 0 to 1 oxygen or sulfur heteroatoms.

[0232] In some preferred embodiments, R 3is selected from F, Cl, —CH—C(O)OH, —C(O)OH, —C(O)—NH, —S(O)—CH, —S(O)—NH, —S(O)—NH—C(O)CH, tetrazolyl and pyrazolyl.

[0233] In some preferred embodiments, p is 1 or 2.

[0234] In some more preferred embodiments,

[0235] [ka]

[0236] teeth,

[0237] [ka]

[0238] Each of these is selected from a separate and independent R 3 and optionally substituted by R 3 is, when present, independently as defined above.

[0239] In some embodiments,

[0240] [ka]

[0241] teeth,

[0242] [ka]

[0243] Each of these is selected from a separate and independent R 3 and optionally substituted by R 3 is, when present, independently as defined above.

[0244] In some preferred embodiments,

[0245] [ka]

[0246] teeth,

[0247] [ka]

[0248] In some more preferred embodiments,

[0249] [ka]

[0250] teeth,

[0251] [ka]

[0252] is.

[0253] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is CR 7 In other embodiments, X is C(R 7 )2. In other embodiments, X is N.

[0254] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein Y is CR 8 In other embodiments, Y is C(R 8 )2. In other embodiments, Y is N.

[0255] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein Z is O. In other embodiments, Z is S. In other embodiments, Z is NH.

[0256] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is CR 7 and Y is CR 8 and Z is NH.

[0257] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is CR 7 and Y is CR 8 and Z is O.

[0258] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is CR 7 and Y is CR 8 and Z is S.

[0259] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is CR 7 and Y is N and Z is NH.

[0260] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is N and Y is CR 8 and Z is NH.

[0261] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), wherein X is C(R 7 )2 and Y is C(R 8 )2 and Z is NH.

[0262] In some preferred embodiments, the present application provides compounds of formula (I), including compounds of formulas (I-1) to (I-8), wherein R is:

[0263] [ka]

[0264] is.

[0265] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-8), which have the structure of Formula (I-9):

[0266] [ka]

[0267] (In the formula, R 1 , R 2 , R 4 , R 5 , R 7 , R 8 and L 1 are each as defined in the above embodiment).

[0268] In some preferred embodiments, the compound of formula (I) has the structure of formula (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17), or (I-18):

[0269] [ka]

[0270] (In the formula, 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 above embodiment).

[0271] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-18), wherein: R 4 If present, 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 Haloalkyl, -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 AlkyleneC(O)OR 6a , -OC 1~4 AlkyleneC(O)NR 6a R 6b , C 3~6 Cycloalkyl and -OC 1~4 Alkylene-C 3~6 cycloalkyl, wherein C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, -SC1~4 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 AlkyleneC(O)OR 6a , -OC 1~4 AlkyleneC(O)NR 6a R 6b , C 3~6 Cycloalkyl and -OC 1~4 Alkylene-C 3~6 each cycloalkyl is optionally substituted with one or more D; R 5 If present, 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 Haloalkyl, -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 AlkyleneC(O)OR6a , -OC 1~4 AlkyleneC(O)NR 6a R 6b , C 3~6 Cycloalkyl and -OC 1~4 Alkylene-C 3~6 cycloalkyl.

[0272] In some preferred embodiments, R 4 If present, 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 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 is optionally substituted with one or more D; R 5 If present, 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.

[0273] In other embodiments, R 4 and R 5 If present, H, halogen, OH, SH, CN, -NR 6a R 6b , C 1~4 Alkyl, C1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, -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 AlkyleneC(O)OR 6a , -OC 1~4 AlkyleneC(O)NR 6a R 6b , C 3~6 Cycloalkyl and -OC 1~4 Alkylene-C 3~6 cycloalkyl.

[0274] In some preferred embodiments, R 4 and R 5 If present, 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.

[0275] In other embodiments, R 4 and R 5 If present, halogen, OH, SH, CN, -NR 6a R 6b , C1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, -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 AlkyleneC(O)OR 6a , -OC 1~4 AlkyleneC(O)NR 6a R 6b , C 3~6 Cycloalkyl and -OC 1~4 Alkylene-C 3~6 cycloalkyl.

[0276] In some preferred embodiments, R 4 and R 5 If present, 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.

[0277] In some preferred embodiments, R 6a and R 6b If present, H and C 1~4alkyl.

[0278] In some preferred embodiments, R 4 when present, is independently selected from H, F, Cl, OH, SH, CN, -NH, -NHCH, -NH(CH), methyl, ethyl, CF, vinyl, ethynyl, -O-CH, -O-CD, -S-CH, -S-CD and cyclopropyl; R 5 When present, R is independently selected from H, F, Cl, OH, SH, CN, —NH, —NHCH, —NH(CH), methyl, ethyl, CF, vinyl, ethynyl, —O—CH, —S—CH, and cyclopropyl. 4 -OC 1~4 Alkyl, -O-deuterated C 1~4 alkyl or cyclopropyl, and R 5 is H or C 1~4 In some more preferred embodiments, R 4 is -O-CH3, -O-CD3 or cyclopropyl, and / or R 5 is methyl.

[0279] In some preferred embodiments, R 4 and R 5 When present, R is independently selected from H, F, Cl, OH, SH, CN, -NH, -NHCH, -NH(CH), methyl, ethyl, CF, vinyl, ethynyl, -O-CH, -S-CH, and cyclopropane. 4 and R 5 When present, is independently selected from F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropane.

[0280] In other embodiments, R 4 is —O—CH3. In some preferred embodiments, R 5 is H or methyl. In some preferred embodiments, R5 is methyl.

[0281] In yet other embodiments, R 4 -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 is methyl.

[0282] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-18), wherein R 7 and R 8 If present, H, halogen, OH, SH, CN, NH, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, C 1~4 Alkyl and C 3~6 cycloalkyl.

[0283] In some preferred embodiments, R 7 and R 8 are each independently selected from H, F, Cl, OH, SH, CN, NH, —NH(CH), —N(CH), methyl, ethyl and cyclopropyl, preferably H, F, Cl, methyl, ethyl and cyclopropyl.

[0284] In some embodiments, the present application provides compounds of Formula (I), including compounds of Formulas (I-1) to (I-18), wherein: L 1 teeth, * -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)-, * The bond marked by connects to the phenyl ring B, R 4a and R 4b H, deuterium, halogen, OH, SH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, 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 attached, form C 3~4 It forms a cycloalkyl or a 4- to 5-membered heterocycloalkyl.

[0285] In some preferred embodiments, L 1 teeth, * -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)-, * The bond marked by connects to the phenyl ring B,

[0286] R4a and R 4b are H, deuterium, F, Cl, OH, SH, CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, 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 attached, form C 3~4 It forms a cycloalkyl or a 4- to 5-membered heterocycloalkyl.

[0287] In other embodiments, L 1 teeth, * -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)-, * The bond marked by connects to the phenyl ring B, R 4a and R 4b H, deuterium, halogen, OH, SH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, 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 attached, form C 3~4 It forms a cycloalkyl or a 4- to 5-membered heterocycloalkyl.

[0288] In some preferred embodiments, L 1 teeth, * -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)-, * The bond marked by connects to the phenyl ring B, R 4a and R 4b are H, deuterium, F, Cl, OH, SH, CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, 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 attached, form C 3~4 It forms a cycloalkyl or a 4- to 5-membered heterocycloalkyl.

[0289] In other embodiments, L1 teeth, * -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)-, * The bond marked by connects to the phenyl ring B and R 4a and R 4b are H, F, Cl, OH, SH, CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, 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 are each independently selected from

[0290] In some preferred embodiments, R 5a and R 5b If present, H and C 1~4 alkyl.

[0291] In some preferred embodiments, R 4a and R 4b are H, deuterium, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b , -C(O)OR5a 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, —NH, —C(O)OH, —C(O)OCH, —C(O)—NH, and —C(O)—NCH. In some preferred embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropanyl group.

[0292] In other embodiments, R 4a and R 4b are each independently selected from H, F, Cl, OH, SH, CN, —NH2, —C(O)OH, —C(O)OCH3, —C(O)—NH2, and —C(O)—NCH3.

[0293] In some preferred embodiments, R 4c is H, C 1~4 Alkyl and C 1~4 haloalkyl.

[0294] In some preferred embodiments, R 4c is selected from H, methyl, ethyl, —CH2F, —CHF2, and —CF3.

[0295] In some preferred embodiments, L 1 teeth, * -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-

[0296] [ka]

[0297] is selected from * The bond marked by connects to the phenyl ring B.

[0298] In other embodiments, L 1 teeth, * -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-,

[0299] [ka]

[0300] More preferably, * -CH2-NH- and * -C(O)-NH-; * The bond marked by connects to the phenyl ring B.

[0301] In some more preferred embodiments, L 1 teeth,* -CH2-NH-, * -CD2-NH-, * -C(CH3)2-NH-, * -C(O)-NH- and

[0302] [ka]

[0303] is selected from * The bond marked by connects to the phenyl ring B.

[0304] In some preferred embodiments, the present application provides a compound of the structure of formula (I-19):

[0305] [ka]

[0306] Compounds of formula (I) are provided, having the formula:

[0307] In some embodiments of the compound according to formula (I-19), L 1 teeth, * -CR 4a R 4b -NR 4c -and * -C(O)-NR 4c - selected from * The bond marked by connects to the phenyl ring B, R 4a and R 4b are each independently selected from H and deuterium; R 4c is H, R 4 -OC 1~6 Alkyl and C 3~6 cycloalkyl, -OC 1~6 Alkyl and C 3~6 cycloalkyl is optionally substituted with one, two, three or more D; R 5 is C 1~6 alkyl, Ring D is C 4~6 cycloalkyl or 5- to 8-membered bridged heterocycloalkyl; R 6 is the following: C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH and CN; -C 1~6 Alkylene-O-HaloC 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkylene-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, when present, is selected from halogen, OH, NH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 optionally substituted independently with one, two or more substituents independently selected from haloalkoxy; 4-7 membered heterocycloalkyl and -C 1~6 alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, NH, CN, C 1~6 Alkyl and C 1~6 haloalkyl), and -NH(4-7 membered heterocycloalkyl) is selected from n is 1.

[0308] In some such embodiments, ring D is preferably cyclohexane or

[0309] [ka]

[0310] More preferably, the moiety

[0311] [ka]

[0312] teeth,

[0313] [ka]

[0314] In some preferred embodiments, L 1 teeth, * -CH2-NH-, * -CD2-NH- and * -C(O)-NH-; * The bond marked by connects to the phenyl ring B.

[0315] In some preferred embodiments, R 4 -OC 1~4 Alkyl and C 3~6 cycloalkyl, wherein -OC 1~4 Alkyl and C 3~6 Cycloalkyl is optionally substituted with one, two, three or more D. More preferably, R 4 -OC 1~2 Alkyl and C 3~6 cycloalkyl, wherein -OC 1~2 Alkyl and C 3~6 The cycloalkyl is optionally substituted with one, two, three or more Ds, respectively.

[0316] In some preferred embodiments, R 5 is C 1~4 Alkyl, more preferably C 1~2 alkyl.

[0317] In some more preferred embodiments, R 4 is -O-CH3, -O-CD3 or cyclopropyl, and R 5 is methyl.

[0318] In some preferred embodiments, R 6 is the following: C 1~6 Alkyl, C 2~4 Alkenyl and C 2~4 alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH and CN; -C 1~4 Alkylene-O-HaloC 1~4 alkyl, -NH(4-6 membered heterocycloalkyl), C 3~6 Cycloalkyl and -C 1~4 Alkylene-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, when present, is selected from halogen, OH, NH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 optionally substituted independently with one, two or more substituents independently selected from haloalkoxy; 4-7 membered heterocycloalkyl and -C 1~4 alkylene-4 to 7-membered heterocycloalkyl, wherein said 4 to 7-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, NH, CN, C 1~4 Alkyl and C 1~4 haloalkyl) is selected from.

[0319] In some more preferred embodiments, R 6 is the following: C 1~6 Alkyl, C2~4 Alkenyl and C 2~4 alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH and CN; -C 1~4 Alkylene-O-HaloC 1~4 alkyl, -NH(4-6 membered heterocycloalkyl), C 3~6 Cycloalkyl and -C 1~4 Alkylene-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, if present, is substituted with halogen and C 1~4 haloalkyl), 4-6 membered heterocyclic alkyl and -C 1~4 alkyl-4 to 6 membered heterocyclic alkyl, wherein the 4 to 6 membered heterocyclic alkyl, if present, is selected from the group consisting of deuterium, halogen, CN and C 1~4 and optionally substituted with one, two or more substituents independently selected from alkyl. is selected from Halo elements or halogens, when present, are independently selected from F and Cl.

[0320] In some preferred embodiments, R 6 is the following: 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-HaloC 1~4 alkyl, -NH(4-6 membered heterocycloalkyl), C 3~6 Cycloalkyl and -C 1~4 Alkylene-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, when present, is substituted with halogen, C1~4 Haloalkyl and C 1~4 optionally substituted independently with one, two or more substituents independently selected from haloalkoxy; 4-6 membered heterocycloalkyl and -C 1~4 alkylene-4 to 6-membered heterocycloalkyl, wherein the 4 to 6-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, CN and C 1~4 and optionally substituted independently with one, two or more substituents independently selected from alkyl. is selected from Halo elements or halogens, when present, are independently selected from F and Cl.

[0321] In some more preferred embodiments, R 6 is the following: 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 one O or S heteroatom), C 3~6 Cycloalkyl and -C 1~4 Alkylene-C 3~6 Cycloalkyl (C 3~6 Cycloalkyl, when present, is selected from the group consisting of F, C 1~4 Fluoroalkyl and C 1~4 fluoroalkoxy), 4-6 membered heterocycloalkyl and -C 1~4 alkylene-4 to 6-membered heterocycloalkyl, wherein the 4 to 6-membered heterocycloalkyl independently contains one N heteroatom and is selected from the group consisting of deuterium, F, CN, and C 1~4 and 4-6 membered heterocycloalkyl optionally substituted with one, two or more substituents independently selected from alkyl. is selected from.

[0322] In some more preferred embodiments, R 6 is methyl, ethyl

[0323] [ka]

[0324] In some preferred embodiments, the compound of formula (I-19) has the structure of one of formulas (I-20) to (I-27):

[0325] [ka]

[0326] [ka]

[0327] [ka]

[0328] In some preferred embodiments, the moiety

[0329] [ka]

[0330] [ka]

[0331] In some such embodiments, R 4 is -O-CH3 or cyclopropyl, and R 5 is preferably methyl. In some embodiments, R 6 is C substituted by 1, 2, 3, 4 or more substituents independently selected from halogen and OH;1~4 In some preferred embodiments, R 6 is 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 is C substituted by 1, 2, 3, 4 or more substituents independently selected from F and OH 1~6 In some preferred embodiments, R 6 is substituted by 1, 2, 3 or more F and 0 or 1 OH, 1~6 In some preferred embodiments, R 6 is substituted by 1, 2, 3 or more F and 0 or 1 OH, 3~6 In some more preferred embodiments, R 6 teeth,

[0332] [ka]

[0333] In some embodiments, the compound of formula (I-19) has a structure selected from formulas (I-28) to (I-31):

[0334] [ka]

[0335] In some such embodiments, R 4 is -O-CH3 or cyclopropyl, and R 5 is preferably methyl. In some embodiments, R 6 is the N(R 7a ) 2- or 4- to 7-membered heterocycloalkyl. In some embodiments, R 6is selected from -NH(4-6 membered heterocycloalkyl) and 4-6 membered heterocycloalkyl having one N heteroatom, said 4-6 membered heterocycloalkyl having one N heteroatom is linked to the remainder of the molecule through said N heteroatom and is selected from the group consisting of deuterium, halogen, OH, NH, CN, C 1~4 Alkyl and C 1~4 In some preferred embodiments, R is optionally substituted with one, two, three or more substituents independently selected from haloalkyl. 6 is selected from -NH(4-6 membered heterocycloalkyl) and 4-6 membered heterocycloalkyl having one N heteroatom, said 4-6 membered heterocycloalkyl having one N heteroatom being linked to the remainder of the molecule through said N heteroatom and is selected from the group consisting of deuterium, F, Cl, CN and C 1~4 In some preferred embodiments, R is optionally substituted with one, two, three or more substituents independently selected from alkyl. 6 is selected from -NH (4-6 membered heterocycloalkyl having one O or S heteroatom) and 4-6 membered heterocycloalkyl having one N heteroatom, where the 4-6 membered heterocycloalkyl having one N heteroatom is linked to the remainder of the molecule through the N heteroatom and is optionally substituted with one, two, three or more substituents independently selected from deuterium, F, CN and C1-4 alkyl. In some more preferred embodiments, R 6 teeth,

[0336] [ka]

[0337] The present invention encompasses compounds obtained by any configuration of the various embodiments.

[0338] 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, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is

[0339] [ka]

[0340] [ka]

[0341] [ka]

[0342] [ka]

[0343] [ka]

[0344] [ka]

[0345] [ka]

[0346] [ka]

[0347] [ka]

[0348]

change

[0349]

change

[0350]

change

[0351]

change

[0352]

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[0353]

change

[0354]

change

[0355]

change

[0356]

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[0357]

change

[0358]

change

[0359]

change

[0360]

change

[0361]

change

[0362]

change

[0363]

change

[0364]

change

[0365]

change

[0366]

change

[0367]

change

[0368]

change

[0369]

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[0370]

change

[0371]

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[0372]

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[0373]

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[0374]

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[0375]

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[0376]

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[0377]

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[0378]

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[0379]

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[0380] Pharmaceutical Compositions and Uses In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), including compounds of formulae (I-1) to (I-18), or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof, according to the present invention, and a pharmaceutically acceptable carrier. The pharmaceutical composition is preferably a solid, liquid, or semi-solid formulation.

[0381] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), including compounds of formulae (I-1) to (I-18), or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof according to the present invention, and another therapeutically active agent.

[0382] In another aspect, the present invention provides a compound of formula (I), including compounds of formulae (I-1) to (I-18), according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present application, or a pharmaceutical composition according to the present invention, for use as a medicament.

[0383] In another aspect, the present invention provides a method of modulating the activity of the alternative complement pathway in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I), including compounds of formulae (I-1) to (I-18), or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof, according to the present application; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the present application.

[0384] In some embodiments, the compounds, pharmaceutical compositions or pharmaceutical compositions according to the invention are used to prevent or treat a disease, disorder or condition mediated by complement activation, particularly a disease, disorder or condition mediated by activation of the alternative complement pathway.

[0385] In another aspect, the present invention provides 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 alternative complement pathway, in an individual, comprising the step of administering to said individual a therapeutically effective amount of a compound of formula (I), including compounds of formulae (I-1) to (I-18), or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof, according to the present invention; or administering to said individual a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0386] In another aspect, the present invention provides a compound of formula (I), including compounds of formulae (I-1) to (I-18), according to the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis / trans isomer, isotopically labeled compound (preferably, deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, or use of a pharmaceutical composition according to the present invention, in the production 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 alternative complement pathway.

[0387] In some embodiments, the disease, disorder, or condition is age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot chorioretinopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic anterior ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion; neuropathy: multiple sclerosis, stroke, Guillain-Barré syndrome. , traumatic brain injury, Parkinson's disease; conditions caused by inappropriate or unwanted complement activation: hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 (IL-2)-induced toxicity during IL-2 treatment; inflammatory diseases: inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, post-pump syndrome during balloon angioplasty, cardiopulmonary or renal bypass, atherosclerosis, Renal ischemia, mesenteric artery reperfusion after aortic reconstruction; infection 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), other renal diseases with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and Escherichia coli-induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), Selected from immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), hepatic fibrosis, hemolytic anemia, myasthenia gravis; tissue regeneration, nerve regeneration; respiratory disorders: dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and pulmonary infarction, pneumonia, fibrosing pneumoconiosis, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

[0388] In some embodiments, the disease, disorder, or condition is age-related macular degeneration (AMD), geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot chorioretinopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barre syndrome. syndrome, traumatic brain injury, Parkinson's disease, disorders caused by inappropriate or unwanted complement activation, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 (IL-2) treatment, inflammatory diseases, inflammation associated with autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, balloon angioplasty pump syndrome, cardiopulmonary or renal bypass, atherosclerosis, Hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection 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 (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (HUS) aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing pneumoconiosis, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

[0389] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle that is co-administered with a therapeutic agent and that, within the scope of sound medical judgment, is suitable for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0390] Unless otherwise specified, the term "treating," as used herein, refers to reversing, ameliorating, inhibiting the progression of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition, or preventing the disorder or condition, or one or more symptoms of such disorder or condition.

[0391] As used herein, the term "individual" includes humans or non-human animals. Exemplary human individuals (referred to as patients) include those suffering from a disease (e.g., a disease described herein) or normal individuals. In this application, "non-human animals" includes all mammals, such as vertebrates (e.g., birds, amphibians, reptiles), including non-mammals, as well as non-human primates, poultry, and / or livestock animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0392] In other embodiments, pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. [Example]

[0393] The embodiments of the present application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are merely intended to illustrate the present application and should not be construed as limiting the scope of the present application. Unless otherwise specified, the experimental conditions in the examples are conventional conditions or conditions recommended by the manufacturer. Reagents or equipment for which no manufacturer is specified are conventional commercially available products.

[0394] NMR was measured using a Bruker Avance III400 NMR spectrometer, and the chemical shifts (δ) were measured at 10 -6 The concentrations are given in ppm. The solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6) with tetramethylsilane (TMS) as the internal standard.

[0395] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B). The liquid chromatography-mass spectrometry (LCMS) conditions were as follows: Agilent (Agilent 1260 Infinity II-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 to 95% over 2 min, flow rate: 2 mL / min, UV detection wavelength: 220 nm and 254 nm.

[0396] High-performance liquid chromatography (HPLC) condition 1: Agilent HPLC system (Agilent 1260 Infinity II); 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 to 95% gradient flow in 10 min; flow rate: 1.2 mL / min; UV detection wavelength: 220 nm and 254 nm.

