Difluoroalkyl substituted piperidine compound as well as pharmaceutical composition, preparation method and application thereof

Abstract

The invention relates to a difluoroalkyl substituted piperidine compound as well as a pharmaceutical composition, a preparation method and application thereof, and particularly provides a difluoroalkyl substituted piperidine compound shown in a formula (I) which can be used for preparing medicines, especially medicines for preventing and / or treating complement bypass mediated diseases or symptoms. Each group in the formula (I) is as defined in the specification. # imgabs0 #

Description

[0001] The present invention claims priority to a prior application with patent application number 202311392275.X, entitled “Difluoroalkyl substituted piperidine compounds and pharmaceutical compositions, preparation methods and uses thereof”, filed with the State Intellectual Property Office of China on October 25, 2023. The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present application belongs to the field of medicine, and specifically relates to a difluoroalkyl-substituted piperidine compound and a pharmaceutical composition, a preparation method and use thereof, which can be used as a complement factor B inhibitor. Background Art

[0003] Complement is a class of soluble pattern recognition molecules in the immune system that can perform a variety of effector functions. Under natural conditions, complement components exist in the form of inactive zymogens. A variety of specific and nonspecific immunological mechanisms decompose these inactive zymogens to produce active large and small fragments. Among them, large fragments usually stay on the surface of pathogens or cells, causing the latter to lyse or accelerate their clearance; small fragments leave the cell surface and mediate a variety of inflammatory responses. The activation of complement consists of two closely related processes, which form a cascade reaction of complement activation. Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the alternative pathway. Although the initiation mechanisms and activation orders of the three complement activation pathways are different, they have a common terminal pathway. Among them, the activation of the alternative pathway does not rely on antigen-antibody complexes. Usually, C3b deposited on the cell surface combines with factor B and becomes a state that is easily decomposed by factor D in the serum. In this process, factor B is decomposed into Ba and Bb; then C3b and Bb form a complex to become the C3 convertase C3bBb in the alternative pathway; in this process, complement factor B plays an early and core role in the activation of the alternative pathway of the complement cascade. Here, C3b is both a product that appears after the C3 convertase decomposes C3, and a component of the C3 convertase of the alternative pathway, thus forming a feedback amplification mechanism in which the classical pathway and the alternative pathway influence each other. Current studies have found that a variety of diseases such as hematologic, autoimmune, inflammatory, and neurodegenerative diseases are related to abnormal complement system function.

[0004] The small molecule complement factor B inhibitor developed by Novartis AG is used to treat diseases such as age-related macular degeneration (AMD). The currently disclosed patents related to the same target include: WO2013164802, WO2013192345, WO2014143638, WO2015009616, WO2015066241, WO2019043609A1 and WO2022028527A1, etc.

[0005] Inflammation and immune-related diseases are diverse and difficult to cure. There are unmet clinical needs in these areas, and new small molecule drugs need to be developed for medical treatment. Summary of the invention

[0006] The present application provides a compound represented by formula (IG) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in:

[0009] n is 1 or 2;

[0010] G 1 CR 8 or N;

[0011] G 2 CR 9 or N;

[0012] R 8 and R 9 are the same or different and are each independently selected from H, OH, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and 3-8 membered cycloalkyl;

[0013] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl;

[0014] R 2 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and 3-8 membered cycloalkyl;

[0015] R 3 and R 4 are the same or different, each independently selected from H, D, halogen and C 1-6 alkyl;

[0016] R 5 Selected from -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)NHS(O)2R 10 、-S(O)2R 10 、-P(O)(OH)R 11, -B(OH)2 and 5-membered heteroaryl, wherein the 5-membered heteroaryl may be optionally selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and amino are substituted by one or more substituents;

[0017] R 6 Selected from H, D, halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from D, halogen, hydroxy, cyano and NR 12 R 13 is substituted by one or more substituents;

[0018] R 7 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0019] R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, NH2 and 3-8 membered cycloalkyl;

[0020] R 11 Selected from H, OH, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0021] R 12 and R 13 are the same or different and are independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 3-8 membered cycloalkyl;

[0022] R a and R b are the same or different and are each independently selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and 3-8 membered cycloalkyl.

