Complement factor b inhibitor, pharmaceutical composition thereof, and use thereof

Abstract

The present application relates to a complement factor B inhibitor of formula (I), a pharmaceutical composition thereof, and the use thereof.

Description

Complement factor b inhibitors, pharmaceutical compositions thereof and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a novel complement factor B inhibitor, a pharmaceutical composition thereof and uses thereof. BACKGROUND

[0002] The complement system is an important part of the body's innate immunity, and plays an important role in pathogen immune surveillance and maintenance of tissue homeostasis. The complement system is involved in the occurrence and development of various diseases, such as nervous system diseases Alzheimer's disease (AD), neuromyelitis optica (NMO), myasthenia gravis (gMG), eye diseases such as age-related macular degeneration (AMD), uveitis, glaucoma, kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and IgA nephropathy, and blood diseases such as cold agglutinin disease, paroxysmal nocturnal hemoglobinuria (PNH), and thrombotic microangiopathy (TMAs).

[0003] The complement system is activated through three independent and cross-linked pathways, namely the classical pathway (CP), the alternative pathway (AP) and the lectin pathway (LP). Complement factor B (CFB) is an important factor in the complement alternative pathway (AP), mainly synthesized by hepatocytes and macrophages, and is an important component in the activation of the complement alternative pathway. CFB is involved in the body's defense and plays an important role in cell damage and inflammation. CFB is a trypsin-like serine protease that exists in the form of a zymogen in the blood circulation. FB is the main component of the activated AP pathway, which is activated and combined with C3b, and then cleaved by FD to produce a C3 convertase complex (C3bBb) containing FB catalytic subunit (Bb), which continues to cut C3 to produce more C3b, thereby amplifying the activation of the entire complement system. Due to uncontrolled circulation of C3, a large amount of active C3b and terminal complement factors are deposited in the glomerulus, causing changes in glomerular structure and function, and further triggering complement system-related kidney diseases.

[0004] Currently, several drugs targeting the complement system have been approved for marketing, such as C5 inhibitors Culizumab and Ravulizumab, and C3 inhibitor Pegcetacoplan, which are indicated for atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria (PNH), etc. However, it is found in clinical practice that PNH patients using C5 or C3 inhibitors cannot completely block AP activation, and there is still mild to moderate extravascular hemolysis, and there is still a large amount of unmet clinical needs for complement-related diseases.

[0005] LNP023 (WO2015009616A1 and WO2019043609A1) is the first small molecule FB targeting inhibitor developed by Novartis, which is used for treating complement system-related kidney diseases, including: paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), etc., and the PNH indication has been approved for marketing in December 2023.

[0006] There is still an urgent need in the art to develop new complement system FB small molecule inhibitors to increase clinical research and meet the treatment of various diseases or conditions caused by complement abnormalities. SUMMARY

[0007] The present application provides compounds that modulate, and preferably inhibit, the activation of the complement alternative pathway. In some embodiments, the present application provides compounds that modulate, and preferably inhibit, the activity of complement factor B (FB) and / or FB-mediated activation of the complement pathway.

[0008] The novel FB small molecule inhibitors of the present application have high affinity for FB, can inhibit the catalytic activity of FB, have obvious inhibitory effect on the activation of the complement alternative pathway, and thus have the potential to inhibit the amplification of the complement system caused by C3 activation, and prevent and treat diseases, disorders or conditions mediated by complement activation, in particular diseases, disorders or conditions mediated by the activation of the complement alternative pathway. The compounds of the present application have more excellent properties such as improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less likely to develop resistance, etc.

[0009] In one aspect, the present application provides a compound of formula (I) as defined hereinafter:

[0010] or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In another aspect, the present application provides a pharmaceutical combination comprising a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, and another therapeutically active agent.

[0013] In another aspect, the present application provides a method of modulating the activity of the complement alternative pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a 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 pharmaceutical combination according to the present application.

[0014] In another aspect, the present application provides a method of preventing or treating a disease, disorder or condition mediated by complement activation, in particular a disease, disorder or condition mediated by the activation of the complement alternative pathway, in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a 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 pharmaceutical combination according to the present application.

[0015] In another aspect, the present application provides the use of a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present application, or a pharmaceutical combination according to the present application, for 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 complement alternative pathway, in an individual.

[0016] In another aspect, the present application provides the use of a compound of formula (I) according to the present application, or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present application, or a pharmaceutical combination according to the present application, for 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 complement alternative pathway, in an individual.

[0017] In some embodiments the disease, disorder or condition is selected from age-related macular degeneration (AMD), macular geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological diseases, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, disorders resulting from inappropriate or undesirable 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, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric arterial reperfusion following aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or other renal diseases with evidence of glomerular C3 deposition (e.g. membranous nephropathy (MN) and E. coli induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic disease, Goodpasture's syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity. DETAILED DESCRIPTION

[0018] DEFINITIONS

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or replacements of the technical terms that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by one of ordinary skill in the art, the following definitions are set forth to better define the present application.

[0020] The terms "comprising," "including," "having," "containing," or "involving," and any other variant thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps (i.e., such terms also cover the terms "consisting essentially of" and "consisting of").

[0021] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0022] As used herein, the term "alkyl" means a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be regarded as derived from an alkane by the loss of one hydrogen atom. In some embodiments, an alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "alkyl" refers to a straight-chain or branched-chain group having 1 to 6 carbon atoms. 2-6 "alkyl," "C 2-5 "alkyl," "C 1-4 "alkyl," "C 1-6 Examples of "alkyl" groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. The alkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as a "haloalkyl," e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl).

[0023] As used herein, the term "alkylene" represents a straight-chain or branched divalent saturated aliphatic hydrocarbon. In some embodiments, an alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms, for example methylene, ethylene, propylene, or butylene.

[0024] As used herein, the term "heteroalkyl" means an alkyl group as defined herein, in which one or more CH2groups in the backbone are replaced by a heteroatom, each independently selected from O, S, S(O), S(O)2, NR', and combinations thereof, wherein R' is a hydrogen atom or a C 1-6 "alkyl" or halo-C 1-6Alkyl. As used herein, the prefix "x-membered" or "x- to y-membered" in conjunction with heteroalkyl indicates the total number of C atoms and heteroatom members in the heteroalkyl backbone chain. In some embodiments, heteroalkyl can be, for example, 2- to 6-membered heteroalkyl, 2- to 5-membered heteroalkyl, or 2- to 4-membered heteroalkyl (e.g., -CH2OCH2CH3, -CH2N(CH3)CH2CH3). The heteroalkyl group can be attached to the rest of the molecule through a heteroatom or carbon atom in the backbone chain.

[0025] As used herein, the term "alkenyl" means a straight-chain or branched- chain monovalent aliphatic hydrocarbon group which contains one or more double bonds. In some embodiments, the alkenyl group has 2-6 carbon atoms ("C 2-6 alkenyl"). The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When a compound of the application contains an alkenyl group, the compound can exist as pure E (entgegen) form, pure Z (zusammen) form, or as any mixture of these forms. The term "alkenylene" is the corresponding divalent group, including, for example, "C 2-6 alkenylene", "C 2-4 alkenylene", and the like. Specific examples include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, allenylidene, pentenylidene, hexenylidene, and the like.

[0026] As used herein, the term "alkynyl" means a straight-chain or branched- chain monovalent aliphatic hydrocarbon group which contains one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 alkynyl"), for example, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. The alkynyl group is optionally substituted with one or more (such as 1 to 3) same or different substituents. The term "alkynylene" is the corresponding divalent group, including, for example, "C 2-6 alkynylene", "C 2-4 alkynylene", and the like. Examples include, but are not limited to , and the like. The alkynylene group is optionally substituted with one or more (such as 1 to 3) same or different substituents.

[0027] As used herein, the terms "cycloalkyl," "hydrocarbon ring," and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl") and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably having 3-8, more suitably having 3-7, 3-6, 4-6, or 5-6) ring carbon atoms, including, but not limited to, (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonanyl, (cyclo)butenyl, (cyclo)pentenyl, (cyclo)hexenyl, (cyclo)heptenyl, (cyclo)octenyl, (cyclo)nonenyl, and the like.

[0028] As used herein, the term "fused" means that two or more cyclic structures share two adjacent atoms with each other.

[0029] As used herein, the term "bridged" or "bridging" or "bridged" means that two or more cyclic structures share two non-adjacent atoms with each other.

[0030] As used herein, the term "spiro" or "spiroed" means that two or more cyclic structures share one atom with each other.

[0031] As used herein, the terms "cycloalkyl" or "cycloalkylene" refer to saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, or bicyclic including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl groups have 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C3-C6cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). The cycloalkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl. 3-6 As used herein, the terms "cycloalkyl" or "cycloalkylene" refer to saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, or bicyclic including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl groups have 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C3-C6cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). The cycloalkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0032] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to a monocyclic, fused, spiro, or bridged ring radical that is either saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")), having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms selected from C(=0), 0, S, S(=0), S(=0)2, and NR a’ wherein R a’ represents a hydrogen atom or C 1-6 alkyl or C 1-6 haloalkyl. The heterocyclyl group can be attached to the remainder of the molecule by any one of the carbon atoms or the nitrogen atom, if present. The "heterocyclyl" can be a monocyclic or a polycyclic ring system (polycyclic ring systems include, but are not limited to, bicyclic, tricyclic, tetracyclic, or pentacyclic ring system radicals). For example, a 3-12 membered heterocyclyl is a radical having 3-12 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0033] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. An aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -N02, C 1-6 alkyl, etc.).

[0034] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which can be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition, can in each case be benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0035] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

[0036] The term "substituted" means that one or more (e.g. one, two, three or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0037] If a group is described as "optionally substituted" or "optionally substituted" that group can be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on that carbon (to the extent there are any hydrogens present) can be replaced with an independently selected optional substituent, alone and / or together. If a nitrogen of a group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on that nitrogen (to the extent there are any hydrogens present) can each be replaced with an independently selected optional substituent. Optional substituents can be selected from: deuterium, halogen, OH, SH, CN, NO2, 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, -O-C 2-6 alkenyl, -O-C 2-6 alkynyl, -S-C 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, -C1-6 Alkylene-CN, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 Alkyl)2, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 0-6 Alkylene -C(O)OH, -C 0-6 Alkylene-C(O)OC 1-6 Alkyl, -C 0-6 Alkylene -C(O)NH2, -C 0-6 Alkylene-C(O)NH(C) 1-6 Alkyl), -C 0-6 Alkylene-C(O)N(C) 1-6 Alkyl)2, -C 0-6 Alkylene-S(O)2C 1-6 Alkyl, -C 0-6 Alkylene -S(O)2NH2, -C 0-6 Alkylene-S(O)2NH(C) 1-6 Alkyl), -C 0-6 Alkylene-S(O)2N(C) 1-6 Alkyl)2、-NH-C(O)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 group, -NH-C(O)NH2, -NH-C(O)NH(C 1-6 Alkyl), -NH-C(O)N(C 1-6 Alkyl)2、-NH-S(O)2-C 1-6 Alkyl, -N(C) 1-6 alkyl)-S(O)2-C 1-6 Alkyl, -C 0-6 Alkylene-C 3-10 cycloalkyl, -C 0-6 alkylene-(3-10 membered heterocyclic group), -C 0-6 alkylene-phenyl and -C 0-6 Alkylene-(5-10-membered heteroaryl).

[0038] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0039] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

[0040] Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0041] When a bond to a substituent is shown as a dashed line ("dashed bond") passing through the middle of a ring, then such substituent can be bonded to any atom in the ring which can be substituted unless otherwise stated. Where a useable ring member carries a substitutable hydrogen atom, when the dashed bond is bonded to the useable ring member, the substitutable hydrogen atom has been replaced in fact (i.e., is not present).

[0042] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to those of the present application, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as deuterium ( 2 H), tritium ( 3 H); isotopes of carbon, such as 11 C, 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O, 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes are 3 H) and carbon-14 ( 14 C), are particularly preferred for their ease of preparation and detectability. Positron emission isotopes such as 11 C, 18 F, 15 O and 13N) Substitution can be used in positron emission tomography (PET) studies to test substrate receptor occupancy. Isotopically labeled compounds of the application can be prepared by methods analogous to those described in the accompanying Schemes and / or in the Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the application include those wherein the solvent can be isotopically substituted, for example, D20, acetone-d6 or DMSO-d6. In some embodiments, isotopically labeled compounds of the application are deuterium.

[0043] The term "stereoisomers" denotes isomers having the same chemical constitution but differing in the arrangement of atoms or groups in space. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Particular individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the application can exist as mixtures of two or more structurally isomeric forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0044] The term "diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not a mirror image of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical methods, such as electrophoresis and chromatography.

[0045] The term "enantiomers" refers to two stereoisomers of a compound that are non- superimposable mirror images of each other.

[0046] The term "chiral" refers to molecules which have a mirror image that is not superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image.

[0047] Compounds of the application can be prepared in racemic form or, if appropriate, by enantioselective synthesis or by resolution, as single enantiomers.

[0048] The term "racemate," "racemic" or "racemic mixture" refers to an equimolar mixture of two enantiomeric isomers lacking optical activity.

[0049] As used herein, the terms “cis-trans isomers” or “geometric isomers” arise from the fact that the single bonds of double or cyclic carbon atoms cannot rotate freely. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures.

[0050] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs). Thick solid lines may be used when the compound contains two chiral centers. and thick dashed lines The chemical bonds in the compound are depicted to show the relative relationship between the two chiral centers, but do not imply any absolute stereochemistry. For example, Indicates that R is connected on the ring. a The key and connection R b The bonds are in cis form with each other, and Coverage and Two corresponding isomers.

[0051] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0052] The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0053] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts.

[0054] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0055] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium, and other similar salts.

[0056] A review of suitable salts is given in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.

[0057] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release a free acid or alcohol form of a compound of the present application). The compounds of the present application can also be esters themselves.

[0058] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0059] The compounds of the present application can exist in the form of solvates, preferably hydrates, wherein the compound of the present application contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0060] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0061] The term "N-oxide" also known as oxoamine, is a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0062] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances produced through metabolism of a compound of the application in the body. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the application includes metabolites of compounds of the application, including those produced by the in vivo conversion of a compound of the application into a metabolic product.

[0063] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that possess little or no pharmacological activity themselves but, upon administration, are converted in the body to the active compounds of the application by, for example, hydrolytic cleavage. In general, such prodrugs will be derivatized at a functional group of the compound of the application, for example, by a group that is readily removed in vivo, for example, by solubilization or enzymatic cleavage. Prodrugs of the present application can be prepared by attaching certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) to appropriate functional groups present in the compounds of the application.

[0064] The present application also encompasses compounds of the present application containing protecting groups. During any process for the preparation of a compound of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, thus forming protecting derivatives of the compounds of the present application. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0065] As used herein, the term "about" refers to ± 10% of the indicated value, preferably ± 5%, more preferably ± 2%.

[0066] Compounds

[0067] In one aspect, the present application provides a compound of Formula (I):

[0068] or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterium), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0069] wherein:

[0070] R 1 each independently selected from the group consisting of deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;

[0071] R 2 is selected from the group consisting of hydrogen, deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;

[0072] R 3 is selected from the group consisting of hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6deuteroalkoxy, -S(C 1-6 alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -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-CN or -C 1-6 alkylene-NR 3a R 3b ;

[0073] R 3a and R 3b are independently at each occurrence selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0074] R 4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkyl, -NH(C 1-6 alkyl), -S(C 1-6 haloalkyl), -N(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl), or -S(C 3-6 halocycloalkyl);

[0075] R g , R h each independently is selected from hydrogen or deuterium;

[0076] n is selected from 0, 1, 2, 3, or 4;

[0077] represents a single or double bond;

[0078] with the proviso that the compound is not

[0079] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically-labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0080] wherein:

[0081] R 1 each independently is selected from deuterium, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuterated alkyl), -N(C 1-6 deuterated alkyl)2, C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;

[0082] R 2 selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0083] R 3 selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, -S(C 1-6 alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -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-CN or -C 1-6 alkylene-NR 3a R 3b ;

[0084] R 3a and R 3b are independently at each occurrence selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0085] R 4 selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C 1-6 alkyl, C 2-6alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl, or -C 1-6 alkylene-3-12 membered heterocyclyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl, or -C 1-6 alkylene-3-12 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl), or -S(C 3-6 halocycloalkyl);

[0086] R g , R h are each independently selected from hydrogen or deuterium;

[0087] n is selected from 0, 1, 2, 3, or 4;

[0088] represents a single or double bond.

[0089] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0090] wherein:

[0091] R 1 each independently selected from deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0092] R 2 selected from deuterium, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy or 4-7 membered heterocyclyl;

[0093] R 3 selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, -S(C1-6 alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -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-CN or -C 1-6 alkylene-NR 3a R 3b ;

[0094] R 3a and R 3b are independently at each occurrence selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0095] R 4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl), or -S(C 3-6 halocycloalkyl);

[0096] R g , R h are each independently selected from hydrogen or deuterium;

[0097] n is selected from 0, 1, 2, 3, or 4;

[0098] represents a single or double bond.

[0099] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically-labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0100] wherein:

[0101] R 1 are each independently selected from deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;

[0102] R 2 selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0103] R 3 selected from deuterium, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or -C 1-6 alkylene-CN;

[0104] R 3a and R 3b are at each occurrence independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0105] R 4 selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl), or -S(C 3-6 halocycloalkyl);

[0106] R g , R h each independently selected from hydrogen or deuterium;

[0107] n is selected from 0, 1, 2, 3, or 4;

[0108] denotes a single or double bond.

[0109] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically-labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0110] wherein:

[0111] R 1 each independently selected from deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6alkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0112] R 2 selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 1-6 R 1-6 alkyl), -N(C 1-6 alkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0113] R 3 selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b alkyl), -N(C 1-6 alkyl), -N(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 1-6 alkoxy, -N(C 1-6 haloalkoxy, -N(C 1-6 haloalkoxy, -N(C 1-6 alkyl), -N(C 3-6 cycloalkyl, 4-7 membered heterocyclyl, -N(C 6-10 aryl, 5-10 membered heteroaryl, -N(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-CN or -C 1-6 alkylene-NR 3a R 3b ;

[0114] R 3a and R 3b is independently at each occurrence selected from C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0115] R 4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl, or -C 1-6 alkylene-3-12 membered heterocyclyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S(C 1-6 alkyl), -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3-10 cycloalkyl, or -C 1-6 alkylene-3-12 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C3-6 halocycloalkyl), -S(C 3-6 halocycloalkyl), -S(C 3-6 halocycloalkyl), -S(C

[0116] R g , R h each independently is selected from hydrogen or deuterium;

[0117] n is selected from 0, 1, 2, 3 or 4;

[0118] denotes a single or double bond.

[0119] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate or a pharmaceutically acceptable salt thereof,

[0120] wherein:

[0121] R 1 each independently is selected from deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6 deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0122] R 2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuteroalkyl), -N(C 1-6deuteroalkyl)2, C 1-6 deuteroalkyl, C 1-6 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;

[0123] R 3 selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, -S(C 1-6 alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -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-CN or -C 1-6 alkylene-NR 3a R 3b ;

[0124] R 3a and R 3b are independently at each occurrence selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0125] R 4 is selected from deuterium or -S(C 1-6 alkyl); said -S(C 1-6 alkyl) is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl), or -S(C 3-6 halocycloalkyl);

[0126] R g , R h are each independently selected from hydrogen or deuterium;

[0127] n is selected from 0, 1, 2, 3, or 4;

[0128] denotes a single or double bond.

[0129] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0130] wherein:

[0131] R 1 are each independently selected from deuterium, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuterated alkyl), -N(C 1-6 deuterated alkyl)2, C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl;

[0132] R 2 is selected from deuterium, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, C 1-6 haloalkyl, C 1-6 haloalkoxy, -NH(C 1-6 deuterated alkyl), -N(C 1-6 deuterated alkyl)2, C 1-6 deuterated alkyl, C1-6 deuterated alkyl or 4-7 membered heterocyclyl;

[0133] R 3 selected from deuterium, 4-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or -C 1-6 alkylene-CN;

[0134] R 3a and R 3b are each independently selected from C 1-6 haloalkyl or C 1-6 deuterated alkyl;

[0135] R 4 selected from deuterium or -S(C 1-6 alkyl), said -S(C 1-6 alkyl) is optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 halocycloalkyl);

[0136] R g , R h are each independently selected from hydrogen or deuterium;

[0137] n is selected from 0, 1, 2, 3 or 4;

[0138] denotes a single or a double bond.

[0139] In the present application, as one of the embodiments, the compound of formula (I), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated compound), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

[0140] wherein:

[0141] R 1 each independently is selected from halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2;

[0142] R 2 is selected from hydrogen, halogen, OH, SH, CN, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl or C 3-6 cycloalkyl;

[0143] R 3 is selected from hydrogen, halogen, OH, SH, CN, -NR 3a R 3b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, -S(C 1-6 alkyl), C 3-6 cycloalkyl, -C 1-6 alkylene-OC 1-6 alkyl, -OC 1-6 alkylene-OC 1-6 alkyl, -C 1-6 alkylene-OH or -C 1-6 alkylene-NR 3a R 3b ;

[0144] R 3a and R 3b are independently at each occurrence selected from H or C 1-6 alkyl;

[0145] R 4 is selected from hydrogen, halogen, OH, CN, SH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH(C 1-6haloalkyl), -N(C 1-6 haloalkyl), -N(C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3- 10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl), -N(C 3-10 cycloalkyl, 3-12 membered heterocyclyl, -C 1-6 alkylene-C 3- 10 cycloalkyl or -C 1-6 alkylene-3-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents selected from the group consisting of deuterium, halogen, OH, CN, NH2, SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(C 1- 6alkyl), -S(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 1-6 haloalkyl), -N(C 1-6 haloalkyl)2, -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(C 1-6 haloalkyl), -S(=O)2(C 1-6 haloalkyl), -O(C 3-6 cycloalkyl), -O(C 3-6 halocycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 halocycloalkyl);

[0146] R g , R h each independently selected from hydrogen or deuterium;

[0147] n is selected from 0, 1, 2, 3 or 4;

[0148] denotes a single or a double bond.

[0149] In some embodiments, R g , R h are each hydrogen.

[0150] In some embodiments, the compounds of the present application are not:

[0151] In some embodiments, the compounds of the present application of formula (I) have the structure of formula (I-1) or (I-2):

[0152] In some embodiments, the compounds of the present application of formula (I) have the structure of formula (I-3) or (I-4):

[0153] In some embodiments, n is selected from 0, 1 or 2; preferably, n is selected from 0 or 1; preferably, n is 0.

[0154] In some embodiments, the compounds of the present application of formula (I) have the structure of one of formula (II-1) to (II-6):

[0155] In some embodiments, the compounds of the present application of formula (I) have the structure of formula (II-1):

[0156] In some embodiments, the compounds of the present application of formula (I) have the structure of one of formula (II-7) to (II-18):

[0157] In some embodiments, the compounds of the present application of formula (I) have the structure of formula (II-7):

[0158] In some embodiments, the compounds of the present application of formula (I) have the structure of one of formula (II-19) to (II-30):

[0159] In some embodiments, the compounds of the present application of formula (I) have the structure of formula (II-19):

[0160] In some embodiments, R 1 is selected from deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 1-4alkyl, C 1-4 alkoxy, -NH(C 1-4 haloalkyl), -N(C 1-4 haloalkyl)2, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NH(C 1-4 deuteroalkyl), -N(C 1-4 deuteroalkyl)2, C 1-4 deuteroalkyl, C 1-4 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

[0161] In some embodiments, R 1 is selected from halogen or C 1-4 alkyl.

[0162] In some embodiments, R 1 is selected from F, Cl or methyl.

[0163] In some embodiments, R 2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkoxy, -NH(C 1-4 haloalkyl), -N(C 1-4 haloalkyl)2, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NH(C 1-4 deuteroalkyl), -N(C 1-4 deuteroalkyl)2, C 1-4 deuteroalkyl, C 1-4 deuteroalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl.

[0164] In some embodiments, R 2 is selected from hydrogen, halogen or C 1-4 alkyl.

[0165] In some embodiments, R 2 is selected from hydrogen or halogen.

[0166] In some embodiments, R 2 is selected from hydrogen, F or Cl.

[0167] In some embodiments, R 2 is hydrogen.

[0168] In some embodiments, R 3selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR 3a R 3b , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 deuteroalkoxy, -S(C 1-4 alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -C 1-4 alkylene-OC 1-4 alkyl, -OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-CN or -C 1-4 alkylene-NR 3a R 3b .

[0169] In some embodiments, R 3a and R 3b are independently at each occurrence selected from H, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 deuteroalkyl.

[0170] In some embodiments, R 3 is selected from halogen, CN, C 1-4 alkyl, -S(C 1-4 alkyl), -NR 3a R 3b , C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocyclyl or -C 1-4 alkylene-OC 1-4 alkyl.

[0171] In some embodiments, R 3a and R 3b are independently at each occurrence selected from H or C 1-4 alkyl.

[0172] In some embodiments, R 3 is selected from F, Cl, CN, C 1-4 alkyl, -S(C 1-4 alkyl), -NR 3a R 3b , C 1-4 alkoxy, C 3-6cycloalkyl, 4-7 membered heterocyclyl, or -C 1-4 alkylene-OC 1-4 alkyl.

[0173] In some embodiments, R 3a and R 3b are independently selected at each occurrence from H or C 1-4 alkyl; preferably R 3a and R 3b wherein one is H and the other is C 1-4 alkyl.

[0174] In some embodiments, R 3 is selected from CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl.

[0175] In some embodiments, R 3 is C 1-4 alkyl.

[0176] In some embodiments, R 3 is selected from CN, C 1-4 alkyl, -S(C 1-4 alkyl), C 1-4 alkoxy, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl.

[0177] In some embodiments, R 3 is selected from F, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, -NHCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, cyclobutyl, oxetanyl (e.g. ), thietanyl (e.g. ), or azetidinyl (e.g. ).

[0178] In some embodiments, R 3 is selected from CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, cyclobutyl, oxetanyl, -OCH3, cyclopropyl, or -OCH2CH3.

[0179] In some embodiments, R 3 is selected from CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, cyclobutyl, or oxetanyl.

[0180] In some embodiments, R 4 is selected from C 1-4 alkyl, C2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S(C 1-4 alkyl), -NH(C 1-4 haloalkyl), -N(C 1-4 haloalkyl)2, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, -C 1-4 alkylene-C 3-6 cycloalkyl or -C 1-4 alkylene-4-7 membered heterocyclyl; said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S(C 1-4 alkyl), -NH(C 1-4 haloalkyl), -N(C 1-4 haloalkyl)2, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, -C 1-4 alkylene-C 3-6 cycloalkyl or -C 1-4 alkylene-4-7 membered heterocyclyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from deuterium, halogen, OH, CN, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, -S(C 1-4 alkyl), -S(C 1-4 haloalkyl), -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NH(C 1-4 haloalkyl), -N(C 1-4 haloalkyl)2, -S(=O)(C 1-4 alkyl), -S(=O)2(C 1-4 alkyl), -S(=O)(C 1-4 haloalkyl), -S(=O)2(C 1-4 haloalkyl), -O(C 3-6 cycloalkyl), or -O(C 3-6 halocycloalkyl).

[0181] In some embodiments, R 4 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl; said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halogen, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 Halogenated alkyl groups), -S(O)(C 1-6 Halogenated alkyl groups), -S(O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 Substitution of the halogenated cycloalkyl group; the C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-10 C in cycloalkyl 3-10 The cycloalkyl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 atoms selected from halogens, C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups.

[0182] In some implementation schemes, R 4 Selected from C 1-4 Alkyl, C 3-6 cycloalkyl or -C 1-4 Alkylene-C 3-6 cycloalkyl; the C 1- The 4 alkyl groups are optionally surrounded by 1, 2, 3, 4, 5, or 6 alkyl groups selected from halogens, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -S(C 1-4 Halogenated alkyl groups), -S(=O)(C 1-4 Halogenated alkyl groups), -S(=O)2(C 1-4 (halogenated alkyl) or -O(C) 3-6 Substitution of the halogenated cycloalkyl group; the C 3-6 cycloalkyl or -C 1-4 Alkylene-C 3-6 C in cycloalkyl 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 atoms selected from halogens, C 1-4 Halogenated alkyl or C 1-4 Substituents of haloalkoxy groups.