[0397] High-performance liquid chromatography (HPLC) condition 2: Agilent HPLC system (Agilent 1260 Infinity II); 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 to 95% gradient flow in 5 min; flow rate: 1.2 mL / min; UV detection wavelength: 220 nm and 254 nm.

[0398] High-performance liquid chromatography (HPLC) condition 3: Shimadzu HPLC system (Shimadzu 2020 series, equipped with an LC-30AD xs pump and an SPD-M20A detector); column: Kinetex C18, 2.1 x 50 mm, 1.7 µm; mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile; gradient: B%: 0 to 30% gradient flow in 7 min; flow rate: 1.2 mL / min; UV detection wavelength: 220 nm and 254 nm.

[0399] High-performance liquid chromatography (HPLC) condition 4: Shimadzu HPLC system (Shimadzu 2020 series, equipped with an LC-30AD xs pump and an SPD-M20A detector); column: Kinetex C18, 2.1 x 50 mm, 1.7 µm; mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile; gradient: B%: 0 to 60% gradient flow in 7 min; flow rate: 1.2 mL / min; UV detection wavelength: 220 nm and 254 nm.

[0400] Reverse phase purification was performed using a Biotage Isolera flash purification system.

[0401] Thin-layer chromatography (TLC) separation and purification were performed using TLC silica gel plates (Merck aluminum plates (20 cm x 20 cm x 1 mm) or Yantai GF254 plates).

[0402] The microwave reaction was carried out using a Biotage Initiator+ (400 W, room temperature to 300° C.) microwave reactor.

[0403] Reaction monitoring was usually carried out by TLC or LCMS. Common eluent systems included dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate, and the solvent ratio was adjusted based on the polarity of the compounds or modified with triethylamine.

[0404] Column chromatography was performed using 100-200 mesh silica gel. Typical eluent systems included dichloromethane / methanol, petroleum ether / ethyl acetate, and the solvent ratio was adjusted based on the polarity of the compounds or modified with a small amount of triethylamine.

[0405] Reagents and solvents in this application were purchased from Aldrich Chemical Company, Energy Chemical, J&K Scientific, Shanghai Bide Pharmatech Ltd., Pharmablock and Shanghai Titan Technology Co.,Ltd.

[0406] Abbreviations in the conventional synthetic methods and synthetic examples of compounds and intermediates of this application have the following meanings:

[0407] [Table 1]

[0408] Example 1 Synthesis Examples Preparation of Compounds 1, 1-P1, and 1-P2

[0409] [ka]

[0410] 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 (DMF, 35 mL), followed by the addition of triethylamine (3.06 g, 30.30 mmol). The mixture was heated to 120 °C and stirred for 5 h. The reaction was monitored by LCMS and TLC. Water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 70 mL). The combined organic phase was washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 10% methanol / dichloromethane gradient) to give compound 1-2. MS m / z (ESI): = 279.0 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.05-7.95 (m, 2H), 7.87-7.79 (m,2H), 7.73 (t, J = 1.1 Hz, 1H), 7.28 (t, J = 1.3 Hz, 1H), 6.93 (d, J = 1.1 Hz,1H), 4.39 (t, J = 6.8 Hz, 2H), 3.67 (t, J = 6.8 Hz, 2H)

[0411] Step 2: Compound 1-2 (600 mg, 2.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride 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 under a carbon monoxide (CO) atmosphere and stirred for 24 h. The reaction was monitored by LCMS and TLC. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with saturated brine (50 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 10% methanol / dichloromethane gradient) to give compound 1-3. MS m / z (ESI):= 259.0 [M+H] + .1 H NMR (400 MHz,DMSO-d6) δ 8.14-8.05 (m, 4H), 7.67 (d, J =1.2 Hz, 1H), 7.22 (t, J = 1.3 Hz, 1H), 6.87 (d, J = 1.1 Hz, 1H), 4.34 (t, J =6.8 Hz, 2H), 3.89 (s, 3H), 3.66 (t, J = 6.8 Hz, 2H)

[0412] Step 3: Compound 1-3 (160 mg, 0.59 mmol), hydroxylamine hydrochloride (61 mg, 0.88 mmol), and sodium acetate (145 mg, 1.77 mmol) were dissolved in ethanol (6 mL). The mixture was heated to 90 °C and stirred for 2 h. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by normal-phase silica gel column chromatography (5% to 10% methanol / dichloromethane gradient) to give compound 1-4. MS m / z (ESI): = 274.1 [M+H] +

[0413] Step 4: Compound 1-4 (124 mg, 0.45 mmol) was dissolved in ethyl acetate (EA, 8 mL), followed by the addition of palladium on carbon (10%, 120 mg, 1.13 mmol). The mixture was stirred at room temperature under a hydrogen (H) atmosphere for 16 hours. The reaction was monitored by LCMS and TLC. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give compound 1-5. MS m / z (ESI): = 260.0 [M+H] +

[0414] Step 5: Compound 1-6 (117 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (218.42 mg, 0.57 mmol) and N,N-diisopropylethylamine (123.58 mg, 0.96 mmol). The mixture was stirred at room temperature for 5 minutes, and then compound 1-5 (99.37 mg, 0.38 mmol) was added to it. The reaction was stirred for an additional 2 hours and monitored by LCMS. The reaction mixture was gradient purified by reverse-phase column chromatography (12% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 1-7. MS m / z (ESI): = 547.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.84 (d, J = 8.4 Hz, 1H), 8.36(s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 3.8 Hz, 1H), 7.58-7.50 (m, 3H),7.35 (s, 1H), 6.99 (s, 1H), 6.53 (d, J = 3.7 Hz, 1H), 5.04 (s, 1H), 4.23 (t, J= 6.9 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.58 (s, 3H), 2.33-2.24 (m, 2H),1.59 (s, 9H)

[0415] Step 6: Compound 1-7 (15 mg, 0.03 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL), methanol (MeOH, 1 mL), and water (1 mL), followed by the addition of lithium hydroxide (LiOH, 12.6 mg, 0.30 mmol). The mixture was heated to 50 °C and stirred for 16 h. The reaction was monitored by LCMS. Upon completion, the pH of the reaction mixture was adjusted to neutral, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 1. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.67 (d, J = 8.4Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.47 (d, J = 8.0Hz, 2H), 7.33 (t, J = 2.8 Hz, 1H), 7.23 (s, 1H), 6.93 (s, 1H), 6.83 (s, 1H),6.46 (t, J = 2.5 Hz, 1H), 5.02 (q, J = 7.9 Hz, 1H), 4.10 (t, J = 6.9 Hz, 2H),3.87 (s, 3H), 2.50 (s, 3H), 2.23 (d, J = 7.2 Hz, 2H)

[0416] Step 7: Chiral separation of compound 1-7 (100 mg, 0.18 mmol) was carried out using an AD-H column (100 mm × 4.6 mm, 5 μm; mobile phase: A: carbon dioxide, B: [7.0 N ammonia-methanol]; gradient: B%: 30%) to give compounds 1-7-P1 and 1-7-P2.

[0417] SFC analysis method: Column: AD-H 4.6 × 100 mm, 5 μm; Mobile phase: A: carbon dioxide, B: methanol (0.2% ammonia); Gradient: B%: 30%, 6.0 min gradient elution; Flow rate: 3.0 mL / min; Detection wavelength: 220 nm.

[0418] Compound 1-7-P1: Retention time: 1.993 min, MS m / z(ESI):=547.2[M+H] + .

[0419] Compound 1-7-P2: Retention time: 3.060 min, MS m / z(ESI):=547.2[M+H] + .

[0420] Step 8: Compound 1-7-P1 (30 mg, 0.054 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), followed by the addition of lithium hydroxide (26 mg, 0.60 mmol). The mixture was heated to 50°C and stirred for 16 hours. The reaction was monitored by LCMS. Upon completion, the pH of the reaction mixture was adjusted to neutral, filtered, and concentrated. The crude product was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 1-P1. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 8.68 (d, J = 8.3Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.34(t, J = 2.8 Hz, 1H), 7.23 (s, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 6.46 (t, J = 2.5Hz, 1H), 5.02 (q, J = 7.8 Hz, 1H), 4.10 (t, J = 6.9 Hz, 2H), 3.88 (s, 3H), 2.23(q, J = 7.1 Hz, 2H)

[0421] Compound 1-P2 was obtained from compound 1-7-P2 according to a method similar to that used to prepare 1-P1 from 1-7-P1. MS m / z (ESI):= 433.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.69 (d, J = 8.4Hz, 1H), 7.97-7.90 (m, 2H), 7.72 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.34 (t, J= 2.8 Hz, 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 = 7.7 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 2.24(q, J = 7.2 Hz, 2H)

[0422] Example 2 Preparation of compounds 2-P1 and 2-P2

[0423] [ka]

[0424] Step 1: At room temperature, 2-1 (4.5 g, 37.45 mmol) and tert-butanesulfinamide (5 g, 36.44 mmol) were dissolved in dichloromethane (100 mL). Titanium(IV) isopropoxide (12.47 g, 54.66 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 70 mL). The combined organic phase was washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 10% ethyl acetate / petroleum ether gradient) to give compound 2-2.

[0425] Step 2: Under nitrogen protection, 2-2 (5.5 g, 23.17 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature. A solution of 4-methoxyphenylmagnesium bromide in THF (46.00 mL, 1 M) was slowly added dropwise at -78 °C, and the reaction was stirred at -78 °C for 2 h. After completion, water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (10% to 50% ethyl acetate / petroleum ether gradient) to give compound 2-3. MS m / z (ESI): = 346.2 [M+H] + .

[0426] Step 3: Under nitrogen protection, 2-3 (1.0 g, 2.89 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature. Sodium hydride (0.23 g, 2.30 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 0.5 h. Benzyl bromide (0.50 g, 2.89 mmol) was added, and the reaction was stirred at room temperature for 2 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 20% ethyl acetate / petroleum ether gradient) to give compound 2-4.

[0427] 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 the mixture was stirred at room temperature for 0.5 h. After completion, the organic solvent was removed under reduced pressure, and saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organic phase was washed with saturated brine (30 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (25% to 50% ethyl acetate / petroleum ether gradient) to give compound 2-5. MS m / z (ESI): = 332.2 [M+H] + .

[0428] Step 5: 2-5 (2.5 g, 7.54 mmol) was dissolved in dichloromethane (30 mL). Boron tribromide (1.45 mL, 15.08 mmol) was added at -30 °C, and the reaction was stirred at room temperature for 0.5 h. After completion, the reaction was quenched with water at -30 °C, and the pH was adjusted to 8-9 with aqueous ammonia. The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organic phase was washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (50% to 100% ethyl acetate / petroleum ether gradient) to give compound 2-6. MS m / z (ESI): = 318.2 [M+H] + .

[0429] Step 6: At room temperature, 2-6 (1.6 g, 5.04 mmol) and N,N-diisopropylethylamine (1.95 g, 15.12 mmol) were dissolved in dichloromethane (30 mL). N-phenylbis(trifluoromethanesulfonimide) (2.34 g, 6.55 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 3 h. After completion, water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 50% ethyl acetate / petroleum ether gradient) to give compound 2-7. MS m / z (ESI): = 450.2 [M+H] + .

[0430] Step 7: Compound 2-7 (2.1 g, 4.67 mmol) was dissolved in dimethyl sulfoxide (10 mL) and methanol (10 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride dichloromethane complex (0.38 g, 0.47 mmol) and triethylamine (0.94 g, 9.34 mmol). The mixture was purged with carbon monoxide three times and stirred at 80 °C for 16 h. After completion, water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 50% ethyl acetate / petroleum ether gradient) to give compound 2-8. MS m / z (ESI): = 360.2 [M+H] + .

[0431] Step 8: Compound 2-8 (500 mg, 1.39 mmol) was dissolved in methanol (10 mL), followed by the addition of palladium on carbon (50 mg). The mixture was purged with hydrogen three times and stirred at room temperature for 16 hours. After completion, the reaction mixture was filtered and concentrated to give compound 2-9. MS m / z (ESI): = 270.2 [M+H] + .

[0432] Step 9: 2-9 (220 mg, 0.82 mmol) and 1-6 (274.34 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (465.88 mg, 1.23 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.63 mmol). The reaction was stirred at room temperature for 2 hours. Upon completion, water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (20 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% to 5% methanol / dichloromethane gradient) to give compound 2-10. MS m / z (ESI): = 557.3 [M+H]+ .

[0433] Step 10: 2-10 (100 mg, 0.18 mmol) was dissolved in water (1 mL), methanol (2 mL), and tetrahydrofuran (2 mL), followed by the addition of lithium hydroxide (75.38 mg, 1.80 mmol). The reaction was stirred at 50 °C for 16 h. Upon completion, the pH was adjusted to 5-6. The reaction mixture was concentrated to give the crude product, which was purified by reverse-phase column chromatography (15%-100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 2. MS m / z (ESI): = 443.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 12.82 (s, 1H), 11.05 (s, 1H),8.62 (d, J = 8.2 Hz, 1H), 8.03-7.85 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H),7.36-7.21 (m, 5H), 7.24-7.15 (m, 1H), 6.83 (s, 1H), 6.53 (dd, J = 3.0, 1.9 Hz,1H), 5.10 (td, J = 8.9, 5.1 Hz, 1H), 3.88 (s, 3H), 2.78 (ddd, J = 14.3, 9.5,5.2 Hz, 1H), 2.66 (ddd, J = 13.9, 9.2, 7.0 Hz, 1H), 2.50 (s, 3H),2.19-1.97 (m,2H).

[0434] Step 11: Chiral separation of compound 2-10 (500 mg, 0.90 mmol) was carried out using an AD-H column (4.6 × 100 mm, 5 μm; mobile phase: A: carbon dioxide, B: [7.0 N ammonia-methanol]; gradient: B%: 35%) to give compounds 2-10-P1 and 2-10-P2.

[0435] SFC analysis method: Color: AD-H 4.6×100mm, 5μm; Mobile phase: A: carbon dioxide, B: metalol (0.2% ammonium); Concentration blending: B%: 35%, 5.0% concentration blending dissolution; Flow rate: 3.0mL / min; Emission wavelength: 220nm.

[0436] Compound 2-10-P1: Retention time: 1.512 min, MS m / z (ESI): = 557.3 [M+H] + , 1 H NMR (400 MHz, メタノール-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).

[0437] Compound 2-10-P2: Retention time: 2.668 min. MS m / z (ESI): = 557.2 [M+H] + , 1 H NMR (400 MHz, メタノール-d4) δ 8.02-7.94 (m, 2H), 7.57(d, J = 3.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.30-7.20 (m, 4H), 7.20-7.12 (m, 1H),6.91 (s, 1H), 6.68 (d, J = 3.8 Hz, 1H), 5.14 (dd, J = 9.4, 5.4 Hz, 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).

[0438] 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), followed by the addition of lithium hydroxide (30 mg). The reaction was heated to 50 °C and stirred for 16 h. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid (1 N), filtered, and concentrated to give the crude product, which was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L aqueous formic acid) gradient) to give 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).

[0439] Compound 2-P2 was obtained from compound 2-10-P2 according to a method similar to that used to prepare 2-P1 from 2-10-P1. MS m / z (ESI):= 443.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 12.87 (s, 1H), 11.07 (s, 1H),8.64 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H),7.33 (t, J = 2.8 Hz, 1H), 7.32-7.27 (m, 2H), 7.26-7.22 (m, 2H), 7.22-7.17 (m,1H), 6.83 (s, 1H), 6.52 (t, J = 2.4 Hz, 1H), 5.10 (td, J = 9.0, 5.3 Hz, 1H),3.88 (s, 3H), 2.78 (ddd, J = 14.3, 9.5, 5.2 Hz, 1H), 2.66 (ddd, J = 13.7, 9.0,6.9 Hz, 1H), 2.50 (s, 3H), 2.17-1.97 (m, 2H). Example 3 Preparation of compounds 3, 3-P1 and 3-P2

[0440] [ka]

[0441] Step 1: At 0 °C, a solution of phenylmagnesium bromide in THF (8.77 mL, 1 M, 8.77 mmol) was slowly added dropwise to a solution of compound 3-1 (1.6 g, 9.75 mmol) in THF (10 mL). The reaction was stirred at 30 °C for 2 h and monitored by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 15% ethyl acetate / petroleum ether gradient) to give compound 3-2.

[0442] Step 2: Compound 3-2 (1.4 g, 5.78 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of magnesium dioxide (5.02 g, 57.79 mmol). The reaction was stirred at 20° C. under a nitrogen atmosphere for 18 hours and monitored by LCMS. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give compound 3-3. MS m / z (ESI): = 241.1 [M+H] + .

[0443] Step 3: Compound 3-3 (950 mg, 3.95 mmol) was dissolved in methanol (10 mL), followed by the addition of hydroxylamine hydrochloride (548.97 mg, 7.90 mmol) and sodium acetate (648.04 mg, 7.90 mmol). The reaction was stirred at 70 °C under a nitrogen atmosphere for 18 h and monitored by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 15% ethyl acetate / petroleum ether gradient) to give compound 3-4. MS m / z (ESI): = 256.1 [M+H] + .

[0444] Step 4: Compound 3-4 (1.05 g, 4.11 mmol) was dissolved in ethanol (10 mL), followed by the addition of ammonium acetate (0.32 g, 4.11 mmol) and zinc powder (1.34 g, 20.57 mmol). The reaction was stirred at 80 °C under a nitrogen atmosphere for 18 h and monitored by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 20% methanol / dichloromethane gradient) to give compound 3-5.

[0445] Step 5: Compound 3-6 (1.15 g, 3.97 mmol) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of compound 3-5 (800 mg, 3.32 mmol). The mixture was stirred at 25 °C for 30 minutes, and then sodium triacetoxyborohydride (1.40 g, 6.62 mmol) was added. The reaction was stirred at 25 °C under a nitrogen atmosphere for 18 hours and monitored by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% to 10% ethyl acetate / petroleum ether gradient) to give compound 3-7. MS m / z (ESI): = 515.3 [M+H] + .

[0446] Step 6: Compound 3-7 (500 mg, 0.97 mmol) was dissolved in methanol (5 mL) and water (1 mL), followed by the addition of lithium hydroxide (122.3 mg, 2.91 mmol). The reaction was stirred at 50 °C under a nitrogen atmosphere for 18 h and monitored by LCMS. Dilute hydrochloric acid (1 M) was added to adjust the pH to 5-6, and the solid was filtered off to give the crude product. The crude product was purified by reverse-phase preparative HPLC (flow rate: 25 mL / min, 14%-95% acetonitrile / buffer (0.1 mol / L formic acid in water) gradient) to give compound 3. MS m / z (ESI): = 401.5 [M+H] + , HPLC: 95.07%, 1HNMR (400 MHz, DMSO-d6) δ 10.90 (d, J = 2.9Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 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, 1.8 Hz, 1H), 4.91 (s, 1H), 3.83 (s, 2H), 3.72 (s, 3H),2.45 (s, 3H).

[0447] Step 7: Compound 3 (180 mg, 0.01 mmol) was further subjected to chiral separation (column: DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 30%) to give compounds 3-P1 and 3-P2.

[0448] SFC analysis method: Column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine); Gradient: B%: 30% for 5 min, gradient flow; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0449] Compound 3-P1: Retention time: 1.900 min, MS m / z (ESI):= 401.5 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.18 (d, J = 2.3Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.55-7.51 (m, 2H), 7.40 (d, J = 7.3 Hz, 2H),7.31-7.26 (m, 3H), 7.22-7.18 (m, 1H), 6.71 (s, 1H), 6.19 (dd, J =3.1, 1.9 Hz,1H), 4.90 (s, 1H), 3.82 (s, 2H), 3.72 (s, 3H), 2.45 (s, 3H).

[0450] Compound 3-P2: Retention time: 2.774 min, MS m / z (ESI): = 401.5 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.16 (s, 1H), 7.89-7.86 (m, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.32-7.26 (m, 3H), 7.21 (t, J = 7.3 Hz, 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).

[0451] (Example 4) Compound 4, 4-P1 and 4-P2 modulation

[0452]

change

[0453] Step 1: To a solution of compound 3-5 (220 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL), 2-(7-azabenzotriazol-1-yl)-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. The reaction was stirred at 30 °C for 18 h and monitored by LCMS. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 15% ethyl acetate / petroleum ether gradient) to give compound 4-1. MS m / z(ESI):=529.1[M+H] + .

[0454] Step 2: Compound 4-1 (370 mg, 0.70 mmol) was dissolved in methanol (5 mL) and water (1 mL), followed by the addition of lithium hydroxide (40.80 mg, 0.97 mmol). The reaction was stirred at 50 °C under a nitrogen atmosphere for 18 h and monitored by LCMS. The pH was adjusted to 5-6 by adding dilute hydrochloric acid (1 N), and the solid was filtered off to give the crude product. The crude product was purified by reverse-phase column chromatography (flow rate: 25 mL / min, 38%-68% acetonitrile / buffer (0.1 mol / L formic acid in water) gradient) to give compound 4. MS m / z (ESI): = 415.1 [M+H] + , 1H NMR (400 MHz,DMSO-d6) δ 12.98 (s, 1H), 11.15 (s, 1H),9.11 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H),7.49-7.43 (m, 3H), 7.40 (t, J = 2.8 Hz, 1H), 7.36-7.32 (m, 1H), 6.90 (s, 1H),6.73 (dd, J = 3.0, 2.0 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 2.56(s, 3H).

[0455] Step 3: Compound 4 (200 mg, 0.48 mmol) was further subjected to chiral separation (column: DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 15%) to give compounds 4-P1 and 4-P2.

[0456] SFC analysis method: Column: Chiralpak AD-3 150 mm x 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine); Gradient: B%: 40% gradient flow over 5 min; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0457] Compound 4-P1: Retention time: 2.175 min, MS m / z (ESI):= 415.1 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 11.09 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 8.0 Hz, 3H), 7.34 (dd, J = 5.8, 3.0 Hz, 2H), 7.28 (t, J = 7.1 Hz,1H), 6.84 (s, 1H), 6.68 (dd, J = 3.1, 2.0 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H),3.87 (s, 3H), 2.50 (s, 3H).