[0023] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, wherein the compound represented by (IG) is a compound represented by formula (IG-1),

[0024]

[0025] R 1 , R 2 , R 3 , R 4 , R5 , R a , R b , R 6 , R 7 , n, G 1 and G 2 As defined in formula (IG).

[0026] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, wherein the compound represented by (IG) is a compound represented by formula (I),

[0027]

[0028] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, G 1 and G 2 As defined in formula (IG).

[0029] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0030] in:

[0031] n is 1 or 2;

[0032] G 1 CR 8 or N;

[0033] G 2 CR 9 or N;

[0034] R 8 and R 9 are the same or different and are each independently selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and 3-8 membered cycloalkyl;

[0035] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl;

[0036] R 2 Selected from H, halogen, C 1-6Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and 3-8 membered cycloalkyl;

[0037] R 3 and R 4 are the same or different, each independently selected from H, D, halogen and C 1-6 alkyl;

[0038] R 5 Selected from -COOH, -C(O)NHS(O)2R 10 、-S(O)2R 10 、-P(O)(OH)R 11 , -B(OH)2, 5-membered heteroaryl;

[0039] R 6 Selected from H, D, halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from D, halogen, hydroxy, cyano and NR 12 R 13 is substituted by one or more substituents;

[0040] R 7 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0041] R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, NH2 and 3-8 membered cycloalkyl;

[0042] R 11 Selected from H, OH, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0043] R 12 and R 13 are the same or different and are independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 3-8 membered cycloalkyl.

[0044] In some embodiments, the compound represented by formula (IG) or formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof,

[0045]

[0046] G 1 , G 2 , R 1 , R 2, R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in this application.

[0047] In some embodiments, the compound represented by formula (IG), formula (IG-1) or formula (I) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 8 , and G 2 CR 9 Or, G 1 CR 8 , and G 2 N; or G 1 is N, and G 2 CR 9 ; R 8 and R 9 As defined in this application.

[0048] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I) or Formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 alkyl.

[0049] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0050]

[0051] in:

[0052] R 1 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in this application.

[0053] In some embodiments, the compound represented by formula (IG) or a pharmaceutically acceptable salt thereof is a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof,

[0054]

[0055] in:

[0056] R 1 , R 5 , R 6 , R 7 , R 8 and R9 As defined in this application.

[0057] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-3 Alkoxy, deuterated C 1-3 Alkoxy and 3-6 membered cycloalkyl.

[0058] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-3 Alkoxy or deuterated C 1-3 Alkoxy.

[0059] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl, methoxy, trideuterated methoxy and cyclopropyl.

[0060] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl, methoxy and trideuterated methoxy.

[0061] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 It is cyclopropyl.

[0062] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl.

[0063] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)NHSO2R 10 、-S(O)2R 10, -P(O)(OH)2, -P(O)(OH)(CH3), -B(OH)2, tetrazolyl and R 10 It is methyl or NH2.

[0064] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -COOH, -C(O)NHS(O)2R 10 、-S(O)2R 10 , -P(O)(OH)2, -P(O)(OH)(CH3), -B(OH)2 and tetrazolyl, R 10 It is methyl or NH2.

[0065] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -COOH,

[0066] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 5 It is -COOH.

[0067] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from H, halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally selected from halogen, hydroxy, cyano and NR 12 R 13 is substituted by one or more substituents; R 12 and R 13 are the same or different and are each independently selected from H or C 1-3 alkyl.

[0068] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from H, F, methyl, NH2CH2-, NH2CH2CH2-, HOCH2-, HOCH2CH2-, CH3NHCH2-, CH3NHCH2CH2-.