[0183] In some implementation schemes, R 4 Selected from C 1-4 Alkyl; the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, 4, 5, or 6 atoms selected from halogens, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -S(C 1-4 (halogenated alkyl) or -O(C) 3-6 Substitution of halogenated cycloalkyl groups.

[0184] In some implementation schemes, R 4 Selected from C 1-4 Alkyl; the C1-4 alkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of halo, C 1-4 alkoxy, or C 1-4 haloalkoxy.

[0185] In some embodiments, R 4 is selected from the group consisting of (preferably ), (preferably ), (preferably ), (preferably ), (preferably ),

[0186] In some embodiments, R 4 is selected from the group consisting of (preferably ), (preferably ), (preferably ), (preferably ).

[0187] In some embodiments, R 4 is selected from the group consisting of (preferably ) or (preferably ).

[0188] In some embodiments, the compounds of the present application have the structure according to Formula (III-1):

[0189] wherein:

[0190] n is selected from 0 or 1;

[0191] p is selected from 0, 1, 2, or 3;

[0192] Q is selected from halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, -S(C 1-6 haloalkyl), -S(=O)(C 1-6 haloalkyl), or -S(=O)2(C 1-6 haloalkyl);

[0193] R a R b each independently is selected from H, deuterium, halogen, CN, OH, NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; or R

[0194] L is selected from -CR L1 R L2 -, -C 3-6 cycloalkylene-, -C 3-6 halocycloalkylene-, -O-C 3-6 cycloalkylene-*, -O-C 3-6 halocycloalkylene-*, -S-C 3-6 cycloalkylene-*, or -S-C 3-6 halocycloalkylene-*, wherein the bond marked with “*” is connected to Q;

[0195] R L1 R L2 each independently is selected from H, deuterium, halogen, CN, OH, NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; or R L1 R L2 and the carbon atom to which they are attached together form C 3-6 cycloalkyl, 4-7 membered heterocyclyl;

[0196] R 1 R 2 R 3 R g R h as defined in any of the preceding aspects.

[0197] In some embodiments, the compounds of the present application have the structure according to any one of formulae (III-4) to (III-7):

[0198] In some embodiments, the compounds of the present application have the structure according to any one of formulae (III-4) to (III-7):

[0199] In some embodiments, the compounds of the present application have the structure according to any one of formulae (III-8) to (III-11):

[0200] In some embodiments, n is selected from 0.

[0201] In some embodiments, p is selected from 0, 1, or 2.

[0202] In some embodiments, p is 1.

[0203] In some embodiments, Q is selected from F, Cl, Br, C 1-3 haloalkyl, C 1-3 haloalkoxy, -S(C 1-3 haloalkyl), -S(=O)(C 1-3 haloalkyl), or -S(=O)2(C 1-3 haloalkyl).

[0204] In some embodiments, Q is selected from C 1-3 haloalkyl (e.g., C 1-3 fluoroalkyl), C 1-3 haloalkoxy (e.g., C 1-3 fluoroalkoxy).

[0205] In some embodiments, Q is selected from C 1-3 haloalkyl (e.g., C 1-3 fluoroalkyl).

[0206] In some embodiments, Q is selected from F, -OCF3, -OCF2H, -CF3, -CF2H, -SCF3, -SCF2H, -S(=O)CF3, -S(=O)2CF3, or -OCH2CF3.

[0207] In some embodiments, Q is selected from -OCF3or -CF3.

[0208] In some embodiments, Q is -CF3.

[0209] In some embodiments, R a , R b are each independently selected from H, deuterium, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

[0210] In some embodiments, R a , R b are each independently selected from H or C 1-6 alkyl.

[0211] In some embodiments, R a , R b are each independently selected from H or C 1-3 alkyl.

[0212] In some embodiments, R a , R b are each H, or R a , Rb one is H and the other is C 1-3 alkyl; more preferably, R a , R b are each H.

[0213] In some embodiments, L is selected from -CR L1 R L2 -, -C 3-6 cycloalkylene- or -O-C 3-6 halocycloalkylene-*; wherein the bond marked with "*" is connected to Q.

[0214] In some embodiments, L is selected from -CR L1 R L2 -.

[0215] In some embodiments, R L1 , R L2 are each independently selected from H, C 1-6 alkyl or C 1-6 alkoxy; or R L1 , R L2 and the carbon atom to which they are attached form a C 3-6 cycloalkyl.

[0216] In some embodiments, R L1 , R L2 are each independently selected from H, C 1-3 alkyl or C 1-3 alkoxy.

[0217] In some embodiments, R L1 , R L2 are each H, or R L1 , R L2 one is H and the other is C 1-3 alkyl or C 1-3 alkoxy.

[0218] In some embodiments, R L1 , R L2 one is H and the other is C 1-3 alkoxy.

[0219] In some embodiments, L is selected from -CR L1 R L2 -,

[0220] In some embodiments, L is selected from -CH2-, -CH(CH3)-, -CH(OCH3)-,

[0221] In some embodiments, L is selected from -CH2-, -CH(CH3)-, or -CH(OCH3)-.

[0222] In some embodiments, L is -CH(OCH3)-.

[0223] In some embodiments, the compounds of the present application have the structure of formula (IV-1):

[0224] wherein R 1 , R 2 , R 3 , R g , R h , n, R a , R b , R L1 , R L2 are as defined in any of the preceding embodiments.

[0225] In some embodiments, the compounds of the present application have the structure of formula (IV-2):

[0226] In some embodiments, the compounds of the present application have the structure of formula (IV-3):

[0227] In some embodiments, the compounds of the present application are selected from:

[0228] In some embodiments, the compounds of the present application have the structure of formula (I-18):

[0229] wherein ring D is a 5-10 membered bridged heterocycloalkyl;

[0230] R 4 is selected from:

[0231] H, halogen, OH, SH, CN, or N(R 7a )2,

[0232] C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl,

[0233] -O-C 1-6 alkyl, -O-haloC1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl or -C 1-6 alkylene-O-haloC 1-6 alkyl,

[0234] C 3-10 cycloalkyl, -C 1-6 alkylene-C 3-10 cycloalkyl, -O-C 1-6 alkylene-C 3-10 cycloalkyl or -C(O)-C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl or C 1-6 haloalkoxy, and

[0235] 3-10 membered heterocycloalkyl or -C 1-6 alkylene-3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl or C 1-6 haloalkoxy;

[0236] R 7a each independently selected from the group consisting of: H, C 1-6 alkyl, -(CH2) q -C 3-10 cycloalkyl or -(CH2) q -3-10 membered heterocycloalkyl, q is selected from an integer between 0 and 6, and the C 1-6 alkyl, -(CH2) q -C 3-10 cycloalkyl or -(CH2) q -3-10 membered heterocycloalkyl, each independently optionally substituted with 1, 2, or more substituents independently 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 1-6alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy substituted; and

[0237] m is 1, 2 or 3;

[0238] L 1 is selected from: *-CR g R h -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 g R h - or *-NR 4c -C(S)-, wherein the bond marked with * is connected to the phenyl ring B;

[0239] R g and R h are each independently selected from the group consisting of 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 g and R h together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl;

[0240] R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

[0241] R 3 is selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -S-C 1-6 alkyl, -S(O)2-C 1-6 alkyl, -C 1-6alkylene-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 alkyleneC(O)OR 6a , -OC 1-6 alkyleneC(O)NR 6a R 6b , C 3-10 cycloalkyl or -OC 1-6 alkylene-C 3-10 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -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 alkyleneC(O)OR 6a , -OC 1-6 alkyleneC(O)NR 6a R 6b , C 3-10 cycloalkyl or -OC 1-6 alkylene-C 3-10 cycloalkyl are each optionally substituted with one or more deuterium (D);

[0242] R 5 is selected from the group consisting of: H, halogen, OH, SH, CN, -NR 6a R 6b , C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene-SH or C 3-10 Cyclic hydrocarbon group; and

[0243] R 5a R 5b R 6a or R 6b Each time it appears, it is independently selected from H or C. 1-6 alkyl;

[0244] R 2 or R 8 Each of these elements is independently selected from: H, halogen, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 3-10 Cyclic hydrocarbon group;

[0245] In some implementation schemes, R 4 Selected from: H, halogen, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-CN, -OC 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, -OC 1-6 Alkyl-C 3-10 Cyclic hydrocarbon group, and optionally one, two or more independently selected from halogen, OH, SH, NH2, CN, C 1-6 Alkyl or C 1-6 The C-substituent of the haloalkyl group 3-10 Cyclic hydrocarbon group; and

[0246] R g or R h Each is independently selected from H, halogen, OH, SH, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 5a R 5b -C(O)OR5a or -C(O)-NR 5a R 5b ; and

[0247] R 5 is selected from: 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 cycloalkyl.

[0248] In some embodiments, ring D is a 5-8 membered bridged heterocycloalkyl.

[0249] In some embodiments, ring D is wherein, A is the point of attachment to ring A, L1 is the point of attachment to L 1 ;

[0250] In some embodiments, R 4 is selected from:

[0251] H, halogen, OH, SH, CN, or N(R 7a )2,

[0252] C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl,

[0253] -O-C 1-6 alkyl, -O-haloC 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-O-haloC 1- 6alkyl,

[0254] C 3-6 cycloalkyl, -C 1-6 alkylene-C 3-6 cycloalkyl, -O-C 1-6 alkylene-C 3-6 cycloalkyl, or -C(O)-C 3-6 cycloalkyl, wherein the C3-6 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy, and

[0255] 4-7 membered heterocycloalkyl, or -C 1-6 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and

[0256] R 7a each independently selected from the group consisting of: H, C 1-6 alkyl, -(CH2) q -C 3-6 cycloalkyl, or -(CH2) q -4-7 membered heterocycloalkyl, q is selected from an integer between 0 and 4, and the C 1-6 alkyl, the -(CH2) q -C 3-6 cycloalkyl, and the -(CH2) 3-6 cycloalkyl, and the -(CH2) q 4-7 membered heterocycloalkyl of the -4-7 membered heterocycloalkyl is each independently optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy.

[0257] In some preferred embodiments, 1 R 7a in N(R 7a )2 is H.

[0258] In some preferred embodiments, R 4 is selected from:

[0259] H, F, Cl, OH, SH, CN, or NH2,

[0260] -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NH(C 3-6 cycloalkyl), or -NH(4-7 membered heterocycloalkyl), wherein the C 1-4 alkyl of said -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2, the C 3-6 cycloalkyl of said -NH(C 3-6 cycloalkyl, and the 4-7 membered heterocycloalkyl of said -NH(4-7 membered heterocycloalkyl) are each independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 alkyl, or C 1-6 haloalkyl,

[0261] -NH(C 1-4 alkylene)-(C 3-6 cycloalkyl), -NH(C 1-4 alkylene)-CN, C 1-4 alkyl, C 1-6 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 haloalkyl-OH, -C 1-4 alkylene-SH, -C 1-4 haloalkyl-SH, -C 1-4 alkylene-CN, -C 1-4 haloalkyl-CN, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 1-4 alkyl, -O-haloC 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkyl, or -C 1-4 alkyl-O-haloC 1-4 alkyl,

[0262] C 3-6 cycloalkyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -O-C 1-4 alkylene-C 3-6 cycloalkyl, or -C(O)-C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl at each occurrence is independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 alkyl, C1-4 haloalkyl or C 1-4 haloalkyl or C

[0263] 4-7 membered heterocycloalkyl or -C 1-4 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl at each occurrence is independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkyl or C

[0264] In some more preferred embodiments, R 4 is selected from:

[0265] H, OH, or SH,

[0266] -NH(C 1-4 alkyl), -NH(C 3-6 partially unsaturated cycloalkyl), or -NH(4-6 membered heterocycloalkyl), the C 1-4 alkyl in said -NH(C 1-4 alkyl, the C 3-6 alkyl in said -NH(C 3-6 partially unsaturated cycloalkyl, and the 4-6 membered heterocycloalkyl in said -NH(4-6 membered heterocycloalkyl) are each independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-4 alkyl or C 1-4 haloalkyl,

[0267] -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-haloC 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkyl or C 1-4 alkyl-O-haloC 1-4alkyl,

[0268] C 3-6 cycloalkyl, -C 1-4 Alkylene-C 3-6 cycloalkyl or -OC 1-4 Alkylene-C 3-6 cycloalkyl, wherein the C 3-6 Each cycloalkyl group is independently and optionally selected from one, two or more deuterium, halogen, OH, SH, NH2, CN, C in each occurrence. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Substitution of halogenated alkoxy groups, and

[0269] 4-7 membered heterocyclic alkyl or -C 1-4 Alkylene-4-7-membered heterocyclic alkyl groups, wherein the 4-7-membered heterocyclic alkyl group, each time appearing, is independently and optionally selected by one, two or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups.

[0270] In other implementations, R 4 Selected from: H, halogen, OH, SH, CN, N(R) 7a 2. C 1-6 Alkyl, -OC 1- 6-alkyl or -OC 1-6 Alkyl-C 3-6 Cycloalkyl groups, and optionally one, two or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The C-substituent of the halogenated alkoxy group 3-6 Cycloalkyl groups, optionally composed of one, two or more independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 4-7 membered heterocyclic alkyl groups substituted with haloalkoxy groups.

[0271] In some preferred embodiments, R 4 Selected from: H, halogen, OH, SH, CN, NH2, -NH(C) 1-6alkyl), -N(C 1-6 alkyl, -N(C 3-10 cycloalkyl), C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-SH, -C 1-6 alkylene-CN, -O-C 1-6 alkyl, -O-haloC 1-6 alkyl, -O-C 1-6 alkyl-C 3-10 cycloalkyl, and optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and each R 3-10 cycloalkyl, optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and each R 1-6 alkyl, and the C 1-6 alkyl in the -NH(C 1-6 alkyl), and the C 3-10 cycloalkyl in the -NH(C 3-10 cycloalkyl are each independently optionally substituted with 1, 2, or more substituents independently 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, C 1-6 haloalkyl, or C 1-6 haloalkoxy.

[0272] In some preferred embodiments, R 4 is selected from the group consisting of: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NH(C 3-6 cycloalkyl), -NH(C 1-4 alkylene)-(C3-6 cycloalkyl), -NH(C 1-4 alkylene)-CN, C 1-4 alkyl, C 1-4 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, -O-C 1-4 alkyl, -O-haloC 1-4 alkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, and optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, or C 1-4 haloalkyl; C 3-6 cycloalkyl, optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; 4-7 membered heterocycloalkyl; said -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2; C 1-4 alkyl, and C 3-6 cycloalkyl in said -NH(C 3-6 cycloalkyl are each independently optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 alkyl, or C 1-6 haloalkyl.

[0273] In some preferred embodiments, R 4 is selected from the group consisting of: H, OH, SH, -NH(C 1-4 alkyl), -N(C 3-6 partially unsaturated cycloalkyl), -N(C 1-4 alkylene)-(C 3-6 cycloalkyl), -N(C 1-4 alkylene)-CN, C 1-4 alkyl, C 1-4 haloalkyl, -O-C 1-4 alkyl, -O-haloC 1-4 alkyl, -O-C 1-4 alkyl-C 3-6Cycloalkyl groups, and optionally one, two or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl or C 1-4 The C-substituent of the alkyl halogroup 3-6 Cycloalkyl groups, optionally composed of one, two or more independently selected from deuterium, halogen, OH, SH, NH2, CN, C 1-4 Alkyl or C 1-4 4-7 membered heterocyclic alkyl groups substituted with haloalkyl groups; the -NH(C 1-4 C in alkyl) 1-4 Alkyl groups, and the -NH(C) group 3-6 C in partially unsaturated cyclic hydrocarbon groups 3-6 Each of the partially unsaturated cyclic hydrocarbon groups is independently and optionally selected by one, two or more independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C. 1-4 Alkyl or C 1-4 Substituents of haloalkyl groups.

[0274] In some preferred embodiments, R 4 Selected from the groups listed in group C:

[0275] (Group C)H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, difluorocyclopropyl, amino, -NHCH3, -N(CH3) 2、 -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl -NH-cyclobutane, Or -O-CH2-cyclopropyl.

[0276] In some embodiments, group C further includes the following groups:

[0277] Cyclopropyl,

[0278] In other implementations, R 4 Selected from H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN、 -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, cyclopropyl, difluorocyclopropyl, amino, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclobutane, -O-CH2-cyclopropyl or

[0279] In some embodiments, R 4 is selected from: H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2CHF2, -CH2CN, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, cyclopropyl, difluorocyclopropyl, amino, -NHCH3, -N(CH3) 2、 -NHCH2CH3, -NHCH2CN, -NHCH2CF3, -NH-cyclopropyl, -NHCH2-cyclopropyl, -NH-cyclobutane, -O-CH2-cyclopropyl or

[0280] In other embodiments, R 4 is selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, -O-C 1-4 alkyl, -O-haloC 1-4 alkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, and optionally substituted with 1, 2, or more groups independently selected from halogen, OH, SH, NH2, CN, C1-4 alkyl or C 1-4 haloalkyl substituted C 3-6 cycloalkyl.

[0281] In some preferred embodiments, R 4 is selected from: H, OH, SH, C 1-4 alkyl, C 1-4 haloalkyl, -O-C 1-4 alkyl, -O-haloC 1-4 alkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, and optionally substituted with 1, 2, or more substituents independently selected from halo, OH, SH, NH2, CN, C 1-4 alkyl or C 1-4 haloalkyl substituted C 3-6 cycloalkyl.

[0282] In some preferred embodiments, R 4 is selected from: H, OH, SH, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, difluorocyclopropyl, or -O-CH2-cyclopropyl.

[0283] In some preferred embodiments, m is 1.

[0284] In some embodiments, ring D is wherein, A is the point of attachment to ring A, L1 is the point of attachment to L 1 .

[0285] In some more preferred embodiments, moiety is wherein, A is the point of attachment to ring A, L1 is the point of attachment to L 1 .

[0286] In some embodiments, R 4 is selected from:

[0287] H, F, Cl, OH, SH, CN, NH2,

[0288] -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NH(C 3-6 cycloalkyl), -NH(4-7 membered heterocycloalkyl), wherein said -NH(C 1-4 alkyl) and -N(C 1-4C in (C1-C6 alkyl)2 1-4 alkyl, the -NH(C 3-6 C in (C3-C6 cycloalkyl)2 3-6 cycloalkyl and 4-7 membered heterocycloalkyl in the -NH(4-7 membered heterocycloalkyl) is each independently optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 alkyl or C 1-6 substituted by 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH2, CN, C

[0289] -NH(C 1-4 alkylene)-(C 3-6 cycloalkyl), -NH(C 1-4 alkylene)-CN, C 1-4 alkyl, C 1-6 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 haloalkyl-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 1-4 alkyl or -O-haloC 1-4 alkyl,

[0290] C 3-6 cycloalkyl, -C 1-4 alkylene-C 3-6 cycloalkyl or -O-C 1-4 alkyl-C 3-6 cycloalkyl, wherein the C 3- 6cycloalkyl is independently optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, and

[0291] 4-7 membered heterocycloalkyl or -C 1-4 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is independently optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.

[0292] In some preferred embodiments, R4 selected from:

[0293] C 1-4 alkyl, C 1-6 haloalkyl, -C 1-4 haloalkyl-OH, -C 1-4 alkylene-CN or C 2-4 alkynyl,

[0294] C 3-6 cycloalkyl or -C 1-4 alkylene-C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, and

[0295] 4-7 membered heterocycloalkyl or -C 1-4 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy, and

[0296] -NH(4-7 membered heterocycloalkyl), wherein the 4-7 membered heterocycloalkyl is each independently optionally substituted with 1, 2, or more substituents independently selected from the group consisting of deuterium, halogen, OH, oxo, SH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl.

[0297] In some more preferred embodiments, R 4 selected from:

[0298] C 1-4 alkyl, C 1-6 haloalkyl, -C 1-4 haloalkyl-OH, -C 1-4 alkylene-CN, C 2-4 alkynyl or -NH(4-6 membered heterocycloalkyl),

[0299] C 3-6 cycloalkyl or -C 1-4 alkylene-C 3-6cycloalkyl, wherein the C 3-6 cycloalkyl is independently and optionally substituted with 1, 2, or more substituents independently selected from halo, C 1-4 haloalkyl, or C 1-4 haloalkoxy, and

[0300] 4-7 membered heterocycloalkyl, or -C 1-4 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is independently and optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, NH2, CN, or C 1-4 alkyl at each occurrence is independently and optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, NH2, CN, or C

[0301] In other embodiments, R 4 is selected from: H, F, Cl, OH, SH, CN, NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NH(C 3-6 cycloalkyl), -NH(C 1-4 alkylene)-(C 3-6 cycloalkyl), -NH(C 1-4 alkylene)-CN, C 1- 4alkyl, C 1-4 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, and optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, SH, NH2, CN, C 1-4 alkyl, or C 1-4 haloalkyl; the -NH(C 3-6 cycloalkyl is optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, SH, NH2, CN, oxo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; the C 1-4 alkyl in the -NH(C 1-4 alkyl)2, and the C 1-4 alkyl in the -NH(C 3-6 cycloalkyl) is optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, SH, NH2, CN, C 3-6each cycloalkyl is independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH2, CN, C1-4alkyl, or C1-4haloalkyl. 1-6 alkyl or C 1-6 haloalkyl.

[0302] In some preferred embodiments, R 4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, and C3-6cycloalkyl optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4alkyl, or C1-4haloalkyl. 1-4 alkyl and C 1-4 haloalkyl. 3-6 cycloalkyl optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C1-4alkyl, or C1-4haloalkyl. 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.

[0303] In some preferred embodiments, ring D is a 5-8 membered bridged heterocycloalkyl, R 4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, and C3-6cycloalkyl optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4alkyl, or C1-4haloalkyl. moieties are wherein, A is a point of attachment to ring A, L1 is a point of attachment to L 1 .

[0304] In some embodiments, R 3 is independently selected at each occurrence from H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl, -S-C1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b -C 1-4 Alkylene-NR 6a -C(O)R 6b -OC 1-4 Alkylene C(O)OR 6a -OC 1-4 Alkylene C(O)NR 6a R 6b C 3-6 cycloalkyl and -OC 1-4 Alkylene-C 3-6 cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl groups, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b -C 1-4 Alkylene-NR 6a -C(O)R 6b -OC 1-4 Alkylene C(O)OR 6a -OC 1-4 Alkylene C(O)NR 6a R 6b C 3-6 cycloalkyl or -OC 1-4 Alkylene-C 3-6 Each cycloalkyl group is optionally substituted with one or more D atoms, and

[0305] R 5independently at each occurrence selected from the group consisting of: 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 alkylene C(O)NR 6a R 6b , C 3-6 cycloalkyl or -OC 1-4 alkylene-C 3-6 cycloalkyl.

[0306] In some preferred embodiments, R 3 independently at each occurrence selected from the group consisting of: 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 or C 3-6 cycloalkyl, wherein said 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 or C 3-6 cycloalkyl are each optionally substituted with one or more D, and

[0307] R5 independently at each occurrence selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 1-4 alkyl, -S-C 1-4 alkyl or C 3-6 cycloalkyl. In other embodiments, R 3 or R 5 independently at each occurrence selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -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 alkylene C(O)NR 6a R 6b , C 3-6 cycloalkyl or -OC 1-4 alkylene-C 3-6 cycloalkyl. In some preferred embodiments, R 3 or R 5 independently at each occurrence selected from: H, halogen, OH, SH, CN, -NR 6a R 6b , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -O-C1-4 Alkyl, -SC 1-4 Alkyl or C 3-6 Cycloalkyl.

[0308] In other implementations, R 3 Or R 5 Each time it appears, it is independently selected from: halogen, OH, SH, CN, -NR. 6a R 6b C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl groups, -SC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene-NR 6a R 6b -C 1-4 Alkylene-NR 6a -C(O)R 6b -OC 1-4 Alkylene C(O)OR 6a -OC 1-4 Alkylene C(O)NR 6a R 6b C 3-6 cycloalkyl or -OC 1-4 Alkylene-C 3-6 Cycloalkyl. In some preferred embodiments, R 3 Or R 5 Each time it appears, it is independently selected from: halogen, OH, SH, CN, -NR. 6a R 6b C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl or C 3-6 Cycloalkyl.

[0309] In some preferred embodiments, R 6a Or R 6bis independently selected at each occurrence from H or C 1-4 alkyl.

[0310] In some preferred embodiments, R 3 is independently selected at each occurrence from: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, and cyclopropyl, and R 5 is independently selected at each occurrence from: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, or cyclopropyl. In some more preferred embodiments, R 3 is -O-C 1-4 alkyl, -O-deuterated C 1-4 alkyl, or cyclopropyl, and R 5 is H or C 1-4 alkyl. In some more preferred embodiments, R 3 is -O-CH3, -O-CD3, or cyclopropyl, and / or R 5 is methyl.

[0311] In some preferred embodiments, R 3 and R 5 is independently selected at each occurrence from: H, F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, or cyclopropyl. In some more preferred embodiments, R 3 and R 5 is independently selected at each occurrence from: F, Cl, OH, SH, CN, -NH2, -NHCH3, -NH(CH3)2, methyl, ethyl, CF3, vinyl, ethynyl, -O-CH3, -S-CH3, or cyclopropyl.

[0312] In some preferred embodiments, R 3 is -O-CH3. In some preferred embodiments, R 5 is H or methyl. In some preferred embodiments, R 5 is methyl.

[0313] In some preferred embodiments, R 3 is -O-C 1-4 alkyl, and R 5 is hydrogen or C 1-4 alkyl. In some preferred embodiments, R 3is -O-CH3, and R 5 is methyl.

[0314] In some embodiments, R 2 and R 8 are each independently at each occurrence selected from the group consisting of: H, halogen, OH, SH, CN, NH2, -NH(CH3), -N(CH3)2, methyl, ethyl, or cyclopropyl, preferably H, F, Cl, methyl, ethyl, or cyclopropyl. 1-4 alkyl), -N(C 1-4 alkyl)2, C 1-4 alkyl, or C 3-6 cycloalkyl.

[0315] In some preferred embodiments, R 2 and R 8 are each independently at each occurrence selected from the group consisting of: H, F, Cl, OH, SH, CN, NH2, -NH(CH3), -N(CH3)2, methyl, ethyl, or cyclopropyl, preferably H, F, Cl, methyl, ethyl, or cyclopropyl.

[0316] In some embodiments, L 1 is selected from the group consisting of: *-CR g R h -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 g R h -, or *-NR 4c -C(S)-, wherein the bond marked with * is connected to the phenyl ring B; and

[0317] R g and R h are each independently selected from the group consisting of 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 g or R h together with the carbon atom to which they are both attached form a C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl.

[0318] In some preferred embodiments, L 1 is selected from the group consisting of: *-CRg R h -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 g R h - or *-NR 4c -C(S)-, wherein the bond marked with * is connected to the phenyl ring B; and R g and R h are each independently selected from the group consisting of: H, deuterium, F, CI, OH, SH, CN, C 1-4 alkyl, C 1-4 haloalkyl, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b , preferably H, F, CI, OH, SH, CN, CH3, CF3, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b ; or R g or R h together with the carbon atom to which they are both attached form a C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl.

[0319] In other embodiments, L 1 is selected from the group consisting of: *-CR g R h -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 g R h - or *-NR 4c -C(S)-, wherein the bond marked with * is connected to the phenyl ring B; and

[0320] R g and R heach independently selected from H, deuterium, F, CI, 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 g or R h together with the carbon atom to which they are both attached form a C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl.

[0321] In some preferred embodiments, L 1 is selected from: *-CR g R h -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 g R h - or *-NR 4c -C(S)-, wherein the bond marked with * is connected to the phenyl ring B; and

[0322] R g or R h each independently selected from H, deuterium, F, CI, OH, SH, CN, C 1-4 alkyl, C 1-4 haloalkyl, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b ; or R g or R h together with the carbon atom to which they are both attached form a C 3-4 cycloalkyl or 4-5 membered heterocycloalkyl.

[0323] In other embodiments, L 1 is selected from: *-CR g R h -NR 4c -, *-C(O)-NR 4c -, *-C(S)-NR 4c -, *-S(O)2-NR 4c -, *-NR4c -C(O)-, *-NR 4c -S(O)2-, *-NR 4c -CR g R h - or *-NR 4c -C(S)-, where the bond marked with * is connected to the phenyl ring B; and R g and R h are each independently selected from the group consisting of H, F, Cl, OH, SH, CN, C 1-4 alkyl, C 1-4 haloalkyl, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b , preferably H, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b .

[0324] In some preferred embodiments, R 5a and R 5b are at each occurrence independently selected from H or C 1-4 alkyl.