[0458] Compound 4-P2: Retention time: 2.316 min, MS m / z (ESI): = 415.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 11.09 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H), 7.95-7.91 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.44-7.41 (m, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 2.8 Hz, 1H), 7.29 (d,J = 7.1 Hz, 1H), 6.84 (s, 1H), 6.68 (dd, J = 3.0, 1.9 Hz, 1H), 6.46 (d, J = 8.4Hz, 1H), 3.87 (s, 3H), 2.50 (s, 3H).

[0459] (Example 5) Compound 5, 5-P1 and 5-P2 modulation

[0460]

change

[0461] Step 1: Compound 5-1 (2 g, 7.24 mmol) was dissolved in tetrahydrofuran (20 mL). At -40 °C, a solution of isopropylmagnesium chloride-lithium chloride in THF (6.44 mL, 1.3 M) was added, and the mixture was stirred for 50 minutes. Copper(I) iodide (0.41 g, 2.17 mmol) was then added, followed by stirring at 0 °C for 10 minutes. Cyclobutanecarbonyl chloride (1.29 g, 10.87 mmol) in THF (20 mL) was added at -40 °C, and the temperature was raised to 0 °C after 5 minutes and stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 8% ethyl acetate / petroleum ether gradient) to give compound 5-2.

[0462] 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 h. The reaction was monitored by LCMS and TLC. After completion, the solid was filtered off, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (5% to 10% methanol / dichloromethane gradient) to give compound 5-3. MS m / z (ESI): = 220.1 [M+H] + .

[0463] Step 3: Compound 5-3 (255 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (1 mL). Under an ice bath, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (476.34 mg, 1.25 mmol) was added, followed by the dropwise addition of a solution of N,N-diisopropylethylamine (0.42 mL, 2.51 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was allowed to warm 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, and the reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (2% to 5% methanol / dichloromethane gradient) to give compound 5-4. MS m / z (ESI): = 507.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.67 (d, J = 8.0 Hz, 1H),8.01-7.95 (m, 2H), 7.57 (d, J = 3.8 Hz, 1H), 7.52-7.47 (m, 2H), 6.91 (s, 1H),6.72 (dd, J = 3.8, 1.5 Hz, 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).

[0464] Step 4: Compound 5-4 (190 mg, 0.38 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (157 mg) was added, and the mixture was heated to 50 °C and stirred for 5 h. The reaction was monitored by LCMS. The pH was adjusted to neutral with dilute hydrochloric acid (1 N), and the reaction mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 5. MS m / z (ESI): = 393.1 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.05 (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 = 2.8 Hz, 1H), 6.81(s, 1H), 6.59 (dd, J = 3.0, 1.9 Hz, 1H), 5.06 (t, J = 8.8 Hz, 1H), 3.86 (s,3H), 2.75-2.67 (m, 1H), 2.49 (s, 3H), 2.05-1.72 (m, 6H).

[0465] Step 5: Chiral separation of compound 5 (70 mg, 0.18 mmol) was performed using a Chiralpak AS column (150 × 4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B: 5%–40%) to give compounds 5-P1 and 5-P2.

[0466] SFC analysis method: Column: ChiralPak AD, 50 × 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine); Gradient: B%: 5% to 40% gradient flow for 5 min, hold at 40% for 5 min, hold at 5% for 2.5 min; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0467] Compound 5-P1: Retention time: 3.201 min, MS m / z (ESI): = 393.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.48 (d, J = 8.1Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 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).

[0468] Compound 5-P2: Retention time: 3.736 min, MS m / z (ESI): = 393.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.48 (d, J = 8.2Hz, 1H), 7.99-7.81 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 2.8 Hz, 1H), 6.81 (s, 1H), 6.59 (dd, J = 3.0, 2.0 Hz, 1H), 5.05 (t, J = 8.7 Hz, 1H), 3.85(s, 3H), 2.74-2.66 (m, 1H), 2.49 (s, 3H), 2.05-1.73 (m, 6H).

[0469] (Example 6) Compound 6, 6-P1 and 6-P2 modulation

[0470]

change

[0471] Step 1: Compounds 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 h. The reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was purified by reverse-phase column chromatography (12% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 6-1. MS m / z (ESI): = 493.4 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 7.92 (d, J = 7.9 Hz, 2H), 7.57(s, 1H), 7.44 (d, J = 7.9 Hz, 2H), 6.83 (s, 1H), 6.36 (d, J = 3.6 Hz, 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).

[0472] 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 and stirred for 16 h. The reaction was monitored by LCMS. Upon completion, the pH was adjusted to neutral, and the reaction mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase column chromatography (12% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 6. MS m / z (ESI): = 379.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 10.87 (s, 1H), 7.91 (d, J = 8.1Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.70 (s, 1H), 6.13(t, J = 2.5 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J = 12.3 Hz, 1H), 3.57 (d, J = 12.3Hz, 1H), 3.50 (d, J = 9.2 Hz, 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).

[0473] Step 3: Chiral separation of compound 6-1 (330 mg, 0.67 mmol) was carried out using an IG column (100 mm × 4.6 mm, 5 μm; mobile phase: A: carbon dioxide, B: 0.2% ammonia-methanol; gradient: B%: 25%) to give compounds 6-1-P1 and 6-1-P2.

[0474] SFC analytical method: 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 for 5 min; Flow rate: 5.0 mL / min; Detection wavelength: 220 nm.

[0475] Compound 6-1-P1 retention time: 1.212 minutes, compound 6-1-P2 retention time: 1.550 minutes. MS m / z(ESI):=493.1[M+H] + .

[0476] 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 and stirred for 16 h. The reaction was monitored by LCMS. Upon completion, the pH was adjusted to neutral, and the reaction mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) gradient) to give compound 6-P1. MS m / z (ESI): = 379.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 10.87 (s, 1H), 7.91 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.70 (s, 1H), 6.13(s, 1H), 3.73 (s, 3H), 3.69 (d, J = 12.3 Hz, 1H), 3.58 (d, J = 12.3 Hz, 1H),3.51 (d, J = 9.1 Hz, 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).

[0477] Compound 6-P2 was obtained from compound 6-1-P2 according to a method similar to that used to prepare 6-P1 from 6-1-P1. MS m / z (ESI):= 379.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 10.87 (s, 1H), 7.91 (d, J = 8.0Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 2.9 Hz, 1H), 6.70 (s, 1H), 6.14(t, J = 2.5 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J = 12.3 Hz, 1H), 3.58 (d, J = 12.3Hz, 1H), 3.52 (d, J = 9.1 Hz, 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).

[0478] Example 7 Preparation of Compound 7

[0479] [ka]

[0480] Step 1: Compound 7-1 (1.52 mL, 20.81 mmol) and compound 7-2 (9.59 mL, 62.44 mmol) were dissolved in methanol (30 mL). Piperidine was added to the reaction mixture, which was then stirred at 85 °C for 12 h. The reaction was monitored by LCMS. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (5% to 20% ethyl acetate / petroleum ether gradient) to give compound 7-3. MS m / z (ESI): = 257.0 [M+H] + .

[0481] Step 2: Ammonium acetate (751.97 mg, 9.76 mmol) and sodium cyanoborohydride (613 mg, 9.76 mmol) were added to a methanol solution (10 mL) of compound 7-3 (500 mg, 1.95 mmol). The reaction mixture was stirred at 80 °C for 12 h and monitored by LCMS. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (3% to 10% methanol / dichloromethane gradient) to give compound 7-4. MS m / z (ESI): = 260.2 [M+H] + .

[0482] Step 3: Compound 7-4 (70 mg, 0.27 mmol) and compound 1-6 (82.42 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetra-methyluronium hexafluorophosphate (112.91 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.68 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction was monitored by LCMS. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic phase was washed with water (2 × 150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% to 5% methanol / dichloromethane gradient) to give compound 7-5. MS m / z (ESI): = 547.4 [M+H] + .

[0483] Step 4: Water (2 mL) and lithium hydroxide (0.02 mL, 0.62 mmol) were added to a methanol solution (2 mL) of compound 7-5 (100 mg, 0.16 mmol). The mixture was heated to 60 °C and stirred for 12 h. The reaction was monitored by LCMS. The pH was adjusted to 5 with 1 N dilute hydrochloric acid, and the reaction mixture was concentrated. The crude product was purified by reverse-phase preparative HPLC (flow rate: 25 mL / min, 28%-38% acetonitrile / buffer (0.01 mol / L formic acid in water) gradient) to give compound 7. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 12.97-12.27 (m, 1H), 11.04 (s,1H), 8.60 (d, J = 8.2 Hz, 1H), 7.98-7.86 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H),7.51-7.43 (m, 1H), 7.32 (t, J = 2.8 Hz, 1H), 6.81 (s, 1H), 6.54 (dd, J = 3.0,2.0 Hz, 1H), 6.07 (d, J = 1.9 Hz, 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).

[0484] Example 8 Preparation of compounds 8, 8-P1 and 8-P2

[0485] [ka]

[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. The reaction mixture was stirred at 50 °C for 16 h and monitored by LCMS. Water (100 mL) was added to the reaction mixture, which was then 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 to give the crude product. The crude product was purified by silica gel column chromatography (4% to 8% petroleum ether / ethyl acetate gradient) to give compound 8-2. MS m / z (ESI): = 257.1 [M+H] + .

[0487] Step 2: Compound 8-2 (783 mg, 3.05 mmol) and palladium on carbon (700 mg, 6.60 mmol) were dissolved in ethyl acetate (250 mL). The mixture was stirred at room temperature under a hydrogen atmosphere (15 Psi) for 16 hours and monitored by LCMS. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give 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 periodinane (1.8 g, 4.28 mmol) was added, and the mixture was stirred at room temperature for 2 hours and monitored by LCMS. Saturated sodium carbonate solution (20 mL) and saturated sodium thiosulfate solution (20 mL) were added to the reaction mixture, which was then 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 to give the crude product. The crude product was purified by silica gel column chromatography (3% to 10% dichloromethane / methanol gradient) to give compound 8-4. MS m / z (ESI): = 259.2 [M+H] + . 1H NMR (400 MHz,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 = 7.5 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H).

[0489] Step 4: Compound 8-4 (643 mg, 2.49 mmol) was dissolved in methanol (10 mL). 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 under an argon atmosphere and stirred for 3 days. 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 phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0% to 10% dichloromethane / methanol gradient) to give 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). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (759 mg, 2.00 mmol) and N,N-diisopropylethylamine (516 mg, 4.00 mmol) were added, and the mixture was stirred for 5 min. Compound 1-6 (345 mg, 1.33 mmol) was then added, and the reaction was allowed to proceed at room temperature for 2 h. The reaction mixture was monitored by LCMS. The reaction mixture was poured into water (30 mL) 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 to give the crude product. The crude product was purified by silica gel column chromatography (5% to 12% dichloromethane / methanol gradient) to give 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 and stirred for 10 h. The reaction was monitored by LCMS. The pH was adjusted to neutral, and the reaction mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase column chromatography (15% to 100% acetonitrile / buffer (0.01 mol / L formic acid in water) gradient) to give compound 8. MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 1.3 Hz, 1H),8.06-8.00 (m, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 3.1 Hz, 1H), 7.10 (d,J = 1.2 Hz, 1H), 6.85 (s, 1H), 6.76 (d, J = 3.1 Hz, 1H), 5.25 (t, J = 7.4 Hz,1H), 3.96 (s, 3H), 2.84 (septet, J = 7.8 Hz, 2H), 2.56 (s,3H), 2.26 (q, J = 7.5 Hz, 2H).

[0492] Step 7: Chiral separation of compound 8 (40 mg, 0.092 mmol) was carried out using a ChiralPak IG column (250 mm × 30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-ethanol]; gradient: B%: 40%) to give compounds 8-P1 and 8-P2.

[0493] SFC analysis method: Column: ChiralPak IG, 100 mm x 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine); Gradient: B%: 40% gradient flow for 5 min, hold at 40% for 5 min, hold at 5% for 2.5 min; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0494] Compound 8-P1: Retention time: 2.062 min, MS m / z (ESI): = 433.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 11.04 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.69 (s, 1H), 7.53 (d, J =8.1 Hz, 2H), 7.32 (t, J = 2.8 Hz, 1H), 6.82 (d, J = 10.5 Hz, 2H), 6.55 (t, J =2.5 Hz, 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] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.04 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.53 (d, J =8.0 Hz, 2H), 7.32 (t, J = 2.8 Hz, 1H), 6.81 (s, 2H), 6.55 (d, J = 2.5 Hz, 1H), 5.12 (q, J = 7.7 Hz, 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) Compound 9, 9-P1 and 9-P2 modulation

[0497]

change

[0498] Step 1: Compound 7-2 (500 mg, 2.81 mmol) was dissolved in ethanol (5 mL). 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 reaction mixture was stirred in a microwave reactor at 110° C. for 18 hours. The reaction was monitored by LCMS. The reaction mixture was directly concentrated to give compound 9-1, which was used directly in the next step. MS m / z (ESI): = 222.1 [M+H] + .

[0499] 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, followed by the slow addition of di-tert-butyl dicarbonate (1.20 mL, 5.60 mmol). The reaction mixture was stirred at 20 °C for 3 h and monitored by LCMS. The reaction mixture was diluted with water (30 mL) and dichloromethane (30 mL). The aqueous phase was extracted with dichloromethane (2 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (80%-90% ethyl acetate / petroleum ether gradient) to give compound 9-2. MS m / z (ESI): = 322.16 [M+H] + .

[0500] 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. The reaction was stirred at 100 °C for 3 h and monitored by LCMS. The reaction mixture was concentrated and diluted with water (30 mL) and dichloromethane (30 mL). The aqueous phase was extracted with dichloromethane (2 × 30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 9-3. MS m / z (ESI): = 337.17 [M+H] + .

[0501] Step 4: Compound 9-3 (167 mg, 0.50 mmol) was dissolved in ethanol (10 mL). Raney nickel (50 mg, 0.85 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere at 20° C. for 18 hours and monitored by LCMS. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give compound 9-4. MS m / z (ESI): = 323.19 [M+H] + .

[0502] Step 5: Compound 9-4 (160 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide (5 mL). Compound 1-6 (151.53 mg, 0.50 mmol), N,N-diisopropylethylamine (0.25 mL, 1.49 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (283.06 mg, 0.74 mmol) were added. The reaction mixture was stirred at 20 °C for 18 hours and monitored by LCMS. The reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (50% to 80% ethyl acetate / petroleum ether gradient) to give compound 9-5. MS m / z (ESI): = 610.31 [M+H] + .

[0503] Step 6: Compound 9-5 (200 mg, 0.33 mmol) was dissolved in hydrogen chloride in dioxane (10 mL, 4 M). The mixture was stirred at 20° C. for 30 minutes and monitored by LCMS. The reaction mixture was directly concentrated to give compound 9-6. MS m / z (ESI):=510.25 [M+H] + .

[0504] Step 7: Compound 9-6 (160 mg, 0.31 mmol) was dissolved in methanol (5 mL). 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 h and monitored by LCMS. The reaction mixture was directly concentrated to give the crude product, which was purified by reverse-phase column chromatography (flow rate: 30 mL / min, 22% to 100% acetonitrile / buffer (0.225% formic acid in water) gradient) to give compound 9. MS m / z (ESI): = 396.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 11.05 (s, 1H), 8.70 (d, J = 8.0Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 2.8Hz, 1H), 6.81 (s, 1H), 6.58 (d, J = 2.5 Hz, 1H), 5.23 (q, J = 7.9, 7.4 Hz, 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).

[0505] Step 8: Compound 9 (100 mg, 0.25 mmol) was further subjected to chiral separation (column: ChiralPak IG, 250 mm × 30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-methanol]; gradient: B%: 30%) to give compounds 9-P1 and 9-P2.

[0506] SFC analysis method: Column: ChiralPak IG, 100 mm x 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine); Gradient: B%: 5% to 40% gradient flow for 5 min, hold at 40% for 5 min, hold at 5% for 2.5 min; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0507] Compound 9-P1: Retention time: 1.253 minutes. MS m / z (ESI):= 396.2 [M+H] + . 1H NMR (400 MHz, メタノール-d4) δ 8.49 (s, 1H), 8.03 (d, J =8.0 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 3.0 Hz, 1H), 6.83 (d, J =2.4 Hz, 2H), 5.37 (t, J = 7.5 Hz, 1H), 3.91 (s, 3H), 3.14 (ddt, J = 28.0, 12.6,7.2 Hz, 2H), 2.76 (s, 3H), 2.54 (s, 3H), 2.29 (q, J = 7.2 Hz, 2H).

[0508] Compound 9-P2: Retention time: 2.784 min. MS m / z (ESI): = 396.2 [M+H] + . 1 H NMR (400 MHz, メタノール-d4) δ 8.00 (s, 2H), 7.50 (d, J =6.9 Hz, 2H), 7.31 (d, J = 3.0 Hz, 1H), 6.84 (d, J = 3.2 Hz, 2H), 5.35 (t, J =7.6 Hz, 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).

[0509] (Example 10) Compound 10, 10-P1 and 10-P2 modulation

[0510]

change

[0511] Step 1: Triphenylphosphine (22.4 g, 85.60 mmol) was dissolved in toluene (400 mL) and stirred until homogeneous, followed by the addition of compound 10-1 (20.0 g, 77.82 mmol). The mixture was stirred at 80° C. under nitrogen protection for 16 hours. The reaction was monitored by LCMS and TLC. The reaction product precipitated, filtered, and the filter cake was washed with toluene. The filter cake was collected to give compound 10-2. MS m / z (ESI): = 440.0 [M-Br+H] + .

[0512] Step 2: Compound 10-2 (38.0 g, 73.20 mmol) was dissolved in dichloromethane (40 mL) and sodium carbonate solution (200 mL, 10%) was added. The mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (3 x 200 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 10-3. MS m / z (ESI): = 439.0 [M+H] + . 1 H NMR (400 MHz,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).

[0513] Step 3: Compound 10-3 (1.9 g, 4.42 mmol) was dissolved in dichloromethane (10 mL) and 4,4,4-trifluorobutanal (558 mg, 4.42 mmol) was added. 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 mixture, which was then extracted with dichloromethane (3 × 50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0% to 25% ethyl acetate / petroleum ether to give compound 10-4. MS m / z (ESI): = 287.0 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.11 (s, 4H), 7.25 (d, J = 15.4Hz, 1H), 7.02 (dd, J = 13.5, 7.5 Hz, 1H), 3.90 (s, 3H), 2.63-2.55 (m, 4H).

[0514] Step 4: Compound 10-4 (472 mg, 1.65 mmol) was dissolved in 1,4-dioxane (30 mL), and tert-butylsulfinamide (599 mg, 4.95 mmol) and tetraethoxytitanium (1.8 g, 8.25 mmol) were added to it. 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 mixture, which was then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 25% ethyl acetate / petroleum ether to give compound 10-5. MS m / z (ESI): = 404.1 [M+H] + .

[0515] Step 5: Compound 10-5 (181 mg, 0.45 mmol) was dissolved in methanol (3 mL) and sodium borohydride (51 mg, 1.35 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 10-6. MS m / z (ESI): = 405.9 [M+H] + .

[0516] Step 6: Compound 10-6 (160 mg, 0.39 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrogen chloride in ethyl acetate (3 mL) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated to give compound 10-7. MS m / z (ESI): = 302.0 [M+H] + .

[0517] Step 7: Compound 10-7 (100 mg, 0.33 mmol) was dissolved in ethanol (2 mL) and palladium on carbon (5%, 20 mg, 0.19 mmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere (15 Psi) for 16 hours. The reaction was monitored by LCMS. The solution was filtered and the filtrate was concentrated to give compound 10-8. MS m / z (ESI): = 304.1 [M+H] + .

[0518] 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-azabenzotriazol-1-yl)-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 mixture. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, 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] + .

[0519] 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 pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid (1 N), and the reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 10. MS m / z (ESI): = 463.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.51 (d, J = 8.2Hz, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 2.9Hz, 1H), 6.81 (s, 1H), 6.55 (t, J = 2.5 Hz, 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).

[0520] Chiralpak 10: Chiralpak AD-3 50×4.6mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-Econite]; concentration blending: B%: 5%~40%), compound 10-P1, 10-P2, etc.

[0521] SFC analysis method: Camera: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: A: Carbon dioxide, B: Etanol (0.05% DEA); Concentration blending: B%: 5%~40% concentration blending flow in 4 min, 40%~5% hold in 0.2 min, 5% hold in 1.8 min, 5% hold in 2.5 min; Flow rate: 3.0 mL / min; Emission wavelength: 220 nm.

[0522] Compound 10-P1: Retention time: 2.607 min, MS m / z (ESI): = 463.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 11.05 (s, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.02-7.83 (m, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.32 (t,J = 2.8 Hz, 1H), 6.81 (s, 1H), 6.54 (dd, J = 3.0, 1.9 Hz, 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, 7.6 Hz, 2H), 1.57–1.38 (m, 4H).

[0523] Compound 10-P2: Retention time: 2.915 min, MS m / z (ESI): = 463.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.04 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.00-7.89 (m, 2H), 7.58-7.45 (m, 2H), 7.32 (t, J =2.8 Hz, 1H), 6.81 (s, 1H), 6.54 (dd, J = 3.0, 1.9 Hz, 1H), 5.11 (q, J = 8.2 Hz,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).

[0524] (Example 11) Compound 11, 11-P1 and 11-P2 modulation

[0525]

change

[0526] Step 1: To a solution of compound 10-8 (150 mg, 0.52 mmol) in methanol (5 mL), compound 3-6 (150 mg, 0.52 mmol) and sodium cyanoborohydride (81.5 mg, 1.23 mmol) were added, followed by two drops of acetic acid. The mixture was stirred at room temperature under argon protection 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 organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 10% dichloromethane / methanol to give compound 11-1. MS m / z (ESI): = 577.6 [M+H] + .