[0069] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from H, halogen or C 1-3 alkyl.

[0070] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 7 is H, methyl or ethyl.

[0071] In some embodiments, the compound represented by formula (IG) or formula (IG-1) or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and are each independently H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and 3-6 membered cycloalkyl.

[0072] In some embodiments, the compound represented by formula (IG) or formula (IG-1) or a pharmaceutically acceptable salt thereof, wherein R a and R b The same or different and each independently H, methyl.

[0073] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 the same or different and each independently H, OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and 3-6 membered cycloalkyl.

[0074] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are the same or different and are each independently selected from H, OH, halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0075] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are the same or different and are each independently selected from H, OH, F, Cl, methyl, methoxy, difluoromethyl, and cyclopropyl.

[0076] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from methyl, NH2.

[0077] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from OH and methyl.

[0078] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 The same or different, and each independently selected from H, methyl.

[0079] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy; R 5 is -COOH; R 6 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from halogen, hydroxy, NH2 or NHCH3; R 7 For H.

[0080] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy; R 5 is -COOH; R 6 Halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted by one or more substituents selected from halogen, hydroxy, NH2 or NHCH3; R 7 For H.

[0081] In some embodiments, the compound represented by Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy; R 5 is -COOH; R 6 H; R 7 For H.

[0082] Exemplary specific compounds of the compounds described herein include, but are not limited to, the structures in Table A below:

[0083] Table A

[0084]

[0085]

[0086]

[0087]

[0088] Exemplary specific compounds of the compounds shown in the present application include, but are not limited to, the structures in Table B below:

[0089] Table B

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] On the other hand, the present application provides an isotope-labeled compound of formula (IG), formula (IG-1), formula (I), formula (I-1), formula (II) or formula (II-1), or a compound shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0097] On the other hand, the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound shown in the aforementioned formula (IG), formula (IG-1), formula (I), formula (I-1), formula (II) or formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0098] On the other hand, the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound shown in the aforementioned formula (IG), formula (IG-1), formula (I), formula (I-1), formula (II) or formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0099] On the other hand, the present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and its use in the preparation of a medicament for regulating the activity of the complement alternative pathway in a subject; preferably, its use in the preparation of a medicament for preventing and / or treating diseases or conditions affected by the regulation of the complement alternative pathway.

[0100] The present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and its use in the preparation of a medicament for inhibiting the expression or activity of complement factor B; preferably, its use in the preparation of a medicament for preventing and / or treating diseases or conditions mediated by complement factor B.

[0101] The present application also provides a compound shown in formula (IG), formula (IG-1), formula (I), formula (I-1), formula (II) or formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and its use in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases or respiratory diseases; preferably, its use in the preparation of a medicament for preventing and / or treating paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (h ... HUS, diabetic retinopathy (DR), complications of hemodialysis, hemolytic anemia or hemodialysis, neuromyelitis optica (NMO), arthritis, rheumatoid arthritis, psoriatic arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, liver fibrosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia Use of leventinese in drugs for diseases such as Sorsby fundus dystrophy, delayed retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion disorder, myocardial infarction, balloon angioplasty, post-cardiopulmonary bypass or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

[0102] The present application also provides a method for regulating the activity of the complement alternative pathway in a subject, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope label, or the aforementioned pharmaceutical composition containing the same.

[0103] The present application also provides a method for preventing and / or treating diseases or conditions affected by the regulation of the complement alternative pathway, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition containing the same.

[0104] The present application also provides a method for inhibiting the expression or activity of complement factor B, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition containing the same.

[0105] The present application also provides a method for preventing and / or treating diseases or conditions mediated by complement factor B, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition containing the same.

[0106] The present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a medicine.

[0107] The present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a complement alternative pathway regulator.

[0108] The present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a complement factor B inhibitor.