[0325] In some preferred embodiments, R g and R h are each independently selected from the group consisting of H, deuterium, F, Cl, OH, SH, CN, CH3, CF3, NR 5a R 5b , -C(O)OR 5a or -C(O)-NR 5a R 5b . In some preferred embodiments, R g or R h are each independently selected from the group consisting of H, deuterium, F, Cl, OH, SH, CN, -NH2, -C(O)OH, -C(O)OCH3, -C(O)-NH2, or -C(O)-NCH3. In some preferred embodiments, R g or R h together with the carbon atom to which they are both attached form a cyclopropane group.

[0326] In other embodiments, R g or R heach independently selected from H, F, CI, OH, SH, CN, -NH2, -C(0)OH, -C(0)OCH3, -C(O)-NH2, or -C(O)-NCH3.

[0327] In some preferred embodiments, R 4c is selected from H, C 1-4 alkyl or C 1-4 haloalkyl.

[0328] In some preferred embodiments, R 4c is selected from H, methyl, ethyl, -CH2F, -CHF2, or -CF3.

[0329] In some preferred embodiments, L 1 is selected from: *-CH2-NH-, *-CF2-NH-, *-CD2-NH-, *-CH(CF3)-NH-, *-C(CH3)2-NH-, *-CH2-N(CH3)-, *-CH2-N(CH2CH3)-, *-CH2-N(CH2F)-, *-C(O)-NH-, *-C(S)-NH-, *-S(O)2-NH-, *-NH-CH2-, *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O)2-, wherein the bond marked with * is connected to the phenyl ring B.

[0330] In some other embodiments, L 1 is selected from: *-CH2-NH-, *-CF2-NH-, *-CH(CF3)-NH-, *-CH2-N(CH3)-, *-CH2-N(CH2CH3)-, *-CH2-N(CH2F)-, *-C(O)-NH-, *-C(S)-NH-, *-S(O)2-NH-, *-NH-CH2-, *-NH-CF2-, *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O)2-, More preferably *-CH2-NH- and *-C(O)-NH-, wherein the bond marked with * is connected to the phenyl ring B.

[0331] In some more preferred embodiments, L 1 is selected from: *-CH2-NH-, *-CD2-NH-, *-C(CH3)2-NH *-C(O)-NH- or wherein the bond marked with * is connected to the phenyl ring B.

[0332] In some preferred embodiments, the compounds according to the application have the structure according to Formula (I-19):

[0333] In some embodiments of the compound according to formula (I-19), L 1 is selected from -CR g R h -NR 4c - and -C(O)-NR 4c wherein the bond marked with * is connected to the phenyl ring B;

[0334] R g or R h are each independently selected from H or deuterium;

[0335] R 4c is H;

[0336] R 3 is selected from -O-C 1-6 alkyl or C 3-6 cycloalkyl, wherein the -O-C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, 3, or more D;

[0337] R 5 is selected from C 1-6 alkyl;

[0338] Ring D is a 5-8 membered bridged heterocycloalkyl; preferably wherein A is a point of attachment to ring A, L1 is a point of attachment to L 1 ;

[0339] R 4 is selected from:

[0340] C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, 6, or more substituents independently selected from halogen, OH, NH2, or CN;

[0341] -C 1-6 alkylene-O-halogenated C 1-6 alkyl,

[0342] C 3-6 cycloalkyl or -C 1-6 alkylene-C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is independently optionally substituted with 1, 2, or more substituents independently selected from halogen, OH, NH2, CN, C 1-6 alkyl, C 1-6 halogenated alkyl, or C1-6 substituted by a substituent selected from halo, OH, NH2, CN, C

[0343] 4-7 membered heterocycloalkyl or -C 1-6 alkylene-4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is, at each occurrence, independently optionally substituted with 1, 2, or more substituents independently selected from deuterium, halo, OH, NH2, CN, C 1-6 alkyl or C 1-6 haloalkyl, and

[0344] -NH(4-7 membered heterocycloalkyl); and

[0345] m is 1.

[0346] In some such embodiments, ring D is preferably wherein A is a point of attachment to ring A, L1 is a point of attachment to L 1 . More preferably, moiety is wherein A is a point of attachment to ring A, L1 is a point of attachment to L 1 .

[0347] In some preferred embodiments, L 1 is selected from -*CH2-NH-, -*CD2-NH-, or -*C(O)-NH-, wherein the bond marked with * is connected to the phenyl ring B.

[0348] In some preferred embodiments, R 3 is selected from -O-C 1-4 alkyl or C 3-6 cycloalkyl, wherein the -O-C 1-4 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, 3, or more D. More preferably, R 3 is selected from -O-C 1-2 alkyl or C 3-6 cycloalkyl, wherein the -O-C 1-2 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, 3, or more D.

[0349] In some preferred embodiments, R 5 is selected from C 1-4 alkyl, more preferably C 1-2 alkyl.

[0350] In some more preferred embodiments, R 3is -O-CH3, -O-CD3, or cyclopropyl, and R 5 is methyl.

[0351] In some preferred embodiments, R 4 is selected from:

[0352] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 1-6 C1-6alkenyl, or C1-6alkynyl, 2-4 C1-6alkenyl, or C1-6alkynyl, 2-4 C1-6alkenyl, or C1-6alkynyl,

[0353] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN,

[0354] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 3-6 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 3-6 C1-6alkenyl, or C1-6alkynyl, 3-6 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl,

[0355] C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl.

[0356] In some more preferred embodiments, R 4 is selected from:

[0357] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 1-6 C1-6alkenyl, or C1-6alkynyl, 2-4 C1-6alkenyl, or C1-6alkynyl, 2-4 C1-6alkenyl, or C1-6alkynyl,

[0358] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 1-4 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN,

[0359] C1-6alkyl optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, NH2, or CN, 3-6 C1-6alkenyl, or C1-6alkynyl, 1-4 C1-6alkenyl, or C1-6alkynyl, 3-6 C1-6alkenyl, or C1-6alkynyl,3-6 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, CN, or C 1-4 substituted by substituents of haloalkyl,

[0360] 4-6 membered heterocycloalkyl or -C 1-4 alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, CN, or C 1-4 substituted by substituents of alkyl, and

[0361] wherein halo or halogen above is independently at each occurrence selected from F or Cl.

[0362] In some more preferred embodiments, R 4 is selected from:

[0363] 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 or -NH(4-6 membered heterocycloalkyl),

[0364] C 3-6 cycloalkyl or -C 1-4 alkylene-C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from halogen, C 1-4 haloalkyl or C 1-4 substituted by substituents of haloalkoxy,

[0365] 4-6 membered heterocycloalkyl or -C 1-4 alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from deuterium, halogen, CN, or C 1-4 substituted by substituents of alkyl, and

[0366] wherein halo or halogen above is independently at each occurrence selected from F or Cl.

[0367] In some more preferred embodiments, R 4 is selected from:

[0368] C 1-4 alkyl, C 1-6 fluoroalkyl, -C 1-4 fluoroalkyl-OH, -C1-4 alkylene-CN, C 2-4 alkynyl or -NH(4-6 membered heterocycloalkyl having 1 O or S heteroatom),

[0369] C 3-6 cycloalkyl or -C 1-4 alkylene-C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl is independently at each occurrence optionally substituted with 1, 2, or more substituents independently selected from F, C 1-4 fluoroalkyl or C 1-4 fluoroalkoxy, and

[0370] 4-6 membered heterocycloalkyl or -C 1-4 alkylene-4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl at each occurrence is independently 4-6 membered heterocycloalkyl having 1 N heteroatom and is optionally substituted with 1, 2, or more substituents independently selected from deuterium, F, CN, or C 1-4 alkyl.

[0371] In some more preferred embodiments, R 4 is selected from methyl, ethyl,

[0372] In some more preferred embodiments, the compound of Formula (I-19) has the structure according to Formula (I-20) or (I-21):

[0373] preferably has the structure according to Formula (I-24) or (I-25)

[0374] more preferably has the structure according to Formula (I-24)

[0375] In some preferred embodiments, moieties are wherein A is a point of attachment to ring A, L1 is a point of attachment to L 1 .

[0376] In some such embodiments, preferably, R 3 is -O-CH3or cyclopropyl, and R 5 is methyl. In some embodiments, R 4 is selected from C 1-4 alkyl substituted with 1, 2, 3, 4, or more substituents independently selected from halogen and OH. In some preferred embodiments, R4 C selected from the group consisting of C substituted with 1, 2, 3, 4, or more substituents independently selected from the group consisting of F, Cl, and OH 1-6 alkyl. In some preferred embodiments, R 4 C selected from the group consisting of C substituted with 1, 2, 3, 4, or more substituents independently selected from the group consisting of F, Cl, and OH 1-6 alkyl. In some preferred embodiments, R 4 C selected from the group consisting of C substituted with 1, 2, 3, or more F and 0 or 1 OH 1-6 alkyl. In some preferred embodiments, R 4 C selected from the group consisting of C substituted with 1, 2, 3, or more F and 0 or 1 OH 3-6 alkyl. In some more preferred embodiments, R 4 selected from the group consisting of

[0377] The present application encompasses compounds resulting from any combination of the various embodiments.

[0378] In some embodiments, the present application provides the compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemic, 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 selected from the group consisting of:

[0379] In some embodiments, the present application provides the compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemic, 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 selected from the group consisting of:

[0380] In some embodiments, the present application provides the compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemic, 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 selected from the group consisting of:

[0381] In some embodiments, the present application 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 selected from:

[0382] Pharmaceutical compositions and uses

[0383] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) according to the present application, including the compounds of formula (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), 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. The pharmaceutical composition is preferably a solid, liquid or semi-solid formulation.

[0384] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) according to the present application, including the compounds of formula (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), 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.

[0385] In another aspect, the present application provides a compound of formula (I), including compounds of formula (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof according to the present application, or a pharmaceutical composition according to the present application, or a pharmaceutical combination according to the present application, for use as a medicament.

[0386] In another aspect, the present application provides a method of modulating the activity of the complement alternative pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I), including compounds of formula (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a 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; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present application.

[0387] In some embodiments, the compound, the pharmaceutical composition, or the pharmaceutical combination according to the present application is used 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 complement alternative pathway.

[0388] In another aspect, the present application provides a method of preventing or treating a disease, disorder or condition mediated by complement activation, in particular a disease, disorder or condition mediated by activation of the complement alternative pathway, in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula (I), including compounds of formula (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystal form, a hydrate, a solvate, or a 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; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present application.

[0389] In another aspect, the present application provides the use of a compound of formula (I), including compounds of formula (I-1) to (I-4), formula (II-1) to (II-30), formula (III-1) to (III-11), formula (IV-1) to (IV-3), or a stereoisomer, a tautomer, a diastereomer, a racemate, a cis-trans isomer, an isotopically labeled compound (preferably deuterated), an N-oxide, a metabolite, an ester, a prodrug, a crystalline form, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof according to the present application, or the pharmaceutical composition according to the present application, or the medicament according to the present application, for 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 complement alternative pathway, in an individual.

[0390] In some embodiments the disease, disorder or condition is selected from age-related macular degeneration, macular geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological diseases, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, disorders resulting from inappropriate or undesirable 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, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric arterial reperfusion following aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN) or other kidney diseases with evidence of glomerular C3 deposition (e.g. membranous nephropathy (MN) and E. coli induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic disease, Goodpasture's syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex related inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

[0391] In some embodiments, the disease, disorder, or condition is selected from age-related macular degeneration (AMD), macular geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, avian retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, post-surgical inflammation, retinal vein occlusion, neurological diseases, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, disorders resulting from inappropriate or undesirable 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, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric arterial reperfusion following aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerulopathy (C3G), immunoglobulin A nephropathy (IgAN), or other renal diseases with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, respiratory distress, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic disease, Goodpasture's syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity.

[0392] A "pharmaceutically acceptable carrier" in the present application refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, and which is nontoxic to the subject to which it is administered at dosages and in amounts utilized. A pharmaceutically acceptable carrier is one that is compatible with the treatment regimen and that does not destroy the pharmacological activity of the treatment agent or cause an unacceptable level of side effects.

[0393] Unless otherwise indicated, the term "treatment" as used herein means reversing, alleviating, inhibiting the progress of, or preventing a condition or a symptom of a condition to which such term applies, or one or more symptoms of such condition or symptom.

[0394] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) having a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory models (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0395] In another embodiment, the pharmaceutical composition of the present application can further comprise one or more additional therapeutic or prophylactic agents. BRIEF DESCRIPTION OF DRAWINGS

[0396] Figures 1A, 1B show the therapeutic effects of LNP023 and the compound of the present application on sheep anti-rat Fx la serum-induced passive Heyman nephritis in rats in Experimental Example 8A.

[0397] Figures 2A, 2B show the therapeutic effects of LNP023 and the compound of the present application on sheep anti-rat Fx la serum-induced passive Heyman nephritis in rats in Experimental Example 8B.

[0398] Figures 3A, 3B, 3C, 3D, 3E, 3F, 4A, 4B, 4C, and 4D show the therapeutic effects of LNP023 and the compound of the present application on sheep anti-rat Fx la serum-induced passive Heyman nephritis in rats in Experimental Example 8C.

[0399] Figures 5A, 5B show the inhibitory effects of LNP023 and the compound of the present application on lipopolysaccharide LPS-induced complement activation in rats in Experimental Example 9A.

[0400] Figures 6A, 6B, 6C, 6D, 6E, and 6F show the inhibitory effects of LNP023 and the compound of the present application on lipopolysaccharide LPS-induced complement activation in rats in Experimental Example 9B.

[0401] Figure 7 shows the inhibitory effects of LNP023 and the compound of the present application on lipopolysaccharide LPS-induced complement activation in rats in Experimental Example 9C.

[0402] EXAMPLES

[0403] Embodiments of the present application will be described in detail with reference to the following examples, but the present application is not limited to the following examples. The following examples are merely illustrative of the present application and should not be viewed as limiting the scope of the present application. Unless otherwise indicated, the specific conditions used in the examples are not to be construed as limiting the conditions used in the present application. Unless otherwise indicated, the reagents or instruments used in the examples are commercially available conventional products.

[0404] NMR was measured using a Bruker Avance III 400 NMR instrument, and the chemical shift (δ) was measured in ppm relative to the solvent peak.-6 (ppm) are given as units. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), etc., and the internal standard is tetramethylsilane (TMS).

[0405] MS was determined by Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B), and the LCMS determination conditions were as follows: Agilent (agilent 1260 infinity II-G6125B), chromatographic column: Waters CORTECS C18+, 2.7 μm, 4.6 mm x 30 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 0-95% gradient flow 0-2 minutes, flow rate: 2 mL / min, ultraviolet detection wavelength range is 220 and 254 nm.

[0406] High performance liquid chromatography (HPLC) determination conditions one: Agilent high pressure liquid chromatograph (agilent 1260 infinity II), chromatographic column: Agilent EC-C18, 2.7 μm, 4.6 x 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow 10 minutes, flow rate: 1.2 mL / min, ultraviolet detection wavelength range is 220 and 254 nm.

[0407] High performance liquid chromatography (HPLC) determination conditions two: Agilent high pressure liquid chromatograph (agilent 1260 infinity II), chromatographic column: Agilent EC-C18, 2.7 μm, 4.6 x 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid-10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow 5 minutes, flow rate: 1.2 mL / min, ultraviolet detection wavelength range is 220 and 254 nm.

[0408] High performance liquid chromatography (HPLC) determination conditions three: Shimadzu high pressure liquid chromatograph (Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector), chromatographic column: Kinetex C18, 2.1 x 50 mm, 1.7 μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-30% gradient flow 7 minutes, flow rate: 1.2 mL / min, ultraviolet detection wavelength range is 220 and 254 nm.

[0409] High performance liquid chromatography (HPLC) determination condition four: Shimadzu high pressure liquid chromatograph (Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector), chromatographic column: Kinetex C18, 2.1x50mm, 1.7μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-60% gradient flow for 7 minutes, flow rate: 1.2mL / min, ultraviolet detection wave band is 220 and 254nm.

[0410] Reverse phase purification uses Biotage Isolera rapid purification system.

[0411] Thin layer chromatography separation and purification is thin layer chromatography silica gel plate (Meck produced aluminum plate (20cm x 20cm x 1mm), or Yantai produced GF 254).

[0412] Microwave reaction uses Biotage Initiator+ (400W, RT ~ 300℃) microwave reactor.

[0413] Reaction monitoring commonly uses TLC or LCMS, and common developing agent systems are dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate, and the volume ratio of the solvents is adjusted according to the polarity of the compound or adjusted by adding triethylamine.

[0414] Column chromatography uses silica gel of 100-200 mesh. Common eluent systems are dichloromethane / methanol, petroleum ether / ethyl acetate, and the volume ratio of the solvents is adjusted according to the polarity of the compound, or a small amount of triethylamine can be added for adjustment.

[0415] The reagents and solvents of the present application are purchased from Aldrich Chemical Company, Anpel, Bailingwei Technology, Shanghai Bide Pharmaceutical Technology Co., Ltd., Astra, and Shanghai Titan Technology Co., Ltd.

[0416] In the conventional synthesis method and the synthesis examples of the compounds and intermediates of the present application, the meanings of each abbreviation are as shown below.

[0417] Synthetic examples

[0418] Example 1: Preparation of compound 1

[0419] Step 1 : Compound 1-1 (10 g, 62.26 mmol) and 4-methoxybenzyl chloride (10.13 mL, 74.71 mmol) were dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (25.81 g, 186.78 mmol) was added, stirred at room temperature for 18 hours, the reaction was monitored by LCMS. Ice water (50 mL) was added to quench, extracted with dichloromethane for 3 times (3 x 60 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 5% to 30% ethyl acetate / petroleum ether) to give compound 1-2. MS m / z (ESI): 246.2 [M+H] + .

[0420] Step 2: Compound 1-2 (14 g, 57.06 mmol), p-toluenesulfonylmethyl isocyanide (16.71 g, 85.60 mmol) and tert-butyl alcohol (8.13 mL, 85.60 mmol) were dissolved in tetrahydrofuran (140 mL), a solution of potassium tert-butoxide in tetrahydrofuran (114.1 mL, 1.0 M, 114.1 mmol) was added dropwise at 0 °C, the reaction solution was stirred at 0 °C for 1 hour, then raised to room temperature and continued to stir for 24 hours, the reaction was monitored by LCMS. The reaction solution was added to saturated ammonium chloride solution to quench, extracted with ethyl acetate for 3 times (3 x 200 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 5% to 30% ethyl acetate / petroleum ether) to give compound 1-3. MS m / z (ESI): 257.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.27-7.22 (m, 2H), 6.90-6.84 (m, 2H), 3.73 (s, 3H), 3.32 (s, 2H), 3.10 (p, J = 2.9 Hz, 2H), 2.99 (tt, J = 11.1, 6.9 Hz, 1H), 1.98-1.90 (m, 2H), 1.79-1.69 (m, 4H), 1.60-1.52 (m, 2H).

[0421] Step 3: Compound 1-3 (4.88 g, 19.04 mmol), ethyl p-fluorobenzoate (5.12 mL, 38.07 mmol) were dissolved in tetrahydrofuran (50 mL) under nitrogen protection, then lithium bis(trimethylsilyl)amide in tetrahydrofuran (28.6 mL, 1.0 M, 28.6 mmol) was added dropwise at 0 °C, then the system was allowed to warm to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched by saturated ammonium chloride solution, extracted with ethyl acetate (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 5% to 60% ethyl acetate / petroleum ether) to give compound 1-4. MS m / z (ESI): 405.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.05-7.95 (m, 2H), 7.72-7.62 (m, 2H), 7.32-7.25 (m, 2H), 6.92-6.83 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.47 (s, 2H), 3.31 (s, 2H), 2.35-2.27 (m, 2H), 2.16 (tt, J = 13.8, 6.0 Hz, 6H), 1.32 (t, J = 7.1 Hz, 3H).

[0422] Step 4: Compound 1-4 (20 g, 49.44 mmol) was dissolved in ethanol (150 mL), then saturated sodium hydroxide solution (150 mL, 3042 mmol) was added. The reaction was carried out at 100 °C for 3 days. The reaction was monitored by LCMS. The reaction was concentrated under reduced pressure until most of the ethanol was removed. The remaining liquid was added to 6N hydrochloric acid at 0 °C to adjust the pH to about 3. A large amount of solid was precipitated. The solid was filtered off and dried under vacuum to give compound 1-5. MS m / z (ESI): 395.2 [M+H] + .

[0423] Step 5: Compound 1-5 (12.5 g, 31.69 mmol) was dissolved in N,N- dimethylformamide (200 mL), potassium carbonate (13.14 g, 95.06 mmol) and iodoethane (5.07 mL, 63.38 mmol) were added slowly at 0 °C, the reaction was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS to be completed, the reaction was quenched by adding water (300 mL) and extracted with ethyl acetate for 3 times (3 x 200 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 20% - 40% ethyl acetate / petroleum ether) to give compound 1-6. MS m / z (ESI): 423.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.83 (m, 2H), 7.50 - 7.43 (m, 2H), 7.38 (s, 1H), 7.25 - 7.18 (m, 2H), 6.97 (s, 1H), 6.87 - 6.81 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 5H), 3.72 (s, 3H), 3.37 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.12 (s, 2H), 2.94 (d, J = 12.9 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0424] Step 6: Compound 1-6 (2.00 g, 4.73 mmol) was dissolved in ethanol (40 mL), 10% palladium on carbon (0.50 g), ammonium formate (2.98 g, 47.34 mmol) were added, stirred at 80 °C for 8 hours, the reaction was monitored by LCMS to be completed. The reaction was filtered and concentrated under reduced pressure to give compound 1-7. MS m / z (ESI): 303.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.83 (m, 2H), 7.50 - 7.43 (m, 2H), 7.38 (s, 1H), 7.25 - 7.18 (m, 2H), 6.97 (s, 1H), 6.87 - 6.81 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 (q, J = 7.1 Hz, 5H), 3.72 (s, 3H), 3.37 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.12 (s, 2H), 2.94 (d, J = 12.9 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0425] Step 7: Compound 1-8 (4 g, 17.46 mmol), sodium thiocyanate (2.12 g, 26.19 mmol) were dissolved in N,N-dimethylformamide (60 mL) and heated to 60 °C for 3 h, then the reaction was allowed to cool to room temperature, cuprous thiocyanate (2.80 g, 23.05 mmol), cesium fluoride (13.26 g, 87.31 mmol), (trifluoromethyl)trimethylsilane (6.46 g, 45.40 mmol) were added sequentially and stirring was continued at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-20% ethyl acetate / petroleum ether) to afford compound 1-9. 1 H NMR (400 MHz, Chloroform-d) δ 8.02-7.96 (m, 2H), 7.54-7.49 (m, 1H), 7.39 (dd, J = 8.4, 7.1 Hz, 2H), 4.54-4.45 (m, 2H), 3.20 (t, J = 6.5 Hz, 2H).

[0426] Step 8: Compound 1-9 (1 g, 4.00 mmol) was dissolved in a mixture of methanol (4 mL), THF (4 mL) and water (4 mL), lithium hydroxide (0.50 g, 11.99 mmol) was added and heated to 60 °C for 3 h. The reaction was monitored by LCMS. The reaction was quenched with ice water and extracted with dichloromethane (3 x 40 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure at room temperature to afford compound 1-10. 1 H NMR (400 MHz, Chloroform-d) δ 3.81 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H).

[0427] Step 9: Compound 1-10 (600 mg, 4.11 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.57 mL, 4.11 mmol) was added, p-toluenesulfonyl chloride (939.31 mg, 4.93 mmol) was added at 0 °C and the reaction was continued at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with ice water and extracted with dichloromethane (3 x 40 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-20% ethyl acetate / petroleum ether) to afford compound 1-11. 1H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.78 (m, 2H), 7.56 - 7.46 (m, 2H), 4.21 (t, J = 6.0 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H).

[0428] Step 10: Compound 1-11 (360 mg, 1.20 mmol) was dissolved in N,N- dimethylformamide (10 mL), compound 1-7 (434.96 mg, 1.44 mmol), N,N- diisopropylethylamine (309.88 mg, 2.40 mmol) were added, the reaction was warmed to 85 °C and stirred overnight, the reaction was monitored by LCMS. After the reaction solution was cooled to room temperature, ice water was added to quench the reaction, and extracted with ethyl acetate three times (3 x 40 mL), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to give compound 1-12. MS m / z (ESI): 431.2 [M+H] + .

[0429] Step 11: Compound 1-12 (380 mg, 0.88 mmol) was dissolved in acetonitrile (4 mL) and water (2 mL), [bis(trifluoroacetoxy)iodo]benzene (762.77 mg, 1.77 mmol) was added, stirred at room temperature for 3 hours, the reaction was monitored by LCMS. Ice water was added to the reaction solution, and the pH was adjusted to more than 7 with saturated sodium bicarbonate solution, a solid was precipitated, which was filtered off, the filtrate was extracted with ethyl acetate three times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to give compound 1-13. MS m / z (ESI): 403.1 [M+H] + .

[0430] Step 12: Compound 1-13 (170 mg, 0.42 mmol) was dissolved in acetonitrile (6 mL), compound 1-14 (95.90 mg, 0.51 mmol) was added, and the mixture was stirred at 60 °C overnight, then sodium cyanoborohydride (53.08 mg, 0.84 mmol) was added, and the reaction was continued at room temperature for 2 h. The reaction was monitored by LCMS. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to obtain compound 1-15. MS m / z (ESI): 676.3 [M+H] + .

[0431] Step 13: Compound 1-15 (150 mg, 0.22 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), and lithium hydroxide (372.53 mg, 8.88 mmol) was added. The reaction was stirred at 60 °C for 1 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, and dilute HCl (2.0 M) was added slowly dropwise to adjust the pH to 5-7. A large amount of solid precipitated, and the obtained solid crude product was purified by reverse phase column chromatography [Model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 548.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.91 (t, J = 2.5 Hz, 1H), 3.61 (s, 3H), 3.41 (s, 2H), 3.26 (s, 2H), 3.14 (t, J = 6.5 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.40 (s, 3H), 2.22 (d, J = 10.4 Hz, 4H), 1.97 (d, J = 13.5 Hz, 2H), 1.79 - 1.69 (m, 2H). The purified product (75 mg, 0.14 mmol) was dissolved in methanol (5 mL), and 1 N hydrochloric acid in methanol (0.42 mL, 0.42 mmol) was added slowly dropwise. After stirring for 30 min, the methanol was evaporated at room temperature, 5 mL of deionized water was added, and the mixture was sonicated to homogeneity. The resulting compound 1 was obtained by lyophilization. MS m / z (ESI): 548.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.04 (s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.62 (s, 2H), 7.24 (s, 1H), 6.67 (s, 1H), 5.92 (t, J = 2.5 Hz, 1H), 4.19-4.13 (m, 2H), 4.07-4.03 (m, 2H), 3.66 (s, 3H), 3.51-3.36 (m, 4H), 3.30-3.21 (m, 2H), 2.71-2.54 (m, 4H), 2.42 (s, 3H), 2.11-1.98 (m, 2H).

[0432] Example 2: Preparation of compound 2

[0433] Step 1: Into a 500 mL single necked flask was placed compound 2-1 (4.9 g, 34.01 mmol) dissolved in dichloromethane (100 mL), at 0 °C was added triethylamine (9.43 mL, 68.01 mmol) and p-toluenesulfonyl chloride (7.78 g, 40.81 mmol) sequentially, the system was replaced by nitrogen, and the reaction was allowed to proceed at room temperature for 6 hours. After the reaction was completed as monitored by LCMS, the reaction was quenched by slowly pouring into ice water at room temperature, extracted with dichloromethane three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 10% ethyl acetate / petroleum ether) to give compound 2-2. MS m / z (ESI): 299.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.83-7.76 (m, 2H), 7.52-7.45 (m, 2H), 4.20-4.13 (m, 2H), 4.03 (q, J = 9.3 Hz, 2H), 3.81-3.74 (m, 2H), 2.43 (s, 3H).