[0527] Step 2: Compound 11-1 (152 mg, 0.27 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide (114 mg, 2.7 mmol) was added. The mixture was heated to 50° C. and stirred for 16 hours. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to neutral, and the reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) and lyophilized to obtain compound 11. MS m / z (ESI): = 449.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.92 (d, J = 8.1Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.25 (t, J = 2.8 Hz, 1H), 6.68 (s, 1H), 6.19(t, J = 2.4 Hz, 1H), 3.72 (s, 3H), 3.64 (d, J = 13.7 Hz, 3H), 2.43 (s, 3H), 2.09 (td, J = 10.9, 6.4 Hz, 2H), 1.69-1.45 (m, 2H), 1.39-1.05 (m, 4H).

[0528] ステップ3: Sub-いで compound 11 (100mg, 0.22mmol) をキラルisolation (カラム: Chiralpak AS 150×4.6mm ID, 3μm; mobile phase: A: carbonic acid, B: [0.05% DEA-エタノール]; concentration blending: B%: 5%~40%), compound 11-P1 and compound 11-P2.

[0529] SFC analysis method: Camera: ChiralPak AS, 150×4.6mm ID, 3μm; Mobile phase: A: Carbon diacid, B: Etanol (0.05% DEA); Concentration blending: B%: 5%~40% concentration blending flow in 5 min, 40% hold in 2.5 min, 5% hold in 2.5 min; Flow rate: 2.5 mL / min; Emission wavelength: 220 nm.

[0530] Compound 11-P1: Retention time: 3.588 min, MS m / z (ESI): = 449.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.94-7.91 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.25 (t, J = 2.8 Hz, 1H), 6.68 (s, 1H), 6.19 (dd, J =3.0, 1.9 Hz, 1H), 3.72 (s, 3H), 3.65 (d, J = 14.0 Hz, 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)

[0531] Compound 11-P2: Retention time: 4.091 min, MS m / z (ESI): = 449.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.93 (d, J = 8.2Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 2.9 Hz, 1H), 6.68 (s, 1H), 6.20(dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.43 (s, 3H), 2.15-2.04(m, 2H), 1.58 (d, J = 45.7 Hz, 2H), 1.38-1.25 (m, 3H), 1.16-1.07 (m, 1H).

[0532] (Example 12) Compound 12, 12-P1 and 12-P2 modulation

[0533]

change

[0534] Step 1: Compound 5-1 (5.0 g, 19.08 mmol) was dissolved in tetrahydrofuran (70 mL), and isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (16.1 mL, 1.3 M) was added at −40° C. The mixture was stirred for 50 minutes, followed by the addition of copper(I) iodide (1.1 g, 5.72 mmol). The mixture was stirred at 0° C. for 10 minutes, and then a solution of 12-1 (3.8 g, 28.62 mmol) in tetrahydrofuran (20 mL) was added at −40° C. After 5 minutes, the temperature was raised to 0° C., and the mixture was stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 7% petroleum ether / ethyl acetate to give compound 12-2. MS m / z (ESI): = 233.1 [M+H] + .

[0535] 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 and reacted for 5 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, quenched with dilute hydrochloric acid (1 N), and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 10% dichloromethane / methanol to give compound 12-3. MS m / z (ESI): = 234.1 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 7.89 (d, J = 8.2 Hz, 2H), 7.47(d, J = 8.2 Hz, 2H), 3.84 (s, 3H), 3.63 (d, J = 8.5 Hz, 1H), 2.05-1.91 (m, 1H), 1.83-1.58 (m, 4H), 1.40-1.01 (m, 4H).

[0536] Step 3: Compound 12-3 (251 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (586 mg, 1.54 mmol) was added under ice bath. A solution of N,N-diisopropylethylamine (0.51 mL, 3.09 mmol) in N,N-dimethylformamide (2 mL) was added dropwise to the reaction mixture. The mixture was transferred to room temperature and stirred for 15 minutes. A solution of compound 1-6 (240 mg, 1.03 mmol) in N,N-dimethylformamide (2 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 15% to 30% petroleum ether / ethyl acetate to give compound 12-4. MS m / z (ESI): = 521.4 [M+H] + .

[0537] 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 pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid (1N), and the reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 12. MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.03 (s, 1H), 8.60 (d, J = 8.3Hz, 1H), 7.90 (d, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.30 (t, J = 2.8 Hz, 1H), 6.80(s, 1H), 6.57 (dd, J = 3.0, 1.9 Hz, 1H), 4.90 (t, J = 8.8 Hz, 1H), 3.84 (s,3H), 2.48 (s, 3H), 2.33 (q, J = 8.4 Hz, 1H), 1.79 (t, J = 6.2 Hz, 1H),1.68-1.41 (m, 5H), 1.37-1.19 (m, 2H).

[0538] Step 5: Compound 12 (100 mg, 0.24 mmol) was then subjected to chiral separation (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 give compounds 12-P1 and 12-P2.

[0539] SFC analytical method: Column: Chiralpak IG-3 100 × 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: methanol (0.05% DEA); Gradient: B%: 40% gradient flow over 8 min; Flow rate: 2.5 mL / min; Detection wavelength: 220 nm.

[0540] Compound 12-P1: Retention time: 1.945 min, MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 2.8Hz, 1H), 6.80 (s, 1H), 6.61-6.55 (m, 1H), 4.90 (t, J = 8.8 Hz, 1H), 3.84 (s,3H), 2.48 (s, 3H), 2.34 (d, J = 7.8 Hz, 1H), 1.79 (d, J = 7.7 Hz, 1H), 1.62 (s, 3H), 1.48 (d, J = 20.3 Hz, 3H), 1.38-1.32 (m, 1H).

[0541] Compound 12-P2: Retention time: 4.040 min. MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 11.04 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.93-7.85 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.30 (t,J = 2.8 Hz, 1H), 6.80 (s, 1H), 6.56 (dd, J = 3.1, 2.0 Hz, 1H), 4.90 (t, J = 8.8Hz, 1H), 3.84 (s, 3H), 2.48 (s, 3H), 2.33 (q, J = 8.3 Hz, 1H), 1.83-1.75 (m,1H), 1.67-1.57 (m, 2H), 1.55-1.39 (m, 3H), 1.41-1.32 (m, 1H), 1.23 (s, 1H).

[0542] (Example 13) Compound 13, 13-P1 and 13-P2 modulation

[0543] [ka]

[0544] Step 1: Compound 12-3 (100 mg, 0.43 mmol) was dissolved in methanol (5 mL), and compound 3-6 (99 mg, 0.34 mmol), sodium cyanoborohydride (67 mg, 1.07 mmol), and two drops of acetic acid were added. The mixture was stirred under argon protection for 16 hours. 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 organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 40% to 50% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 13-1. MS m / z (ESI): = 507.4 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 7.86 (d, J = 7.9 Hz, 2H), 7.49(d, J = 3.8 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 6.73 (s, 1H), 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).

[0545] Step 2: Compound 13-1 (190 mg, 0.38 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), and lithium hydroxide (126 mg, 1.9 mmol) was added. The mixture was heated to 50 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to neutral with dilute hydrochloric acid (1 N), and the reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 13. MS m / z (ESI): = 393.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 10.85 (d, J = 2.6 Hz, 1H), 7.92(d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.25 (t, J = 2.8 Hz, 1H), 6.69(s, 1H), 6.11 (dd, J = 3.1, 1.9 Hz, 1H), 3.73 (s, 3H), 3.64 (d, J = 12.2 Hz,1H), 3.55 (d, J = 12.2 Hz, 1H), 3.35 (d, J = 8.7 Hz, 1H), 2.44 (s, 3H), 1.95(q, J = 8.3 Hz, 1H), 1.79-1.68 (m, 1H), 1.44 (d, J = 7.8 Hz, 3H), 1.37-1.28 (m,1H), 1.21-0.93 (m, 3H).

[0546] Step 3: Compound 13 (98 mg, 0.25 mmol) was then subjected to chiral separation (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; gradient: B%: 5% to 40%) to give compounds 13-P1 and 13-P2.

[0547] SFC analysis method: Camera: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: A: Carbon dioxide, B: Etanol (0.05% DEA); Concentration blending: B%: 5%~40% concentration blending flow in 4 min, 40%~5% hold in 0.2 min, 5% hold in 1.8 min, 5% hold in 2.5 min; Flow rate: 3.0 mL / min; Emission wavelength: 220 nm.

[0548] Compound 13-P1: Retention time: 2.462 min, MS m / z (ESI): = 393.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.92 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.1 Hz, 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).

[0549] Compound 13-P2: Retention time: 2.847 min, MS m / z (ESI): = 393.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.93 (d, J = 7.9Hz, 2H), 7.47 (d, J = 8.0 Hz, 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).

[0550] (Example 14) Preparation of compounds 14, 14-P1 and 14-P2

[0551] [ka]

[0552] Step 1: Compound 5-1 (4 g, 15.26 mmol) was dissolved in tetrahydrofuran (8 mL), and isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (12.88 mL, 1.3 M) was added at −40° C. The mixture was stirred for 50 minutes, followed by the addition of copper(I) iodide (0.87 g, 4.58 mmol). The mixture was stirred at 0° C. for 10 minutes, and then a solution of cyclohexanecarbonyl chloride (3.36 g, 22.90 mmol) in tetrahydrofuran (4 mL) was added at −40° C. After 5 minutes, the temperature was raised to 0° C., and the mixture was stirred for 2 hours. The reaction was monitored by LCMS and TLC. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 5% ethyl acetate / petroleum ether to give compound 14-1. MS m / z (ESI): = 247.1 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.12 (s, 4H), 3.94 (s, 3H),3.53-3.44 (m, 1H), 1.89-1.70 (m, 5H), 1.49-1.19 (m, 5H).

[0553] 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 protection for 16 h. The reaction was monitored by LCMS and TLC. After completion, the reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 3% methanol / dichloromethane to give compound 14-2. MS m / z (ESI): = 248.1 [M+H] + .

[0554] Step 3: Compound 14-2 (120 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (224 mg, 0.59 mmol) and N,N-diisopropylethylamine (101 mg, 0.79 mmol). The mixture was stirred at room temperature for 5 minutes, and then 1-6 (97 mg, 0.39 mmol) was added, followed by continued stirring for 2 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 12% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 14-3. MS m / z (ESI): = 535.4 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 8.62 (d, J = 8.6 Hz, 1H),7.97-7.90 (m, 2H), 7.61 (d, J = 3.7 Hz, 1H), 7.54-7.47 (m, 2H), 6.95 (s, 1H),6.54 (d, J = 3.8 Hz, 1H), 4.89 (t, J = 8.4 Hz, 1H), 3.86 (d, J = 3.2 Hz, 6H),2.56 (s, 3H), 1.87 (d, J = 12.3 Hz, 1H), 1.77-1.68 (m, 2H), 1.58 (s, 11H), 1.32(d, J = 12.4 Hz, 1H), 1.17-0.90 (m, 5H).

[0555] Step 4: Compound 14-3 (220 mg, 0.41 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), followed by the addition of lithium hydroxide (138 mg, 3.29 mmol). The mixture was heated to 50°C and stirred for 6 hours. The reaction was monitored by LCMS. After completion, the pH of the reaction mixture was adjusted to neutral, and the mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 14. MS m / z (ESI): = 421.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 2.9 Hz, 1H), 6.82 (s, 1H), 6.61 (t, J = 2.5 Hz, 1H), 4.93 (t, J = 8.1 Hz, 1H), 3.87 (s, 3H), 2.49 (s, 3H), 1.86 (d, J = 12.2 Hz, 1H), 1.74 (t, J = 10.4 Hz, 2H), 1.62 (d, J = 16.0 Hz, 2H), 1.39 (d, J = 12.5 Hz, 1H), 1.20 - 0.98 (m, 5H).

[0556] Step 5: The chiral separation of compound 14 (100 mg, 0.24 mmol) was performed using a ChiralPak AD column (50×4.6 mm I.D., 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-ethanol]; concentration gradient: B%: 5% - 40%) to obtain compound 14-P1 and compound 14-P2.

[0557] SFC analysis method: Column: Chiralpak AD-3 50×4.6 mm I.D., 3 μm; mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA); concentration gradient: B%: 5% - 40% concentration gradient flow for 4 minutes, hold at 40% - 5% for 0.2 minutes, hold at 5% for 1.8 minutes; flow rate: 3.0 mL / min; detection wavelength: 220 nm.

[0558] Compound 14-P1: Retention time: 2.986 minutes, MS m / z (ESI): = 421.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.04 (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 = 2.8 Hz, 1H), 6.81(s, 1H), 6.59 (dd, J = 3.0, 2.0 Hz, 1H), 4.93 (t, J = 8.1 Hz, 1H), 3.87 (s,3H), 2.49-2.47 (m, 3H), 1.73 (m, 5H), 1.38 (d, J = 12.4 Hz, 1H), 1.21-0.95 (m,5H).

[0559] Compound 14-P2: Retention time: 3.523 min. MS m / z (ESI): = 421.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 11.04 (s, 1H), 8.56 (d, J = 8.5 Hz, 1H), 7.93-7.87 (m, 2H), 7.49-7.43 (m, 2H), 7.30 (t, J =2.8 Hz, 1H), 6.81 (s, 1H), 6.59 (dd, J = 3.0, 2.0 Hz, 1H), 4.93 (t, J = 8.1 Hz,1H), 3.87 (s, 3H), 2.49-2.47 (m, 3H), 1.85 (d, J = 12.3 Hz, 1H), 1.79-1.56 (m,4H), 1.38 (d, J = 12.6 Hz, 1H), 1.21-0.97 (m, 5H).

[0560] (Example 15) Compound 15, 15-P1 and 15-P2 modulation

[0561]

change

[0562] Step 1: Compound 14-2 (3.0 g, 12.01 mmol) was dissolved in methanol (30 mL), followed by the addition of compound 3-6 (3.5 g, 12.11 mmol), sodium cyanoborohydride (2.3 g, 35.44 mmol), and one drop of acetic acid. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a 5% to 10% methanol / dichloromethane gradient to give compound 15-1. MS m / z (ESI): = 521.4 [M+H] + .

[0563] 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), followed by the addition of lithium hydroxide (444 mg, 10.25 mmol). The mixture was heated to 50 °C and stirred for 10 hours. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to neutral, and the mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) and lyophilized to obtain compound 15. MS m / z (ESI): = 407.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 2.9 Hz, 1H), 6.68 (s, 1H), 6.14 (dd, J = 3.1, 1.9 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J = 12.1 Hz, 1H), 3.56 (d, J = 12.1 Hz, 1H), 3.42 (d, J = 6.6 Hz, 1H), 2.43 (s, 3H), 1.76 (d, J = 12.7 Hz, 1H), 1.58 (m, 4H), 1.29 (d, J = 12.7 Hz, 1H), 1.16 - 0.91 (m, 3H), 0.80 (dt, J = 25.2, 11.4 Hz, 2H).

[0564] Step 3: Chiral separation of compound 15 (453.80 mg, 1.12 mmol) was performed using a Chiralpak AD-3 column (150×4.6 mm I.D., 3 μm; mobile phase: A: carbon dioxide, B: [0.05% DEA-methanol]; concentration gradient: B%: 30%) to obtain compound 15-P1 and compound 15-P2.

[0565] SFC analysis method: Column: Chiralpak AD-3 150×4.6 mm I.D., 3 μm; mobile phase: A: carbon dioxide, B: ethanol (0.05% DEA); concentration gradient: B%: 30% concentration gradient flow for 9 minutes; flow rate: 2.5 mL / min; detection wavelength: 220 nm.

[0566] Compound 15-P1: Retention time: 1.892 minutes, MS m / z (ESI): = 407.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.08 (s, 1H), 9.00 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.0 Hz, 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).

[0567] Compound 15-P2: Retention time: 2.273 min. MS m / z (ESI): = 407.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 11.08 (s, 1H), 8.92 (d, J = 74.1 Hz, 2H), 7.99 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 3.1 Hz, 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).

[0568] (Example 16) Modulation of compound 16-P1 and 16-P2

[0569] [ka]

[0570] Step 1: Compound 16-1 (2.5 g, 10.90 mmol) was dissolved in tetrahydrofuran (20 mL), and borane-tetrahydrofuran complex (24 mL, 24 mmol, 1.0 M) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS and TLC. Sodium hydroxide solution (10%, 10 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried, and concentrated to give compound. 1 H NMR (400 MHz, CDCl3) δ 4.41 (s, 1H), 4.15 (s, 1H), 3.56 (d, J = 12.0 Hz, 2H), 3.32-3.26(m, 2H), 1.85 (dq, J = 6.6, 4.0, 3.4 Hz, 3H), 1.71-1.67 (m, 2H), 1.46 (s, 9H),1.39-1.21 (m, 1H).

[0571] Step 2: Compound 16-2 (2.42 g, 11.24 mmol) was dissolved in dichloromethane (50 mL), and Dess-Martin periodinane (5.72 g, 13.49 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate / petroleum ether to give compound 16-3. 1 H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 4.25 (s, 1H), 3.34 (s, 2H), 2.90 (s, 1H), 2.47 (dd, J= 15.9, 7.2 Hz, 1H), 2.09 (s, 1H), 1.86 (q, J = 7.0 Hz, 2H), 1.64 (s, 1H), 1.45(s, 9H).

[0572] Step 3: Compound 5-1 (2.4 g, 9.16 mmol) was dissolved in tetrahydrofuran (5 mL), and isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (7.75 mL, 10.08 mmol, 1.3 M) was added at −40° C. under nitrogen protection. After stirring for 50 min, a solution of compound 16-3 (1.95 g, 9.16 mmol) in tetrahydrofuran (5 mL) was added at −40° C. After 5 min, the temperature was raised to 0° C., and the mixture was stirred for 2 h. The reaction was monitored by LCMS and TLC. Ammonium chloride solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to give compound 16-4. MS m / z(ESI):=350.2[M+H] + .

[0573] Step 4: Compound 16-4 (2.42 g, 6.93 mmol) was dissolved in dichloromethane (20 mL) and Dess-Martin periodinane (3.82 g, 9.00 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate / petroleum ether to give compound 16-5. MS m / z (ESI): = 348.1 [M+H] + .

[0574] 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). The mixture was stirred at 80 °C under argon protection for 16 h. The reaction was monitored by LCMS and TLC. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 3% methanol / dichloromethane to give compound 16-6. MS m / z (ESI): = 349.6 [M+H] + .

[0575] Step 6: Compound 1-6 (508 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (759 mg, 2 mmol) and N,N-diisopropylethylamine (430 mg, 3.33 mmol). The mixture was stirred at room temperature for 5 minutes, and then 16-6 (580 mg, 1.66 mmol) was added, followed by continued stirring for 2 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 17% ethyl acetate / petroleum ether to give 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) was obtained.

[0576] Step 7: Compound 16-7-P1 (460 mg, 0.72 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL, 4 M) and stirred at 25° C. for 0.5 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give compound 16-8-P1. MS m / z (ESI): = 536.4 [M+H] +Compound 16-8-P2 was obtained from compound 16-7-P2 following the same procedure as for 16-7-P1 to 16-8-P1. MS m / z (ESI): = 536.4 [M+H] + .

[0577] Step 8: Compound 16-8-P1 (415 mg, 0.72 mmol) was dissolved in methanol (6 mL), and a solution of lithium hydroxide (90.7 mg, 2.16 mmol) in water (1 mL) was added at 25 °C. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. After completion, the pH of the reaction mixture was adjusted to neutral, and the mixture was filtered to obtain a filtrate. The filtrate was concentrated to obtain a crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 16-P1. MS m / z (ESI): = 422.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.66 (m, 1H), 7.76(d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 2.7 Hz, 1H), 6.79(s, 1H), 6.65-6.61 (m, 1H), 5.18 (dd, J = 14.7, 7.6 Hz, 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).

[0578] Compound 16-P2 was obtained from compound 16-8-P2 following the same procedure as that for 16-P1 from 16-8-P1. MS m / z (ESI):= 422.3 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.66 (M, 1H), 7.76(d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 2.7 Hz, 1H), 6.79(s, 1H), 6.65-6.61 (m, 1H), 5.18 (dd, J = 14.7, 7.6 Hz, 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).

[0579] Example 17 Preparation of compounds 17, 17-P1 and 17-P2

[0580] [ka]

[0581] Step 1: 4-Iodobenzonitrile (5.01 g, 21.86 mmol) was dissolved in tetrahydrofuran (50 mL), and isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (12.93 mL, 16.81 mmol, 1.3 M) was added at -50 °C. After stirring for 1 h, a solution of 17-1 (1.65 g, 16.81 mmol) in tetrahydrofuran (10 mL) was added. After 5 min, the temperature was raised to 0 °C, and the mixture was stirred for 2 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 15% to 20% ethyl acetate / petroleum ether to give compound 17-2. MS m / z (ESI):= 202.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 7.80-7.73 (m, 2H), 7.55-7.48 (m,2H), 5.38 (d, J = 4.7 Hz, 1H), 4.40 (dd, J = 7.3, 4.6 Hz, 1H), 2.13-2.00 (m,1H), 1.62-1.40 (m, 6H), 1.33-1.19 (m, 2H).

[0582] 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. The mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (20 mL) and extracted with dichloromethane (3 × 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 15% to 20% ethyl acetate / petroleum ether to give compound 17-3. MS m / z (ESI): = 200.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.16-8.08 (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).

[0583] Step 3: Compound 17-3 (500 mg, 2.51 mmol) was dissolved in methanol (10 mL), followed by the addition of ammonium acetate (2.32 g, 30.11 mmol) and sodium cyanoborohydride (630.77 mg, 10.04 mmol). The reaction mixture was stirred at 60 °C under nitrogen protection for 16 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with hydrochloric acid (1 N) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 3% to 5% methanol / dichloromethane to give compound 17-4. MS m / z (ESI): = 201.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 8.0 Hz, 2H), 7.47 (d, J =8.0 Hz, 2H), 3.80 (d, J = 9.5 Hz, 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).

[0584] Step 4: Compound 1-6 (571.69 mg, 1.87 mmol) was dissolved in N,N-dimethylformamide (6 mL), and a solution of 2-(7-azabenzotriazol-1-yl)-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) was added at 0 °C. The temperature was raised to room temperature and stirred for 15 minutes, after which a solution of 17-4 (450 mg, 2.25 mmol) in N,N-dimethylformamide (2 mL) was added dropwise. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 20% to 25% ethyl acetate / petroleum ether to give compound 17-5. MS m / z (ESI): = 488.2 [M+H] + .