[0109] The present application also provides a compound shown in Formula (IG), Formula (IG-1), Formula (I), Formula (I-1), Formula (II) or Formula (II-1), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for preventing and / or treating diseases or conditions mediated by complement factor B.

[0110] The disease or disorder described in the present application is selected from the group consisting of autoimmune diseases, inflammatory diseases, blood diseases and neurodegenerative diseases.

[0111] The disease or disorder described in the present application is selected from paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis , psoriatic arthritis, hepatic inflammation, dermatomyositis and amyotrophic lateral sclerosis, liver fibrosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion condition, myocardial infarction, balloon angioplasty, cardiopulmonary bypass or renal bypass post-pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, etc.

[0112] On the other hand, the present application also provides an intermediate compound represented by formula (IGA) or (IGA-1) or a salt thereof,

[0113]

[0114] in:

[0115] R w C(O)OR c OR P(O)(OR c )R 11 ;

[0116] R c C 1-6 alkyl;

[0117] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl;

[0118] R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R a , R b , R 11 , n, G 1 and G 2 As defined in formula (IG).

[0119] The present application also provides an intermediate compound represented by formula (IA) or formula (IA-1) or a salt thereof,

[0120]

[0121] in:

[0122] R w C(O)OR c OR P(O)(OR c )R 11 ;

[0123] R c C 1-6 alkyl;

[0124] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl;

[0125] R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 11 , n, G 1 and G 2 As defined in formula (I).

[0126] The present application also provides an intermediate compound represented by formula (IIA) or formula (IIA-1) or a salt thereof,

[0127]

[0128] in:

[0129] Rw C(O)OR c OR P(O)(OR c )R 11 ;

[0130] R c C 1-6 alkyl;

[0131] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl;

[0132] R 1 , R 6 , R 7 , R 8 , R 9 and R 11 As defined in formula (II).

[0133] Exemplary specific compounds of the intermediate compounds shown in the present application include, but are not limited to, the structures in Table C below:

[0134] Table C

[0135]

[0136]

[0137]

[0138] On the other hand, the present application provides a method for preparing a compound represented by formula (IG), comprising hydrolyzing and deprotecting a compound represented by formula (IGA) to obtain a compound represented by formula (IG),

[0139]

[0140] Among them, R w C(O)OR c OR P(O)(OR c )R 11 ;

[0141] R 5 C(O)OH or P(O)(OH)R 11 ;

[0142] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl;

[0143] R1 , R 2 , R 3 , R 4 , R 6 , R 7 , R a , R b , R 11 , n, G 1 and G 2 As defined in formula (IG).

[0144] The preparation of the compounds represented by formula (IG-1), formula (I), formula (I-1), formula (II) and formula (II-1) can refer to the preparation method of formula (IG), and the formula (IGA) is replaced with the corresponding intermediate compounds represented by formula (IGA-1), formula (IA), formula (IA-1), formula (IIA) and formula (IIA-1) to obtain the corresponding compounds.

[0145] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0146] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope label. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope label. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope label.

[0147] In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt or an isotope-labeled substance thereof.

[0148] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.

[0149] When used as a drug, the compounds of the present application can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single bolus form, or it can be administered, for example, by a continuous infusion pump.

[0150] In preparing the compositions of the present application, the active ingredient is usually mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0151] The "excipient" mentioned in the present application refers to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants and lubricants.

[0152] On the other hand, the pharmaceutically acceptable salts of the compounds described in the present application may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form internal salts.

[0153] On the other hand, the compounds of the present invention may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, and mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present application. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0154] In the chemical structures of the compounds described in this application, the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations, Indicates the presence of axial chirality.

[0155] key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0156] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. "Tautomer" refers to structural isomers of different energies that can be interconverted via low energy barriers. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization and lactam-lactam isomerization. All tautomeric forms of all compounds in the present application are within the scope of the present application. The name of the compound named in a single manner does not exclude any tautomer.