[0434] Step 2: Into a 50 mL single necked flask was placed a solution of compound 1-7 (2 g, 6.61 mmol) in N,N-dimethylformamide (40 mL), N,N-diisopropylethylamine (5.84 mL, 33.53 mmol) was added slowly at 0 °C, the reaction was maintained at 0 °C for 0.5 h, then compound 2-2 (2.03 g, 6.81 mmol) was added to the reaction, the reaction was continued to stir at 85 °C for 16 h, the reaction was monitored by TLC. The reaction was quenched by ice water, extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 40% ethyl acetate / pet. ether) to give compound 2-3. MS m / z (ESI): 429.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 6.96 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.04 (q, J = 9.4 Hz, 2H), 3.62 (s, 2H), 3.23 (s, 2H), 2.90 (d, J = 13.4 Hz, 2H), 2.45 (s, 2H), 1.78 (d, J = 35.6 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0435] Step 3: Into a 250 mL single necked flask was placed a solution of compound 2-3 (2.3 g, 5.37 mmol) in acetonitrile (30 mL) and water (15 mL), then [bis(trifluoroacetoxy)iodo]benzene (4.64 g, 10.74 mmol) was added slowly at 0 °C, the reaction was continued to stir at room temperature for 2 h, the reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 60% ethyl acetate / pet. ether) to give compound 2-4. MS m / z (ESI): 401.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.1 Hz, 2H), 7.64 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.93 (d, J = 165.8 Hz, 6H), 3.32 (s, 2H), 2.04 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H).

[0436] Step 4: Compound 2-4 (300 mg, 0.75 mmol) was dissolved in acetonitrile (8 mL), compound 1-14 (216.76 mg, 0.75 mmol) and 5 drops of acetic acid were added, and stirred at room temperature overnight. Then sodium borohydride (85.02 mg, 2.25 mmol) and methanol (2 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction solution was slowly added to ice water to quench, extracted with ethyl acetate three times (30 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-30 ethyl acetate / petroleum ether) to obtain compound 2-5. MS m / z (ESI): 674.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.2 Hz, 2H), 7.59 - 7.52 (m, 3H), 6.77 (s, 1H), 6.18 (d, J = 3.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.13 - 4.04 (m, 2H), 3.67 (s, 4H), 3.36 (s, 3H), 3.31 (s, 2H), 2.75 - 2.5 (m, 2H), 2.48 (s, 3H), 2.12 (m, 6H), 1.79 (s, 2H), 1.57 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H).

[0437] Step 5: Compound 2-5 (330 mg, 0.49 mmol) was dissolved in a mixed solvent of methanol (5 mL), water (5 mL) and tetrahydrofuran (5 mL), lithium hydroxide (822.05 mg, 19.59 mmol) was added, and the reaction was continued at 60 °C for 2 hours. The reaction was monitored by LCMS. Then the reaction was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to the reaction solution to adjust the pH value to about 5-7. A large amount of solid was precipitated, and the obtained solid crude product was purified by reverse phase column [model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: CAN; gradient: B%: 0%-95%)] to obtain the purified product. 1H NMR (400 MHz, Methanol-d4) δ 7.90 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 3.1 Hz, 1H), 6.65 (s, 1H), 5.89 (d, J = 3.1 Hz, 1H), 4.17 - 3.99 (m, 6H), 3.72 (s, 3H), 3.55 (s, 2H), 3.30 (s, 2H), 2.78 (d, J = 8.9 Hz, 2H), 2.67 - 2.49 (m, 4H), 2.43 (s, 3H), 2.12 (d, J = 10.1 Hz, 2H). The purified product (135 mg, 0.25 mmol) was dissolved in methanol (3 mL), and 4N hydrochloric acid-methanol solution (0.20 mL) was slowly added dropwise under stirring at room temperature. After stirring for 5 min, methanol was removed at room temperature, then 5 mL of deionized water was added, and the mixture was uniformly ultrasonicated and then freeze-dried to obtain compound 2. MS m / z (ESI): 546.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.61 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 2.9 Hz, 1H), 6.66 (s, 1H), 5.90 (dd, J = 3.1, 1.9 Hz, 1H), 4.17 (q, J = 9.4 Hz, 2H), 4.03 (d, J = 31.5 Hz, 4H), 3.64 (s, 3H), 3.23 (d, J = 5.5 Hz, 2H), 2.61 (dd, J = 20.8, 12.0 Hz, 4H), 2.45 (s, 1H), 2.41 (s, 3H), 2.01 (d, J = 22.5 Hz, 3H).

[0438] Example 3: Preparation of compound 3

[0439] Step 1: Compound 3-1 (500 g, 2992.22 mmol) was dissolved in DMF (6 L), then potassium carbonate (496.3 g, 3590.66 mmol), benzyl bromide (511.7 g, 2992.22 mmol) were added in turn, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction liquid was poured into water, and a large amount of solid was precipitated. The filter cake was obtained by filtration, and then dried under vacuum to obtain compound 3-2. MS m / z (ESI): 258.2 [M+H] + .

[0440] Step 2: Compound 3-2 (277 g, 1076.61 mmol) was dissolved in DMF (2 L), then DMF-DMA (384.87 g, 3229.83 mmol) and tetrahydro pyrrole (382.84 g, 5383.05 mmol) were added successively, the reaction was stirred at 90 °C overnight, the completion of the reaction was monitored by TLC. Water (5 L) was added to the reaction, extracted with ethyl acetate for 3 times (3 x 1 L), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 3-3. MS m / z (ESI): 339.2 [M+H] + .

[0441] Step 3: Compound 3-3 (160 g, 472.8 mmol) was dissolved in ethyl acetate (1.5 L), Raney nickel (15 mL in water) was added, after hydrogen replacement, the reaction was carried out at room temperature overnight, the completion of the reaction was monitored by LCMS and TLC. The reaction was filtered to remove Raney nickel, the filtrate was concentrated to give compound 3-4. MS m / z (ESI): 238.2 [M+H] + .

[0442] Step 4: Compound 3-4 (100 g, 421.41 mmol) was dissolved in acetonitrile (1 L), di-tert-butyl dicarbonate (183.94 g, 842.82 mmol) and 4-dimethylaminopyridine (51.48 g, 421.41 mmol) were added, stirred at room temperature overnight, the completion of the reaction was monitored by LCMS and TLC. Water (500 mL) was added to the reaction, extracted with ethyl acetate for 3 times (3 x 300 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% ~ 10% ethyl acetate) to give compound 3-5. MS m / z (ESI): 338.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.50 - 7.43 (m, 3H), 7.41 - 7.36 (m, 2H), 7.34 - 7.29 (m, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 3.8 Hz, 1H), 5.09 (s, 2H), 2.61 (s, 3H), 1.62 (s, 9H).

[0443] Step 5: Compound 3-5 (115 g, 340.82 mmol) was dissolved in ethanol (1.2 L), 10% palladium carbon (10 g) and ammonium formate (21.49 g, 340.82 mmol) were added successively, and the mixture was stirred at 50 °C overnight. The reaction was monitored by LCMS. The reaction solution was filtered to remove the palladium carbon, and excess ethanol was removed by concentration under reduced pressure. The residue was slurried with dichloromethane / petroleum ether (v / v = 1 / 1) and filtered to obtain compound 3-6. MS m / z (ESI): 248.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.52 (d, J = 3.7 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 3.7 Hz, 1H), 2.45 (s, 3H), 1.57 (s, 9H).

[0444] Step 6: Paraformaldehyde (19.60 g, 647.01 mmol) and triethylamine (71.75 mL, 517.61 mmol) were dissolved in tetrahydrofuran (500 mL), and magnesium chloride (46.20 g, 485.26 mmol) was added at room temperature. After stirring for 0.5 h, compound 3-6 (40 g, 161.75 mmol) was added, and the mixture was stirred at 70 °C overnight. The reaction was monitored by LCMS. The excess solid was filtered off, and water (500 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (3 x 300 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid crude was slurried with ethyl acetate / petroleum ether (v / v = 1 / 5) and filtered to obtain compound 3-7. MS m / z (ESI): 276.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.48 (s, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.75 (s, 1H), 2.53 (s, 3H), 1.59 (s, 9H).

[0445] Step 7: Compound 3-7 (33 g, 119.87 mmol) and triethylamine (49.85 mL, 359.61 mmol) were dissolved in dichloromethane (350 mL), triflic anhydride (29.84 mL, 179.80 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. The reaction was monitored to completion by LCMS and TLC. Water (300 mL) was added to the reaction, and dichloromethane (3 x 300 mL) was used to extract, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 10% ethyl acetate) to obtain compound 3-8. MS m / z (ESI): 408.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 10.49 (s, 1H), 7.77 (d, J = 3.7 Hz, 1H), 7.51 (d, J = 3.7 Hz, 1H), 7.09 (s, 1H), 2.73 (s, 3H), 1.65 (s, 9H).

[0446] Step 8: Compound 3-8 (8 g, 19.64 mmol) was dissolved in 1,4-dioxane (50 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.44 g, 1.96 mmol), potassium carbonate (5.43 g, 39.28 mmol), methylboronic acid (11.76 g, 196.39 mmol) were added, and the reaction was allowed to proceed at 100 °C overnight under nitrogen protection. The reaction was monitored to completion by LCMS. Ice water was added to quench the reaction, and ethyl acetate (3 x 100 mL) was used to extract, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 100% ethyl acetate) to obtain compound 3-9. MS m / z (ESI): 274.2 [M+H] + .

[0447] Step 9: Compound 3-10 (2 g, 18.50 mmol) was dissolved in acetonitrile (20 mL), tert-butyl bromoacetate (7.22 g, 37.01 mmol), and potassium hydroxide (3.11 g, 55.51 mmol) were added, and the reaction was allowed to proceed at 60 °C overnight. The reaction was monitored to completion by TLC. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 100% ethyl acetate / petroleum ether) to obtain compound 3-11. 1 H NMR (400 MHz, DMSO-d6) δ 4.12-4.01 (m, 1H), 3.96 (s, 2H), 2.93-2.80 (m, 2H), 2.61-2.51 (m, 2H), 1.42 (s, 9H).

[0448] Step 10: Compound 3-11 (4 g, 18.00 mmol) was dissolved in tetrahydrofuran (50 mL), lithium aluminum hydride (1.02 g, 27.00 mmol) was added portion wise at 0 °C, the reaction was stirred at 0 °C for half an hour, then it was allowed to warm to room temperature and stirred overnight, the reaction was monitored by TLC. The reaction was quenched using 1.0 M dilute HC1, extracted with dichloromethane three times (3 x 50 mL), the organic layers were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at room temperature to get compound 3-12. 1 H NMR (400 MHz, DMSO-d6) δ 4.64 (t, J = 5.5 Hz, 1H), 4.04 - 3.94 (m, 1H), 3.51 - 3.47 (m, 2H), 3.37 - 3.35 (m, 2H), 2.93 - 2.80 (m, 2H), 2.50 - 2.40 (m, 2H).

[0449] Step 11: Compound 3-12 (2.5 g, 16.43 mmol) was dissolved in dichloromethane (40 mL), triethylamine (4.56 mL, 32.86 mmol) was added, p-toluenesulfonyl chloride (3.76 g, 19.72 mmol) was added portion wise at 0 °C, the reaction was stirred at room temperature overnight, the reaction was monitored by LCMS. The reaction was directly concentrated under reduced pressure, the crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to get compound 3-13. MS m / z (ESI): 307.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.77 - 7.71 (m, 2H), 7.33 - 7.25 (m, 2H), 4.13 - 4.05 (m, 2H), 3.89 - 3.77 (m, 1H), 3.53 - 3.44 (m, 2H), 2.79 - 2.62 (m, 2H), 2.43 - 2.29 (m, 5H).

[0450] Step 12: Compound 3-13 (1.5 g, 4.90 mmol) was dissolved in N,N- dimethylformamide (20 mL), compound 1-7 (1.48 g, 4.90 mmol), N,N- diisopropylethylamine (1.90 g, 14.69 mmol) were added and the reaction was stirred at 85 °C overnight, the reaction was monitored by LCMS. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine solution and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0-100% ethyl acetate / petroleum ether) to give compound 3-14. MS m / z (ESI): 437.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 4.32 - 4.27 (m, 2H), 4.01 - 3.94 (m, 1H), 3.58 - 3.36 (m, 4H), 2.95 (d, J = 13.6 Hz, 2H), 2.89 - 2.79 (m, 2H), 2.67 - 2.53 (m, 2H), 2.49 - 2.40 (m, 2H), 2.04 - 1.74 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0451] Step 13: To a 100 mL single necked flask was added compound 3-14 (1.30 g, 2.98 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) at 0 °C, then [bis(trifluoroacetoxy)iodo]benzene (2.57 g, 5.96 mmol) was added slowly and the reaction was stirred at room temperature for 16 hours, the reaction was monitored by LCMS. The reaction was quenched by the slow addition of saturated aqueous sodium bicarbonate solution at room temperature, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane (3 x 40 mL), the combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0-60% ethyl acetate / petroleum ether) to give compound 3-15. MS m / z (ESI): 409.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 4.29 (d, J = 7.1 Hz, 2H), 4.05 - 3.99 (m, 1H), 3.48 (d, J = 6.1 Hz, 2H), 3.28 (s, 2H), 2.90 - 2.83 (m, 2H), 2.56 - 2.51 (m, 2H), 2.48 - 2.41 (m, 2H), 2.33 - 2.24 (m, 2H), 1.91 - 1.78 (m, 4H), 1.73 - 1.64 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0452] Step 14: Compound 3-15 (300 mg, 0.73 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (201 mg, 0.73 mmol) and 5 drops of acetic acid were added, and the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (83 mg, 2.19 mmol) and methanol (3 mL) were added, and the reaction was continued to stir at room temperature for 1 hour, and the reaction was monitored by LCMS. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate three times (3 x 40 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether) to obtain compound 3-16. MS m / z (ESI): 666.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 3.7 Hz, 1H), 6.82 (s, 1H), 5.85 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.00 - 3.95 (m, 1H), 3.42 (t, J = 6.1 Hz, 2H), 3.39 (s, 2H), 2.89 - 2.80 (m, 2H), 2.55 (t, J = 6.2 Hz, 2H), 2.50 - 2.39 (m, 7H), 2.32 - 2.19 (m, 4H), 2.06 - 1.99 (m, 5H), 1.87 - 1.80 (m, 2H), 1.56 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H).

[0453] Step 15: Compound 3-16 (250 mg, 0.38 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (630.20 mg, 15.02 mmol) was added, and the reaction was heated to 60 °C for 1 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature, and a dilute HC1 solution (2.0 M) was added slowly dropwise to adjust the pH to about 5-7. A large amount of solid precipitated, and the resulting solid was filtered and purified by reverse phase chromatography [type: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HC03 / H20; B: CAN); gradient: (B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 538.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.80 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.68-5.62 (m, 1H), 4.03-3.94 (m, 1H), 3.49-3.41 (m, 4H), 2.85 (ddt, J = 12.8, 11.0, 7.0 Hz, 2H), 2.54 (d, J = 7.3 Hz, 2H), 2.45 (d, J = 5.0 Hz, 2H), 2.34 (s, 3H), 2.27 (d, J = 13.5 Hz, 4H), 2.05 (s, 5H), 1.84 (s, 2H). The purified product (77.8 mg, 0.14 mmol) was dissolved in methanol (3 mL), and a 4N HC1-methanol solution (0.10 mL) was added slowly dropwise with stirring. After stirring for 5 min, the methanol was evaporated at room temperature, and 5 mL of deionized water was added. After ultrasonic treatment, the solution was freeze-dried to obtain compound 3. MS m / z (ESI): 538.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.73 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 2.9 Hz, 1H), 6.63 (s, 1H), 5.72 - 5.66 (m, 1H), 4.16 - 3.99 (m, 4H), 3.75 (t, J = 4.9 Hz, 2H), 3.47 (s, 2H), 3.20 (d, J = 5.4 Hz, 2H), 2.89 (ddd, J = 14.8, 12.4, 7.4 Hz, 2H), 2.67 (t, J = 14.5 Hz, 2H), 2.57 (dd, J = 14.3, 5.1 Hz, 4H), 2.35 (s, 3H), 2.12 (s, 2H), 2.05 (s, 3H), 1.83 (s, 1H).

[0454] Example 4: Preparation of compound 4

[0455] Step 1 : Compound 1-3 (10.5 g, 40.96 mmol) and compound 4-1 (8.95 g, 53.25 mmol) were dissolved in tetrahydrofuran (200 mL), and a solution of lithium bis(trimethylsilyl)amide (1.0 N, 81.92 mL, 81.92 mmol) was added dropwise slowly at 0 °C. The reaction was allowed to proceed at room temperature for 16 hours, and the reaction was monitored by LCMS. The reaction was quenched with ice water and extracted with ethyl acetate three times (3 x 100 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 10% to 30% ethyl acetate / petroleum ether) to obtain compound 4-2. MS m / z (ESI): 405.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 - 7.76 (m, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.92 - 6.83 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.43 (s, 2H), 3.35 (s, 2H), 2.70 (s, 3H), 2.36 - 2.26 (m, 4H), 2.18 (q, J = 6.8, 4.5 Hz, 4H).

[0456] Step 2: Compound 4-2 (9.7 g, 23.98 mmol) and saturated sodium hydroxide solution (70 mL, 1420 mmol) were dissolved in ethanol (200 mL) and reacted at 100 °C for 3 days, monitoring the reaction completion by LCMS. The reaction solution was added dropwise with 6N hydrochloric acid at 0 °C to adjust the pH value to about 3, and a large amount of solid was precipitated. The solid was filtered and dried under vacuum to obtain compound 4-3. MS m / z (ESI): 409.2 [M+H] + .

[0457] Step 3: Compound 4-3 (1.5 g, 3.67 mmol) was dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (1.52 g, 11.02 mmol) and iodoethane (0.88 mL, 11.02 mmol) were slowly added at 0 °C. The reaction was stirred at room temperature for 16 hours, and the reaction completion was monitored by LCMS. The reaction solution was quenched with ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 10%-30% ethyl acetate / petroleum ether) to obtain compound 4-4. MS m / z (ESI): 437.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.74-7.61 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.28-6.97 (m, 4H), 6.84 (d, J = 8.2 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 3.34 (s, 2H), 3.15 (s, 2H), 2.87 (d, J = 13.4 Hz, 2H), 2.54 (s, 2H), 2.06 (d, J = 13.5 Hz, 2H), 1.85 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0458] Step 4: Compound 4-4 (200 mg, 0.46 mmol) was dissolved in dioxane (5 mL), and 10% palladium-carbon (50 mg) and ammonium formate (433.35 mg, 6.87 mmol) were added under nitrogen protection. The reaction was reacted at 100 °C for 32 hours, and the reaction completion was monitored by LCMS. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was rotary evaporated to obtain compound 4-5. MS m / z (ESI): 317.2 [M+H] + .

[0459] Step 5: Compound 4-6 (50 g, 384.41 mmol) was dissolved in dichloromethane (500 mL), triethylamine (106.6 mL, 768.82 mmol) and p-toluenesulfonyl chloride (87.94 g, 461.29 mmol) were added sequentially at 0 °C, after the addition was completed, the reaction liquid was stirred at room temperature for 16 hours, the reaction was monitored by LCMS. Water (500 mL) was added to the reaction liquid, extracted with dichloromethane 3 times (3 x 400 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 10% ethyl acetate / petroleum ether) to obtain compound 4-7. MS m / z (ESI): 285.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 4.29 - 4.23 (m, 4H), 2.43 (s, 3H).

[0460] Step 6: Compound 4-5 (1.89 g, 5.98 mmol) and compound 4-7 (1.7 g, 5.98 mmol) were dissolved in N,N-dimethylformamide (30 mL), N,N-diisopropylethylamine (5.21 mL, 29.90 mmol) was slowly added at 0 °C, the reaction was reacted at room temperature for 32 hours, the reaction was monitored by LCMS. Water (50 mL) was added to the reaction liquid to quench, and extracted with ethyl acetate 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 10% to 30% ethyl acetate / petroleum ether) to obtain compound 4-8. MS m / z (ESI): 429.2 [M+H] + .

[0461] Step 7: Compound 4-8 (1.4 g, 3.03 mmol, crude) was dissolved in acetonitrile (10 mL) and water (5 mL), [bis(trifluoroacetoxy)iodo]benzene (2.62 g, 6.07 mmol) was added, and the reaction was reacted at room temperature for 3 hours, the reaction was monitored by LCMS. Saturated sodium bicarbonate solution was added to the reaction liquid, the pH value was adjusted to >7, and extracted with ethyl acetate 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 100% ethyl acetate / petroleum ether) to obtain compound 4-9. MS m / z (ESI): 401.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 5.9, 2.1 Hz, 2H), 4.30 - 4.23 (m, 2H), 4.10 (t, J = 5.6 Hz, 2H), 2.71 (s, 3H), 2.58 (t, J = 5.6 Hz, 2H), 2.34 - 2.30 (m, 2H), 2.22 - 2.17 (m, 2H), 1.86 - 1.81 (m, 4H), 1.40 - 1.35 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0462] Step 8: Compound 4-9 (180 mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), compound 1-14 (156.07 mg, 0.54 mmol) was added, and the reaction was heated to 60 °C overnight. Sodium cyanoborohydride (56.56 mg, 0.90 mmol) was added at room temperature, and the reaction was continued at room temperature for 2 h, and the reaction was monitored by LCMS. The reaction was added to ice water (40 mL), and extracted with ethyl acetate (3 x 40 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 60% ethyl acetate / petroleum ether) to obtain compound 4-10. MS m / z (ESI): 674.4 [M+H] + .

[0463] Step 9: Compound 4-10 (260 mg, 0.39 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), and lithium hydroxide (654.58 mg, 15.60 mmol) was added, and the reaction was heated to 60 °C for 1 h, and the reaction was monitored by LCMS. The reaction was cooled to room temperature, and diluted HCl (2.0 M) was slowly added dropwise to adjust the pH value to be less than 5-7, and a large amount of solid was precipitated, and the obtained solid crude product was purified by reverse phase column [model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 546.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.85 (d, J = 2.4 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 2.8 Hz, 1H), 6.68 (s, 1H), 6.13 (dd, J = 3.1, 1.9 Hz, 1H), 4.09 (t, J = 5.7 Hz, 2H), 3.70 (s, 3H), 3.48 (s, 2H), 2.62 (s, 3H), 2.59 (t, J = 5.8 Hz, 2H), 2.43 (s, 3H), 2.21 (d, J = 3.1 Hz, 4H), 2.19 - 1.96 (m, 3H), 1.94 - 1.69 (m, 3H). The purified product (49 mg, 0.09 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.07 mL) was added slowly dropwise under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 4. MS m / z (ESI): 546.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.87 (d, J = 2.5 Hz, 1H), 10.17 (s, 1H), 7.83 - 7.76 (m, 2H), 7.49 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 2.8 Hz, 1H), 6.66 (s, 1H), 6.06 (dd, J = 3.1, 1.9 Hz, 1H), 4.56 (t, J = 5.1 Hz, 2H), 4.08 (s, 2H), 3.66 (s, 3H), 3.42 - 3.33 (m, 2H), 2.81 (d, J = 14.5 Hz, 2H), 2.59 (s, 3H), 2.58 (s, 5H), 2.41 (s, 3H), 2.13 (s, 1H), 2.00 (s, 2H).

[0464] Example 5: Preparation of compound 5

[0465] Step 1: Into a 1000 mL single necked flask was placed a solution of compound 4-7 (66 g, 232.19 mmol) and compound 1-7 (14.04 g, 46.44 mmol) in N,N- dimethylformamide (300 mL), followed by the slow addition of N,N-diisopropylethylamine (38.48 mL, 232.19 mmol) and the reaction was allowed to stir at room temperature for 40 h, monitoring the reaction completion by LCMS. The reaction was quenched by slowly adding the reaction mixture into ice cold water (400 mL) and extracted with ethyl acetate (3 x 300 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-80% ethyl acetate / petroleum ether) to afford compound 5-1. MS m / z (ESI): 415.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.4 Hz, 2H), 7.48 - 7.42 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.25 (s, 2H), 2.89 (s, 4H), 2.73 (s, 2H), 2.55 (s, 2H), 1.79 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0466] Step 2: Into a 250 mL single necked flask was placed a solution of compound 5-1 (9 g, 21.72 mmol) in acetonitrile (60 mL) and water (30 mL), followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (18.77 g, 43.43 mmol) and the reaction was allowed to stir at room temperature for 16 h, monitoring the reaction completion by LCMS. The reaction was quenched by slowly adding the reaction mixture into saturated sodium bicarbonate solution at room temperature and extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-50% ethyl acetate / petroleum ether gradient) to afford compound 5-2. MS m / z (ESI): 387.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (m, 2H), 7.54 (d, J = 8.5 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 3.8 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.27 (d, J = 7.1 Hz, 2H), 2.06 (dd, J = 13.7, 3.8 Hz, 2H), 1.87 - 1.75 (m, 4H), 1.72 - 1.65 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0467] Step 3: Compound 3-9 (3.4 g, 12.07 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL), methanol (10 mL) and water (10 mL), lithium hydroxide (5.07 g, 120.73 mmol) was added, the reaction was heated to 60 °C and stirred for 3 hours, the reaction was monitored by LCMS to be completed. The reaction was cooled to room temperature, quenched with ice water, extracted with ethyl acetate three times (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to give compound 5-3. MS m / z (ESI): 174.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 10.63 (s, 1H), 7.32 - 7.25 (m, 2H), 6.80 (s, 1H), 2.69 (s, 3H), 2.46 (s, 3H).

[0468] Step 4: Compound 5-2 (4.5 g, 11.65 mmol) was dissolved in acetonitrile (5 mL), compound 5-3 (2.02 g, 11.65 mmol) and acetic acid (1 mL) were added, the reaction was stirred at room temperature overnight. Then sodium borohydride (1.3 g, 34.95 mmol) and methanol (2 mL) were added, the reaction was continued to stir at room temperature for 0.5 hours, the reaction was monitored by LCMS to be completed. The reaction was slowly added to ice water to quench, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 20% ethyl acetate / petroleum ether) to give compound 5-4. MS m / z (ESI): 544.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.66 (t, J = 2.5 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 5.7 Hz, 2H), 3.43 (s, 2H), 2.68 - 2.59 (m, 2H), 2.36 - 2.22 (m, 7H), 2.01 (d, J = 19.2 Hz, 5H), 1.91 (s, 3H), 1.87 - 1.77 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0469] Step 5: Compound 5-4 (2.7 g, 4.97 mmol) was dissolved in a mixture of tetrahydrofuran (15 mL), methanol (15 mL) and water (15 mL), lithium hydroxide (4.17 g, 99.33 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. Diluted hydrochloric acid (1.0 M) was slowly added to the reaction solution, and the pH was adjusted to about 5-7. A large amount of solid was precipitated, and the solid was filtered, washed with pure water, and dried under vacuum to obtain the purified product. MS m / z (ESI): 516.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.80 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.68 - 5.62 (m, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.44 (s, 2H), 3.30 (s, 2H), 2.62 (s, 2H), 2.34 (s, 3H), 2.27 (t, J = 10.5 Hz, 4H), 2.04 (s, 5H), 1.81 (s, 2H). The purified product (2.3 g, 4.46 mmol) was dissolved in methanol (30 mL), and 4N hydrochloric acid-methanol solution (3.35 mL) was slowly added dropwise with stirring. After stirring for 15 minutes, the methanol was evaporated at room temperature, then 20 mL of deionized water was added, and the mixture was sonicated and freeze-dried to obtain compound 5. MS m / z (ESI): 516.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 10.86 (s, 1H), 9.78 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.70 (t, J = 2.5 Hz, 1H), 4.54 (s, 2H), 4.12 (s, 2H), 3.46 (s, 2H), 3.40 (d, J = 5.6 Hz, 2H), 2.71 (t, J = 15.5 Hz, 2H), 2.58 (d, J = 8.1 Hz, 2H), 2.45 (s, 1H), 2.35 (s, 3H), 2.13 (s, 2H), 2.05 (s, 3H), 1.85 (s, 1H).

[0470] Example 6: Preparation of compound 6

[0471] Step 1 : Compound 3-9 (800 mg, 2.93 mmol) was dissolved in methanol (10 mL), sodium borohydride (221 mg, 5.85 mmol) was added at 0 °C, the reaction was stirred at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by the addition of ice water, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether) to give compound 6-1. 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 3.8 Hz, 1H), 6.90 (s, 1H), 6.78 (d, J = 3.8 Hz, 1H), 4.84 (s, 1H), 4.66 (s, 2H), 2.47 (s, 3H), 2.36 (s, 3H), 1.59 (s, 9H).

[0472] Step 2: Compound 6-1 (690 mg, 2.51 mmol) was dissolved in N,N- dimethylformamide (5 mL), N-chlorosuccinimide (1 g, 7.52 mmol) was added, the reaction was stirred at 40 °C for 16 hours, the reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether) to give compound 6-2. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.03 (s, 1H), 4.94 (s, 2H), 4.91 (s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.59 (s, 9H).