[0585] Step 5: Compound 17-5 (260 mg, 0.53 mmol) was dissolved in toluene (5 mL), followed by the addition of Lawesson's reagent (646.99 mg, 1.60 mmol). The temperature was raised to 110 °C, and the mixture was stirred for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 20% to 25% ethyl acetate / petroleum ether to give compound 17-6. MS m / z (ESI): = 504.2 [M+H] + .

[0586] Step 6: Compound 17-6 (300 mg, 0.60 mmol) was dissolved in isopropanol (1.5 mL) and water (4.5 mL), followed by the addition of barium hydroxide (408.23 mg, 2.38 mmol). The mixture was heated to 100 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to neutral with hydrochloric acid (1 N), and the mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous formic acid) to obtain compound 17. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 12.81 (s, 1H), 10.95 (s, 1H),10.60 (d, J = 8.4 Hz, 1H), 7.95-7.88 (m, 2H), 7.58-7.52 (m, 2H), 7.25 (t, J =2.8 Hz, 1H), 6.72 (s, 1H), 6.13 (dd, J = 3.0, 1.9 Hz, 1H), 5.61 (dd, J = 10.5,8.4 Hz, 1H), 3.68 (s, 3H), 2.46 (s, 3H), 1.87-1.80 (m, 1H), 1.68-1.17 (m, 8H).

[0587] Step 7: Chiral separation of compound 17 (100 mg, 0.24 mmol) was carried out using a ChiralCel OJ column (250 × 30 mm ID, 10 μm; mobile phase: A: carbon dioxide, B: [0.05% diethylamine-methanol]; gradient: B%: 30%–40%) to give compound 17-P1 and compound 17-P2.

[0588] SFC analysis method: Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine); Gradient: B%: 5% to 40% gradient flow for 5 min, hold at 40% for 5 min, hold at 5% for 2.5 min; Flow rate: 150 mL / min; Detection wavelength: 220 nm.

[0589] Compound 17-P1: Retention time: 2.501 min. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400 MHz, メタノール-d4) δ 8.04-7.97 (m, 3H),7.59-7.53 (m, 3H), 7.17 (d, J = 3.0 Hz, 1H), 6.72 (s, 1H), 6.31 (d, J = 3.1 Hz,1H), 5.65 (d, J = 10.6 Hz, 1H), 3.73 (s, 3H), 2.53 (d, J = 8.2 Hz, 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).

[0590] Compound 17-P2: Retention time: 2.498 min. MS m / z (ESI): = 423.2 [M+H] + . 1 H NMR (400 MHz, メタノール-d4) δ 10.43 (s, 1H), 8.00 (d, J= 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 2.3 Hz, 1H), 6.72 (s,1H), 6.31 (d, J = 2.9 Hz, 1H), 5.65 (d, J = 10.6 Hz, 1H), 3.73 (s, 3H),2.55-2.49 (m, 1H), 2.48 (s, 3H), 2.01-1.91 (m, 1H), 1.70 (m, 4H), 1.59-1.51 (m,1H), 1.47-1.40 (m, 1H), 1.31 (td, J = 12.5, 6.7 Hz, 2H).

[0591] (Example 18) Modulation of compounds 18-P1, 18-P2, 18-P3 and 18-P4

[0592]

change

[0593] Step 1: Compound 18-1 (6.8 g, 29.66 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of borane-tetrahydrofuran complex (29.66 mL, 2 M) was added at 0° C. The mixture was stirred at 0° C. for 4 hours. The reaction was monitored by LCMS and TLC. The reaction mixture was directly concentrated to give compound 18-2. MS m / z (ESI): = 160 [M-55] + .

[0594] 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 portionwise at 0 °C. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 15% ethyl acetate / petroleum ether to give compound 18-3. MS m / z (ESI): = 158 [M-55] + .

[0595] Step 3: Compound 5-1 (3 g, 14.07 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (14.07 mL, 1.3 M) was slowly added dropwise under nitrogen protection at −40° C. After stirring for 1 h, a solution of 18-3 (3 g, 14.07 mmol) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was stirred at −40° C. for an additional 3 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to give compound 18-4. MS m / z (ESI): = 372 [M+Na] + .

[0596] 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 portionwise at 0 °C. The mixture was stirred at room temperature for 4 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to give compound 18-5. MS m / z (ESI): = 292 [M-55] + .

[0597] 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), and sodium cyanoborohydride (725.37 mg, 11.51 mmol) was added. The mixture was stirred under reflux at 80 °C for 16 h. The reaction was monitored by LCMS. The mixture was directly concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 50% ethyl acetate / petroleum ether to give compound 18-6. MS m / z (ESI): = 349 [M+H] + .

[0598] Step 6: Compound 1-6 (547 mg, 1.79 mmol), 2-(7-azabenzotriazol-1-yl)-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. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 50% ethyl acetate / petroleum ether to give compound 18-7. MS m / z(ESI):=636[M+H] + .

[0599] Step 7: Compound 18-7 (600 mg, 0.94 mmol) was dissolved in dioxane (8 mL), and hydrochloric acid (4.0 mL, 8.00 mmol, 2 M) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction mixture was directly concentrated to give compound 18-8. MS m / z (ESI): = 536 [M+H] + .

[0600] Step 8: Compound 18-8 (500 mg) was dissolved in a mixture of 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. The pH of the reaction mixture was adjusted to approximately 4 with hydrochloric acid (1 M), and the mixture was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using 30% methanol / dichloromethane, followed by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 18-P1. MS m / z (ESI): = 422 [M+H]+. HPLC (Measurement Condition 1) Retention Time: 2.233 min. 1 H NMR (400 MHz,DMSO-d6) δ 11.05 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H),7.91 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.31 (s, 1H), 6.80 (s, 1H),6.52 (s, 1H), 4.98 (t, J = 9.1 Hz, 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).

[0601] Compound 18-P2 was obtained. MS m / z (ESI): = 422 [M+H] + .HPLC (Measurement conditions 1) Retention time: 2.291 minutes. 1H NMR (400 MHz, DMSO-d6)δ 11.04 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 7.81 (d, J =7.9 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 2.8 Hz, 1H), 6.78 (s, 1H),6.60-6.53 (m, 1H), 5.00 (t, J = 8.5 Hz, 1H), 3.84 (s, 3H), 3.44-3.37 (m, 1H),2.48 (s, 3H), 2.41 (d, J = 8.5 Hz, 1H), 2.17-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.54 (dd, J = 14.9, 8.9 Hz, 2H), 1.45-1.30 (m, 2H).

[0602] Compound 18-P3 was obtained. MSm / z (ESI): = 422 [M+H] + HPLC (Determination Condition 1) Holding time: 2.278 min. 1 H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.75 (d, J =7.9 Hz, 2H), 7.37-7.28 (m, 3H), 6.78 (s, 1H), 6.64-6.57 (m, 1H), 4.91 (t, J =9.0 Hz, 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)

[0603] Compound 18-P4 was obtained. MSm / z (ESI): = 422 [M+H] + HPLC (Determination Condition 1) Holding time: 2.316 min. 1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.82 (s,2H), 7.39 (s, 2H), 7.30 (d, J = 3.4 Hz, 1H), 6.79 (s, 1H), 6.54 (d, J = 3.0 Hz,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).

[0604] Example 19 Preparation of compounds 19-P1, 19-P2, 19-P3 and 19-P4

[0605] [ka]

[0606] 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), and sodium cyanoborohydride (130.0 mg, 2.07 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 5% methanol / dichloromethane to give compound 19-1. MS m / z (ESI): = 592.3 [M+H] + .

[0607] Step 2: Compound 19-1 (300 mg, 0.51 mmol) was dissolved in methanol (1 mL) and water (3 mL), and lithium hydroxide (63.8 mg, 2.66 mmol) was added. The mixture was heated to 50° C. and stirred for 16 hours. The reaction was monitored by LCMS. After completion, the pH of the reaction mixture was adjusted to neutral, and the mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 20% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to obtain compound 19-P1. MS m / z (ESI): = 478.3 [M+H] + .HPLC (Measurement conditions 3) Retention time: 2.337 minutes. 1 HNMR (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 = 6.5 Hz, 2H), 4.19 (t, J = 6.6 Hz, 1H),3.91 (s, 3H), 3.39-3.33 (m, 1H), 2.66 (q, J = 8.3 Hz, 1H), 2.52 (s, 3H),2.07-1.91 (m, 2H), 1.83-1.73 (m, 1H), 1.57 (q, J = 7.5 Hz, 1H), 1.47-1.28 (m,2H).

[0608] Compound 19-P2 was obtained. MS m / z (ESI): = 478.3 [M+H]+. HPLC (measurement condition 3) retention time: 2.517 minutes. 1H NMR (400 MHz, メタノール-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 = 6.6 Hz, 1H), 3.91 (s, 3H), 3.29-3.11 (m, 2H),2.60-2.45 (m, 4H), 2.18 (dt, J = 13.5, 7.0 Hz, 1H), 1.90 (q, J = 9.0, 7.2 Hz,1H), 1.57 (p, J = 5.4, 4.5 Hz, 3H), 1.43 (dt, J = 13.0, 8.6 Hz, 1H).

[0609] Compound 19-P3 was obtained. MSm / z (ESI): = 478.3 [M+H]+. HPLC (Measurement Condition 3) Holding time: 2.573 minutes. 1 H NMR (400 MHz, メタノール-d4) δ 7.96 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 3.1 Hz, 1H), 6.80 (s, 1H), 6.72 (d, J =3.1 Hz, 1H), 5.03 (d, J = 9.4 Hz, 1H), 4.76 (dt, J = 9.9, 7.0 Hz, 2H), 4.53(dt, J = 8.2, 6.5 Hz, 2H), 4.17-4.10 (m, 1H), 3.90 (s, 3H), 3.38-3.32 (m, 1H),2.69 (q, J = 8.3 Hz, 1H), 2.54-2.48 (m, 3H), 2.06 (dt, J = 19.3, 7.2 Hz, 2H),1.71 (dt, J = 13.7, 8.1 Hz, 1H), 1.60-1.42 (m, 3H).

[0610] Compound 19-P4 was obtained. MS m / z (ESI): = 478.3 [M+H]+. HPLC (determination condition 3) Holding time: 2.787 min. 1 H NMR (400 MHz, メタノール-d4) δ 7.97 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 3.1 Hz, 1H), 6.81 (s, 1H), 6.70 (d, J =3.1 Hz, 1H), 5.04 (d, J = 8.9 Hz, 1H), 4.73 (t, J = 7.0 Hz, 1H), 4.60 (t, J =7.0 Hz, 1H), 4.48 (t, J = 6.4 Hz, 1H), 4.40 (t, J = 6.5 Hz, 1H), 4.06 (t, J =6.6 Hz, 1H), 3.92 (s, 3H), 3.19-3.09 (m, 1H), 2.52 (s, 4H), 1.88 (dq, J = 21.2,7.9, 7.4 Hz, 2H), 1.83-1.66 (m, 2H), 1.59 (dt, J = 12.2, 6.4 Hz, 1H), 1.25 (dt,J = 12.2, 9.3 Hz, 1H).

[0611] (Example 20) Modulation of compounds 20-P1, 20-P2, 20-P3 and 20-P4

[0612]

change

[0613] Step 1: Compound 18-1 (5 g, 21.81 mmol) was dissolved in tetrahydrofuran (100 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (98.13 mL, 98.13 mmol, 1 M) was added at 0° C. The mixture was stirred for 1 hour and then heated to 65° C. overnight. The reaction was monitored by LCMS and TLC. The reaction was quenched at 0° C. by slowly adding excess sodium sulfate decahydrate, and the mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain compound 20-1. MS m / z (ESI): = 130 [M+H] + .

[0614] Step 2: Compound 20-1 (2.3 g) was dissolved in dichloromethane (50 mL) and triethylamine (5.39 g, 53.41 mmol) was added. Di-tert-butyl dicarbonate (4.27 g, 19.58 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 15% ethyl acetate / petroleum ether to give compound 20-2. MS m / z (ESI): = 230 [M+H] + .

[0615] 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 added slowly at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 15% ethyl acetate / petroleum ether to give compound 20-3. MS m / z (ESI): = 172 [M-55] + .

[0616] Step 4: Compound 5-1 (732.08 mg, 2.79 mmol) was dissolved in tetrahydrofuran (15 mL), and a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (2.79 mL, 1.3 M) was slowly added dropwise under nitrogen protection at −40° C. After stirring for 1 hour, a solution of compound 20-3 (635 mg, 2.79 mmol) in tetrahydrofuran (5 mL) was added, and the mixture was stirred for an additional 3 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to give compound 20-4. MS m / z (ESI): = 386 [M+Na] + .

[0617] 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 portionwise at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate / petroleum ether to give compound 20-5. MS m / z (ESI): = 362 [M+H] + .

[0618] Step 6: Compound 20-5 (700 mg, 1.94 mmol) and ammonium acetate (149.28 mg, 1.94 mmol) were dissolved in methanol (20 mL), and sodium cyanoborohydride (122.01 mg, 1.94 mmol) was added. The mixture was stirred under reflux at 80 °C for 16 hours. The reaction was monitored by LCMS. The mixture was directly concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 50% ethyl acetate / petroleum ether to give compound 20-6. MS m / z (ESI): = 363 [M+H] + .

[0619] Step 7: Compound 1-6 (496.99 mg, 1.63 mmol), 2-(7-azabenzozol-1-yl)-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 was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 50% ethyl acetate / petroleum ether to give compound 20-7. MS m / z (ESI): = 650 [M+H] + .

[0620] Step 8: Compound 20-7 (570 mg, 0.88 mmol) was dissolved in dioxane (5 mL) and hydrochloric acid (5 mL, 2 M) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction mixture was directly concentrated to give compound 20-8. MS m / z (ESI): = 550 [M+H] + .

[0621] Step 9: Compound 20-8 (482 mg) was dissolved in methanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL), and lithium hydroxide (84.01 mg, 3.51 mmol) was added. The mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to approximately 4 with hydrochloric acid (1 M), and the mixture was directly concentrated to give the crude product. The crude product was purified by silica gel column chromatography using 30% methanol / dichloromethane, followed by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 20-P1. MS m / z (ESI): = 436 [M+H] + . HPLC (measurement condition 3) retention time: 2.396 minutes. 1 HNMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.64(d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.39-7.24 (m, 3H), 6.81 (s, 1H),6.65 (dd, J = 3.0, 1.9 Hz, 1H), 4.90 (t, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.33 (s,1H), 2.80-2.63 (m, 1H), 2.52 (d, J = 1.8 Hz, 1H), 2.49 (s, 3H), 2.43 (s, 3H),1.94 (s, 2H), 1.82-1.67 (m, 1H), 1.58 (d, J = 8.3 Hz, 1H), 1.38 (s, 1H), 1.28(d, J = 9.8 Hz, 1H).

[0622] Compound 20-P2 was obtained. MS m / z (ESI): = 436 [M+H] + .HPLC (Measurement conditions 3) Retention time: 2.545 minutes. 1H NMR (400 MHz, DMSO-d6)δ 11.04 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 7.83 (d, J =7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 2.7 Hz, 1H), 6.78 (s, 1H),6.62-6.46 (m, 1H), 4.98 (t, J = 8.3 Hz, 1H), 3.84 (s, 3H), 3.19-3.11 (m, 1H),2.48 (s, 3H), 2.42 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H), 2.14-2.01 (m, 1H), 1.75 (d, J = 7.5 Hz, 1H), 1.60 (d, J = 5.4 Hz, 1H), 1.53-1.31 (m, 3H).

[0623] Compound 20-P3 was obtained. MSm / z (ESI): = 436 [M+H] + HPLC (Determination Condition 3) Holding Time: 2.582 min. 1 H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.76 (d, J =7.9 Hz, 2H), 7.44-7.25 (m, 3H), 6.77 (s, 1H), 6.59 (d, J = 2.7 Hz, 1H), 4.92(t, J = 8.9 Hz, 1H), 3.82 (s, 3H), 3.39 (s, 1H), 2.73-2.64 (m, 1H), 2.52 (d, J= 3.5 Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H), 2.05 (s, 1H), 1.91 (s, 1H), 1.67–1.41 (m, 4H).

[0624] Compound 20-P4 was obtained. MSm / z (ESI): = 436 [M+H] + HPLC (Determination Condition 3) Holding Time: 2.755 min. 1H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.61 (d, J = 8.3 Hz, 1H), 7.75 (d, J =8.0 Hz, 2H), 7.40-7.24 (m, 3H), 6.78 (s, 1H), 6.56 (dd, J = 3.0, 2.0 Hz, 1H),4.87 (t, J = 9.1 Hz, 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).

[0625] Example 21 Preparation of Compound 21

[0626] [ka]

[0627] 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 min, the reaction was warmed to room temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. The reaction mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 45% to 50% ethyl acetate / petroleum ether to give compound 21-2. MS m / z (ESI): = 256.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.47-7.25 (m, 5H),5.12 (s, 2H), 3.70 (t, J = 6.3 Hz, 4H), 2.39 (t, J = 6.3 Hz, 4H).

[0628] Step 2: Compound 5-1 (1.08 g, 4.12 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (4.46 mL, 1.3 M) was added at -78 °C, and the mixture was stirred 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 reaction was warmed to 0 °C and stirred for 1 hour. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 45% to 50% ethyl acetate / petroleum ether to give compound 21-3. MS m / z (ESI):= 392.2 [M+Na] + . 1 H NMR (400 MHz,DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 2H), 7.63(d, J = 8.3 Hz, 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, 4.8 Hz, 2H), 1.60(d, J = 13.3 Hz, 2H).

[0629] Step 3: Compound 21-3 (430 mg, 1.16 mmol) was dissolved in chloroacetonitrile (8 mL). Acetic acid (0.2 mL) and concentrated sulfuric acid (0.2 mL) were added dropwise successively at 0 °C. After stirring for 5 minutes, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (80 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 45% to 50% ethyl acetate / petroleum ether to give compound 21-4. MS m / z (ESI): = 445.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.53 (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 =13.2 Hz, 2H), 3.84 (s, 3H), 3.16-3.06 (m, 2H), 2.32 (d, J = 13.1 Hz, 2H), 1.83(dt, J = 13.4, 6.8 Hz, 2H).

[0630] Step 4: Compound 21-4 (630 mg, 1.42 mmol) was dissolved in ethanol (10 mL). Thiourea (538.94 mg, 7.08 mmol) and acetic acid (0.2 mL) were added sequentially, and the reaction was heated to 85 °C and stirred for 16 h. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a 45%-50% ethyl acetate / petroleum ether gradient to give compound 21-5. MS m / z (ESI): = 352.1 [M-NH2] + . 1 H NMR (400 MHz, chloroform-d) δ 7.92-7.88(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 = 3.7 Hz, 2H), 3.45-3.35 (m, 2H), 2.06 (s, 2H), 1.83 (td, J = 12.8, 4.6Hz, 2H), 1.57 (d, J = 13.0 Hz, 2H).

[0631] Step 5: Compound 1-6 (250 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (2 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (467 mg, 1.23 mmol) was added under ice bath, and a solution of N,N-diisopropylethylamine (0.41 mL, 2.46 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 15 minutes. A solution of compound 21-5 (362 mg, 0.98 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 45% to 50% ethyl acetate / petroleum ether to give compound 21-6. MS m / z (ESI): = 656.7 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 8.52 (s, 1H), 7.94 (d, J = 8.3 Hz,2H), 7.66-7.61 (m, 3H), 7.41-7.33 (m, 5H), 6.97 (s, 1H), 6.45 (d, J = 3.7 Hz,1H), 5.11 (d, J = 7.9 Hz, 2H), 4.05-3.99 (m, 2H), 3.89 (s, 3H), 3.85 (d, J =6.2 Hz, 3H), 3.28-3.16 (m, 2H), 2.57 (s, 3H), 2.45 (s, 2H), 1.87 (td, J = 13.1,4.4 Hz, 2H), 1.58 (s, 9H).

[0632] Step 6: Compound 21-6 (500 mg, 0.76 mmol) was dissolved in ethyl acetate (6 mL) and stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated to give compound 21-7. MS m / z (ESI): = 522.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.31 (s, 1H), 7.96-7.91 (m, 2H),7.64-7.60 (m, 3H), 6.98 (s, 1H), 6.55 (d, J = 3.8 Hz, 1H), 3.94 (s, 3H), 3.85(s, 3H), 2.94 (t, J = 12.1 Hz, 2H), 2.83 (d, J = 12.5 Hz, 2H), 2.57 (s, 3H),2.33 (d, J = 12.7 Hz, 2H), 1.80 (dd, J = 13.4, 9.3 Hz, 2H), 1.58 (s, 9H).

[0633] Step 7: Compound 21-7 (50 mg, 0.096 mmol) was dissolved in methanol (2 mL). Acetic acid (2 drops), paraformaldehyde (25.90 mg, 0.29 mmol), and sodium cyanoborohydride (15.06 mg, 0.24 mmol) were added sequentially, and the reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched by adding water (10 mL), 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 to give the crude product. The crude product was purified by reverse-phase column chromatography using a 20%-30% acetonitrile / water gradient to give compound 21-8. MS m / z (ESI): = 536.2 [M+H] + .

[0634] 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 reaction was heated to 60 °C and stirred for 2 h. The reaction was monitored by LCMS. The pH was adjusted to neutral with hydrochloric acid (1 N). The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 21. MS m / z (ESI): = 422.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.57 (s, 1H),8.01-7.94 (m, 2H), 7.64-7.53 (m, 2H), 7.34 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H),6.35 (t, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.52 (d, J = 12.3 Hz, 2H), 3.38 (s,3H), 3.18 (q, J = 11.9, 11.3 Hz, 2H), 2.83 (d, J = 4.4 Hz, 2H), 2.73 (d, J =14.1 Hz, 2H), 2.49 (s, 3H).