[0157] The present application also includes some isotopically labeled compounds of the present application that are identical to the structures described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 All isotopic changes of the compounds of the present application, whether radioactive or not, are included in the scope of the present application.

[0158] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium, or more. Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0159] The "therapeutically effective amount" of the present application refers to the amount of active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by researchers, veterinarians, physicians or other clinicians, and includes one or more of the following: (1) Prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) Suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms). (3) Relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms). For drugs or pharmacologically active agents, a "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0160] The term "pharmaceutically acceptable" in this application refers to compounds, materials, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0161] The term "patient" as used herein refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0162] Beneficial Effects

[0163] The present application provides a small molecule compound that can be used as a complement factor B inhibitor, and the compound or pharmaceutical composition can be used to effectively treat or prevent diseases mediated by complement factor B. Compounds of this structure have good biological activity.

[0164] Definition and explanation of terms

[0165] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0166] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof, etc. The alkyl group may be substituted or unsubstituted.

[0167] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0168] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferably, the alkoxy (C 2-alkyl) group contains from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms. 1-12 Alkoxy), more preferably an alkoxy group containing 1 to 6 carbon atoms (C 1-6 Alkoxy). Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy and butoxy. The alkoxy group may be substituted or unsubstituted.

[0169] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0170] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between each monocycle in the system, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0171]

[0172] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0173]

[0174] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0175]

[0176] The cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0177] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g. 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0178] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, in which one atom (called spiral atom) is shared between each monocyclic ring in the system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0179]

[0180] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radicals include:

[0181]

[0182] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0183]

[0184] The heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0185] The heterocyclic group may be substituted or unsubstituted.

[0186] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0187]

[0188] Aryl groups can be substituted or unsubstituted.

[0189] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0190]

[0191] A heteroaryl group can be substituted or unsubstituted.

[0192] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0193] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0194] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the compound are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl and p-methoxybenzyl, etc. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.

[0195] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.

[0196] The term "heterocyclyloxy" refers to heterocyclyl-O- wherein heterocyclyl is as defined herein.

[0197] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0198] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0199] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0200] The term "halogen" refers to F, Cl, Br or I.

[0201] The term "hydroxy" refers to -OH.

[0202] The term "amino" refers to -NH2.

[0203] The term "cyano" refers to -CN.

[0204] The term "nitro" refers to -NO2.

[0205] The term "oxo" or "oxo" refers to "=0".

[0206] The term "carbonyl" refers to C=O.

[0207] The term "carboxy" refers to -C(O)OH.

[0208] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein.

[0209] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0210] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated () bond. DETAILED DESCRIPTION

[0211] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0212] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0213] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker ASCEND TM-400 NMR, the solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid phase mass spectrometer.

[0214] HPLC determination was performed using Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 um column).

[0215] Chiral HPLC analysis was performed using THARSFC X5.

[0216] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0217] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0218] High performance liquid phase preparation used Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0219] Shimadzu LC-20AP and THARSFC PREP 80 were used for chiral preparative column chromatography.

[0220] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0221] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0222] The microwave reaction was carried out using a Biotage initiator+ type microwave reactor.

[0223] Unless otherwise specified in the experimental examples, the reactions were carried out under argon or nitrogen atmosphere.

[0224] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.

[0225] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0226] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, which ranges from 20°C to 30°C.

[0227] Those skilled in the art should understand that the chiral compounds separated can be distinguished by the order of retention time in the chiral chromatographic column. Therefore, the chiral compounds separated according to the order of retention time are distinguished by corresponding number suffixes such as P1 and P2. That is, for example, suffix P1 corresponds to a chiral compound with a certain chiral structure that is eluted from the chiral chromatographic column earlier, and suffix P2 corresponds to a chiral compound with a certain chiral structure that is eluted from the chiral chromatographic column later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it directly corresponds to the compounds with number suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with number suffixes P1 and P2 shall be based on the objectively corresponding absolute configuration marked by the specific retention time.