[0473] Step 3: Compound 6-2 (490 mg, 1.58 mmol) was dissolved in 1,2-dichloroethane (30 mL), activated MnO2(3.44 g, 39.50 mmol) was added, the reaction was stirred at 50 °C for 16 hours, the reaction was monitored by LCMS. The reaction was filtered, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~10% ethyl acetate / petroleum ether) to obtain compound 6-3. MS m / z (ESI): 308.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.03 (s, 1H), 4.94 (s, 2H), 4.91 (s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.59 (s, 9H).

[0474] Step 4: Compound 6-3 (260 mg, 0.84 mmol) and compound 5-2 (415 mg, 1.10 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, the reaction was stirred at room temperature for 16 hours, the reaction was monitored by LCMS, a large amount of imine was generated. Then sodium borohydride (95 mg, 2.52 mmol) and methanol (3 mL) were added, the reaction was continued to stir at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~20% ethyl acetate / petroleum ether) to obtain compound 6-4. MS m / z (ESI): 678.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 6.96 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.08 - 4.01 (m, 2H), 3.63 (d, J = 6.9 Hz, 2H), 3.25 (s, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.40 - 2.35 (m, 3H), 2.31 (d, J = 14.3 Hz, 2H), 2.14 (d, J = 11.2 Hz, 5H), 2.07 - 2.00 (m, 2H), 1.74 - 1.61 (m, 3H), 1.56 (s, 9H), 1.32 (d, J = 7.0 Hz, 3H).

[0475] Step 5: Compound 6-4 (200 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (495 mg, 11.80 mmol) was added, the reaction was stirred at 60 °C for 2 hours, the reaction was monitored by LCMS until completion. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M dilute hydrochloric acid, a large amount of solid was precipitated, the solid was filtered and the crude product was purified by reverse phase chromatography column [type: Waters-Xbridge-C18-10 pm-19x250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 550.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.86 (d, J = 7.7 Hz, 2H), 7.48 (s, 2H), 7.32 (d, J = 2.7 Hz, 1H), 6.71 (s, 1H), 4.05 (t, J = 5.8 Hz, 2H), 3.60 (s, 2H), 3.25 (s, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 2H), 2.16 (d, J = 7.1 Hz, 2H), 2.10 (s, 3H), 2.05 (d, J = 12.6 Hz, 2H), 1.68 (s, 2H), 1.48 (s, 1H). The purified product (110 mg, 0.20 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.15 mL) was slowly dropped under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, ultrasonic was uniform, then freeze-drying to obtain compound 6. MS m / z (ESI): 550.2 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.07 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 2.8 Hz, 1H), 6.73 (s, 1H), 4.54 (t, J = 5.2 Hz, 2H), 4.10 (s, 2H), 3.69 (s, 2H), 3.36 (q, J = 5.3 Hz, 2H), 2.75 (d, J = 14.9 Hz, 2H), 2.60 - 2.51 (m, 6H), 2.34 (s, 3H), 2.05 (s, 3H).

[0476] Example 7: Preparation of compound 7

[0477] Step 1: Into a 100 mL single necked flask, compound 3-8 (2 g, 4.91 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), potassium ethylene trifluoroborate (1.97 g, 14.73 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (0.37 g, 0.49 mmol) and potassium carbonate (1.36 g, 9.82 mmol) were added sequentially under nitrogen protection, and the reaction was carried out at 90 °C for 16 hours. The reaction was detected by LCMS to be completed. After the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate three times (3 x 50 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% ~ 20% ethyl acetate / petroleum ether) to obtain compound 7-1. MS m / z (ESI): 286.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.85 (d, J = 3.7 Hz, 1H), 7.64 (dd, J = 17.3, 11.0 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 3.7 Hz, 1H), 5.81 (dd, J = 17.3, 1.3 Hz, 1H), 5.53 (dd, J = 11.0, 1.3 Hz, 1H), 2.62 (s, 3H), 1.61 (s, 9H).

[0478] Step 2: Into a 100 mL single necked flask, was placed a solution of compound 7-1 (1 g, 3.50 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL), followed by the addition of PtO2(0.80 g, 3.50 mmol), hydrogen was replaced, and the reaction was stirred at room temperature for 1 h, the reaction was monitored by LCMS. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give compound 7-2. MS m / z (ESI): 288.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.11 (s, 1H), 3.08 (q, J = 7.5 Hz, 2H), 2.58 (s, 3H), 1.23 (t, J = 7.5 Hz, 3H), 1.60 (s, 9H).

[0479] Step 3: Into a 100 mL single necked flask, was placed a solution of compound 7-2 (100 mg, 0.35 mmol) in acetonitrile (5 mL), followed by the addition of compound 5-2 (134.47 mg, 0.35 mmol) and 3 drops of acetic acid, the reaction was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (221.26 mg, 1.04 mmol) was added, the reaction was stirred at room temperature overnight, the reaction was monitored by LCMS. The reaction was quenched by slowly adding ice water at room temperature, extracted with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase gradient: 0%~20% ethyl acetate / petroleum ether) to give compound 7-3. MS m / z (ESI): 658.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 6.84 (s, 1H), 5.78 (d, J = 3.8 Hz, 1H), 4.35 (t, J = 7.1 Hz, 2H), 4.07 (s, 2H), 3.43 (d, J = 5.8 Hz, 2H), 3.29 (s, 2H), 2.60 (s, 2H), 2.42 (s, 3H), 2.32 (d, J = 7.4 Hz, 4H), 2.21 (d, J = 7.4 Hz, 2H), 1.99 (t, J = 7.0 Hz, 2H), 1.83 (s, 2H), 1.56 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H).

[0480] Step 4: Compound 7-3 (50 mg, 0.08 mmol) was dissolved in a mixture solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), lithium hydroxide (127.58 mg, 3.04 mmol) was added, and the reaction was heated to 60 °C for 1 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature, and diluted HC1 (2.0 M) was added slowly dropwise to adjust the pH to about 5-7. A large amount of solid precipitated, and the solid was filtered and purified by reverse phase column [type: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to give the purified product. MS m / z (ESI): 530.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.79 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.08 (t, J = 2.8 Hz, 1H), 6.62 (s, 1H), 5.58 (dd, J = 3.1, 1.9 Hz, 1H), 4.07 (t, J = 5.8 Hz, 2H), 3.47 (s, 2H), 3.32 (s, 3H), 2.61 (t, J = 5.7 Hz, 2H), 2.37 - 2.22 (m, 9H), 2.00 (d, J = 11.8 Hz, 2H), 1.82 (s, 2H), 0.98 (t, J = 7.5 Hz, 3H). The purified product (50 mg, 0.09 mmol) was dissolved in methanol (3 mL), and 4N HC1-methanol solution (0.09 mL) was added slowly dropwise with stirring. After stirring for 5 min, the methanol was evaporated at room temperature, and 5 mL of deionized water was added. After ultrasonic treatment, the solution was lyophilized to give compound 7. MS m / z (ESI): 530.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.99 (dd, J = 8.4, 2.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 5.62 (s, 1H), 4.58 (d, J = 18.2 Hz, 2H), 4.12 (s, 2H), 3.50 (s, 2H), 3.41 (d, J = 5.5 Hz, 2H), 2.74 (d, J = 15.5 Hz, 2H), 2.59 (d, J = 8.4 Hz, 3H), 2.36 (s, 3H), 2.33 (t, J = 7.6 Hz, 2H), 2.15 (d, J = 7.7 Hz, 2H), 1.78 (s, 1H), 0.98 (t, J = 7.5 Hz, 3H).

[0481] Example 8: Preparation of compound 8

[0482] Step 1 : Into a 20 mL microwave tube was placed a solution of compound 3-8 (1.0 g, 2.45 mmol) in 1,4-dioxane (10 mL) and water (2 mL), isopropenylboronic acid pinacol ester (1.24 g, 7.36 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (0.18 g, 0.25 mmol) and potassium carbonate (1.02 g, 7.36 mmol) were added sequentially under nitrogen protection, and the reaction was microwaved at 100 °C for 2 hours, the reaction was monitored by LCMS to be complete. The reaction was allowed to cool to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate three times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, the obtained crude was purified by silica gel chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether) to give compound 8-1. MS m / z (ESI): 300.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.86 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.20 (s, 1H), 5.47 (q, J = 1.6 Hz, 1H), 4.89 (q, J = 2.1, 1.0 Hz, 1H), 2.61 (s, 3H), 2.19 (d, J = 1.2 Hz, 3H), 1.61 (s, 9H).

[0483] Step 2: Into a 100 mL single necked flask, was placed a solution of compound 8-1 (650 mg, 2.17 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL), followed by the addition of platinum dioxide (100 mg), the reaction was protected by hydrogen replacement, and stirred at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was filtered, and the filtrate was concentrated under reduced pressure, the resulting crude was purified by silica gel chromatography column (mobile phase gradient: 0% - 30% ethyl acetate / petroleum ether) to give compound 8-2. MS m / z (ESI): 302.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.37 (d, J = 3.7 Hz, 1H), 7.26 (s, 1H), 4.07 - 3.97 (m, 1H), 2.60 (s, 3H), 1.60 (s, 9H), 1.31 (s, 3H), 1.29 (s, 3H).

[0484] Step 3: Into a 100 mL single necked flask, was placed a solution of compound 8-2 (120 mg, 0.40 mmol) in acetonitrile (5 mL), followed by the addition of compound 5-2 (185 mg, 0.48 mmol) and 5 drops of acetic acid, and stirred at room temperature overnight, the reaction was monitored by LCMS, there was a large amount of imine generated. Then sodium borohydride (38 mg, 1.00 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued to stir at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting crude was purified by silica gel chromatography column (mobile phase gradient: 0% - 40% ethyl acetate / petroleum ether) to give compound 8-3. MS m / z (ESI): 672.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 6.94 (s, 1H), 5.77 (s, 1H), 5.71 (d, J = 3.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 5.8 Hz, 2H), 3.45 (d, J = 5.3 Hz, 2H), 3.30 (s, 2H), 3.18 (d, J = 5.2 Hz, 1H), 2.62 (t, J = 5.9 Hz, 2H), 2.45 (s, 3H), 2.33 - 2.21 (m, 4H), 2.00 (t, J = 7.5 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.56 (s, 9H), 1.35 (s, 3H), 1.04 (d, J = 6.8 Hz, 6H).

[0485] Step 4: Compound 8-3 (110 mg, 0.16 mmol) was dissolved in a mixture solvent of methanol (4 mL), water (4 mL) and tetrahydrofuran (4 mL), lithium hydroxide monohydrate (275 mg, 6.55 mmol) was added, and the reaction was carried out at 60 °C for 2 hours. The reaction was monitored by LCMS until it was completed. The reaction was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to about 5-7. A large amount of solid was precipitated, and the obtained solid crude product was purified by a reverse phase column [type: Waters-Xbridge-C18-10 μm-19x250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 544.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.78 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.07 (t, J = 2.8 Hz, 1H), 6.72 (s, 1H), 5.55-5.50 (m, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.49 (s, 2H), 3.28 (s, 2H), 2.83-2.74 (m, 1H), 2.63 (d, J = 5.8 Hz, 2H), 2.36 (s, 3H), 2.32-2.22 (m, 4H), 2.01 (d, J = 12.7 Hz, 2H), 1.84 (s, 2H), 1.14 (s, 1H), 1.03 (d, J = 6.8 Hz, 6H). The purified product (35 mg, 0.06 mmol) was dissolved in methanol (5 mL), 1 N hydrochloric acid-methanol solution (0.18 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 8. MS m / z (ESI): 544.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.95 (s, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.75 (s, 1H), 5.51 (t, J = 2.4 Hz, 1H), 4.55 (t, J = 5.2 Hz, 2H), 4.13 (s, 2H), 3.53 (d, J = 4.8 Hz, 2H), 3.41 (d, J = 5.3 Hz, 2H), 2.75 (d, J = 15.3 Hz, 2H), 2.61 (d, J = 8.5 Hz, 2H), 2.47 (s, 2H), 2.37 (s, 3H), 2.18 (s, 2H), 1.72 (s, 1H), 1.05 (d, J = 6.8 Hz, 6H).

[0486] Example 9: Preparation of compound 9

[0487] Step 1: Into a 10 mL single necked flask was placed a solution of compound 3-8 (500 mg, 1.2 mmol) in toluene (30 mL) and water (6 mL), followed by the addition of cyclobutylboronic acid (1.17 g, 4656 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (89.0 mg, 0.1 mmol) and cesium carbonate (1.170 mg, 3.6 mmol), replaced with nitrogen, and reacted at 100 °C for 16 hours, the reaction was monitored by LCMS. The reaction was quenched by water, extracted with ethyl acetate for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude was purified by silica gel column chromatography (mobile phase gradient: 0% - 40% ethyl acetate / petroleum ether) to give compound 9-1. MS m / z (ESI): 314.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.35 (d, J = 3.7 Hz, 1H), 7.18 (s, 1H), 4.33 (p, J = 8.9 Hz, 1H), 2.62 (s, 3H), 2.36 (ddq, J = 10.5, 4.9, 2.7, 2.2 Hz, 2H), 2.26 (ddt, J = 11.2, 9.6, 4.3 Hz, 2H), 1.93 - 1.83 (m, 2H), 1.60 (s, 9H).

[0488] Step 2: Compound 5-2 (200 mg, 0.52 mmol), compound 9-1 (162.21 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid was added, the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, the reaction was continued to stir at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography (mobile phase gradient: 0% - 20% ethyl acetate / petroleum ether) to give compound 9-2. MS m / z (ESI): 684.4 [M+H] + .

[0489] Step 3: Compound 9-2 (200 mg, 0.33 mmol) was dissolved in a mixture solvent of tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (490.90 mg, 11.70 mmol) was added, the reaction was stirred at 60 °C for 1 hour, the reaction was monitored by LCMS until it was completed. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2N dilute hydrochloric acid, a large amount of solid was precipitated, the obtained solid crude was purified by reversed phase column [type: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HC03 / H20 B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 556.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.81 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 2.8 Hz, 1H), 6.84 (s, 1H), 5.86 (dd, J = 3.1, 1.9 Hz, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.44 (s, 2H), 3.30 (s, 2H), 3.11-3.07 (m, 1H), 2.62 (t, J = 5.8 Hz, 2H), 2.39 (s, 3H), 2.35-2.26 (m, 4H), 2.04-1.81 (m, 8H), 1.64 (q, J = 8.4 Hz, 2H). The purified product (75 mg, 0.13 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.10 mL) was slowly dropped under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, after ultrasonic homogenization, freeze-drying was obtained Compound 9. MS m / z (ESI): 556.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.87 (s, 1H), 9.73 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 2.8 Hz, 1H), 6.86 (s, 1H), 5.89 (t, J = 2.6 Hz, 1H), 4.54 (d, J = 5.1 Hz, 2H), 4.14 (s, 2H), 3.44 (dd, J = 20.4, 5.4 Hz, 4H), 3.07 (q, J = 8.9 Hz, 1H), 2.77 (d, J = 14.8 Hz, 2H), 2.67 - 2.58 (m, 2H), 2.45 (s, 1H), 2.40 (s, 3H), 2.17 (s, 2H), 1.91 (dt, J = 19.3, 9.2 Hz, 4H), 1.74 - 1.56 (m, 3H).

[0490] Example 10: Preparation of compound 10

[0491] Step 1 : Compound 3-8 (27 g, 66.28 mmol) was added to a mixture of toluene (810 mL) and water (135 mL), followed by the addition of cyclopropylboronic acid (17.08 g, 198.84 mmol), [1,1 '-bis(diphenylphosphino)ferrocene] palladium dichloride (9.70 g, 13.26 mmol) and potassium carbonate (18.32 g, 132.56 mmol). After purging with nitrogen, the reaction was stirred at 110 °C overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of water and extracted with ethyl acetate (3 x 300 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 10% ethyl acetate / petroleum ether) to give compound 10-1. MS m / z (ESI): 300.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 10.98 (s, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 6.93 (s, 1H), 2.64 (d, J = 0.8 Hz, 3H), 2.48 (td, J = 8.5, 4.3 Hz, 1H), 1.63 (s, 9H), 1.11 - 1.04 (m, 2H), 0.85 - 0.80 (m, 2H).

[0492] Step 2: Compound 5-2 (200 mg, 0.52 mmol), compound 10-1 (155 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, the reaction was continued to stir at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate three times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~20% ethyl acetate / petroleum ether) to obtain compound 10-2. MS m / z (ESI): 670.4 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 3.8 Hz, 1H), 6.56 (s, 1H), 5.98 (d, J = 3.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.06 (t, J = 5.8 Hz, 2H), 3.57 (d, J = 5.6 Hz, 2H), 3.30-3.25 (m, 2H), 2.60 (t, J = 5.7 Hz, 2H), 2.40 (s, 3H), 2.30 (d, J = 13.7 Hz, 2H), 2.20 (d, J = 7.2 Hz, 2H), 2.02-1.95 (m, 2H), 1.80 (s, 2H), 1.56 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H), 1.26-1.22 (m, 2H), 0.60-0.53 (m, 2H), 0.53-0.46 (m, 2H).

[0493] Step 3: Compound 10-2 (220 mg, 0.33 mmol) was dissolved in a mixture solvent of tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (551 mg, 13.14 mmol) was added, the reaction was stirred at 60 °C for 2 hours, the reaction was monitored by LCMS. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M hydrochloric acid, a large amount of solid was precipitated, the crude solid was filtered and purified by reverse phase column [type: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%~95%)] to obtain the purified product. MS m / z (ESI): 542.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.80 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 2.8 Hz, 1H), 6.38 (s, 1H), 5.80 (t, J = 2.6 Hz, 1H), 4.07 (t, J = 5.7 Hz, 2H), 3.62 (s, 2H), 3.29 (s, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 2.30 - 2.23 (m, 3H), 2.01 (d, J = 12.5 Hz, 2H), 1.80 (s, 2H), 1.56 - 1.50 (m, 1H), 1.28 (s, 1H), 0.58 - 0.51 (m, 2H), 0.44 - 0.38 (m, 2H). The purified product (75 mg, 0.14 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.12 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 10. MS m / z (ESI): 542.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 10.87 (s, 1H), 10.11 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.8 Hz, 1H), 6.41 (s, 1H), 5.83 (t, 1H), 4.56 (s, 2H), 4.12 (s, 2H), 3.69 - 3.61 (m, 2H), 3.40 (s, 2H), 2.75 (d, J = 14.7 Hz, 2H), 2.59 (d, J = 8.6 Hz, 2H), 2.53 (s, 2H), 2.34 (s, 3H), 2.11 (s, 2H), 1.60 - 1.50 (m, 1H), 0.58 - 0.51 (m, 2H), 0.46 - 0.39 (m, 2H).

[0494] Example 11: Preparation of compound 11

[0495] Step 1: To a 10 mL single necked flask was added a solution of compound 3-7 (600 mg, 1.2 mmol) in DMF (10 mL), followed by the addition of potassium carbonate (602.4 mg, 4.36 mmol), iodoethane (679.85 mg, 4.36 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of water and extracted with ethyl acetate (3 x 40 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-30% ethyl acetate / pet. ether) to afford compound 11-1. LC-MS: m / z: 304.2 [M+H] + .

[0496] Step 2: To a solution of compound 5-2 (200 mg, 0.52 mmol) and compound 11-1 (157.01 mg, 0.52 mmol) in acetonitrile (5 mL) was added 4 drops of acetic acid and the reaction was stirred at room temperature for 16 h. The reaction was monitored by LCMS. Then sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added and the reaction was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 40 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-20% ethyl acetate / pet. ether) to afford compound 11-2. MS m / z (ESI): 674.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.4 Hz, 2H), 7.59 - 7.51 (m, 3H), 6.75 (s, 1H), 6.17 (dd, J = 3.8, 1.7 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.06 (q, J = 5.9 Hz, 2H), 3.92 (q, J = 6.9 Hz, 2H), 3.37 (s, 2H), 3.26 (s, 2H), 2.46 (d, J = 2.8 Hz, 3H), 2.20 (dd, J = 23.1, 11.1 Hz, 4H), 2.05 - 2.00 (m, 1H), 1.98 (s, 1H), 1.90 (s, 3H), 1.74 (s, 2H), 1.56 (d, J = 4.0 Hz, 9H), 1.36 - 1.30 (m, 3H), 1.25 - 1.18 (m, 3H).

[0497] Step 3: Compound 11-2 (220 mg, 0.33 mmol) was dissolved in a mixture solvent of tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (548 mg, 13.06 mmol) was added, the reaction was stirred at 60 °C for 1 h, the reaction was monitored by LCMS. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M dilute hydrochloric acid, a large amount of solid was precipitated, the obtained solid crude product was purified by reversed phase column [type: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HC03 / H20 B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 546.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 12.87 (s, 1H), 10.80 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.19 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 5.92 (t, J = 2.4 Hz, 1H), 4.07 (t, J = 5.8 Hz, 2H), 3.84 (q, J = 7.0 Hz, 2H), 3.42 (s, 2H), 3.26 (s, 3H), 2.60 (t, J = 5.7 Hz, 2H), 2.38 (s, 3H), 2.26 - 2.17 (m, 4H), 2.05 - 1.97 (m, 2H), 1.75 (s, 2H), 1.18 (t, J = 6.9 Hz, 3H). The purified product (85 mg, 0.16 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.12 mL) was slowly dropped under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, after ultrasonic homogenization, freeze-drying to obtain compound 11. MS m / z (ESI): 546.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.80 (s, 1H), 9.93 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 4.0 Hz, 1H), 6.63 (s, 1H), 5.91 (t, J = 4.0 Hz, 1H), 4.55 (s, 2H), 4.10 (s, 2H), 3.89-3.84 (m, 2H), 3.55 (s, 2H), 3.45-3.38 (m, 3H), 2.69-2.59 (m, 4H), 2.49-2.46 (m, 1H), 2.39 (s, 3H), 2.05-1.98 (m, 2H), 1.19 (t, J = 6.9 Hz, 3H).

[0498] Example 12: Preparation of compound 12

[0499] Step 1: Compound 3-8 (1.0 g, 2.45 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) and zinc cyanide (865 mg, 7.36 mmol) were added. After replacing nitrogen, the reaction was stirred at 100 °C for 2 hours, and the reaction was monitored by LCMS. After the reaction was cooled to room temperature, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (3 x 40 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by a reverse phase column [Model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM FA / H2O; B: ACN; gradient: B%: 0%-95%)] to obtain compound 12-1. MS m / z (ESI): = 185.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.49 (s, 1H), 7.83 (d, J = 3.1 Hz, 1H), 7.53 (s, 1H), 7.25 (d, J = 3.1 Hz, 1H), 2.62 (s, 3H).

[0500] Step 2: Compound 12-1 (120 mg, 0.65 mmol), compound 5-2 (250 mg, 0.65 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, the reaction was stirred at room temperature for 16 hours, the reaction was monitored by LCMS, a large amount of imine was observed. Then sodium borohydride (246 mg, 6.50 mmol) and methanol (3 mL) were added, the reaction was continued to stir at room temperature for 3 hours, the reaction was monitored by LCMS to be complete. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate three times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 35% ethyl acetate / petroleum ether) to obtain compound 12-2. MS m / z (ESI): 555.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 2.9 Hz, 1H), 7.14 (s, 1H), 6.03 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H), 3.57 (d, J = 6.6 Hz, 2H), 3.25 (s, 2H), 2.58 (s, 2H), 2.44 (s, 3H), 2.29 - 2.14 (m, 4H), 2.01 (d, J = 15.1 Hz, 2H), 1.72 (s, 2H), 1.34 (t, J = 7.0 Hz, 3H).

[0501] Step 3: Compound 12-2 (100 mg, 0.18 mmol) was dissolved in a mixture solvent of tetrahydrofuran (2 mL), methanol (2 mL), water (2 mL), lithium hydroxide (37.83 mg, 0.90 mmol) was added, the reaction was stirred at room temperature for 2 hours, the reaction was monitored by LCMS to be complete. Dilute HCl (2.0 M) was slowly added to the reaction, the pH value was adjusted to about 5-7, a large amount of solid was precipitated, the crude solid was filtered and purified by reverse phase column [model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 527.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 2.8 Hz, 1H), 7.14 (s, 1H), 5.98 (d, J = 2.8 Hz, 1H), 4.06 (t, J = 5.8 Hz, 2H), 3.58 (s, 2H), 3.25 (s, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.44 (s, 3H), 2.22 (dd, J = 19.8, 10.6 Hz, 4H), 2.01 (d, J = 13.3 Hz, 2H), 1.72 (s, 2H). The purified product (30 mg, 0.06 mmol) was dissolved in methanol (3 mL), 4M methanolic hydrochloric acid solution (0.05 mL) was added, and methanol was distilled off at room temperature after stirring for 3 hours, then 5 mL of deionized water was added, and after ultrasonic homogenization, it was freeze-dried to obtain compound 12. MS m / z (ESI): 527.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 2.8 Hz, 1H), 7.14 (s, 1H), 5.98 (d, J = 2.8 Hz, 1H), 4.06 (t, J = 5.8 Hz, 2H), 3.58 (s, 2H), 3.25 (s, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.44 (s, 3H), 2.22 (dd, J = 19.8, 10.6 Hz, 4H), 2.01 (d, J = 13.3 Hz, 2H), 1.72 (s, 2H). The purified product (30 mg, 0.06 mmol) was dissolved in methanol (3 mL), 4M methanolic hydrochloric acid solution (0.05 mL) was added, and methanol was distilled off at room temperature after stirring for 3 hours, then 5 mL of deionized water was added, and after ultrasonic homogenization, it was freeze-dried to obtain compound 12. MS m / z (ESI): 527.3 [M+H]

[0502] Example 13: Preparation of compound 13

[0503] Step 1: Into a 500 mL single necked flask was added compound 4-6 (4 g, 18.5 mmol) in acetonitrile (40 mL), then CuI (0.7 g, 3.70 mmol), 2-fluorosulfonyl difluoroacetic acid (6.59 g, 36.99 mmol) and anhydrous sodium sulfate (1 g, 33.00 mmol) were added sequentially at 70 °C, then stirred at 70 °C for 1.5 hours, the reaction was complete by LCMS detection. After the reaction was cooled to room temperature, ice water was added slowly to quench, extracted with ethyl acetate for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column [mobile phase gradient: 0%~20% ethyl acetate / petroleum ether] to obtain compound 13-1. MS m / z (ESI): 284.0 [M+18] + .1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8 Hz, 2H), 7.36 (q, J = 8 Hz, 2H), 6.15 (t, J = 76 Hz, 1H), 4.23-4.20 (m, 2H), 4.04-4.01 (m, 2H), 2.46 (s, 3H).

[0504] Step 2: To a 100 mL single necked flask was added compound 13-1 (1690.71 mg, 6.35 mmol) and compound 1-7 (1600 mg, 5.29 mmol) dissolved in N,N-dimethylformamide (20 mL) at 0 °C, followed by the slow addition of N,N-diisopropylethylamine (4.62 mL, 26.46 mmol) and stirred at 60 °C for 10 h. The reaction was monitored by LCMS. The reaction was quenched by slowly adding water at room temperature, extracted with ethyl acetate (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0-40% ethyl acetate / petroleum ether] to afford compound 13-2. MS m / z (ESI): 397.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.81 (m, 2H), 7.50 - 7.43 (m, 2H), 7.38 (s, 1H), 6.97 (s, 1H), 6.64 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.32 (s, 2H), 3.02 - 2.83 (m, 2H), 2.48 (d, J = 5.4 Hz, 2H), 1.97 - 1.67 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0505] Step 3: To a 100 mL single necked flask was added compound 13-2 (400 mg, 1.01 mmol) dissolved in a mixture of acetonitrile (10 mL) and water (10 mL) at 0 °C, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (871.90 mg, 2.02 mmol) and stirred at room temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0-60% ethyl acetate / petroleum ether] to afford compound 13-3. MS m / z (ESI): 369.1 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.83 (m, 2H), 7.56 (d, J = 8.1 Hz, 2H), 6.69 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.91 (d, J = 7.6 Hz, 2H), 3.31 (s, 2H), 2.59 (s, 2H), 2.27 (s, 2H), 2.09 (d, J = 12.8 Hz, 2H), 1.77 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H).