[0635] Example 22 Preparation of Compound 22

[0636] [ka]

[0637] 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 reaction was stirred at 25 °C for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL) and extracted with dichloromethane (3 x 60 mL). The combined organic phase was washed with saturated brine (100 mL), dried, and concentrated to give compound 22-2. MS m / z (ESI): = 208.2 [M+H] + .

[0638] Step 2: Under a 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 h, the reaction was warmed to room temperature and stirred for 24 h. The reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 5% to 10% ethyl acetate / petroleum ether to give compound 22-3. MS m / z(ESI):=219.2[M+H] + .

[0639] 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 reaction was then warmed to room temperature and stirred for 2 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with 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 to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 5% to 10% ethyl acetate / petroleum ether to give compound 22-4. MS m / z (ESI): = 353.2 [M+H] + .

[0640] 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). 30% hydrogen peroxide solution (2.28 mL, 22.70 mmol) was added dropwise at 0 °C. The reaction was then warmed to room temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 30% to 50% ethyl acetate / petroleum ether to give compound 22-5. MS m / z (ESI): = 371.2 [M+H] + .

[0641] Step 5: Compound 22-5 (200 mg, 0.54 mmol) was dissolved in acetonitrile (1.5 mL) and water (1.5 mL). [Bis(trifluoroacetoxy)iodo]benzene (232.2 mg, 0.54 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (5 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic phase was washed with saturated brine (8 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 30% to 50% ethyl acetate / petroleum ether to give compound 22-6. MS m / z (ESI): = 343.2 [M+H] + .

[0642] Step 6: Compound 22-6 (150 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (4 mL). Compound 1-6 (133.78 mg, 0.44 mmol), N,N-diisopropylethylamine (72.60 μL, 0.44 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166.6 mg, 0.44 mmol) were added, and the reaction was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (10 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 10% to 20% ethyl acetate / petroleum ether to give compound 22-7. MS m / z(ESI):=630.4[M+H] + .

[0643] Step 7: Compound 22-7 (270 mg, 0.43 mmol) was dissolved in methanol (5 mL) and water (2 mL). Lithium hydroxide (20.5 mg, 0.86 mmol) was added, and the reaction was heated to 45 °C and stirred for 16 h. The reaction was monitored by LCMS. The pH was adjusted to neutral with hydrochloric acid (1 M), and the organic phase was concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography using a gradient of 15% to 100% acetonitrile / buffer (0.01 mol / L aqueous ammonium bicarbonate) to give compound 22. MS m / z (ESI): = 516.3 [M+H] + . 1H 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, 5.5Hz, 4H), 1.94-1.83 (m, 2H). The relative stereochemistry of compound 22 was confirmed by 2D NOESY experiments (H14 is H 33 / H 34 (NOE correlation shown).

[0644] Example 23 Preparation of compounds 23-P1 and 23-P2

[0645] [ka]

[0646] Step 1: Compound 23-1 (8.0 g, 50.57 mmol) was dissolved in N,N-dimethylformamide (200 mL). Sodium hydride (4.1 g, 101.25 mmol) was added portionwise under ice-water bath. The reaction was warmed to room temperature and stirred for 20 minutes. Iodoethane (10.2 g, 65.40 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 8% to 12% ethyl acetate / petroleum ether to give compound 23-2. MS m / z (ESI): = 187.1 [M+H] + .1 H NMR (400 MHz,DMSO-d6) δ 3.84 (s, 4H), 3.41 (q, J = 7.0 Hz,2H), 3.35 (dd, J = 7.4, 3.7 Hz, 1H), 1.77-1.62 (m, 4H), 1.55-1.41 (m, 4H), 1.09(t, J = 7.0 Hz, 3H).

[0647] 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 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 8% to 12% ethyl acetate / petroleum ether to give compound 23-3. MS m / z (ESI): = 143.1 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 3.72-3.65 (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 = 7.2 Hz, 3H).

[0648] 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, and the mixture was stirred for 1 h. A solution of compound 23-3 (11 g, 77.36 mmol) in tetrahydrofuran (50 mL) was added at -50 °C. After 5 min, the reaction was warmed to 0 °C and stirred for 2 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic phases were washed with saturated brine (400 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 3% to 5% methanol / dichloromethane to give compound 23-4. MS m / z (ESI): = 261.1 [M-17] + .

[0649] Step 4: Compound 23-4 (800 mg, 2.87 mmol) was dissolved in chloroacetonitrile (5 mL). Acetic acid (1 mL) and concentrated sulfuric acid (1 mL) were added dropwise slowly in sequence at 0 °C, and the reaction was stirred at 0 °C for 30 min. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 45% to 50% ethyl acetate / petroleum ether to give compound 23-5-P1 (MS m / z (ESI): = 354.2 [M+H]). + , retention time: 1.075 min) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (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 = 7.0 Hz, 2H), 2.08 (d, J = 13.2 Hz, 2H), 2.00-1.90 (m,2H), 1.70 (dt, J = 8.5, 3.4 Hz, 4H), 1.12 (t, J = 7.0 Hz, 3H).

[0650] Compound 23-5-P2 was obtained (MS m / z(ESI):=354.2[M+H)). + Duration: 1.042 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (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 = 7.0 Hz, 2H), 2.33 (d, J = 12.8 Hz, 2H), 1.88-1.80 (m,2H), 1.72 (dd, J = 13.5, 3.4 Hz, 2H), 1.47 (q, J = 12.1 Hz, 2H), 1.10 (t, J =7.0 Hz, 3H).

[0651] 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 reaction was heated to 85 °C and stirred for 6 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in dichloromethane, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0% to 30% ethyl acetate / petroleum ether to give compound 23-6-P1. MS m / z (ESI): = 278.5 [M+H] + .

[0652] Compound 23-5-P2 was converted to compound 23-6-P2 according to the procedure for the preparation of 23-6-P1 from 23-5-P1. MS m / z (ESI): = 278.5 [M+H] + .

[0653] Step 6: Compound 23-6-P1 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL). Compound 1-6 (132.1 mg, 0.43 mmol), 2-(7-azabenzotriazol-1-yl)-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. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 30% to 40% ethyl acetate / petroleum ether to give compound 23-7-P1. MS m / z (ESI): = 565.3 [M+H] + .

[0654] Compound 23-6-P2 was converted to compound 23-7-P2 according to the procedure for the preparation of 23-7-P1 from 23-6-P1. MS m / z (ESI): = 565.3 [M+H] + .

[0655] 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). Lithium hydroxide (33.4 mg, 0.80 mmol) was added, and the reaction was stirred at 50 °C for 16 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral with hydrochloric acid (1 M), followed by filtration and concentration. The crude product was purified by reverse-phase column chromatography using a gradient of 0% to 95% acetonitrile / buffer (0.01 mol / L aqueous formic acid) to give compound 23-P1. MS m / z (ESI): = 451.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 12.76 (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 = 2.8 Hz, 1H), 6.83(s, 1H), 6.51 (dd, J = 3.0, 2.0 Hz, 1H), 3.90 (s, 3H), 3.61 (t, J = 3.1 Hz,1H), 3.46 (q, J = 7.0 Hz, 2H), 2.49 (s, 3H), 2.22 (d, J = 12.9Hz, 2H),2.10-1.96 (m, 2H), 1.82 (q, J = 15.1, 14.3 Hz, 4H), 1.15 (t, J = 7.0 Hz, 3H).

[0656] Compound 23-P2 was obtained from compound 23-7-P2 by a method similar to that used to prepare 23-P1 from 23-7-P1. MS m / z (ESI): = 451.3 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 12.74 (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 = 2.8 Hz, 1H), 6.84 (s,1H), 6.54 (dd, J = 3.0, 2.0 Hz, 1H), 3.93 (s, 3H), 3.50 (q, J = 7.0 Hz, 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 = 7.0 Hz, 3H).

[0657] Example 24 Preparation of compounds 24-P1 and 24-P2

[0658] [ka]

[0659] Step 1: Compound 5-1 (92.62 g, 353.44 mmol) was dissolved in tetrahydrofuran (600 mL). Under argon protection at −78° C., isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (294.5 mL, 1.3 M) was added, and the mixture was stirred for 1 hour. Under argon protection at −50° C., a solution of compound 24-1 (46 g, 294.53 mmol) in tetrahydrofuran (200 mL) was added. After 5 minutes, the temperature was raised to 0° C., and the mixture was stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL), and the mixture was extracted with ethyl acetate (3×800 mL). The organic phases were combined, washed with saturated brine (400 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (concentration gradient: 3% to 5% methanol / dichloromethane) to give compound 24-2. MS m / z (ESI): = 275.1 [M-17]+ . 1 H NMR (400 MHz,DMSO-d6) δ 7.95-7.87 (m, 2H), 7.63-7.55 (m,2H), 5.10 (s, 1H), 3.89 (d, J = 2.0 Hz, 4H), 3.84 (s, 3H), 1.95 (d, J = 8.6 Hz,4H), 1.60 (m, 4H).

[0660] Step 2: Compound 24-2 (26 g, 88.94 mmol) was dissolved in chloroacetonitrile (20 mL). At 0 °C, acetic acid (15 mL) and concentrated sulfuric acid (15 mL) were added dropwise, successively. The mixture was stirred at 0 °C for an additional 30 minutes. The reaction was monitored by LCMS and TLC. The reaction was quenched by the addition of saturated sodium bicarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (3 × 800 mL). The organic phases were combined, washed with saturated brine (200 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (gradient: 45% to 50% ethyl acetate / petroleum ether) to give compound 24-3. MS m / z (ESI): = 306.0 [M-17] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.73 (s, 1H), 7.94-7.88 (m, 2H),7.60-7.52 (m, 2H), 4.19 (s, 2H), 3.84 (d, J = 2.1 Hz, 3H), 2.61 (m, 4H), 2.22(t, J = 14.2 Hz, 4H).

[0661] 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, followed by dropwise addition of acetic acid (30 mL). The reaction mixture was heated to 85 °C and stirred for 6 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give the crude product. Dichloromethane was added to the crude product, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (gradient: 4% to 5% methanol / dichloromethane) to give compound 24-4. MS m / z (ESI): = 248.1 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 7.97-7.85 (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, 3.0 Hz, 2H).

[0662] Step 4: Compound 1-6 (1.38 g, 4.53 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under an ice bath, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.58 g, 6.79 mmol) was added, and 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 allowed to warm 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 added dropwise to the reaction mixture, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (80 mL), and the mixture was extracted with ethyl acetate (3 × 70 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (gradient: 30% to 40% ethyl acetate / petroleum ether) to give compound 24-5. MS m / z (ESI): = 535.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.74 (s, 1H), 7.99-7.93 (m, 2H),7.73-7.62 (m, 3H), 6.98 (s, 1H), 6.45 (d, J = 3.7 Hz, 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).

[0663] Step 5: Compound 24-5 (3.00 g, 5.61 mmol) was dissolved in N,N-dimethylformamide (30 mL). Acetic acid (5 drops) and 3,3-difluorotrimethyleneimine hydrochloride (2.18 g, 16.9 mmol) were added, and the mixture was stirred for 30 minutes. Sodium borohydride acetate (3.58 g, 16.85 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient: 5% to 25% ethyl acetate / petroleum ether) to give compound 24-6-P1 (MS m / z (ESI): = 612.3 [M+H]). + , retention time: 0.733 min) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.9 Hz, 2H),6.96 (s, 1H), 6.48 (d, J = 3.7 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.91 (s, 3H),3.85 (s, 3H), 3.56 (t, J = 12.3 Hz, 4H), 2.56 (s, 3H), 2.13 (d, J = 12.7 Hz,2H), 2.04 (t, J = 12.4 Hz, 2H), 1.86 (t, J = 13.3 Hz, 2H), 1.58 (s, 9H), 1.50(d, J = 13.9 Hz, 2H).

[0664] Compound 24-6-P2 was obtained (MS m / z(ESI):=612.3[M+H] + , retention time: 0.887 minutes). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 3.3 Hz, 2H),6.96 (s, 1H), 6.53 (d, J = 3.7 Hz, 1H), 4.31 (t, J = 12.6 Hz, 1H), 3.94 (s,3H), 3.85 (s, 3H), 3.57 (t, J = 12.2 Hz, 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 = 12.4 Hz, 1H).

[0665] Step 6: Compound 24-6-P1 (500 mg, 0.82 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (343 mg, 8.18 mmol) was added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction was monitored by LCMS. The reaction mixture was adjusted to neutral pH with hydrochloric acid (1 M), stirred for 30 minutes, and concentrated to remove tetrahydrofuran. The residue was triturated with methanol, filtered, and the solid was collected. The solid was triturated with water, filtered, dissolved in acetonitrile and water, and lyophilized to give 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 determined as follows: 1 In the H NMR spectrum, 27a / H 29a The peak shape of H 28 In the NOE, H 14 is at the axis position H 14 and H 27a / H 29a A correlation was observed between H 28 and H 14 showed a relative cis configuration. Therefore, compound 24-P1 was determined to have a relative trans configuration.

[0666] Compound 24-P2 was obtained from compound 24-6-P2 by a method similar to that used to prepare 24-P1 from 24-6-P1. MS m / z (ESI): = 498.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 11.03 (s, 1H), 8.21 (s, 1H), 7.88(d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 2.9 Hz, 1H), 6.83(s, 1H), 6.55 (t, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.57 (t, J = 12.3 Hz, 4H),2.45 (s, 3H), 2.25 (t, J = 11.3 Hz, 1H), 1.79-1.63 (m, 4H), 1.47 (q, J = 12.0Hz, 2H).

[0667] Example 25 Preparation of compounds 25-P1 and 25-P2

[0668] [ka]

[0669] Step 1: Compound 25-1 (30.3 g, 154.64 mmol) was dissolved in sulfuric acid (120 mL) and nitric acid (8 mL) in an ice bath, and the mixture was stirred at 0 °C for 2 h. The reaction was monitored by LCMS. Water (1000 mL) was added to quench the reaction, and solid sodium carbonate was added to adjust the pH to neutral. The reaction mixture was extracted with ethyl acetate (3 × 500 mL), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 10% to 16% ethyl acetate / petroleum ether to give compound 25-2. MS m / z (ESI): = 241.0 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 8.63 (s, 1H), 8.15 (s, 1H), 2.58(s, 3H)

[0670] Step 2: Under nitrogen protection at -20 °C, compound 25-2 (1.5 g, 6.25 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and a solution of vinylmagnesium bromide in tetrahydrofuran (25 mL, 1 M, 25 mmol) was added. The mixture was warmed to room temperature and stirred for 1.5 h. The reaction was monitored by LCMS. Saturated ammonium chloride solution (100 mL) was added, followed by water (100 mL) to quench the reaction. The mixture was extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 20% to 30% ethyl acetate / petroleum ether to give compound 25-3. MS m / z (ESI): = 235.0 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 11.96 (s, 1H), 7.69 (t, J = 2.9Hz, 1H), 7.33 (s, 1H), 6.57 (dd, J = 3.1, 1.8 Hz, 1H), 2.56 (s, 3H).

[0671] Step 3: Compound 25-3 (2.0 g, 8.51 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL), followed by the addition of cesium carbonate (5.6 g, 17.19 mmol), [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (625 mg, 0.86 mmol), and cyclopropyl-boronic acid (1.1 g, 12.81 mmol). The mixture was stirred at 90 °C for 16 h. The reaction was monitored by TLC. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 10% to 20% ethyl acetate / petroleum ether to give compound 25-4. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.55 (t, J = 2.9 Hz, 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).

[0672] Step 4: Under nitrogen protection at -78 °C, compound 25-4 (200 mg, 1.02 mmol) was dissolved in toluene (4 mL) and a solution of diisobutylaluminum hydride in hexane (1.6 mL, 1 M, 1.60 mmol) was added. The reaction was stirred at -78 °C for 1.5 h. The reaction was monitored by LCMS. Sodium sulfate decahydrate was added to quench the reaction, and the mixture was stirred for 30 min, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 10% to 20% ethyl acetate / petroleum ether to give compound 25-5. MS m / z (ESI): = 200.0 [M+H] + .

[0673] Step 5: Compound 25-5 (917 mg, 4.60 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (1.92 mL, 13.81 mmol), 4-dimethylamino-pyridine (112 mg, 0.92 mmol), and di-tert-butyl dicarbonate (1.5 g, 6.90 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 5% to 15% ethyl acetate / petroleum ether to give compound 25-6. MS m / z (ESI): = 300.2 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ 10.87 (s, 1H), 7.80 (d, J = 3.7Hz, 1H), 6.94 (s, 1H), 6.70 (d, J = 3.7 Hz, 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).

[0674] Step 6: Compound 25-6 (1.35 g, 4.51 mmol) was dissolved in tetrahydrofuran (9 mL) and water (6 mL), followed by the addition of 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). The mixture was stirred at 0 °C for 30 min. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a gradient of 5% to 25% ethyl acetate / petroleum ether to give compound 25-7. MS m / z (ESI): = 316.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 7.65 (d, J = 3.8 Hz, 1H), 6.74(d, J = 3.8 Hz, 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).

[0675] Step 7: Compound 25-7 (127.53 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazol-1-yl)-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 temperature was raised to room temperature, and the mixture was stirred for 15 minutes. A solution of 24-4 (100 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases w...

Claims

1. Compounds of formula (I): 【Chemistry 1】 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 (In the formula, R １ Is, -L ２ -R Ｌ and L ２ is a direct bond, linear or branched C １～６ Alkylene or linear or branched C ２～６ is alkenylene, Optionally, C １～６ Alkylene or C ２～６ One available carbon atom in an alkenylene is substituted with two substituents, whereby the two substituents together with the carbon atom form an optionally substituted C ３～６ forming a cycloalkylene or an optionally substituted 3- to 6-membered heterocycloalkylene, or optionally, C １～６ Alkylene or C ２～６ The two adjacent carbon atoms in an alkenylene are １～４ Optionally substituted C linked via alkylene ３～６ form a cycloalkylene or are linked via —S—, —O—, —NH— or a straight-chain 2- to 4-membered heteroalkylene to form an optionally substituted 3- to 6-membered heterocycloalkylene; Said C １～６ Alkylene or C ２～６ Alkenylene is a group containing halogen, OH, SH, CN, C １～４ Haloalkyl, —O—C １～４ Alkyl, —NR １ａ R １ｂ , C ３～１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl, C ６～１０ optionally substituted with one, two, three or more substituents independently selected from aryl and 5- to 10-membered heteroaryl; The moiety L is linked to the carbon atom marked by the symbol "#". ２ -R Ｌ The CH ２ is O, S or NR, if present １ｅ and optionally replaced by R Ｌ is R ９ , R １０ , -O-R １０ , -S-R １０ and -NR １ｅ -R １０ is selected from R １０ is H, R １１ , halogen, OH, SH, CN, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —O—C １～６ Alkyl, —O—C ２～６ Alkenyl, —O—C ２～６ Alkynyl, guanidyl and —C １～６ alkylene-guanidyl; １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —O—C １～６ Alkyl, —O—C ２～６ Alkenyl and —O—C ２～６ Alkynyl is halogen, OH, SH and NH ２ and optionally substituted with one, two or more substituents independently selected from R ９ and R １１ is -(CH ２ ) ０～６ -C ３～１０ Cyclic hydrocarbon groups, -(CH ２ ) ０～６ -3 to 10-membered heterocyclic hydrocarbon group, -(CH ２ ) ０～６ -C ５～１０ Bridged cyclic hydrocarbon groups, -(CH ２ ) ０～６ -5 to 10-membered bridged heterocyclyl, -(CH ２ ) ０～６ -C ５～１１ Monospirocyclic hydrocarbon group, -(CH ２ ) ０～６ -5 to 11-membered monospiroheterocyclyl, -(CH ２ ) ０～６ -C ６～１０ Aryl and -(CH ２ ) ０～６ - 5- to 10-membered heteroaryl, each of which is independently selected from: 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 -O-C １～６ Alkyl, —O—C １～６ Alkylene-C ３～１０ Cyclic hydrocarbon group, —O—C 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 and optionally substituted with one, two or more substituents independently selected from Cy is an optionally substituted C ３～１０ Cycloalkyl, optionally substituted C ３～１０ Cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６～１０ selected from aryl and optionally substituted 5-10 membered heteroaryl; R ２ is 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 and R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R ２ａ and R ２ｂ is H, C, if present １～６ Alkyl, C １～６ Haloalkyl, —C １～６ Alkylene -OH, -C １～６ Alkylene -SH, -C １～６ Alkylene-NH ２ and -C １～６ alkylene-CN; R １ｃ and R １ｄ together with the carbon atom to which they are attached, represent an optionally substituted C ３～６ optionally forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl; or R １ and R ２ together with the carbon atoms to which they are attached, marked by the symbol "#", form the following formula: 【Chemistry 2】 forming a portion represented by During the ceremony, Ring D is C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ５～１０ a bridged cycloalkyl or a 5- to 10-membered bridged heterocycloalkyl; R ６ Below: H, halogen, OH, SH, CN, N(R ７ａ ) ２ , C １～６ Alkyl, C ２～６ alkenyl or C ２～６ Alkynyl (which are halogen, OH, SH, NH ２ and CN), -O-C １～６ Alkyl, —O—C １～６ Haloalkyl, —C １～６ Alkylene -O-C １～６ Alkyl, —C １～６ Alkylene -O-C １～６ Haloalkyl, C ３～１０ cyclic hydrocarbon group, -C １～６ Alkylene-C ３～１０ Cyclic hydrocarbon group, —O—C １～６ Alkylene-C ３～１０ Cyclic hydrocarbon group or —C(O)—C ３～１０ Cyclic hydrocarbon group (C ３～１０ Cyclic hydrocarbons, when present, may contain deuterium, halogens, OH, SH, NH ２ , 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 haloalkoxy), and 3- to 10-membered heterocycloalkyl or —C １～６ alkylene-3 to 10 membered heterocycloalkyl (heterocycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , 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 and optionally substituted with one, two or more substituents independently selected from haloalkoxy. is selected from R ７ａ is H, C １～６ Alkyl, -(CH ２ ) ｑ -C ３～１０ A cyclic hydrocarbon group or -(CH ２ ) ｑ - 3 to 10 membered heterocycloalkyl (q is an integer between 0 and 6), １～６ Alkyl, -(CH ２ ) ｑ -C ３～１０ A cyclic hydrocarbon group or -(CH ２ ) ｑ -3 to 10 membered heterocycloalkyl are each selected from deuterium, halogen, OH, SH, NH ２ , 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 optionally substituted with one, two or more substituents independently selected from haloalkoxy; n is 1, 2 or 3; Ring A is C ６～１０ aryl or 5-10 membered heteroaryl; R ３ are halogen, OH, SH, CN, and —NR, respectively. ３ａ R ３ｂ , -C １～４ Alkylene -OH, -C １～４ 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 5-6 membered heteroaryl containing 1-4 N heteroatoms and 0-1 O or S atoms; R ３ａ / R ３ｂ is, if present, H and C １～６ independently selected from alkyl, p is 1, 2 or 3; L １ teeth, ＊ -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)-; ＊ is connected to the phenyl ring B, R ４ａ and R ４ｂ is H, deuterium, halogen, OH, SH, CN, C １～６ Alkyl, C １～６ Haloalkyl, 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 both attached, ３～６ forming a cycloalkyl or a 4- to 7-membered heterocycloalkyl, R ４ｃ is H, C １～６ Alkyl or C １～６ haloalkyl; R is 【Transformation 3】 and During the ceremony, R ４ is 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, —O—C １～６ Alkyl, —O—C １～６ Haloalkyl, —S—C １～６ Alkyl, —S(O) ２ -C １～６ Alkyl, —C １～６ Alkylene -O-C １～６ Alkyl, —OC １～６ Alkylene -O-C 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 Cyclic hydrocarbon groups and -OC １～６ Alkylene-C ３～１０ cyclic hydrocarbon groups, １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —O—C １～６ Alkyl, —O—C １～６ Haloalkyl, —S—C １～６ Alkyl, —S(O) ２ -C １～６ Alkyl, —C １～６ Alkylene -O-C 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 Cyclic hydrocarbon groups and -OC １～６ Alkylene-C ３～１０ the cyclic hydrocarbon groups are each optionally substituted with one or more deuterium atoms (D); R ５ is 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, —O—C １～６ Alkyl, —S—C １～６ Alkyl, —C １～６ Alkylene -OH, -C １～６ Alkylene -SH or C ３～１０ carbocyclyl, R ５ａ , R ５ｂ , R ６ａ and R ６ｂ is, if present, H and C １～６ independently selected from alkyl, X is CR ７ , C(R ７ ) ２ and N; Y is CR ８ , C(R ８ ) ２ and N; Z is selected from O, S and NH; R ７ and R ８ When present, H, halogen, OH, SH, CN, NH ２ , —NH(C １～６ alkyl), -N(C １～６ alkyl) ２ , C １～６ Alkyl and C ３～１０ are independently selected from cyclic hydrocarbon groups; 【Chemistry 4】 represents a double or single bond).