[0228] The reagent names corresponding to the English abbreviations of the reagents are:

[0229] Reagent English abbreviation Reagent name Boc anhydride Di-tert-butyl dicarbonate THF Tetrahydrofuran DMF N,N-Dimethylformamide <![CDATA[H2O]]> water AcOH acetic acid NMP N-Methylpyrrolidone <![CDATA[CDCl3]]> Deuterated chloroform DMSO-d6 Deuterated dimethyl sulfoxide <![CDATA[CD3OD]]> Deuterated methanol PE Petroleum ether EA Ethyl acetate DCM Dichloromethane MeOH Methanol NaOH Sodium hydroxide TMSI Iodinated trimethylsilane DME Ethylene glycol dimethyl ether CbC Benzyl chloroformate DMSO Dimethyl sulfoxide DAST Diethylaminosulfur trifluoride <![CDATA[Ru(bpy)2Cl2]]> Tris(2,2'-bipyridyl)ruthenium dichloride Hex n-Hexane EtOH Ethanol i-PrMgCl.LiCl Isopropylmagnesium chloride-lithium chloride DEA Diethylamine (S)-BINAP (S)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) <![CDATA[Rh(Acac)(C2H4)2]]> Rhodium acetylacetonate

[0230] Example

[0231] Synthesis of intermediate compound A1

[0232]

[0233] Step 1: Synthesis of Compound A1-2

[0234] Boc anhydride (5.68 g) was added to a dichloromethane (50 mL) solution of compound A1-1 (3 g), 4-dimethylaminopyridine (227 mg) and triethylamine (2.26 g), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, a saturated ammonium chloride solution (50 mL) was added to the reaction solution, and dichloromethane was extracted (50 mL×3). The combined organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~10 / 1) to obtain compound A1-2 (4.6 g, yield: 94%). MS m / z(ESI):262.0[M+1] + .

[0235] Step 2: Synthesis of Compound A1

[0236] Oxalyl chloride (3.6 g) was added to a solution of N-methylformanilide (3.8 g) in dichloromethane (80 mL), and the mixture was stirred at room temperature for 3 hours, then the reaction temperature was lowered to -14 ° C, compound A1-2 (2.5 g) was added, and the reaction mixture was naturally warmed to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted with dichloromethane (100 mL × 3), the combined organic phase was washed with water (50 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain compound A1 (1.3 g, yield: 47%). MS m / z (ESI): 290.0 [M + 1] + . 1 H NMR (400MHz, CDCl3) δ 10.65 (s, 1H), 7.65 (d, J = 3.4Hz, 1H), 7.49 (d, J = 3.4Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

[0237] Example 1 (Compound 1-P1)

[0238]

[0239] Step 1: Synthesis of compound 1a

[0240] Under nitrogen protection, potassium tert-butoxide solution (6.54 mL, 6.54 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.44 g, 6.54 mmol) in THF and DMSO (10 mL / 10 mL). After the mixture was stirred at room temperature for 0.5 hours, a solution of compound B1 (2 g, 5.45 mmol) in DMSO (10 mL) was added, and the reaction mixture was stirred at 30°C for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL×3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1~2 / 1) to obtain compound 1a (1.81 g, yield 87.0%). MS m / z(ESI):382.4[M+1] + .

[0241] Step 2: Synthesis of compound 1b

[0242] At room temperature, tri(pentafluorophenyl)borane (1.34 g, 2.62 mmol) was added to a toluene (20 mL) solution of compound 1a (1 g, 2.62 mmol), and the reaction mixture was stirred at 30°C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1~2 / 1) to obtain compound 1b (0.81 g, yield 81.0%). MS m / z(ESI):382.2[M+1] + .