[0506] Step 4: Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), followed by the addition of compound 1-14 (200 mg, 0.69 mmol) and 3 drops of acetic acid, and stirring for 0.5 h. Sodium cyanoborohydride (86.99 mg, 1.38 mmol) was then added, and the reaction was stirred at room temperature overnight. The reaction was monitored to completion by LCMS. The reaction solution was slowly added to ice water to quench, and extracted with ethyl acetate three times (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by a silica gel column [mobile phase gradient: 0-20% ethyl acetate / petroleum ether gradient] to obtain compound 13-4. MS m / z (ESI): 642.2 [M+H] + .

[0507] Step 5: Compound 13-4 (200 mg, 0.31 mmol) was dissolved in a mixture solvent of methanol (7 mL) and water (2 mL), and lithium hydroxide (523.06 mg, 12.47 mmol) was added. The reaction was heated to 60 °C for 1 h, and the reaction was monitored to completion by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (1.0 M) was slowly added dropwise to adjust the pH to about 5-7. A large amount of solid was precipitated, and the resulting solid crude product was purified by a reverse phase column [model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0-95%)] to obtain the purified product. MS m / z (ESI): 514.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.51 (br s, 1H), 10.81 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 2.8 Hz, 1H), 6.85 - 6.47 (m, 2H), 5.91 (dd, J = 3.1, 1.9 Hz, 1H), 3.86 (t, J = 6.0 Hz, 2H), 3.61 (s, 3H), 3.41 (s, 2H), 3.32 (s, 2H), 2.56 (d, J = 6.0 Hz, 2H), 2.40 (s, 3H), 2.30 - 2.11 (m, 4H), 2.02 (d, J = 12.9 Hz, 2H), 1.77 (br s, 2H), 1.52 (br s, 1H). The purified product (50 mg, 0.10 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.18 mL) was added slowly dropwise under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, it was freeze-dried to obtain compound 13. MS m / z (ESI): 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (br s, 1H), 9.80 (br s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 7.23 (s, 1H), 6.96 - 6.56 (m, 2H), 5.98 - 5.87 (m, 1H), 4.19 - 4.36 (m, 3H), 4.09 (s, 2H), 3.37 - 3.48 (m, 2H), 3.25 - 3.34 (m, 2H), 2.75 - 2.54 (m, 7H), 2.41 (s, 3H), 1.94 - 2.11 (m, 2H).

[0508] Example 14: Preparation of compound 14

[0509] Step 1 : Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), compound 3-9 (189.18 mg, 0.69 mmol) and 3 drops of acetic acid were added sequentially, after stirring for 0.5 h, sodium cyanoborohydride (86.99 mg, 1.38 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was monitored to completion by LCMS. The reaction was quenched by slowly adding ice water, and extracted with ethyl acetate three times (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography [mobile phase gradient: 0-20% ethyl acetate / petroleum ether gradient] to obtain compound 14-1. MS m / z (ESI): 626.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 3.7 Hz, 1H), 6.83 (s, 1H), 5.86 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 3.40 (s, 2H), 3.28 (d, J = 10.0 Hz, 2H), 2.41 (s, 3H), 2.23 (d, J = 24.2 Hz, 4H), 2.03 (s, 3H), 1.96 (s, 2H), 1.81 (s, 2H), 1.56 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H).

[0510] Step 2: Compound 14-1 (180 mg, 0.29 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (482.79 mg, 11.51 mmol) was added, and the reaction was heated to 60 °C for 1 h. The reaction was monitored to completion by LCMS. The reaction was cooled to room temperature, and diluted HCl (2.0 M) was added slowly dropwise to adjust the pH value to about 5-7. A large amount of solid precipitated, and the obtained solid crude product was purified by reverse phase column chromatography [model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0-95%)] to obtain the purified product. MS m / z (ESI): 498.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.79 (d, J = 2.7 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.65 (s, 3H), 6.60 (s, 1H), 5.66 (dd, J = 3.1, 1.9 Hz, 1H), 3.85 (t, J = 6.0 Hz, 2H), 3.44 (s, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.28 - 2.19 (m, 4H), 2.08 - 1.97 (m, 5H), 1.84 - 1.77 (m, 2H), 1.16 (s, 1H). The purified product (51 mg, 0.10 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.18 mL) was added slowly dropwise under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, it was freeze-dried to obtain compound 14. MS m / z (ESI): 498.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 10.86 (s, 1H), 9.87 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.31 - 7.05 (m, 2H), 6.53 (s, 1H), 5.71 (dd, J = 3.1, 1.9 Hz, 1H), 4.27 (t, J = 5.1 Hz, 2H), 4.11 (s, 2H), 3.46 (d, J = 4.9 Hz, 2H), 3.31 (d, J = 5.4 Hz, 2H), 2.71 (d, J = 14.7 Hz, 2H), 2.58 (d, J = 8.3 Hz, 2H), 2.46 (s, 1H), 2.35 (s, 3H), 2.20 - 1.98 (m, 5H), 1.85 (s, 1H).

[0511] Example 15: Preparation of compound 15

[0512] Step 1: To a 500 mL single necked flask was added compound 15-1 (8.5 g, 111.71 mmol) in DCM (200 mL) followed by p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (30.97 mL, 223.42 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (mobile phase gradient: 0-20% ethyl acetate in petroleum ether) to afford compound 15-2. MS m / z (ESI): 231.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.99 (s, 1H), 3.86-3.73 (m, 3H), 2.43 (s, 3H), 0.99 (d, J = 6.1 Hz, 3H).

[0513] Step 2: To a 500 mL single necked flask was added compound 15-2 (14 g, 60.80 mmol) in acetonitrile (140 mL) followed by Cul (2.32 g, 12.16 mmol), 2-fluorosulfonyl difluoroacetate (21.65 g, 121.59 mmol) and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C. The reaction mixture was stirred at 70 °C for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water slowly and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (mobile phase gradient: 0-20% ethyl acetate in petroleum ether) to afford compound 15-3. MS m / z (ESI): 281.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 6.65 (t, J = 72 Hz, 1H), 4.46-4.39 (m, 1H), 4.12-4.07 (m, 1H), 4.03-3.97 (m, 1H), 2.43 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H).

[0514] Step 3: To a 500 mL single neck flask was added compound 1-7 (5.24 g, 17.34 mmol) and compound 15-3 (4.63 g, 16.52 mmol) dissolved in N,N-dimethylformamide (200 mL) at room temperature, followed by the slow addition of N,N-diisopropylethylamine (14.43 mL, 82.59 mmol) and the reaction was stirred at 80 °C for 16 h. The reaction was monitored by LCMS. Once the reaction was complete, the reaction was quenched by the slow addition of water and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to afford compound 15-4. MS m / z (ESI): 411.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.38 (s, 1H), 6.97 (s, 1H), 6.90 - 6.50 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.21 - 4.13 (m, 1H), 3.34 (s, 2H), 2.93 (d, J = 13.4 Hz, 2H), 2.42 - 2.35 (m, 1H), 2.32 - 2.25 (m, 1H), 1.90 - 1.66 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H).

[0515] Step 4: To a 100 mL single neck flask was added compound 15-4 (3 g, 7.31 mmol) dissolved in a mixture of acetonitrile (80 mL) and water (40 mL) at room temperature, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (6.32 g, 14.62 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the precipitated solid was filtered off. The mother liquor was extracted with dichloromethane (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to afford compound 15-5. MS m / z (ESI): 383.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 6.97 - 6.50 (s, 1H), 4.29 (d, J = 7.1 Hz, 2H), 4.24 - 4.18 (m, 1H), 3.22 (d, J = 8.2 Hz, 2H), 2.49 - 2.44 (m, 1H), 2.40 - 2.35 (m, 1H), 2.24 (t, J = 6.5 Hz, 2H), 2.08 (d, J = 6.4 Hz, 2H), 1.79 (d, J = 6.5 Hz, 4H), 1.71 - 1.63 (m, 2H), 1.31 (s, 3H), 1.23 (d, J = 6.2 Hz, 3H).

[0516] Step 5: Compound 15-5 (300 mg, 0.75 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (204 mg, 0.75 mmol) and 5 drops of acetic acid were added, and stirred at room temperature overnight. Then sodium borohydride (85 mg, 2.24 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour, and the reaction was monitored by LCMS. The reaction solution was slowly added to water at room temperature to quench, extracted with ethyl acetate for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% ~ 20% petroleum ether / ethyl acetate) to obtain compound 15-6. MS m / z (ESI): 640.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 3.8 Hz, 1H), 6.97 - 6.50 (s, 1H), 6.82 (s, 1H), 5.85 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (s, 1H), 3.39 (d, J = 5.6 Hz, 2H), 3.24 (s, 2H), 2.41 (s, 3H), 2.24 (dd, J = 33.6, 11.0 Hz, 5H), 2.02 (s, 3H), 1.99 (s, 3H), 1.79 (s, 2H), 1.56 (s, 9H), 1.44 (d, J = 7.4 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 4.7 Hz, 3H).

[0517] Step 6: Compound 15-6 (300 mg, 0.47 mmol) was dissolved in a mixture solvent of tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (787 mg, 18.76 mmol) was added, and the reaction was heated to 60 °C for 2 hours. The reaction was monitored by LCMS until completion. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M dilute hydrochloric acid, and a large amount of solid was precipitated. The solid was filtered and the crude product was purified by reverse phase column [Model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 512.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.80 (t, J = 2.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.91-6.51 (m, 2H), 5.67-5.61 (m, 1H), 4.19 (q, J = 6.2 Hz, 1H), 3.44 (s, 2H), 3.26 (s, 2H), 2.48-2.42 (m, 1H), 2.37 (d, J = 5.0 Hz, 1H), 2.34 (s, 3H), 2.31-2.21 (m, 4H), 2.04 (s, 3H), 2.03-1.97 (m, 2H), 1.80 (d, J = 8.6 Hz, 2H), 1.18 (d, J = 6.2 Hz, 3H). The purified product (120 mg, 0.23 mmol) was dissolved in methanol (3 mL), and 4N hydrochloric acid-methanol solution (0.17 mL) was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated at room temperature, then 5 mL of deionized water was added, and the mixture was sonicated and freeze-dried to obtain compound 15. MS m / z (ESI): 512.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.59 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 2.8 Hz, 1H), 6.83 (dd, J = 77.2, 73.6 Hz, 1H), 6.63 (s, 1H), 5.68 (dd, J = 3.1, 1.9 Hz, 1H), 4.83 (s, 1H), 4.10 (d, J = 11.0 Hz, 2H), 3.46 (s, 2H), 3.21 (d, J = 5.0 Hz, 2H), 2.72 (t, J = 12.3 Hz, 2H), 2.57 (t, J = 14.0 Hz, 3H), 2.44 (d, J = 14.8 Hz, 1H), 2.35 (s, 3H), 2.13 (dt, J = 21.2, 10.0 Hz, 2H), 2.04 (s, 3H), 1.81 (s, 1H), 1.28 (d, J = 6.2 Hz, 3H).

[0518] Example 16: Preparation of compound 16

[0519] Step 1: Into a 500 mL single necked flask was placed a solution of compound 16-1 (8.5 g, 111.71 mmol) in dichloromethane (200 mL) followed by the addition of p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (15.48 mL, 111.71 mmol) at 0 °C. The reaction was allowed to react at room temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution and extracted with DCM (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether) to give compound 16-2. MS m / z (ESI): 231.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.76 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.98 (d, J = 4.3 Hz, 1H), 3.84 - 3.73 (m, 3H), 2.42 (s, 3H), 0.98 (d, J = 5.7 Hz, 3H).

[0520] Step 2: Into a 25 mL single necked flask was placed a solution of compound 16-2 (10 g, 33.00 mmol) in acetonitrile (200 mL), followed by cuprous iodide (1.26 g, 6.60 mmol), 2-fluorosulfonyl difluoroacetate (11.75 g, 66.01 mmol) and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C, then continue to stir at 70 °C for 1.5 hours, the reaction was monitored by LCMS. After the reaction solution was cooled to room temperature, quenched by ice water slowly, extracted with ethyl acetate for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 10% ethyl acetate / petroleum ether) to give compound 16-3. MS m / z (ESI): 281.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.76 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 6.85 - 6.44 (m, 1H), 4.42 (pd, J = 6.5, 2.9 Hz, 1H), 4.09 (dd, J = 10.9, 3.0 Hz, 1H), 4.03 - 3.98 (m, 1H), 2.43 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H).

[0521] Step 3: Into a 250 mL single necked flask was placed a solution of compound 1-7 (6.47 g, 21.41 mmol) and compound 16-3 (6 g, 21.41 mmol) in N,N-dimethylformamide (140 mL) at 0 °C, followed by N,N-diisopropyl ethylamine (18.69 mL, 107.03 mmol) slowly, then continue to react at 100 °C for 3 hours, the reaction was monitored by LCMS. After the reaction solution was cooled to room temperature, quenched by water slowly, extracted with ethyl acetate for 3 times (3 x 200 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to give compound 16-4. MS m / z (ESI): 411.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.84 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (s, 1H), 6.99 (s, 1H), 6.71 (dd, J = 79.0, 75.3 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.15 (p, J = 6.3 Hz, 1H), 3.22 (s, 2H), 2.93 (d, J = 13.5 Hz, 2H), 2.38 (dd, J = 13.3, 6.9 Hz, 1H), 2.28 (dd, J = 13.3, 5.0 Hz, 1H), 1.90-1.78 (m, 4H), 1.77-1.66 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H).

[0522] Step 4: To a 250 mL single necked flask was added a mixture of compound 16-4 (2.7 g, 6.58 mmol) dissolved in acetonitrile (30 mL) and water (15 mL) at 0 °C, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (5.68 g, 13.16 mmol) and allowed to react at room temperature for 1.5 hours, the reaction was monitored by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane (3 x 200 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to give compound 16-5. MS m / z (ESI): 383.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.85 (m, 2H), 7.61-7.53 (m, 2H), 6.77 (dd, J = 78.7, 75.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 3H), 3.32 (s, 2H), 2.44 (s, 2H), 2.25 (d, J = 8.2 Hz, 2H), 2.13 (dd, J = 14.0, 4.0 Hz, 2H), 1.90-1.67 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H).

[0523] Step 5: Compound 16-5 (300 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), compound 3-9 (214.40 mg, 0.78 mmol) and 5 drops of acetic acid were added, and stirred at room temperature overnight. Sodium borohydride (89.02 mg, 2.35 mmol) was added at 0 °C, and the reaction was continued at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched by slowly adding water at room temperature, extracted with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-20% petroleum ether / ethyl acetate) to give compound 16-6. MS m / z (ESI): 640.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 3.8 Hz, 1H), 6.82 (s, 1H), 6.92 - 6.49 (m, 2H), 5.85 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.17 (d, J = 6.6 Hz, 1H), 3.39 (d, J = 5.8 Hz, 2H), 3.24 (s, 2H), 2.41 (s, 3H), 2.28 (d, J = 15.8 Hz, 4H), 2.19 (d, J = 7.5 Hz, 2H), 2.02 (s, 5H), 1.79 (s, 2H), 1.56 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H).

[0524] Step 6: Compound 16-6 (220 mg, 0.34 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (577.15 mg, 13.75 mmol) was added, and the reaction was continued at 60 °C for 2 h. The reaction was monitored by LCMS. The reaction was cooled to room temperature, and diluted with dilute HCl (2.0 M) was added slowly dropwise, and the pH value was adjusted to about 5-7. A large amount of solid was precipitated, and a white solid was obtained by filtration. The crude product was purified by reverse phase column [Model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0-95%)] to give the purified product. MS m / z (ESI): 512.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 2.9 Hz, 1H), 6.71 (m, 1H), 6.60 (s, 1H), 5.63 (s, 1H), 4.18 (q, J = 6.1 Hz, 1H), 3.43 (s, 2H), 3.25 (s, 2H), 2.44 (d, J = 6.8 Hz, 1H), 2.36-2.33 (m, 4H), 2.38-2.22 (m, 4H), 2.04-1.98 (m, 5H), 1.80-1.79 (s, 2H), 1.18 (d, J = 6.3 Hz, 3H). The purified product (100 mg, 0.20 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.15 mL) was added slowly dropwise under stirring, methanol was evaporated at room temperature after stirring for 5 min, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 16. MS m / z (ESI): 512.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.67 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 2.8 Hz, 1H), 6.83 (dd, J = 77.3, 73.6 Hz, 1H), 6.63 (s, 1H), 5.68 (dd, J = 3.1, 1.9 Hz, 1H), 4.85 (s, 1H), 4.10 (d, J = 17.2 Hz, 2H), 3.46 (s, 2H), 3.21 (d, J = 5.3 Hz, 2H), 2.71 (t, J = 11.4 Hz, 2H), 2.57 (t, J = 13.7 Hz, 3H), 2.44 (s, 1H), 2.35 (s, 3H), 2.13 (dt, J = 19.7, 9.7 Hz, 2H), 2.04 (s, 3H), 1.81 (s, 1H), 1.28 (d, J = 6.3 Hz, 3H).

[0525] Example 17: Preparation of compound 17

[0526] Step 1: Into a 500 mL single necked flask was placed a solution of compound 17-1 (30.7 g, 259.88 mmol) in dichloromethane (300 mL) and was added 2,2,2-trichloroacetamidobenzyl chloride (72.19 g, 285.87 mmol) and trifluoromethanesulfonic acid (2.3 mL, 25.99 mmol) sequentially at 0 °C. The reaction was allowed to proceed at room temperature for 2 h, monitored by LCMS. The reaction was quenched by slow addition of sodium bicarbonate solution at room temperature and extracted with dichloromethane (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / petroleum ether gradient) to give compound 17-2. MS m / z (ESI): 209.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 4.46 (s, 2H), 3.60 (s, 3H), 3.58-3.54 (m, 1H), 3.51-3.46 (m, 1H), 2.80-2.69 (m, 1H), 1.08 (d, J = 7.1 Hz, 3H).

[0527] Step 2: Into a 500 mL three necked flask was placed a solution of compound 17-2 (30 g, 144.05 mmol) in tetrahydrofuran (300 mL) and was added lithium aluminum hydride (6.56 g, 172.86 mmol) slowly at 0 °C. The reaction was allowed to proceed at 0 °C for 1 h, monitored by LCMS. The reaction was quenched by slow addition of dilute hydrochloric acid (1 M) at ice water bath and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-30% ethyl acetate / petroleum ether) to give compound 17-3. MS m / z (ESI): 181.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.39-7.19 (m, 5H), 4.44 (s, 2H), 4.42 (t, J = 5.3 Hz, 1H), 3.43-3.35 (m, 2H), 3.31-3.22 (m, 2H), 1.86-1.75 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H).

[0528] Step 3: To a 500 mL single necked flask was added compound 17-3 (21.3 g, 100.44 mmol) in dichloromethane (250 mL) and Dess-Martin periodinane (55.38 g, 130.58 mmol) was added slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. The reaction was quenched by slow addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / pet. ether gradient) to afford compound 17-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (d, J = 1.4 Hz, 1H), 7.37-7.28 (m, 5H), 4.48 (s, 2H), 3.70-3.63 (m, 2H), 2.71-2.62 (m, 1H), 1.02 (d, J = 7.1 Hz, 3H).

[0529] Step 4: To a 500 mL single necked flask was added compound 17-4 (15 g, 84.16 mmol) in dichloromethane (150 mL) and diethylamine sulfide (27.13 g, 168.32 mmol) was added slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. The reaction was quenched by slow addition of saturated sodium bicarbonate solution under ice water bath and extracted with dichloromethane (3 x 100 mL). The combined organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / pet. ether) to afford compound 17-5. 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (d, J = 1.4 Hz, 1H), 7.37-7.28 (m, 5H), 4.48 (s, 2H), 3.70-3.63 (m, 2H), 2.71-2.62 (m, 1H), 1.02 (d, J = 7.1 Hz, 3H).

[0530] Step 5: To a 500 mL single necked flask was added compound 17-5 (4.5 g, 22.47 mmol) in tetrahydrofuran (80 mL) and 10% palladium on carbon (1 g) was added. The reaction was hydrogenated at room temperature for 16 h. The reaction was monitored by TLC. The reaction was filtered directly and dried. The filtrate containing compound 17-6 was used directly for the next reaction.

[0531] Step 6: Into a 500 mL single necked flask was added the tetrahydrofuran solution of compound 17-6 from previous step, at 0 °C p-toluenesulfonyl chloride (5.19 g, 27.25 mmol) and triethylamine (4.60 g, 45.41 mmol) were added slowly, the reaction was allowed to warm to room temperature and stirred for 16 h, the reaction was monitored by LCMS for completion. The reaction was quenched with ice water, extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography [mobile phase gradient: 0% - 10% ethyl acetate / petroleum ether] to afford compound 17-7. MS m / z (ESI): 265.0 [M+H] + .

[0532] Step 7: Into a 250 mL single necked flask was added compound 17-7 (1.3 g, 4.92 mmol) and compound 1-7 (1.49 g, 4.92 mmol) dissolved in N,N-dimethylformamide (50 mL), at 0 °C N,N-diisopropylethylamine (0.64 g, 4.92 mmol) was added slowly, the reaction was allowed to warm to room temperature and stirred for 32 h, the reaction was monitored by LCMS for completion. The reaction was quenched with ice water slowly at room temperature, extracted with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography [mobile phase gradient: 0% - 50% ethyl acetate / petroleum ether] to afford compound 17-8. MS m / z (ESI): 395.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.38 (s, 1H), 6.96 (s, 1H), 6.02 (td, J = 57.1, 2.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.17 (d, J = 17.1 Hz, 2H), 2.93 (d, J = 13.4 Hz, 2H), 2.33 - 2.25 (m, 1H), 2.22 - 2.14 (m, 1H), 2.11 - 1.95 (m, 1H), 1.90 - 1.69 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).

[0533] Step 8: To a 250 mL single necked flask was added a mixture of compound 17-8 (1.4 g, 3.55 mmol) dissolved in acetonitrile (30 mL) and water (15 mL) at 0 °C, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (3.07 g, 7.10 mmol) and the reaction was allowed to stir at room temperature for 16 h. The reaction was quenched by the slow addition of saturated sodium bicarbonate solution at room temperature and the precipitated solid was filtered off. The mother liquor was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0-60% ethyl acetate / petroleum ether) to give compound 17-9. MS m / z (ESI): 367.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 6.12 (td, J = 57.1, 2.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.19 (d, J = 22.7 Hz, 2H), 2.40 - 2.33 (m, 1H), 2.29 - 2.21 (m, 3H), 2.11 - 2.02 (m, 3H), 1.86 - 1.74 (m, 4H), 1.68 (d, J = 14.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H).

[0534] Step 9: Compound 17-9 (250 mg, 0.68 mmol) was dissolved in acetonitrile (8 mL), followed by the addition of compound 3-9 (187 mg, 0.68 mmol) and 5 drops of acetic acid and the reaction was allowed to stir at room temperature overnight. Sodium borohydride (77 mg, 2.05 mmol) and methanol (4 mL) were added at 0 °C and the reaction was allowed to continue at room temperature for 1 h. The reaction was quenched by the slow addition of ice water at room temperature and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0-20% ethyl acetate / petroleum ether gradient) to give compound 17-10. MS m / z (ESI): 624.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 3.7 Hz, 1H), 6.82 (s, 1H), 6.02 (t, J = 57.1 Hz, 1H), 5.84 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.39 (d, J = 5.9 Hz, 2H), 3.20 (d, J = 19.1 Hz, 2H), 2.41 (s, 3H), 2.39 - 2.16 (m, 6H), 2.02 (s, 3H), 2.01 - 1.94 (m, 2H), 1.81 (s, 2H), 1.56 (s, 9H), 1.43 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

[0535] Step 10: Compound 17-10 (200 mg, 0.32 mmol) was dissolved in a mixture solvent of methanol (4 mL), water (4 mL) and tetrahydrofuran (4 mL), lithium hydroxide monohydrate (538 mg, 12.82 mmol) was added, and the reaction was heated to 60 °C for 2 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to about 5-7. A large amount of solid was precipitated, and the obtained solid was filtered and purified by reverse phase column [Model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 496.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.79 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 6.03 (t, J = 56.4 Hz, 1H), 5.67 - 5.60 (m, 1H), 3.44 (s, 2H), 3.20 (d, J = 18.9 Hz, 2H), 2.38 - 2.31 (m, 4H), 2.30 - 2.19 (m, 5H), 2.10 - 1.95 (m, 6H), 1.81 (s, 2H), 1.24 (s, 1H), 0.91 (d, J = 6.8 Hz, 3H). The purified product (95 mg, 0.19 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.16 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 17. MS m / z (ESI): 496.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.87 (s, 1H), 9.58 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.42 - 7.03 (m, 1H), 6.63 (s, 1H), 6.21 (t, J = 56.0 Hz, 1H), 5.70 (dd, J = 3.1, 1.9 Hz, 1H), 4.09 (d, J = 13.6 Hz, 2H), 3.45 (s, 2H), 3.16 - 3.08 (m, 1H), 2.96 - 2.87 (m, 1H), 2.73 - 2.51 (m, 6H), 2.35 (s, 3H), 2.12 (d, J = 8.4 Hz, 2H), 2.05 (s, 3H), 1.85 (s, 1H), 1.10 (d, J = 6.9 Hz, 3H).

[0536] Example 18: Preparation of compound 18

[0537] Step 1: Into a 100 mL single necked flask was placed a solution of compound 18-1 (5 g, 42.33 mmol) in dichloromethane (100 mL), to this was added 2,2,2-trichloroacetamidobenzyl chloride (11.76 g, 46.56 mmol) and trifluoromethanesulfonic acid (0.37 mL, 4.23 mmol) sequentially at 0 °C and the reaction was allowed to warm to room temperature over a period of 2 h, the reaction was monitored to be complete by LCMS. The reaction was quenched slowly at room temperature by the addition of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3 x 100 mL), the combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate in petroleum ether) to afford compound 18-2. MS m / z (ESI): 209.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.26 (m, 5H), 4.46 (s, 2H), 3.60 (s, 3H), 3.56 (dd, J = 9.2, 7.1 Hz, 1H), 3.48 (dd, J = 9.2, 5.5 Hz, 1H), 2.75 (pd, J = 7.1, 5.5 Hz, 1H), 1.08 (d, J = 7.1 Hz, 3H).

[0538] Step 2: Into a 100 mL single necked flask was placed a solution of compound 18-2 (15 g, 72.03 mmol) in tetrahydrofuran (150 mL), to this was added 1 N solution of lithium aluminium hydride (86.43 mL, 86.43 mmol) slowly at 0 °C and the reaction was allowed to proceed for 1 h at 0 °C, the reaction was monitored to be complete by TLC. The reaction was quenched slowly at 0 °C by the addition of dilute hydrochloric acid (1 M) and extracted with ethyl acetate (3 x 200 mL), the combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-30% ethyl acetate in petroleum ether) to afford compound 18-3. MS m / z (ESI): 181.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.22 (m, 5H), 4.44 (s, 2H), 4.42 (t, J = 5.3 Hz, 1H), 3.43 - 3.34 (m, 2H), 3.27 (ddd, J = 13.5, 10.0, 6.0 Hz, 2H), 1.81 (dq, J = 12.8, 6.4 Hz, 1H), 0.87 (d, J = 6.8 Hz, 3H).

[0539] Step 3: To a 500 mL single necked flask was added compound 18-3 (10 g, 55.48 mmol) in dichloromethane (200 mL) and at 0 °C, Dess-Martin periodinane (30.59 g, 72.12 mmol) was added slowly and the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. The reaction was quenched by slow addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / pet. ether gradient) to afford compound 18-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (d, J = 1.4 Hz, 1H), 7.39-7.28 (m, 5H), 4.48 (s, 2H), 3.67 (qd, J = 9.5, 5.5 Hz, 2H), 2.73-2.62 (m, 1H), 1.02 (d, J = 7.1 Hz, 3H).

[0540] Step 4: To a 500 mL single necked flask was added compound 18-4 (6.9 g, 38.71 mmol) in dichloromethane (150 mL) and at 0 °C, diethylamine sulfide (12.48 g, 77.43 mmol) was added slowly and the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. The reaction was quenched by slow addition of saturated sodium bicarbonate solution under ice water bath and extracted with dichloromethane (3 x 100 mL). The combined organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / pet. ether) to afford compound 18-5. 1 H NMR (400 MHz, DMSO-d6) δ 7.39-7.27 (m, 5H), 6.03 (td, J = 56.7, 3.9 Hz, 1H), 4.49 (s, 2H), 3.49-3.38 (m, 2H), 2.24 (ddtt, J = 20.4, 10.5, 6.6, 3.3 Hz, 1H), 0.96 (d, J = 6.9 Hz, 3H).