2. R １ But, -L ２ -R Ｌ and L ２ is a direct bond, R Ｌ But, R ９ 2. The compound of claim 1, wherein:

3. R ９ But C ３～１０ Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C ５～１０ Bridged cyclic hydrocarbon group, 5- to 10-membered bridged heterocyclic group, C ５～１１ Monospirocyclic hydrocarbon groups, 5- to 11-membered monospiroheterocyclic groups, C ６～１０ aryl and 5-10 membered heteroaryl, each of which is selected from the following: 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 -O-C １～６ Alkyl, —O—C １～６ Alkylene-C ３～１０ Cyclic hydrocarbon group, —O—C 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- to 10-membered heterocycloalkyl, —NR １ａ -(optionally substituted C ３～１０ cycloalkyl), -NR １ａ -(optionally substituted C ３～１０ cycloalkenyl), -NR １ａ -(optionally substituted 3- to 10-membered heterocyclic group) and -CR １ｃ R １ｄ —C(O)—NR １ａ R １ｂ and optionally substituted with one, two or more substituents independently selected from the group consisting of: Preferably, R ９ But C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C ５～１０ Bridged cycloalkyl, C ５～１０ Bridged cycloalkenyl, 5- to 10-membered bridged heterocycloalkyl, 5- to 10-membered bridged heterocycloalkenyl, C ５～１１ Monospirocyclic alkyl, C ５～１１ monospirocyclic alkenyl, 5- to 11-membered monospiroheterocycloalkyl, 5- to 11-membered monospiroheterocyclo-alkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from 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 -O-C １～４ Alkyl, —O—C 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- to 10-membered heterocycloalkyl (optionally substituted with one, two or more halogens), —NR １ａ -(optionally substituted C ３～６ cycloalkyl), -NR １ａ -(optionally substituted C ３～１０ cycloalkenyl), -NR １ａ -(optionally substituted 3- to 10-membered heterocyclic group) and -CR １ｃ R １ｄ —C(O)—NR １ａ R １ｂ and optionally substituted with one, two or more substituents independently selected from the group consisting of: １ａ , R １ｂ , R １ｃ and R １ｄ If exists, H, C １～４ Alkyl, C １～４ Haloalkyl, —C １～４ Alkylene -OH, -C １～４ Alkylene -SH, -C １～４ Alkylene-NH ２ and -C １～４ alkylene-CN; R １ｃ and R １ｄ together with the carbon atom to which they are both attached, an optionally substituted C ３～６ optionally forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl; More preferably, R ９ But C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C ５～１０ Bridged cycloalkyl, C ５～１０ Bridged cycloalkenyl, 5- to 10-membered bridged heterocycloalkyl, 5- to 10-membered bridged heterocycloalkenyl, C ５～１１ Monospirocyclic alkyl, C ５～１１ monospirocyclic alkenyl, phenyl, and 5- or 6-membered heteroaryl, each of which is selected from 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 -O-C １～４ Alkyl, —O—C 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 with one, two or more halogens), —NR １ａ -(optionally substituted C ３～１０ cycloalkenyl) and —NR １ａ -(optionally substituted 3- to 10-membered heterocyclic group), and R １ａ and R １ｂ are, if present, H and C, respectively. １～４ independently selected from alkyl, More preferably, R ９ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]heptanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl, azetidinooctyl, dihydropyrrolyl, dihydroimidazolyl, azetidinooctenyl, C ５ , C ６ or C ７ Bridged cycloalkyl (e.g., 【Transformation 5】 ), C ５ , C ６ or C ７ Bridged cycloalkenyl, 6-, 7-, 8- or 9-membered bridged heterocycloalkyl, C ５～１１ and selected from monospirocycloalkyl, 5- to 11-membered monospiroheterocycloalkyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridone group, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidinone group, each of which is selected from F, Cl, OH, SH, CN, NH ２ , C.H. ３ , C.H. ２ CH ３ , C.H. ２ Cl, CF ３ , -CH ２ CF ３ , -CH ２ —OH, —CH ２ -SH, -CH ２ -NH ２ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ -NH-C(O)CH ３ , =O, =CH ２ , -OCH ３ , -OCH ２ CH ３ , —O—CH ２ -cyclopropyl, phenoxy, -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ ) ２ , -NH-C(O)CH ３ , -NH-C(O)NH ２ , 【Transformation 6】 -NH-S(O) ２ CH ３ 、 【Transformation 7】 optionally substituted with one, two or more substituents independently selected from the group consisting of:

3. The compound of claim 1 or 2.

4. R １ But, -L ２ -R Ｌ and L ２ However, linear or branched C １～６ Alkylene or linear or branched C ２～６ is alkenylene, Optionally, C １～６ Alkylene or C ２～６ One available C atom in the alkenylene is substituted by two substituents, and thus the two substituents together with the C atom form an optionally substituted C ３～６ forming a cycloalkylene or an optionally substituted 3- to 6-membered heterocycloalkylene, or optionally, C １～６ Alkylene or C ２～６ The two adjacent carbon atoms in an alkenylene are linear C １～４ C linked by alkylene and optionally substituted ３～６ form a cycloalkylene, or are joined by —S—, —O—, —NH— or a linear 2-4 membered heteroalkylene to form an optionally substituted 3-6 membered heterocycloalkylene; C １～６ Alkylene or C ２～６ Alkenylene is halogen, OH, SH, CN, C １～４ Haloalkyl, —O—C １～４ Alkyl, —NR １ａ R １ｂ , C ３～１０ Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups, C ６～１０ optionally substituted with one, two, three or more substituents independently selected from the group consisting of aryl and 5- to 10-membered heteroaryl; L attached to the carbon atom marked by the symbol "#" ２ -R Ｌ Partial CH ２ (if present) is O, S or NR １ｅ and optionally replaced by R Ｌ But, R １０ , -O-R １０ , -S-R １０ and -NR １ｅ -R １０ 2. The compound of claim 1 selected from:

5. C ３～６ cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and / or 3- to 6-membered heterocycloalkylene is 4- to 6-membered heterocycloalkylene, preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or thiomorpholinyl, and / or L ２ Linear or branched C １～６ Alkylene or linear or branched C ２～６ The optional substituents on the alkenylene are F, Cl, OH, SH, CN, C １～４ Haloalkyl, —O—C １～４ Alkyl, —NH ２ , —NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , C ３～６ Cycloalkyl, 3-6 membered heterocycloalkyl, preferably CF ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -OCH ３ , cyclopropyl and azetidinyl, 10. The compound of claim 1 or 4.

6. R １ But, -CR ａｌ R ｂｌ -(CRclR 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 and R ａｌ , R ｂｌ , R ｃｌ and R ｄｌ When present, each represents H, halogen, OH, SH, CN, C １～４ Alkyl, C １～４ Haloalkyl, —O—C １～４ Alkyl, —NR １ａ R １ｂ , C ３～１０ Cyclic hydrocarbon groups, 3- to 10-membered heterocyclic hydrocarbon groups, C ６～１０ independently selected from aryl and 5-10 membered heteroaryl; Optionally, one CR ｃｌ R ｄｌ R in ａｌ and R ｂｌ or R ｃｌ and R ｄｌ together with the carbon atoms to which they are both attached, =CH ２ , =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 ) ｍ Two adjacent carbon atoms in a linear carbon chain are linear C １～４ Connected by alkylene, C ３～６ form a cycloalkylene, or are joined by —S—, —O—, —NH— or a linear 2- to 4-membered heteroalkylene to form a 3- to 6-membered heterocycloalkylene; R １ａ and R １ｂ If present, H and C １～６ are each independently selected from alkyl, R １ｅ If present, H and C １～４ are each independently selected from alkyl, 5. The compound of claim 1, wherein m is 0, 1, 2, 3, 4, or 5.

7. C ３～６ cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and / or 3- to 6-membered heterocycloalkylene is 4- to 6-membered heterocycloalkylene, preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or thiomorpholinyl, and / or R ａｌ , R ｂｌ , R ｃｌ and R ｄｌ When present, H, F, Cl, OH, SH, CN, C １～４ Haloalkyl, —O—C １～４ Alkyl, —NH ２ , —NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , C ３～６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, preferably H, CF ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -OCH ３ , cyclopropyl, and azetidinyl; and / or One CR ｃｌ R ｄｌ R in ａｌ and R ｂｌ or R ｃｌ and R ｄｌ together with the carbon atoms to which they are both attached, =CH ２ , C ３～６ forming a cycloalkylene or a 3- to 6-membered heterocycloalkylene, and / or 7. The compound of claim 6, wherein m is 0, 1 or 2.

8. Structure of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7): 【Transformation 8】 8. The compound of claim 6 or 7, having the formula: wherein m is preferably 0, 1 or 2.

9. R １０ But, H, R １１ , F, Cl, OH, SH, CN, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, —O—C １～４ Alkyl, —O—C ２～４ Alkenyl, —O—C ２～４ Alkynyl, guanidinyl and —C １～４ alkylene-guanidinyl, １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, —O—C １～６ Alkyl, —O—C ２～４ Alkenyl and —O—C ２～４ Alkynyl is selected from halogen, OH, SH and NH ２ and optionally substituted by one, two or more substituents independently selected from １０ But, H, R １１ , F, Cl, OH, SH, CN, methyl, ethyl, allyl, propargyl, CF ３ , -CH ２ CF ３ , -OCH ３ , -OCH ２ CH ３ , guanidinyl and —CH ２ CH ２ - guanidinyl, and / or R １１ But -(CH ２ ) ０～６ -C ３～１０ Cyclic hydrocarbon groups, -(CH ２ ) ０～６ -3 to 10 membered heterocyclic group, -(CH ２ ) ０～６ -C ５～１０ Bridged cyclic hydrocarbon groups, -(CH ２ ) ０～６ -5 to 10 membered bridged heterocyclic group, -(CH ２ ) ０～６ -C ５～１１ Monospirocyclic hydrocarbon group, -(CH ２ ) ０～６ - 5 to 11-membered monospiroheterocyclic group, -(CH ２ ) ０～６ -C ６～１０ Aryl and -(CH ２ ) ０～６ - 5- to 10-membered heteroaryl, each of which is 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 -O-C １～６ Alkyl, —O—C １～６ Alkylene-C ３～１０ Cyclic hydrocarbon group, —O—C 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- to 6-membered heterocycloalkyl, -(optionally substituted C １～６ alkylene)-C ３～６ cycloalkyl, -(optionally substituted C １～６ alkylene)-(3- to 6-membered heterocycloalkyl), —NR １ａ -(optionally substituted C ３～６ cycloalkyl), -NR １ａ -(optionally substituted 4- to 7-membered heterocyclic group) and -CR １ｃ R １ｄ —C(O)—NR １ａ R １ｂ and optionally substituted with one, two or more substituents independently selected from Preferably, R １１ But -(CH ２ ) ０～３ -C ３～１０ Cycloalkyl, -(CH ２ ) ０～３ -C ３～１０ Cycloalkenyl, -(CH ２ ) ０～３ -3 to 10-membered heterocycloalkyl, -(CH ２ ) ０～３ -3 to 10-membered heterocycloalkenyl, -(CH ２ ) ０～３ -C ５～１０ Bridged cycloalkyl, —(CH ２ ) ０～３ -C ５～１０ Bridged cycloalkenyl, —(CH ２ ) ０～３ -5 to 10 membered bridged heterocycloalkyl, -(CH ２ ) ０～３ -5 to 10-membered bridged heterocycloalkenyl, -(CH ２ ) ０～３ -C ５～１１ Monospirocycloalkyl, -(CH ２ ) ０～３ -C ５～１１ Monospiro-cycloalkenyl, -(CH ２ ) ０～３ -5 to 11-membered monospiroheterocycloalkyl, -(CH ２ ) ０～３ -5 to 11-membered monospiroheterocycloalkenyl, -(CH ２ ) ０～３ -phenyl and -(CH ２ ) ０～３ - 5- or 6-membered heteroaryl, each of which is 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 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 -O-C １～４ Alkyl, —O—C 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- to 6-membered heterocycloalkyl, —NR １ａ -(optionally substituted C ３～６ cycloalkyl), -NR １ａ -(optionally substituted C ３～１０ cycloalkenyl), -NR １ａ -(optionally substituted 4- to 7-membered heterocyclic group) and -CR １ｃ R １ｄ —C(O)—NR １ａ R １ｂ and optionally substituted with one, two or more substituents independently selected from １ａ , R １ｂ , R １ｃ and R １ｄ If present, H, C １～４ Alkyl, C １～４ Haloalkyl, —C １～４ Alkylene -OH, -C １～４ Alkylene -SH, -C １～４ Alkylene-NH ２ and -C １～４ alkylene-CN; R １ｃ and R １ｄ together with the carbon atom to which they are both attached, form an optionally substituted C ３～６ optionally forming a cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl; More preferably, R １１ But C ３～１０ Cycloalkyl, C ３～１０ Cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, C ５～１１ Monospirocycloalkyl, 5- to 11-membered monospiroheterocycloalkyl, —(CH ２ ) ０～３ -phenyl and -(CH ２ ) ０～３ - 5- or 6-membered heteroaryl, each of which is selected from the following groups: 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- to 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- to 7-membered heterocyclic group) and -CR １ｃ R １ｄ —C(O)—NR １ａ R １ｂ and optionally substituted with one, two or more substituents independently selected from １ａ , R １ｂ , R １ｃ and R １ｄ are, if present, H and C, respectively. １～４ alkyl; R １ｃ and R １ｄ together with the carbon atom to which they are both attached, ３～６ optionally forming a cycloalkyl, More preferably, R １１ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinanyl, morpholinyl, thiomorpholinyl, 【Chemistry 9】 Dihydropyrrolyl, dihydroimidazolyl, azacyclooctenyl, 5- to 11-membered monospiroheterocycloalkyl, phenyl, —CH ２ -phenyl, pyrrolyl, -CH ２ -pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, -CH ２ - selected from pyridinyl, pyridone, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrimidinone groups, which are respectively F, Cl, OH, SH, CN, ═O, ═NH, NH ２ , -NHCH ３ , C.H. ３ , C.H. ２ CH ３ , vinyl, ethynyl, CH ２ Cl, CF ３ , -CH ２ CF ３ , -CH ２ —OH, —CH ２ -SH, -CH ２ -NH ２ , -CH ２ -NHCH ３ , -CH ２ -N(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -NHC(O)CH ３ , cyclopropyl, azetidinyl, pyridinyl, 【Chemistry 10】 and -CR １ｃ R １ｄ -C(O)NH ２ and optionally substituted with one, two or more substituents independently selected from １ｃ and R １ｄ together with the carbon atom to which they are both attached to form cyclopropyl, A compound according to any one of claims 1 and 4 to 8.

10. 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 If present, H and C １～４ are each independently selected from alkyl, Preferably, R ２ is H, F, Cl, OH, SH, CN, methyl, ethyl, -CH ２ —OH, —CH ２ -SH, -NH ２ , -NH-C(O)CH ３ , -NH-C(O)OCH ３ , -NH-C(O)NH ２ and —NH—S(O) ２ CH ３ The compound according to any one of claims 1 to 9,

11. Structure of formula (I-8): 【Chemistry 11】 2. The compound of claim 1 having the formula:

12. Ring D is C ３～８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ５～８ is a bridged cycloalkyl or a 5- to 8-membered bridged heterocycloalkyl, and / or R ６ but the following: H, halogen, OH, SH, CN, N(R ７ａ ) ２ , C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl (which are halogen, OH, SH, NH ２ and CN), -O-C １～６ Alkyl, —O-halo-C １～６ Alkyl, —C １～６ Alkylene -O-C １～６ Alkyl, —C １～６ Alkylene-O-halo-C １～６ Alkyl, C ３～６ cycloalkyl, —C １～６ Alkylene-C ３～６ Cycloalkyl, —O—C １～６ Alkylene-C ３～６ Cycloalkyl and —C(O)—C ３～６ Cycloalkyl (as defined above) ３～６ Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , 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 haloalkoxy), 4- to 7-membered heterocycloalkyl and —C １～６ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH ２ , 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 and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from R ７ａ But H, C １～６ Alkyl, -(CH ２ ) ｑ -C ３～６ Cycloalkyl, -(CH ２ ) ｑ - 4 to 7 membered heterocycloalkyl (q is an integer selected from 0 to 4), １～６ Alkyl, -(CH ２ ) ｑ -C ３～６ The C in cycloalkyl ３～６ Cycloalkyl and -(CH ２ ) ｑ - 4- to 7-membered heterocycloalkyl, wherein said 4- to 7-membered heterocycloalkyl is deuterium, halogen, OH, SH, NH ２ , 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 optionally substituted with one, two or more substituents each independently selected from haloalkoxy; Preferably, N(R ７ａ ) ２ R in ７ａ One of them is H, Preferably, R ６ but, H、F、Cl、OH、SH、CN、NH ２ 、 -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , —NH(C ３～６ cyclic hydrocarbon group) and —NH(4- to 7-membered heterocycloalkyl) (—NH(C １～４ alkyl) and —N(C １～４ alkyl) ２ The above C １～４ Alkyl, —NH(C ３～６ cyclic hydrocarbon group) ３～６ The 4- to 7-membered heterocycloalkyl in the cyclic hydrocarbon group and -NH(4- to 7-membered heterocycloalkyl) is selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH ２ , C.N., C. １～６ Alkyl and C １～６ haloalkyl), -NH(C １～４ alkylene)-(C ３～６ cyclic hydrocarbon group), —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, —O—C １～４ Alkyl, —O-halo-C １～４ Alkyl, —C １～４ Alkylene -O-C １～４ Alkyl, —C １～４ Alkyl-O-halo-C １～４ Alkyl, C ３～６ cycloalkyl, —C １～４ Alkylene-C ３～６ Cycloalkyl, —O—C １～４ Alkylene-C ３～６ Cycloalkyl and —C(O)—C ３～６ Cycloalkyl (as defined above) ３～６ Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , C.N., C. １～４ Alkyl, C １～４ Haloalkyl and C １～４ haloalkoxy), and 4- to 7-membered heterocycloalkyl and —C １～４ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH ２ , CN, oxo, C １～４ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～４ Alkoxy, C １～４ Haloalkyl and C １～４ and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from Preferably, R ６ but, H, OH, SH, -NH(C １～４ alkyl), -NH(C ３～６ partially unsaturated cyclic hydrocarbon group) and —NH(4- to 6-membered heterocycloalkyl) (—NH(C １～４ alkyl) １～４ Alkyl, —NH(C ３～６ the C in the partially unsaturated cyclic hydrocarbon group ３～６ The 4- to 6-membered heterocycloalkyl in the partially unsaturated cyclic hydrocarbon group and -NH(4- to 6-membered heterocycloalkyl) is selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH ２ , C.N., C. １～４ Alkyl and C １～４ optionally substituted with one, two or more substituents each independently selected from haloalkyl; -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, —O—C １～４ Alkyl, —O-halo-C １～４ Alkyl, —C １～４ Alkylene -O-C １～４ Alkyl, —C １～４ Alkyl-O-halo-C １～４ Alkyl, C ３～６ cycloalkyl, —C １～４ Alkylene-C ３～６ Cycloalkyl and —O—C １～４ Alkylene-C ３～６ Cycloalkyl (as defined above) ３～６ Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , C.N., C. １～４ Alkyl, C １～４ Haloalkyl and C １～４ haloalkoxy), and 4- to 7-membered heterocycloalkyl and —C １～４ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH ２ , C.N., C. １～４ Alkyl and C １～４ and optionally substituted independently with one, two or more substituents independently selected from haloalkyl. is selected from More preferably, R ６ H, OH, SH, methyl, ethyl, isopropyl, -CF ３ , -CH ２ CF ３ , -CH ２ CHF ２ , 【Chemistry 12】 --H ２ CN、 【Chemistry 13】 -OCH ３ 、-OCH ２ CH ３ 、-OCF ３ ,-OCH ２ CF ３ 、 【Chemistry 14】 cyclopropyl, difluorocyclopropyl, 【Chemistry 15】 Amino, -NHCH ３ , -N(CH ３ ) ２ , -NHCH ２ CH ３ , -NHCH ２ CN, -NHCH ２ CF ３ , —NH-cyclopropyl, —NHCH ２ -cyclopropyl, 【Chemistry 16】 —NH-cyclobutane, 【Chemistry 17】 -O-CH ２ -cyclopropyl and [Chemistry 18] and / or 12. The compound of claim 1 or 11, wherein n is 1.