[0541] Step 5: To a 500 mL single necked flask was added compound 18-5 (4.5 g, 22.47 mmol) in tetrahydrofuran (80 mL) and 10% palladium on carbon (2.39 g) was added and the reaction was hydrogenated at room temperature for 16 h. The reaction was monitored by TLC. The reaction was filtered directly and dried. The filtrate containing compound 18-6 was used directly for the next reaction.

[0542] Step 6: Into a 500 mL single necked flask was added the tetrahydrofuran solution of compound 18-6 from previous step, at 0 °C was added p-toluenesulfonyl chloride (6.23 g, 32.70 mmol) and triethylamine (7.55 mL, 54.50 mmol) slowly, the reaction was stirred at room temperature for 16 h, the reaction was monitored by LCMS. The reaction was quenched by ice water, extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / pet. ether) to afford compound 18-7. MS m / z (ESI): 265.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.84 - 7.78 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 5.98 (td, J = 56.0, 3.9 Hz, 1H), 4.02 (td, J = 6.4, 5.7, 2.4 Hz, 3H), 2.43 (s, 3H), 0.91 (d, J = 7.0 Hz, 3H).

[0543] Step 7: Into a 250 mL single necked flask was added compound 18-7 (1.75 g, 6.61 mmol) and compound 1-7 (2 g, 6.61 mmol) dissolved in N,N-dimethylformamide (50 mL), at 0 °C was added N,N-diisopropylethylamine (5.76 mL, 33.07 mmol) slowly, the reaction was stirred at room temperature for 32 h, the reaction was monitored by LCMS. The reaction was quenched by ice water slowly at room temperature, extracted with ethyl acetate (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude was purified by silica gel column chromatography (mobile phase gradient: 0-50% ethyl acetate / pet. ether) to afford compound 18-8. MS m / z (ESI): 395.2 [M+H] + .

[0544] Step 8: To a 250 mL single necked flask was added a mixture of compound 18-8 (3.4 g, 8.62 mmol) dissolved in acetonitrile (30 mL) and water (15 mL) at 0 °C, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (7.45 g, 17.24 mmol) and the reaction was allowed to stir at room temperature for 16 h. The reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The solid precipitated was filtered off and the mother liquor was extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-100% ethyl acetate / petroleum ether) to give compound 18-9. MS m / z (ESI): 367.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (m, 2H), 7.58 - 7.53 (m, 2H), 6.11 (td, J = 57.2, 2.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.19 (d, J = 22.8 Hz, 2H), 2.37 (dd, J = 12.6, 7.8 Hz, 1H), 2.25 (d, J = 7.2 Hz, 2H), 2.07 (dt, J = 13.6, 4.7 Hz, 3H), 1.81 (s, 3H), 1.68 (d, J = 13.4 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).

[0545] Step 9: To a 250 mL single necked flask was added a mixture of compound 18-9 (300 mg, 0.82 mmol) dissolved in acetonitrile (8 mL) at room temperature, followed by the addition of compound 3-9 (223.77 mg, 0.82 mmol) and 5 drops of acetic acid and the reaction was allowed to stir at room temperature overnight. To this was added sodium borohydride (77 mg, 2.05 mmol) and methanol (4 mL) at 0 °C and the reaction was allowed to continue at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was quenched by slowly adding ice cold water at room temperature. The reaction was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel column chromatography (mobile phase gradient: 0-10% ethyl acetate / petroleum ether) to give compound 18-10. MS m / z (ESI): 624.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 3.7 Hz, 1H), 6.82 (s, 1H), 6.02 (td, J = 57.1, 2.8 Hz, 1H), 5.84 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 6.0 Hz, 2H), 3.20 (d, J = 18.8 Hz, 2H), 2.41 (s, 3H), 2.34 - 2.17 (m, 6H), 2.01 (d, J = 9.7 Hz, 6H), 1.81 (s, 2H), 1.56 (s, 9H), 1.44 (t, J = 6.0 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

[0546] Step 10: Compound 18-10 (220 mg, 0.35 mmol) was dissolved in a mixture solvent of methanol (4 mL), water (4 mL) and tetrahydrofuran (4 mL), lithium hydroxide (591.94 mg, 14.11 mmol) was added, and the reaction was heated to 60 °C for 2 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to about 5-7. A large amount of solid was precipitated, and the obtained solid was filtered and purified by a reverse phase column [Model: Waters-Xbridge-C18-10 μm-19x250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 496.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.79 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 6.19 - 5.88 (m, 1H), 5.64 (dd, J = 3.2, 1.9 Hz, 1H), 3.44 (s, 2H), 3.21 (d, J = 19.0 Hz, 2H), 2.34 (s, 3H), 2.38 - 2.20 (m, 6H), 2.04 (s, 3H), 2.01 (d, J = 13.1 Hz, 2H), 1.81 (s, 2H), 1.23 (s, 1H), 0.91 (d, J = 6.8 Hz, 3H). The purified product (130 mg, 0.26 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.20 mL) was added dropwise slowly under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, after ultrasonic homogenization, freeze-drying was carried out to obtain compound 18. MS m / z (ESI): 496.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.30 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.19 (td, J = 56.0, 2.8 Hz, 1H), 5.69 (dd, J = 3.1, 1.9 Hz, 1H), 4.08 (s, 2H), 3.49 (s, 2H), 3.17 - 3.09 (m, 1H), 2.97 - 2.89 (m, 1H), 2.71 (d, J = 15.0 Hz, 2H), 2.58 - 2.56 (m, 4H), 2.35 (s, 3H), 2.12 (d, J = 8.8 Hz, 2H), 2.05 (s, 3H), 1.85 (s, 1H), 1.09 (d, J = 6.9 Hz, 3H).

[0547] Example 19: Preparation of compound 19

[0548] Step 1 : Compound 18-9 (200 mg, 0.55 mmol) was dissolved in acetonitrile (8 mL), compound 7-2 (156.83 mg, 0.55 mmol) was added, stirred at room temperature overnight. Sodium borohydride (62.42 mg, 1.65 mmol) and methanol (4 mL) were added at 0 °C, the reaction was continued at room temperature for 2 hours, the reaction was monitored by LCMS. The reaction solution was slowly added into ice water at room temperature, extracted with ethyl acetate for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to obtain compound 19-1. MS m / z (ESI): 638.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.95 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 3.7 Hz, 1H), 6.84 (s, 1H), 6.18 - 5.87 (m, 1H), 5.78 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.43 (d, J = 5.8 Hz, 2H), 3.21 (d, J = 18.9 Hz, 2H), 2.42 (s, 3H), 2.36 - 2.17 (m, 8H), 1.99 (t, J = 6.8 Hz, 2H), 1.82 (s, 2H), 1.56 (s, 9H), 1.40 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

[0549] Step 2: Compound 19-1 (156 mg, 0.24 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (410.51 mg, 9.78 mmol) was added, the reaction was continued at 60 °C for 1 hour, the reaction was monitored by LCMS. The reaction solution was cooled to room temperature, diluted HCl (2.0 M) was added slowly, the pH value was adjusted to about 5-7, a large amount of solid was precipitated, the obtained solid crude product was purified by reverse phase column [Model: Waters-Xbridge-C18-10 pm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 510.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.08 (t, J = 2.8 Hz, 1H), 6.62 (s, 1H), 6.03 (t, J = 57.5 Hz, 3H), 5.59 (t, J = 2.4 Hz, 1H), 3.47 (s, 2H), 3.22 (d, J = 18.7 Hz, 3H), 2.37 - 2.20 (m, 9H), 2.01 (d, J = 13.9 Hz, 2H), 1.83 (s, 2H), 0.97 (t, J = 7.5 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). The purified product (50 mg, 0.10 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.29 mL) was added dropwise slowly under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, after ultrasonic homogenization, freeze-drying was carried out to obtain compound 19. MS m / z (ESI): 510.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.87 (s, 1H), 9.72 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 6.23 (td, J = 56.1, 2.8 Hz, 1H), 5.61 (t, J = 2.5 Hz, 1H), 4.10 (d, J = 12.0 Hz, 2H), 3.49 (s, 2H), 3.13 (dt, J = 13.5, 5.6 Hz, 1H), 2.92 (dt, J = 13.1, 5.9 Hz, 1H), 2.77 - 2.53 (m, 7H), 2.35 (d, J = 10.8 Hz, 5H), 2.20 - 2.09 (m, 2H), 1.10 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H).

[0550] Example 20: Preparation of compound 20

[0551] Step 1: To a 100 mL single necked flask was added compound 1-7 (2 g, 6.61 mmol) and (S)-(-)-3,3,3-trifluoro-1,2-epoxypropane (2.22 g, 19.84 mmol) dissolved in N,N-dimethylformamide (30 mL) at room temperature, followed by the slow addition of N,N-diisopropylethylamine (4.27 g, 33.07 mmol) and allowed to react for 16 hours at room temperature. The reaction was monitored by LCMS for completion. The reaction was quenched slowly at room temperature by the addition of ice water and extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to afford compound 20-1. MS m / z (ESI): 415.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.38 (s, 1H), 6.97 (s, 1H), 6.00 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.98 (s, 1H), 3.31 (s, 1H), 3.25 (s, 1H), 2.93 (s, 1H), 2.90 (s, 1H), 2.50 - 2.46 (m, 1H), 2.43 - 2.34 (m, 1H), 1.94 - 1.66 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0552] Step 2: Compound 20-1 (1.3 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (20 mL) and Cs2CO3 (2.04 g, 6.27 mmol) was added. The reaction was stirred at room temperature for 1 hour, then iodomethane (0.33 mL, 4.08 mmol) was added and stirring was continued at room temperature for 16 hours. The reaction was monitored by LCMS for completion. The reaction was quenched slowly at room temperature by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to afford compound 20-2. MS m / z (ESI): 429.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (m, 2H), 7.49 - 7.43 (m, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.97 - 3.86 (m, 1H), 3.49 (s, 3H), 3.29 (s, 2H), 2.99 - 2.91 (m, 2H), 2.49 - 2.38 (m, 2H), 1.91 - 1.69 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0553] Step 3: To a 100 mL single neck flask was added a mixture of compound 20-2 (850 mg, 1.98 mmol) dissolved in acetonitrile (16 mL) and water (8 mL) at room temperature, followed by the slow addition of [bis(trifluoroacetoxy)iodo]benzene (1.71 g, 3.97 mmol) and allowed to react for 2 hours at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the slow addition of saturated sodium bicarbonate solution at room temperature and the precipitated solid was filtered off. The mother liquor was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase gradient: 0% to 10% dichloromethane / methanol) to give compound 20-3. MS m / z (ESI): 401.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (m, 2H), 7.49 - 7.43 (m, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.97 - 3.86 (m, 1H), 3.49 (s, 3H), 3.29 (s, 2H), 2.99 - 2.91 (m, 2H), 2.49 - 2.38 (m, 2H), 1.91 - 1.69 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0554] Step 4: Compound 20-3 (300 mg, 0.60 mmol), compound 3-9 (164 mg, 0.60 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (68 mg, 1.80 mmol) and methanol (3 mL) were added, the reaction was continued to stir at room temperature for 1 hour, the reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~20% ethyl acetate / petroleum ether) to obtain compound 20-4. MS m / z (ESI): 658.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 3.7 Hz, 1H), 6.82 (s, 1H), 5.84 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.95 - 3.88 (m, 1H), 3.49 (s, 3H), 3.39 (d, J = 5.8 Hz, 2H), 3.30 (d, J = 4.6 Hz, 2H), 2.58 - 2.52 (m, 1H), 2.49 - 2.44 (m, 1H), 2.41 (s, 3H), 2.30 (d, J = 13.6 Hz, 2H), 2.21 (d, J = 7.4 Hz, 2H), 2.03 (s, 3H), 2.00 (s, 1H), 1.97 (d, J = 4.1 Hz, 1H), 1.84 - 1.74 (m, 2H), 1.56 (s, 9H), 1.49 - 1.43 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H).

[0555] Step 5: Compound 20-4 (200 mg, 0.30 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL) and water (4 mL), lithium hydroxide monohydrate (510 mg, 12.16 mmol) was added, the reaction was stirred at 60 °C for 2 hours, the reaction was monitored by LCMS. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M hydrochloric acid, a large amount of solid was precipitated, the obtained solid crude product was purified by reversed phase column [Model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 530.2 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.80 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.64 (t, J = 2.5 Hz, 1H), 3.92 (s, 1H), 3.50 (s, 3H), 3.44 (s, 2H), 3.29 (s, 2H), 2.56 (d, J = 13.8 Hz, 2H), 2.35 - 2.23 (m, 7H), 2.04 (s, 3H), 1.99 (s, 2H), 1.81 (s, 2H). The purified product (115 mg, 0.22 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.15 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 20. MS m / z (ESI): 530.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.44 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.70 (t, J = 2.5 Hz, 1H), 4.89 (t, J = 7.8 Hz, 1H), 4.17 (s, 2H), 3.61 (s, 3H), 3.47 (d, J = 8.8 Hz, 2H), 3.37 (s, 1H), 3.23 - 3.16 (m, 1H), 2.75 - 2.52 (m, 6H), 2.35 (s, 3H), 2.22 - 2.09 (m, 2H), 2.05 (s, 3H).

[0556] Example 21: Preparation of compound 21

[0557] Step 1 : Compound 1-7 (1.00 g, 3.31 mmol) was dissolved in ethanol (20 mL) at room temperature, R-(+)-2-trifluoromethyl oxirane (1.11 g, 9.92 mmol) and N,N- diisopropylethylamine (2.14 g, 16.54 mmol) were added, and the reaction was allowed to proceed at room temperature for 16 hours, which was monitored by LCMS. The reaction was quenched by slowly adding ice water at room temperature, extracted with dichloromethane three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude was purified by silica gel chromatography column (mobile phase gradient: 0% - 10% dichloromethane / methanol) to give compound 21-1. MS m / z (ESI): 415.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.82 (m, 2H), 7.53 - 7.43 (m, 2H), 6.97 (s, 1H), 6.00 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.18 - 3.85 (m, 2H), 3.25 (s, 2H), 2.97 - 2.90 (m, 2H), 2.48 - 2.46 (m, 1H), 2.38 (dd, J = 13.3, 7.9 Hz, 1H), 1.99 - 1.65 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0558] Step 2: Compound 21-1 (1000 mg, 2.41 mmol) was dissolved in DMF (20 mL) at room temperature, cesium carbonate (1179.28 mg, 3.62 mmol) and iodomethane (0.39 mL, 4.83 mmol) were added successively under stirring, and the stirring was continued overnight, which was monitored by LCMS. The reaction was quenched by slowly adding saturated ammonium chloride solution at room temperature, extracted with ethyl acetate three times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude was purified by silica gel chromatography column (mobile phase gradient: 0% - 10% dichloromethane / methanol) to give compound 21-2. MS m / z (ESI): 429.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.40 (s, 1H), 6.98 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.92 (td, J = 7.6, 3.4 Hz, 1H), 3.49 (s, 3H), 3.33 (s, 3H), 3.00 - 2.90 (m, 2H), 2.43 (dd, J = 13.5, 7.9 Hz, 1H), 1.93 - 1.67 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).

[0559] Step 3: Compound 21-2 (500 mg, 1.16 mmol) was dissolved in a mixture of acetonitrile (5 mL) and water (5 mL) at room temperature, then [bis(trifluoroacetoxy)iodo]benzene (1.0 g, 5.79 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction was complete by LCMS detection. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, and the precipitated solid was filtered off. The mother liquor was extracted with dichloromethane three times (3 x 50 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by a silica gel column (mobile phase gradient: 0% - 50% ethyl acetate / petroleum ether) to obtain compound 21-3. MS m / z (ESI): 401.2 [M+H] + .

[0560] Step 4: Compound 21-3 (300 mg, 0.75 mmol) was dissolved in acetonitrile (3 mL) at room temperature, and compound 3-9 (204.77 mg, 0.75 mmol) and 3 drops of acetic acid were added in turn. The reaction was stirred overnight. Then sodium borohydride (85.12 mg, 2.25 mmol) and methanol (3 mL) were added, and the reaction was continued to stir at room temperature for 1 hour. The reaction was complete by LCMS detection. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, and extracted with ethyl acetate three times (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by a silica gel column (mobile phase gradient: 0% - 20% ethyl acetate / petroleum ether) to obtain compound 21-4. MS m / z (ESI): 658.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 3.7 Hz, 1H), 6.82 (s, 1H), 5.85 (d, J = 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.97 - 3.84 (m, 1H), 3.49 (s, 3H), 3.40 (d, J = 5.6 Hz, 2H), 3.29 (s, 2H), 2.5 (s, 3H), 2.41 (s, 3H), 2.30 (d, J = 14.4 Hz, 3H), 2.21 (d, J = 7.5 Hz, 2H), 2.03 (s, 3H), 1.81 (s, 2H), 1.56 (s, 9H), 1.47 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H).

[0561] Step 5: Compound 21-4 (250 mg, 0.38 mmol) was dissolved in a mixture solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), lithium hydroxide (638 mg, 15.2 mmol) was added, and the reaction was heated to 60 °C for 1 hour. The reaction was monitored by LCMS. When the reaction was completed, the reaction was cooled to room temperature, and the pH was adjusted to 5-7 using 2M hydrochloric acid. A large amount of solid was precipitated, and the solid was filtered and purified by reverse phase column [type: Waters-Xbridge-C18-10 pm-19x250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m / z (ESI): 530.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.80 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.73 - 5.57 (m, 1H), 3.92 (s, 1H), 3.49 (s, 3H), 3.44 (s, 2H), 3.30 (s, 1H), 2.54 (s, 2H), 2.45 (s, 1H), 2.34 (s, 3H), 2.30 - 2.22 (m, 3H), 2.04 (s, 2H), 1.99 (s, 2H), 1.81 (s, 2H). The purified product (100 mg, 0.19 mmol) was dissolved in methanol (3 mL), 4N hydrochloric acid-methanol solution (0.14 mL) was added slowly dropwise under stirring, after stirring for 5 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 21. MS m / z (ESI): 530.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.70 (d, J = 2.8 Hz, 1H), 5.06 - 4.76 (m, 1H), 4.17 (s, 2H), 3.61 (s, 3H), 3.51 - 3.41 (m, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.20 (s, 1H), 2.71 (d, J = 14.0 Hz, 3H), 2.65 - 2.53 (m, 3H), 2.35 (s, 3H), 2.16 (d, J = 35.2 Hz, 2H), 2.05 (s, 3H), 1.85 (s, 1H).

[0562] Example 22: Preparation of compound 22

[0563] Step 1: Compound 20-3 (200 mg, 0.50 mmol) and compound 1-14 (145 mg, 0.50 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, and the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (57 mg, 1.50 mmol) and methanol (3 mL) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, and extracted with ethyl acetate three times (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 15% ethyl acetate / petroleum ether) to obtain compound 22-1. MS m / z (ESI): 674.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 4.4 Hz, 2H), 7.54 (s, 1H), 6.76 (s, 1H), 6.18 (d, J = 3.9 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.96 - 3.88 (m, 1H), 3.67 (s, 3H), 3.50 (s, 3H), 3.36 (d, J = 6.5 Hz, 2H), 3.29 (s, 2H), 2.57 - 2.52 (m, 1H), 2.48 (s, 3H), 2.26 - 2.13 (m, 4H), 2.03 - 1.95 (m, 2H), 1.77 - 1.66 (m, 3H), 1.57 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H).

[0564] Step 2: Compound 22-1 (180 mg, 0.27 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL), and lithium hydroxide (256 mg, 10.69 mmol) was added. The reaction was stirred at 60 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M hydrochloric acid, and a large amount of solid precipitated. The obtained solid crude product was purified by reverse phase column chromatography [Model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% to 95%)] to obtain the purified product. MS m / z (ESI): 546.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.81 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.21 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.91 (dd, J = 3.1, 1.9 Hz, 1H), 3.93 (s, 1H), 3.61 (s, 3H), 3.51 (s, 3H), 3.41 (s, 2H), 3.29 (s, 2H), 2.59 - 2.51 (m, 2H), 2.40 (s, 3H), 2.27 - 2.19 (m, 4H), 2.05 - 1.98 (m, 2H), 1.80 - 1.72 (m, 2H). The purified product (91.7 mg, 0.17 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.13 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 22. MS m / z (ESI): 546.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.86 (s, 1H), 10.26 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 2.8 Hz, 1H), 6.66 (s, 1H), 5.91 (dd, J = 3.1, 1.9 Hz, 1H), 4.86 (s, 1H), 4.15 (s, 2H), 3.64 (s, 3H), 3.61 (s, 3H), 3.42 (d, J = 9.2 Hz, 2H), 2.71 - 2.52 (m, 6H), 2.41 (s, 3H), 2.21 - 1.92 (m, 4H).

[0565] Example 23: Preparation of compound 23

[0566] Step 1: Compound 20-3 (130 mg, 0.32 mmol) and compound 10-1 (98 mg, 0.32 mmol) were dissolved in acetonitrile (5 mL), 4 drops of acetic acid were added, and the reaction was stirred at room temperature for 16 hours. Then sodium borohydride (37 mg, 0.97 mmol) and methanol (3 mL) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, and extracted with ethyl acetate three times (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 15% ethyl acetate / petroleum ether) to obtain compound 23-1. MS m / z (ESI): 684.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 3.7 Hz, 1H), 6.56 (s, 1H), 5.99 (d, J = 3.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.96 - 3.88 (m, 1H), 3.58 (d, J = 5.8 Hz, 2H), 3.49 (s, 3H), 3.29 (s, 2H), 2.40 (s, 3H), 2.33 (d, J = 13.5 Hz, 2H), 2.21 (d, J = 7.5 Hz, 2H), 2.00 (d, J = 13.2 Hz, 2H), 1.80 (s, 2H), 1.56 (s, 9H), 1.49 (t, J = 5.5 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.27 - 1.21 (m, 1H), 0.61 - 0.54 (m, 2H), 0.51 - 0.45 (m, 2H).

[0567] Step 2: Compound 23-1 (130 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide (182 mg, 7.60 mmol) was added. The reaction was stirred at 60 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was cooled to room temperature, the pH was adjusted to 5-7 using 2M hydrochloric acid, and a large amount of solid was precipitated. The obtained solid crude product was purified by reverse phase column chromatography [Model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% - 95%)] to obtain the purified product. MS m / z (ESI): 556.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.81 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.38 (s, 1H), 5.80 (dd, J = 3.1, 1.9 Hz, 1H), 3.96 - 3.88 (m, 1H), 3.62 (s, 2H), 3.49 (s, 3H), 3.28 (s, 2H), 2.59 - 2.52 (m, 2H), 2.36 - 2.31 (m, 5H), 2.26 (d, J = 7.4 Hz, 2H), 2.02 (d, J = 13.7 Hz, 2H), 1.80 (s, 2H), 1.57 - 49 (m, 1H), 0.58 - 0.52 (m, 2H), 0.44 - 0.39 (m, 2H). The purified product (47.1 mg, 0.08 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid-methanol solution (0.06 mL) was added slowly dropwise under stirring, after stirring for 10 min, methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, freeze-drying was carried out to obtain compound 23. MS m / z (ESI): 556.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.33 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 2.8 Hz, 1H), 6.41 (s, 1H), 5.85 (t, J = 2.5 Hz, 1H), 4.91 - 4.83 (m, 1H), 4.18 (d, J = 6.9 Hz, 2H), 3.61 (s, 5H), 3.38 - 3.31 (m, 1H), 3.25 - 3.15 (m, 1H), 2.79 - 2.56 (m, 5H), 2.34 (s, 3H), 2.14 (d, J = 25.0 Hz, 2H), 1.87 (s, 1H), 1.59 - 1.50 (m, 1H), 0.61 - 0.52 (m, 2H), 0.49 - 0.38 (m, 2H).

[0568] Example 24: Preparation of compound 24

[0569] Step 1: Compound 24-1 (25 g, 138.73 mmol) was dissolved in ethyl acetate (400 mL) under nitrogen protection, and silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol) and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis-tetrafluoroborate (73.72 g, 208.10 mmol) were added, stirred for 10 minutes, then 2-fluoropyridine (35.82 mL, 416.20 mmol) and (trifluoromethyl)trimethylsilane (61.52 mL, 416.20 mmol) were added, the reaction solution was stirred at room temperature overnight in the dark, and the reaction completion was monitored by TLC. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-3% ethyl acetate / petroleum ether) to obtain compound 24-2. 1 H NMR (400 MHz, Chloroform-d) δ 7.37-7.22 (m, 5H), 5.15 (s, 2H), 4.64-4.69 (m, 1H), 1.50 (d, J = 6.9 Hz, 3H).

[0570] Step 2: Compound 24-2 (9.0 g, 36.26 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium aluminum hydride (2.06 g, 54.39 mmol) was added portionwise at 0°C, the reaction solution was first stirred at 0°C for 0.5 hours, then the reaction was carried out at room temperature overnight, and the reaction completion was detected by TLC. The reaction solution was quenched by slowly adding dilute HCl (1M) under ice water bath, extracted with dichloromethane 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 24-3.

[0571] Step 3: Compound 24-3 (5 g) was dissolved in dichloromethane (60 mL), triethylamine (7.02 g, 69.40 mmol) was added, and trifluoromethanesulfonic anhydride (9.79 g, 34.70 mmol) was added at 0°C, and the reaction was carried out at room temperature overnight. The reaction completion was monitored by TLC, the reaction solution was quenched by adding ice water, extracted with dichloromethane 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 24-4.

[0572] Step 4: Compound 24-4 (9 g) was dissolved in N,N-dimethylformamide (30 mL), compound 1-7 (990 mg, 3.26 mmol), N,N-diisopropyl ethylamine (2.93 mL, 16.30 mmol) were added, the reaction was stirred at room temperature overnight, the reaction was monitored by LCMS. The reaction was quenched with water at room temperature, extracted with dichloromethane for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column [Model: Boston ODS 120 g Flash; mobile phase gradient: Water (NH4HCO3 (0.1%)) / CAN = 27% ~ 57%] to obtain compound 24-5. MS m / z (ESI): = 429.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.89 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 4.32 - 4.27 (m, 2H), 3.49 - 3.47 (m, 1H), 3.24 - 3.19 (m, 2H), 2.22 - 1.71 (m, 6H), 1.70 - 1.48 (m, 2H), 1.33 - 1.27 (m, 5H), 1.18 - 1.13 (m, 3H).

[0573] Step 5: Compound 24-5 (130 mg, 0.30 mmol) was dissolved in acetonitrile (2 mL) and water (1 mL) mixed solvent, compound [bis(trifluoroacetoxy)iodo]benzene (262.19 mg, 0.61 mmol) was added, the reaction was stirred at room temperature for 2 hours, the reaction was monitored by LCMS. The reaction was quenched with saturated sodium bicarbonate solution at room temperature, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column (mobile phase gradient: 0% - 100% ethyl acetate / petroleum ether) to obtain compound 24-6. MS m / z (ESI): 401.2 [M+H] + .

[0574] Step 6: Compound 24-6 (200 mg, 0.50 mmol) was dissolved in acetonitrile (5 mL), compound 5-3 (86.51 mg, 0.50 mmol) and 5 drops of acetic acid were added, and the reaction was stirred at room temperature overnight. Then sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by slowly adding saturated sodium bicarbonate solution at room temperature, and extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 100% ethyl acetate / petroleum ether) to obtain compound 24-7. MS m / z (ESI): 558.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.79 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.63 (dd, J = 3.1, 1.9 Hz, 1H), 4.43 (q, J = 6.1 Hz, 2H), 3.44-3.42 (m, 3H), 3.23 (s, 2H), 2.41 (dd, J = 13.6, 5.2 Hz, 2H), 2.34 (s, 3H), 2.26 (t, J = 12.6 Hz, 4H), 2.04 (s, 3H), 1.99 (d, J = 13.3 Hz, 2H), 1.79 (s, 2H), 1.28 (d, J = 6.2 Hz, 3H).

[0575] Step 7: Compound 24-7 (190 mg, 0.34 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide (71.5 mg, 1.7 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was directly purified by a reverse phase column [Model: Waters-Xbridge-C18-10 μm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0% to 95%)] to obtain the purified product. MS m / z (ESI): 530.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.79 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.63 (dd, J = 3.1, 1.9 Hz, 1H), 4.43 (q, J = 6.1 Hz, 1H), 3.44 (s, 2H), 3.23 (s, 2H), 2.41 (dd, J = 13.6, 5.2 Hz, 2H), 2.34 (s, 3H), 2.26 (t, J = 12.6 Hz, 4H), 2.04 (s, 3H), 1.99 (d, J = 13.3 Hz, 2H), 1.79 (s, 2H), 1.28 (d, J = 6.2 Hz, 3H). The purified product (70 mg, 0.132 mmol) was dissolved in methanol (5 mL), 4N methanolic hydrochloric acid (99.1 μί) was added, after stirring for 10 min, the methanol was evaporated at room temperature, then 5 mL of deionized water was added, and after ultrasonic homogenization, it was freeze-dried to obtain compound 24. MS m / z (ESI): 530.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.47 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.13 (t, J = 4.0 Hz, 1H), 6.63 (s, 1H), 5.68-5.67 (m, 1H), 5.13 (s, 1H), 4.10 (d, J = 8.0 Hz, 2H), 3.44 (s, 2H), 2.75-2.51 (m, 4H), 2.40 (s, 5H), 2.35-2.04 (m, 3H), 2.01 (s, 3H), 1.82 (s, 1H), 1.38 (d, J = 6.2 Hz, 3H).

[0576] Example 25: Preparation of compound 25

[0577] Step 1 : Compound 25-1 (25 g, 138.73 mmol) was dissolved in ethyl acetate (400 mL) under nitrogen protection, silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol) and 1 -chloromethyl-4-fluoro- 1,4-diazidobicyclo[2.2.2]octane bis-tetrafluoroborate (73.72 g, 208.10 mmol) were added, stirred for 10 minutes, then 2-fluoropyridine (40.41 g, 416.20 mmol) and (trifluoromethyl)trimethylsilane (59.18 g, 416.20 mmol) were added in turn, then the reaction was stirred at room temperature overnight in the dark, the completion of the reaction was monitored by TLC. The reaction was filtered, the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-3% ethyl acetate / petroleum ether) to obtain compound 25-2. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.34 (m, 5H), 5.23 (s, 2H), 5.18 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H).

[0578] Step 2: Compound 25-2 (19.2 g, 77.36 mmol) was dissolved in tetrahydrofuran (200 mL), lithium aluminum hydride (4.40 g, 116.04 mmol) was added at 0 °C, the reaction was stirred at 0 °C for half an hour, then the temperature was raised to room temperature and reacted overnight, the completion of the reaction was detected by TLC. The reaction was quenched by slowly adding dilute HC1 (1 M) under ice water bath, extracted with dichloromethane for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 25-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.34 (m, 5H), 5.23 (s, 2H), 5.18 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H).

[0579] Step 3: Compound 25-3 (9 g) was dissolved in dichloromethane (100 mL), triethylamine (12.64 g, 124.92 mmol) was added, trifluoromethanesulfonic anhydride (17.62 g, 62.46 mmol) was added at 0 °C, the temperature was recovered to room temperature and reacted overnight, the completion of the reaction was monitored by TLC. The reaction was quenched by adding ice water, extracted with dichloromethane for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 25-4.

[0580] Step 4: Compound 25-4 (17 g) was dissolved in N,N-dimethylformamide (40 mL), then compound 1-7 (1.24 g, 4.10 mmol) and N,N-diisopropyl ethylamine (2.65 g, 20.52 mmol) were added successively, the reaction was stirred at room temperature overnight, the reaction completion was monitored by LCMS. The reaction solution was quenched with ice water at room temperature, extracted with dichloromethane for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by reversed-phase preparation [Model: Boston ODS 120 g Flash; mobile phase gradient: Water (NH4HCO3 (0.1%)) / CAN = 27% ~ 57%] to obtain compound 25-5. MS m / z (ESI): 429.2 [M+H] + .

[0581] Step 5: Compound 25-5 (550 mg, 1.28 mmol) was dissolved in a mixed solvent of acetonitrile (10 mL) and water (5 mL), then compound [bis(trifluoroacetoxy)iodo]benzene (1109.27 mg, 2.57 mmol) was added, the reaction was carried out at room temperature for 2 hours, the reaction completion was monitored by LCMS. The reaction solution was quenched with saturated sodium bicarbonate solution at room temperature, the precipitated solid was filtered off, the mother liquor was extracted with dichloromethane for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column (mobile phase gradient: 0% ~ 100% ethyl acetate / petroleum ether) to obtain compound 25-6. MS m / z (ESI): 401.2 [M+H] + .

[0582] Step 6: Compound 25-6 (120 mg, 0.30 mmol) was dissolved in acetonitrile (3 mL), compound 5-3 (51.91 mg, 0.30 mmol) and 2 drops of acetic acid were added, the reaction was stirred at room temperature overnight. Then sodium borohydride (34.05 mg, 0.90 mmol) and methanol (1 mL) were added, the reaction was continued for 2 hours, the reaction completion was monitored by LCMS. The reaction solution was quenched with saturated sodium bicarbonate solution at room temperature, extracted with dichloromethane for 3 times (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column (mobile phase gradient: 0% ~ 100% ethyl acetate / petroleum ether) to obtain compound 25-7. MS m / z (ESI): 558.4 [M+H] + .

[0583] Step 7: Compound 25-7 (30 mg, 0.05 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), lithium hydroxide (11.29 mg, 0.27 mmol) was added, the reaction was stirred at room temperature overnight, the reaction was monitored by LCMS. The reaction was directly purified by reverse phase preparation [Model: Boston ODS 120 g Flash; mobile phase gradient: Water (NH4HCO3 (0.1%)) / CAN = 27% ~ 57%] to obtain the purified product. MS m / z (ESI): 530.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.70-5.63 (m, 1H), 4.45-4.41 (m, 1H), 3.44 (s, 2H), 3.23 (s, 2H), 2.43-2.38 (m, 2H), 2.34 (s, 3H), 2.25-2.23 (m, 4H), 2.06 (s, 3H), 2.04-1.97 (m, 2H), 1.81-1.76 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H). The purified product (15 mg, 0.03 mmol) was dissolved in methanol (2 mL), 4N hydrochloric acid methanol solution (21 μL) was added, methanol was removed at room temperature after stirring for 10 min, then 5 mL of deionized water was added, ultrasonic was uniform, then freeze-drying to obtain compound 25. MS m / z (ESI): 530.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.60 (s, 1H), 5.70-5.63 (m, 1H), 4.45-4.41 (m, 1H), 3.44 (s, 2H), 3.23 (s, 2H), 2.43-2.38 (m, 2H), 2.34 (s, 3H), 2.25-2.23 (m, 4H), 2.06 (s, 3H), 2.04-1.97 (m, 2H), 1.81-1.76 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H). The purified product (15 mg, 0.03 mmol) was dissolved in methanol (2 mL), 4N hydrochloric acid methanol solution (21 μL) was added, methanol was removed at room temperature after stirring for 10 min, then 5 mL of deionized water was added, ultrasonic was uniform, then freeze-drying to obtain compound 25. MS m / z (ESI): 530.3 [M+H]

[0584] Example 50: Preparation of compound 50

[0585] Step 1 : Compound 1-14 (5 g, 17.28 mmol) was dissolved in a mixture solvent of tetrahydrofuran (10 mL), methanol (10 mL) and water (10 mL), lithium hydroxide (14.5 g, 345.6 mmol) was added, the reaction was heated to 60 °C and stirred for 3 hours, the reaction was monitored by LCMS. The reaction was quenched by adding water, extracted with ethyl acetate for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~100% ethyl acetate / petroleum ether) to obtain compound 50-2. MS m / z (ESI): 190.0 [M+H] + .

[0586] Step 2: Compound 24-6 (80 mg, 0.20 mmol) was dissolved in acetonitrile (3 mL), compound 50-2 (115.42 mg, 0.61 mmol) and 2 drops of acetic acid were added, and stirred at room temperature overnight. Then sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the reaction was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane for 3 times (3 x 40 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0%~100% ethyl acetate / petroleum ether) to obtain compound 50-3. MS m / z (ESI): 574.3 [M+H] + .

[0587] Step 3: Compound 50-3 (65 mg, 0.11 mmol) was dissolved in a mixture solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), lithium hydroxide (13.57 mg, 0.57 mmol) was added, the reaction was stirred at room temperature overnight, the reaction was monitored by LCMS. The reaction was purified by reversed phase preparation [model: Boston ODS 120 g Flash; mobile phase gradient: Water(NH4HCO3(0.1%)) / CAN = 27%~57%] to obtain the purified product. MS m / z (ESI): 546.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.90 (s, 1H), 4.47 - 4.39 (m, 1H), 3.61 (s, 3H), 3.41 (s, 2H), 3.25 - 3.21 (m, 2H), 2.42 - 2.39 (m, 5H), 2.21 - 2.18 (m, 4H), 2.01 - 1.98 (m, 2H), 1.77 - 1.71 (m, 2H), 1.29 (d, J = 6.2 Hz, 3H). The purified product (19 mg, 0.03 mmol) was dissolved in methanol (2 mL), and methanolic hydrochloric acid solution (26.1 μL) was added. After stirring for 10 min, the methanol was evaporated at room temperature, and then 5 mL of deionized water was added. After ultrasonic homogenization, the compound 50 was obtained by lyophilization. MS m / z (ESI): 546.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.86 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.22 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 5.93 - 5.85 (m, 1H), 5.25 - 5.06 (m, 1H), 4.15 - 4.02 (m, 2H), 3.63 (s, 3H), 3.45 - 3.38 (m, 2H), 2.76 - 2.52 (m, 6H), 2.41 (s, 3H), 2.17 - 1.87 (m, 4H), 1.38 (d, J = 6.1 Hz, 3H).

[0588] Example 51: Preparation of compound 51

[0589] Step 1: Compound 1-14 (10 g, 34.56 mmol), sodium dihydrogen phosphate (20.04 g, 167.02 mmol) were added into a mixture solvent of acetonitrile (50 mL) and water (50 mL), hydrogen peroxide (16.76 mL, 167.02 mmol, 30%) was added slowly at 0 °C, stirred for 15 min, then sodium chlorite (9.67 g, 106.89 mmol) was added slowly at 0 °C, the reaction was completed by monitoring LCMS after the addition was completed, the reaction solution was quenched by water, extracted with ethyl acetate for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate), to give compound 51-1 (6 g, 19.65 mmol, 56.86%) as a white solid. MS m / z (ESI): 306.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.68 (d, J = 3.6 Hz, 2H), 6.95 (s, 1H), 6.79 (d, J = 3.6 Hz, 2H), 3.85 (s, 3H), 2.5 (s, 3H), 1.59 (s, 9H).

[0590] Step 2: Compound 51-1 (5.00 g, 16.38 mmol) and potassium carbonate (6.79 g, 49.13 mmol) were dissolved in N,N-dimethylformamide (80 mL), iodomethane (4.65 g, 32.75 mmol) was added dropwise at room temperature, stirred for 3 hours, the reaction was completed by monitoring LCMS and TLC. Quench by ice water (100 mL), extracted with ethyl acetate for 3 times (3 x 100 mL), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 20% ethyl acetate / petroleum ether), to give compound 51-2. MS m / z (ESI): 320.2 [M+H] + .

[0591] Step 3: Compound 51-2 (5.20 g, 16.28 mmol) was dissolved in methanol (120 mL), sodium borodeuteride (1.37 g, 32.57 mmol) was added slowly at 0 °C, stirred for 4 hours at 20 °C, the reaction was completed by monitoring LCMS and TLC. Sodium sulfate decahydrate was added at 0 °C, stirred for 2 hours, filtered, dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0% to 50% ethyl acetate / petroleum ether), to give compound 51-3. MS m / z (ESI): 194.2 [M+H] +.

[0592] Step 4: Compound 51-3 (3.00 g, 15.52 mmol) was dissolved in dichloromethane (120 mL) at room temperature, manganese dioxide (1.48 g, 17.08 mmol) was added, and the reaction was stirred at 50 °C for 24 h. The reaction was monitored by LCMS and TLC. The reaction was filtered and dried, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (mobile phase gradient: 0-50% ethyl acetate / petroleum ether) to give compound 51-4. MS m / z (ESI): 191.2 [M+H] + .

[0593] Step 5: Compound 129-6 (224 mg, 0.60 mmol), compound 51-4 (115 mg, 0.60 mmol), and acetic acid (40 mg, 0.60 mmol) were dissolved in methanol (8 mL). After stirring at 25 °C for 16 h, sodium borohydride (127 mg, 3.02 mmol) was added slowly at 0 °C, and the reaction was stirred at 25 °C for another 2 h. The reaction was monitored by LCMS. The reaction was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (mobile phase gradient: 0-40% ethyl acetate / petroleum ether) to give compound 51-5. MS m / z (ESI): 546.4 [M+H] + .

[0594] Step 6: Compound 51-5 (270 mg, 0.49 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (104 mg, 2.47 mmol) was added. The reaction was stirred at 60 °C for 18 h. The reaction was monitored by LCMS. The reaction was adjusted to neutral pH with dilute HCl (2N) and then concentrated under reduced pressure. The resulting crude product was directly purified by reverse phase column [Model: Waters-Xbridge-C18-10 µm-19 x 250 mm; mobile phase gradient: (A: 10 mM NH4HCO3 / H2O; B: ACN; gradient: B%: 0-95%)] and lyophilized to give compound 51. MS m / z (ESI): 518.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.20 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.90 (dd, J = 3.1, 1.9 Hz, 1H), 3.61 (s, 3H), 3.53 - 3.39 (m, 2H), 3.18 - 3.07 (m, 1H), 2.40 (s, 3H), 2.33 - 2.17 (m, 4H), 2.06 - 1.95 (m, 2H), 1.85 - 1.69 (m, 1H), 1.66 - 1.52 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H).

[0595] Example 52: Preparation of compound 52

[0596] Step 1: Compound 1-7 (500 mg, 1.65 mmol) and 2,2-difluoropropyl 4-methylbenzenesulfonate (477 mg, 4.96 mmol) were dissolved in dimethyl sulfoxide (5 mL), N,N-diisopropylethylamine (641 mg, 4.96 mmol) and sodium iodide (25 mg, 0.17 mmol) were added respectively, stirred at 130 °C under nitrogen atmosphere for 18 hours, the reaction was monitored by LCMS. Ice water (50 mL) was added to the reaction solution, extracted with ethyl acetate f...

Claims

Compounds of formula (I): Or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts. in: R 1 Each is independently selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -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-CN or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from hydrogen, deuterium, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; Indicates a single or double bond; The condition is that the compound is not According to claim 1, a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -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-CN or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from hydrogen, deuterium, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to claim 1 or 2, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from deuterium, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy or 4-7 membered heterocyclic groups; R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -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-CN or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from hydrogen, deuterium, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to any one of claims 1-3, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 3 Selected from deuterium, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl or -C 1-6 Alkylene-CN; R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from hydrogen, deuterium, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to any one of claims 1-4, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -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-CN or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from C. 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from hydrogen, deuterium, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl groups, -S(C 1-6 alkyl), -NH(C) 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3-10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to any one of claims 1-5, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -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-CN or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from deuterium or -S(C 1-6 Alkyl); the -S(C) 1-6 Alkyl groups are optionally selected from deuterium, halogens, OH, CN, NH2, SF5, C by 1, 2, 3, 4, 5, 6 or more. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to any one of claims 1-6, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from deuterium and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from deuterium, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 deuterated alkyl), -N(C) 1-6 (deuterated alkyl)2, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy or 4-7 membered heterocyclic groups; R 3 Selected from deuterium, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl or -C 1-6 Alkylene-CN; R 3a and R 3b Each time it appears, it is independently selected from C. 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 4 Selected from deuterium or -S(C 1-6 alkyl), the -S(C 1-6 Alkyl groups are optionally selected from deuterium, halogens, OH, CN, NH2, SF5, C by 1, 2, 3, 4, 5, 6 or more. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from either hydrogen or deuterium; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound of formula (I) according to any one of claims 1-7, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in: R 1 Each is independently selected from halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2; R 2 Selected from hydrogen, halogens, OH, SH, CN, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 3-6 cycloalkyl; R 3 Selected from hydrogen, halogen, OH, SH, CN, -NR 3a R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -S(C 1-6 Alkyl), C 3-6 cycloalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 alkylene -OH or -C 1-6 Alkylene-NR 3a R 3b ; R 3a and R 3b Each time it appears, it is independently selected from H or C. 1-6 alkyl; R 4 Selected from hydrogen, halogens, OH, CN, SH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3- 10 cycloalkyl or -C 1-6 alkylene-3-12-membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, -C 1-6 Alkylene-C 3- 10 cycloalkyl or -C 1-6 The alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6 or more groups selected from deuterium, halogen, OH, CN, NH2, SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1- 6-alkyl), -S(C 1-6 Halogenated alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl)2、-S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(C 1-6 Halogenated alkyl groups), -S(=O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 cycloalkyl), -O(C 3-6 Halogenated cycloalkyl), -S(C 3-6 cycloalkyl) or -S(C 3-6 Substituents of halogenated cycloalkyl groups; R g R h Each is independently selected from hydrogen or deuterium; preferably, R g R h All are hydrogen; n is selected from 0, 1, 2, 3 or 4; It indicates a single or double bond. The compound according to any one of claims 1-8, wherein the compound is not: The compound according to any one of claims 1-9, wherein the compound of formula (I) has the structure shown in formula (I-1) or (I-2): Preferably, it has the structure shown in (I-3) or (I-4): The compound according to any one of claims 1-10, wherein: n is selected from 0, 1, or 2; Preferably, n is selected from 0 or 1; Preferably, n is 0. The compound according to any one of claims 1-11, wherein the compound has a structure shown in one of formulas (II-1)-(II-6): Preferred Preferably, it has a structure shown in one of formulas (II-7)-(II-18): Preferred More preferably, it has a structure shown in one of formulas (II-19)-(II-30): Preferred The compound according to any one of claims 1-12, wherein: R 1 Selected from deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 Halogenated alkyl), -N(C) 1-4 (halogenated alkyl)2, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -NH(C 1-4 deuterated alkyl), -N(C) 1-4 (deuterated alkyl)2, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; Preferably, R 1 Selected from halogen or C 1-4 alkyl; Preferably, R 1 Selected from F, Cl or methyl. The compound according to any one of claims 1-13, wherein: R 2 Selected from hydrogen, deuterium, halogens, OH, SH, CN, NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 Halogenated alkyl), -N(C) 1-4 (halogenated alkyl)2, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -NH(C 1-4 deuterated alkyl), -N(C) 1-4 (deuterated alkyl)2, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; Preferably, R 2 Selected from hydrogen, halogen or C 1-4 alkyl; Preferably, R 2 Selected from hydrogen or halogen; Preferably, R 2 Selected from hydrogen, F, or Cl; Preferably, R 2 It is hydrogen. The compound according to any one of claims 1-14, wherein: R 3 Selected from hydrogen, deuterium, halogens, OH, SH, CN, -NR 3a R 3b C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy group, -S(C 1-4 Alkyl), C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1- 4-alkylene-OH, -C 1-4 Alkylene-CN or -C 1-4 Alkylene-NR 3a R 3b ; and / or R 3a and R 3b Each time it appears, it is independently selected from H and C. 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Deuterated alkyl groups; Preferably, R 3 Selected from halogens, CN, C 1-4 Alkyl, -S(C) 1-4 Alkyl), -NR 3a R 3b C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or -C 1-4 Alkylene-OC 1-4 Alkyl; and / or R 3a and R 3b Each time it appears, it is independently selected from H or C. 1-4 alkyl; Preferably, R 3 Selected from F, Cl, CN, C 1-4 Alkyl, -S(C) 1-4 Alkyl), -NR 3a R 3b C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or -C 1-4 Alkylene-OC 1-4 Alkyl groups; and / or R 3a and R 3b Each time it appears, it is independently selected from H or C. 1-4 Alkyl; preferably R 3a and R 3b One of them is H, and the other is C. 1-4 alkyl; Preferably, R 3 Selected from CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl; Preferably, R 3 C 1-4 alkyl; Preferably, R 3 Selected from CN, C 1-4 Alkyl, -S(C) 1-4 Alkyl), C 1-4 Alkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; Preferably, R 3 Selected from F, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, -NHCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OCH3, cyclopropyl, cyclobutyl, oxacyclobutyl (e.g.) ), thioheterobutyl (e.g.) ) or nitrogen-containing heterocyclic butyl (e.g. )； Preferably, R 3 Selected from CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, cyclobutyl, oxacyclobutyl, -OCH3, cyclopropyl or -OCH2CH3; More preferably, R 3 Selected from CN, -CH3, -CH2CH3, -CH(CH3)2, -SCH3, cyclobutyl or oxacyclobutyl. The compound according to any one of claims 1-15, wherein: R 4 Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl groups, -S(C 1-4 alkyl), -NH(C) 1-4 Halogenated alkyl), -N(C) 1-4 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 cycloalkyl or -C 1-4 alkylene-4-7-membered heterocyclic group; the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl groups, -S(C 1-4 alkyl), -NH(C) 1- 4-Halogenated alkyl), -N(C) 1-4 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 cycloalkyl or -C 1- The 4-alkylene-4-7-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, 5 or 6 atoms selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -S(C 1-4 alkyl), -S(C 1-4 Halogenated alkyl), -NH(C) 1-4 alkyl), -N(C) 1-4 alkyl)2、-NH(C 1-4 Halogenated alkyl), -N(C) 1-4 (halogenated alkyl)2、-S(=O)(C 1-4 Alkyl), -S(=O)2(C 1-4 Alkyl), -S(=O)(C 1-4 Halogenated alkyl groups), -S(=O)2(C 1-4 Halogenated alkyl), -O(C) 3-6 cycloalkyl) or -O(C 3-6 Substituents of halogenated cycloalkyl groups; Preferably, R 4 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-10 cycloalkyl; the C 1-6 The alkyl group is optionally surrounded by 1, 2, 3, 4, 5, or 6 atoms selected from halogens, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -S(C 1-6 Halogenated alkyl groups), -S(O)(C 1-6 Halogenated alkyl groups), -S(O)2(C 1-6 Halogenated alkyl), -O(C) 3-6 Substitution of the alkyl group (halogenated cycloalkyl); the C 3-10 cycloalkyl, -C 1-6 Alkylene-C 3-10 C in cycloalkyl 3-10 The cycloalkyl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 atoms selected from halogens, C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups; Preferably, R 4 Selected from C 1-4 Alkyl, C 3-6 cycloalkyl or -C 1-4 Alkylene-C 3-6 cycloalkyl; the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, 4, 5, or 6 atoms selected from halogens, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -S(C 1-4 Halogenated alkyl groups), -S(=O)(C 1-4 Halogenated alkyl groups), -S(=O)2(C 1-4 (halogenated alkyl) or -O(C) 3-6 Substitution of the alkyl group (halogenated cycloalkyl); the C 3- 6-cycloalkyl or -C 1-4 Alkylene-C 3-6 C in cycloalkyl 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 atoms selected from halogens, C 1-4 Halogenated alkyl or C 1-4 Substituents of haloalkoxy groups; Preferably, R 4 Selected from C 1-4 Alkyl; the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, 4, 5, or 6 atoms selected from halogens, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -S(C 1-4 (halogenated alkyl) or -O(C) 3-6 Substituents of halogenated cycloalkyl groups; Preferably, R 4 Selected from C 1-4 Alkyl; the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3, 4, 5, or 6 atoms selected from halogens, C 1-4 Alkoxy or C 1-4 Substituents of haloalkoxy groups; Preferably, R 4 Selected from (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 Preferably, R 4 Selected from (Preferred) )、 (Preferred) )、 (Preferred) )or (Preferred) )； Preferably, R 4 Selected from (Preferred) )or (Preferred) )。 The compound according to any one of claims 1-16, wherein the compound has the structure shown in formula (III-1): in: n is selected from 0 or 1; p is selected from 0, 1, 2, or 3; Q is selected from halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(C 1-6 Halogenated alkyl groups), -S(=O)(C 1-6 (halogenated alkyl) or -S(=O)2(C 1-6 (Halogenated alkyl); R a R b Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; L is selected from -CR L1 R L2 -、-C 3-6 Cycloalkylene-, -C 3-6 Halogenated cycloalkyl-, -OC 3-6 Cycloalkylene-*, -OC 3-6 Halogenated cycloalkyl-*, -SC 3-6 Cycloalkylene-* or -SC 3-6 Halogenated cycloalkylene-*, wherein the bond indicated by "*" is connected to Q; R L1 R L2 Each is independently selected from H, deuterium, halogen, CN, OH, NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or R L1 R L2 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 1 R 2 R 3 R g R h As defined in any one of claims 1-15; Preferably, it has the structure shown in formula (III-2) or (III-3): Preferably, it has the structure shown in any of formulas (III-4)-(III-7): Preferably, it has the structure shown in any of formulas (III-8)-(III-11): The compound according to claim 17, wherein: n is selected from 0; p is selected from 0, 1, or 2; Preferably, p is 1. The compound according to claim 17 or 18, wherein: Q is selected from F, Cl, Br, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, -S(C 1-3 Halogenated alkyl groups), -S(=O)(C 1-3 (halogenated alkyl) or -S(=O)2(C 1-3 (Halogenated alkyl); Preferably, Q is selected from C. 1-3 Haloalkyl (e.g., C10) 1-3 (fluoroalkyl) or C 1-3 Halogenated alkoxy groups (e.g., C16) 1-3 (Fluoroalkoxy); Preferably, Q is selected from C. 1-3 Haloalkyl (e.g., C10) 1-3 Fluorinated alkyl groups); Preferably, Q is selected from F, -OCF3, -OCF2H, -CF3, -CF2H, -SCF3, -SCF2H, -S(=O)CF3, -S(=O)2CF3 or -OCH2CF3; More preferably, Q is selected from -OCF3 or -CF3, with -CF3 being preferred. The compound according to any one of claims 17-19, wherein: R a R b Each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, R a R b Each is independently selected from H or C 1-6 alkyl; Preferably, R a R b Each is independently selected from H or C 1-3 alkyl; Preferably, R a R b Both are H, or R a R b One of them is H, and the other is C. 1-3 alkyl; More preferably, R a R b All are H. The compound according to any one of claims 17-20, wherein: L is selected from -CR L1 R L2 -、-C 3-6 Cycloalkylene- or -OC 3-6 Halogenated cycloalkylene-*; wherein the bond indicated by "*" is connected to Q; Preferably, L is selected from -CR L1 R L2 -; and / or R L1 R L2 Each is independently selected from H and C. 1-6 Alkyl or C 1-6 alkoxy; or R L1 R L2 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; Preferably, R L1 R L2 Each is independently selected from H and C. 1-3 Alkyl or C 1-3 Alkoxy; Preferably, R L1 R L2 Both are H, or R L1 R L2 One of them is H, and the other is C. 1-3 Alkyl or C 1-3 Alkoxy; Preferably, R L1 R L2 One of them is H, and the other is C. 1-3 Alkoxy; Preferably, L is selected from -CR L1 R L2 -、 Preferably, L is selected from -CH2-, -CH(CH3)-, -CH(OCH3)-, More preferably, L is selected from -CH2-, -CH(CH3)- or -CH(OCH3)-; preferably -CH(OCH3)-. The compound according to any one of claims 17-21, wherein the compound has the structure shown in formula (IV-1): Preferably, it has the structure shown in formula (IV-2) More preferably, it has the structure shown in formula (IV-3) Where R 1 R 2 R 3 R g R h As defined in any one of claims 1-15, R a R b R L1 R L2 As defined in any one of claims 17-21. The compound according to any one of claims 1-8, 10-22, wherein the compound is selected from: The compound according to any one of claims 1-23, wherein the compound is selected from: Preferred A pharmaceutical composition comprising a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. A pharmaceutical combination comprising a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and another therapeutically active agent. A method for modulating the activity of the complement bypass pathway in an individual, wherein the method includes: The individual is given a therapeutically effective amount of the compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or the individual is given a therapeutically effective amount of the pharmaceutical composition according to claim 25; or the individual is given a therapeutically effective amount of the pharmaceutical combination according to claim 26. Methods for preventing or treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway, wherein said methods include: The individual may be administered a therapeutically effective amount of the compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or the individual may be administered a therapeutically effective amount of the pharmaceutical composition according to claim 25; or the individual may be administered a therapeutically effective amount of the pharmaceutical combination according to claim 26. Preferably, the disease, disorder, or condition is selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological diseases, multiple sclerosis, and other conditions. Wind, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, symptoms caused by inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis. Renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative glomerulonephritis, C3 glomerular disease (C3G), immunoglobulin A nephropathy (IgAN) or other nephropathy with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aH) US), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity. The compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 25, or the pharmaceutical composition according to claim 26, is used as a drug. Use of any compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic compounds, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 25, or the pharmaceutical composition according to claim 26, in the preparation of a medicament for treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway.

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