13. Ring D is C ４～６ cycloalkyl, 4- to 7-membered heterocycloalkyl, C ５～８ a bridged cycloalkyl or a 5- to 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 【Chemistry 19】 More preferably, the part 【Chemistry 20】 but, 【Chemistry 21】 R ６ but, H、F、Cl、OH、SH、CN、NH ２ 、 -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , —NH(C ３～６ cyclic hydrocarbon group), —NH(4- to 7-membered heterocycloalkyl) (—NH(C １～４ alkyl) and —N(C １～４ alkyl) ２ The above C １～４ Alkyl, —NH(C ３～６ cyclic hydrocarbon group) ３～６ The cyclic hydrocarbon group and the 4- to 7-membered heterocycloalkyl in —NH(4- to 7-membered heterocycloalkyl) are each selected from deuterium, halogen, OH, oxo, SH, NH ２ , C.N., C. １～６ Alkyl and C １～６ haloalkyl), -NH(C １～４ alkylene)-(C ３～６ cyclic hydrocarbon group), —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, —O—C １～４ Alkyl, —O-haloC １～４ Alkyl, C ３～６ cycloalkyl, —C １～４ Alkylene-C ３～６ Cycloalkyl and —O—C １～４ Alkyl-C ３～６ Cycloalkyl (as defined above) ３～６ Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , C.N., C. １～４ Alkyl, C １～４ Haloalkyl and C １～４ haloalkoxy), and 4- to 7-membered heterocycloalkyl and —C １～４ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH ２ , 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 and optionally substituted independently with one, two or more substituents independently selected from haloalkoxy. is selected from Preferably, R ６ but the following: 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 (as defined above) ３～６ Cycloalkyl, when present, is substituted with deuterium, halogen, OH, SH, NH ２ , C.N., C. １～４ Alkyl, C １～４ Haloalkyl and C １～４ haloalkoxy), 4- to 7-membered heterocycloalkyl and —C １～４ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, SH, NH ２ , 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 haloalkoxy), and -NH(4- to 7-membered heterocycloalkyl) (The 4- to 7-membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH ２ , C.N., C. １～６ Alkyl and C １～６ and optionally substituted with one, two or more substituents independently selected from haloalkyl. is selected from More preferably, R ６ but the following: 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 (as defined above) ３～６ Cycloalkyl, when present, is substituted with halogen, C １～４ Haloalkyl and C １～４ haloalkoxy), and 4- to 7-membered heterocycloalkyl and —C １～４ alkylene-4 to 7 membered heterocycloalkyl, wherein said 4 to 7 membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, OH, NH ２ , C.N. and C. １～４ and optionally substituted independently with one, two or more substituents independently selected from alkyl.

12. The compound of claim 1 or 11, selected from:

14. Ring A is C ６～１０ Aryl or 5- or 6-membered heteroaryl, preferably phenyl (more preferably 【Chemistry 22】 ), naphthyl, benzopyridyl (preferably quinolinyl, more preferably 【Chemistry 23】 ), pyridyl or thiazolyl, and / or R ３ is halogen, OH, SH, CN, -NR ３ａ R ３ｂ , -C １～４ Alkylene -OH, -C １～４ Alkylene -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 5-membered heteroaryl having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms; and / or Preferably, R ３ is F, Cl, OH, CN, -NH ２ , -CH ２ —OH, —CH ２ -SH, -CH ２ -C(O)OR ３ａ , -CH ２ —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 having 1-4 nitrogen heteroatoms and 0-1 oxygen or sulfur heteroatoms; and / or R ３ａ and R ３ｂ If present, H and C １～４ are each independently selected from alkyl, More preferably, R ３ F, Cl, OH, CN, -NH ２ , -CH ２ —OH, —CH ２ -SH, -CH ２ -C(O)OH, -CH ２ -C(O)OCH ３ , -CH ２ —C(O)—NH ２ , -C(O)OH, -C(O)OCH ３ , —C(O)—NH ２ , -C(O)-NH-S(O) ２ -CH ３ , -S(O) ２ -CH ３ , -S(O) ２ -NH ２ , -S(O) ２ -NH-C(O)CH ３ and 5-membered heteroaryl having 1 to 4 nitrogen heteroatoms and 0 to 1 oxygen or sulfur heteroatoms; More preferably, R ３ is F, Cl, -CH ２ -C(O)OH, -C(O)OH, -C(O)-NH ２ , -S(O) ２ -CH ３ , -S(O) ２ -NH ２ , -S(O) ２ -NH-C(O)CH ３ , tetrazolyl and pyrazolyl, and / or p is 1 or 2; Preferably, 【Chemistry 24】 but, 【Chemistry 25】 each of which is selected from a separate, independent R ３ and optionally replaced by More preferably 【Chemistry 26】 but, 【Chemistry 27】 More preferably 【Chemistry 28】 The compound according to any one of claims 1 to 13,

15. X is CR ７ or X is C(R ７ ) ２ or X is N; 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 and Y is CR ８ and Z is NH; and / or X is CR ７ and Y is CR ８ and Z is O, and / or X is CR ７ and Y is CR ８ and Z is S, and / or X is CR ７ and Y is N and Z is NH; and / or X is N and Y is CR ８ and Z is NH; and / or X is C(R ７ ) ２ and Y is C(R ８ ) ２ and Z is NH; Preferably, R is 【Chemistry 29】 The compound according to any one of claims 1 to 14,

16. Structure of formula (I-9): 【Transformation 30】 16. The compound according to any one of claims 1 to 15, having the formula Preferably, the compound of formula (I) has the structure of formula (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17) or (I-18): 【Chemistry 31】 A compound having the formula:

17. R ４ When present, 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, —O—C １～４ Alkyl, —O—C １～４ Haloalkyl, —S—C １～４ Alkyl, —S(O) ２ -C １～４ Alkyl, —C １～４ Alkylene -O-C 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 AlkyleneC(O)NR ６ａ R ６ｂ , C ３～６ Cycloalkyl and —OC １～４ Alkylene-C ３～６ cycloalkyl; １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, —O—C １～４ Alkyl, —O—C １～４ Haloalkyl, —S—C １～４ Alkyl, —S(O) ２ -C １～４ Alkyl, —C １～４ Alkylene -O-C 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 AlkyleneC(O)NR ６ａ R ６ｂ , C ３～６ Cycloalkyl and —OC １～４ Alkylene-C ３～６ cycloalkyl are each optionally substituted with one or more D; R ５ When present, 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, —O—C １～４ Alkyl, —O—C １～４ Haloalkyl, —S—C １～４ Alkyl, —S(O) ２ -C １～４ Alkyl, —C １～４ Alkylene -O-C 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 AlkyleneC(O)NR ６ａ R ６ｂ , C ３～６ Cycloalkyl and —OC １～４ Alkylene-C ３～６ cycloalkyl; Preferably, R ４ When present, 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, —O—C １～４ Alkyl, —S—C １～４ Alkyl and C ３～６ cycloalkyl; １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, —O—C １～４ Alkyl, —S—C １～４ Alkyl and C ３～６ cycloalkyl are each optionally substituted with one or more D; R ５ When present, 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, —O—C １～４ Alkyl, —S—C １～４ Alkyl and C ３～６ and / or independently selected from cycloalkyl R ６ａ and R ６ｂ If present, H and C １～４ independently selected from alkyl, Preferably, R ４ When present, H, F, Cl, OH, SH, CN, -NH ２ , -NHCH ３ , -NH(CH ３ ) ２ , methyl, ethyl, CF ３ , vinyl, ethynyl, —O—CH ３ , -O-CD ３ , -S-CH ３ , -S-CD ３ and cyclopropyl, R ５ When present, H, F, Cl, OH, SH, CN, -NH ２ , -NHCH ３ , -NH(CH ３ ) ２ , methyl, ethyl, CF ３ , vinyl, ethynyl, —O—CH ３ , -S-CH ３ and cyclopropyl, More preferably, R ４ But -O-C １～４ Alkyl, —O-deuterated C １～４ alkyl or cyclopropyl, and R ５ is H or C １～４ is alkyl, More preferably, R ４ But -O-CH ３ , -O-CD ３ or cyclopropyl, and / or R ５ is methyl, and / or R ７ and R ８ are, when present, H, halogen, OH, SH, CN, NH ２ , —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 When present, H, F, Cl, OH, SH, CN, NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , methyl, ethyl and cyclopropyl, more preferably H, F, Cl, methyl, ethyl and cyclopropyl; and / or L １ but, ＊ -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)-; ＊ The bond marked by connects to the phenyl ring B, and R ４ａ and R ４ｂ H, deuterium, halogen, OH, SH, CN, C １～６ Alkyl, C １～６ Haloalkyl, 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 both attached, ３～４ forming a cycloalkyl or a 4- to 5-membered heterocycloalkyl, and / or R ５ａ and R ５ｂ If present, H and C １～４ independently selected from alkyl, and / or R ４ａ and R ４ｂ H, deuterium, F, Cl, OH, SH, CN, -NH ２ , -C(O)OH, -C(O)OCH ３ , —C(O)—NH ２ and —C(O)—NCH ３ or R ４ａ and R ４ｂ together with the carbon atom to which they are both attached form a cyclopropanyl group, and / or R ４ｃ But H, C １～４ Alkyl and C １～４ haloalkyl, preferably R ４ｃ is H, methyl, ethyl, -CH ２ F, -CHF ２ and -CF ３ is selected from Preferably, L １ but, ＊ -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)-; ＊ The bond marked by connects to the phenyl ring B and R ４ａ and R ４ｂ H, deuterium, F, Cl, OH, SH, CN, C １～４ Alkyl, C １～４ Haloalkyl, NR ５ａ R ５ｂ , —C(O)OR5a and —C(O)—NR ５ａ R ５ｂ , preferably H, F, Cl, OH, SH, CN, CH ３ , C.F. ３ , N.R. ５ａ R ５ｂ , -C(O)OR ５ａ and —C(O)—NR ５ａ R ５ｂ or R ４ａ and R ４ｂ together with the carbon atom to which they are both attached form a C cycloalkyl or a 4-5 membered heterocycloalkyl; Preferably, L １ is ＊ -CH ２ -NH-, ＊ -CF ２ -NH-, ＊ -CD ２ -NH-, ＊ -CH(CF ３ )-NH-, ＊ -C(CH ３ ) ２ -NH-, ＊ -CH ２ -N(CH ３ ), ＊ -CH ２ -N(CH ２ CH ３ ), ＊ -CH ２ -N(CH ２ F), ＊ -C(O)-NH-, ＊ -C(S)-NH-, ＊ -S(O) ２ -NH-, ＊ -NH-CH ２ -, ＊ -NH-CF ２ -, ＊ -NH-C(O)-, ＊ -NH-C(S)-, ＊ -NH-S(O) ２ ​ 【Chemistry 32】 More preferably, ＊ -CH ２ -NH-, ＊ -CD ２ -NH-, ＊ -C(CH ３ ) ２ -NH-, ＊ —C(O)—NH— and 【Transformation 33】 is selected from ＊ The bond marked by connects to the phenyl ring B, A compound according to any one of claims 1 to 16.

18. Structure of formula (I-19): 【Transformation 34】 The compound of claim 1 having the formula: (In the formula, L １ teeth, ＊ -CR ４ａ R ４ｂ -NR ４ｃ - and ＊ —C(O)—NR ４ｃ - is selected from, ＊ The bond marked by connects to the phenyl ring B, R ４ａ and R ４ｂ are each independently selected from H and deuterium; R ４ｃ is H, R ４ is -O-C １～６ Alkyl and C ３～６ cycloalkyl, —O—C １～６ Alkyl and C ３～６ cycloalkyl is optionally substituted with one, two, three or more D; R ５ is C １～６ alkyl, Ring D is C ４～６ cycloalkyl or 5- to 8-membered bridged heterocycloalkyl, preferably cyclohexane or 【Chemistry 35】 R ６ Below: C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl (which are halogen, OH, NH ２ and CN), -C １～６ Alkylene-O-haloC １～６ Alkyl, C ３～６ Cycloalkyl and -C １～６ Alkylene-C ３～６ Cycloalkyl (C ３～６ Cycloalkyl, when present, is substituted with halogen, OH, NH ２ , C.N., C. １～６ Alkyl, C １～６ Haloalkyl and C １～６ haloalkoxy), 4- to 7-membered heterocycloalkyl and —C １～６ alkylene-4 to 7 membered heterocycloalkyl (4 to 7 membered heterocycloalkyl, if present, is selected from deuterium, halogen, OH, NH ２ , C.N., C. １～６ Alkyl and C １～６ haloalkyl), and -NH(4- to 7-membered heterocycloalkyl) is selected from n is 1, Preferably, L １ teeth, ＊ -CH ２ -NH-, ＊ -CD ２ -NH- and ＊ —C(O)—NH—; ＊ the bond marked by connects to the phenyl ring B, and / or Preferably, the part 【Transformation 36】 teeth, 【Chemistry 37】 Preferably, R ４ is -O-C １～４ Alkyl and C ３～６ cycloalkyl, —O—C １～４ Alkyl and C ３～６ Cycloalkyl is optionally substituted with one, two, three or more D, more preferably R ４ is -O-C １～２ Alkyl and C ３～６ cycloalkyl, —O—C １～２ Alkyl and C ３～６ cycloalkyl is optionally substituted with one, two, three or more D, and / or Preferably, R ５ is C １～４ Alkyl, more preferably C １～２ alkyl, and / or More preferably, R ４ is -O-CH ３ , -O-CD ３ or cyclopropyl, and R ５ is methyl, and / or Preferably, R ６ Below: C １～６ Alkyl, C ２～４ Alkenyl and C ２～４ Alkynyl (which are halogen, OH, NH ２ and CN), -C １～４ Alkylene-O-haloC １～４ alkyl, —NH(4-6 membered heterocycloalkyl), C ３～６ Cyclic alkyl and —C １～４ Alkyl-C ３～６ Cyclic alkyl (C ３～６ Cyclic alkyl, when present, is substituted with halogen, OH, NH ２ , C.N., C. １～４ Alkyl, C １～４ Haloalkyl and C １～４ haloalkoxy), 4- to 7-membered heterocycloalkyl and —C １～４ alkyl-4 to 7 membered heterocycloalkyl (4 to 7 membered heterocycloalkyl, if present, is substituted with deuterium, halogen, OH, NH ２ , C.N., C. １～４ Alkyl and C １～４ haloalkyl; is selected from More preferably, R ６ Below: C １～６ Alkyl, C ２～４ Alkenyl and C ２～４ alkynyl, each of which is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH and CN; -C １～４ Alkylene-O-haloC １～４ alkyl, —NH(4-6 membered heterocycloalkyl), C ３～６ Cycloalkyl and -C １～４ Alkylene-C ３～６ Cycloalkyl (C ３～６ Cycloalkyl, when present, is selected from the group consisting of halogen, C １～４ Haloalkyl and C １～４ haloalkoxy), 4-6 membered heterocycloalkyl and -C １～４ alkylene-4 to 6 membered heterocycloalkyl (4 to 6 membered heterocycloalkyl, when present, is substituted with deuterium, halogen, CN and C １～４ and optionally substituted independently with one, two or more substituents independently selected from alkyl. is selected from said halo or halogen, when present, are independently selected from F and Cl; More preferably, R ６ Below: 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-haloC １～４ alkyl, —NH(4-6 membered heterocycloalkyl), C ３～６ Cycloalkyl and -C １～４ Alkylene-C ３～６ Cycloalkyl (as defined above) ３～６ Cycloalkyl, when present, is substituted with halogen, C １～４ Haloalkyl and C １～４ haloalkoxy), 4-6 membered heterocycloalkyl and -C １～４ alkylene-4 to 6-membered heterocycloalkyl, wherein said 4 to 6-membered heterocycloalkyl, if present, is selected from the group consisting of deuterium, halogen, CN and C １～４ and optionally substituted independently with one, two or more substituents independently selected from alkyl. is selected from halo elements or halogens, when present, are independently selected from F and Cl; More preferably, R ６ Below: 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 with one O or S heteroatom); C ３～６ Cycloalkyl and -C １～４ Alkylene-C ３～６ Cycloalkyl (C ３～６ Cycloalkyl, when present, is selected from F, C １～４ Fluoroalkyl and C １～４ fluoroalkoxy), 4-6 membered heterocycloalkyl and -C １～４ alkylene-4 to 6-membered heterocycloalkyl (4 to 6-membered heterocycloalkyl, if present, independently contains one N atom and is selected from the group consisting of deuterium, F, CN and C １～４ and 4-6 membered heterocycloalkyl optionally substituted with one, two or more substituents independently selected from alkyl. is selected from More preferably, R ６ is methyl, ethyl 【Transformation 38】 (selected from).

19. The compound of formula (I-19) has the structure of one of formulas (I-20) to (I-27): 【Chemistry 39】 Preferably, 【Chemistry 40】 19. The compound of claim 18, having the formula:

20. portion 【Chemistry 41】 but, 【Chemistry 42】 R ４ But -O-CH ３ or cyclopropyl, and R ５ is methyl, and / or R ６ is substituted by one, two, three, four or more substituents independently selected from halogen and OH; １～４ alkyl groups, Preferably, R ６ is substituted by one, two, three, four or more substituents independently selected from F, Cl and OH; １～６ alkyl groups, More preferably, R ６ is substituted by one, two, three, four or more substituents independently selected from F and OH; １～６ alkyl groups, More preferably, R ６ is substituted by 1, 2, 3 or more F and 0 or 1 OH; １～６ is selected from the group consisting of alkyl, More preferably, R ６ is substituted by 1, 2, 3 or more F and 0 or 1 OH; ３～６ alkyl groups, More preferably, R ６ but, 【Chemistry 43】 20. The compound of claim 18 or 19, selected from:

21. The compound of formula (I-19) has a structure selected from formulas (I-28) to (I-31): 【Chemistry 44】 19. The compound of claim 18, having the formula:

22. R ４ But -O-CH ３ or cyclopropyl, and R ５ is methyl, and / or R ６ is selected from -NH(4-6 membered heterocycloalkyl) and 4-6 membered heterocycloalkyl having one N heteroatom, wherein the 4-6 membered heterocycloalkyl having one N heteroatom is linked to the remainder of the molecule through the N heteroatom and is selected from deuterium, halogen, OH, NH ２ , C.N., C. １～４ Alkyl and C １～４ optionally substituted with one, two, three or more substituents independently selected from haloalkyl; Preferably, R ６ is selected from —NH(4- to 6-membered heterocycloalkyl) and 4- to 6-membered heterocycloalkyl having one N heteroatom, wherein the 4- to 6-membered heterocycloalkyl having one N heteroatom is linked to the remainder of the molecule through the N heteroatom and is selected from deuterium, F, Cl, CN, and C １～４ optionally substituted with one, two, three or more substituents independently selected from alkyl; More preferably, R ６ is selected from —NH (4-6 membered heterocycloalkyl having one O or S heteroatom) and 4-6 membered heterocycloalkyl having one N heteroatom, wherein the 4-6 membered heterocycloalkyl having one N heteroatom is linked to the remainder of the molecule through the N heteroatom and is selected from deuterium, F, CN, and C １～４ optionally substituted with one, two, three or more substituents independently selected from alkyl; More preferably, R ６ but, 【Chemistry 45】 22. The compound of claim 21 selected from: 【Request Item 23】 【Chemistry 46】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The compound of claim 1 selected from:

24. 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, isotopically labeled compound (preferably deuterated form), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. 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, isotopically labeled compound (preferably in deuterated form), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and another therapeutically active agent.

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

27. 22. A method for preventing or treating a disease, disorder or condition mediated by complement activation, in particular a disease, disorder or condition mediated by activation of the alternative complement pathway, in an individual, the method comprising the step of administering to the individual 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 in deuterated form), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or administering to the individual a therapeutically effective amount of the pharmaceutical composition according to claim 24, or administering to the individual a therapeutically effective amount of the pharmaceutical composition according to claim 25, Preferably, the disease, disorder or condition is age-related macular degeneration (AMD), geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system disease, multiple sclerosis, stroke, Guillain-Barré syndrome. syndromes, traumatic brain injury, Parkinson's disease, disorders of inappropriate or unwanted complement activation, hemodialysis complications, 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, ischemia-reperfusion injury, myocardial infarction, post-pump syndrome during balloon angioplasty, cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, renal ischemia, Mesenteric artery reperfusion after aortic reconstruction, infection 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 (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immunosuppressive therapy (ITT), and immunosuppressive therapy (ITT). pulmonary 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, fibrosing pneumoconiosis, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, microimmune 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, provided for use as a pharmaceutical, or a pharmaceutical composition according to claim 24, or a pharmaceutical composition according to claim 25.

29. Use 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 a pharmaceutical composition according to claim 24, or a pharmaceutical composition according to claim 25, in the manufacture of a medicament for the treatment of a disease, disorder or condition mediated by complement activation, in particular a disease, disorder or condition mediated by activation of the alternative complement pathway, in an individual.

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