[0243] Step 3: Synthesis of compound 1c

[0244] Under nitrogen protection, potassium tert-butoxide solution (7.87 mL, 7.87 mmol) was slowly added to a solution of (methoxymethyl)triphenylphosphonium chloride (2.7 g, 7.87 mmol) in THF (50 mL). After the mixture was stirred at room temperature for 1 hour, a solution of compound 1b (1.0 g, 2.62 mmol) in THF (15 mL) was added, and the reaction mixture was stirred at 30°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 1c (500 mg, yield 46.7%). MS m / z (ESI): 410.3 [M+1] + .

[0245] Step 4: Synthesis of compound 1d

[0246] Dilute hydrochloric acid (2.5 mL, 2M) was added to a tetrahydrofuran (17 mL) solution of compound 1c (500 mg, 1.22 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH>7 by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~5 / 1) to obtain compound 1d (350 mg, yield 89.3%). MS m / z(ESI):396.3[M+1] + .

[0247] Step 5: Synthesis of compound 1e

[0248] Under ice bath, DAST (636 mg, 3.95 mmol) was added to a dichloromethane (12 mL) solution of compound 1d (260 mg, 0.66 mmol), and the reaction mixture was stirred at 0°C for 3 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) for quenching, extracted with DCM (20 mL × 3), and the combined organic phase was washed with saturated sodium bicarbonate solution (20 mL × 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 2 / 1) to obtain compound 1e (200 mg, yield 73.5%). MS m / z (ESI): 418.0 [M+1] + .

[0249] Step 6: Synthesis of Compound 1f

[0250] At room temperature, Pd / C (100 mg) was added to a tetrahydrofuran (10 mL) solution of compound 1e (200 mg, 0.48 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1f (140 mg, yield 100%). MS m / z (ESI): 284.0 [M+1] + .

[0251] Step 7: Synthesis of compound 1g

[0252] At room temperature, sodium acetate borohydride (359 mg, 1.70 mmol) was added to a tetrahydrofuran (7 mL) solution of compound 1f (160 mg, 0.56 mmol) and compound A1 (180 mg, 0.62 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to obtain compound 1g (122 mg, yield 38.9%). MSm / z (ESI): 557.1 [M+1] + .

[0253] Step 8: Synthesis of Compound 1-P1

[0254] At room temperature, sodium hydroxide (72 mg, 1.80 mmol) was added to a mixed solution of compound 1g (100 mg, 0.18 mmol) in tetrahydrofuran / methanol / water (1.5 mL / 1.5 mL / 1.5 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 by adding dilute hydrochloric acid (0.5 M), and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-, 70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 1-P1 (68 mg, yield 85.0%). MS m / z (ESI): 443.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.80 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8. 0Hz,2H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.49(t,J=2.0Hz,1H),6.30-6. 02(m,1H),3.69(s,3H),3.62-3.49(m,2H),3.34-3.33(m,1H),2.57-2.56(m ,1H),2.41(s,3H),2.28-2.22(m,1H),2.09-1.99(m,3H),1.81-1.44(m,4H).

[0255] Example 2 (Compound 2-P1 or 2-P2)

[0256]

[0257] Step 1: Synthesis of compound 2a

[0258] At 0°C, potassium tert-butoxide (16.3 mL, 16.3 mmol) was added to a solution of methyl triphenylphosphonium bromide (5.84 g, 16.3 mmol) in THF (100 mL). The mixture was stirred at 30°C for 30 minutes and then cooled to 0°C. A solution of compound B1 (2 g, 5.4 mmol, CAS: 2408761-20-4) in THF (20 mL) was added, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1~5 / 1) to obtain compound 1a (1.17 g, yield 58.8%). MS m / z(ESI):366.3[M+1]+.

[0259] Step 2: Synthesis of compound 2b

[0260] Ru(bpy)2Cl2 (42 mg, 0.068 mmol) was added to a MeOH (10 mL) solution of compound 2a (500 mg, 1.37 mmol), S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (1.10 g, 2.74 mmol) and pyridine (217 mg, 2.74 mmol) at room temperature, and the reaction mixture was stirred for 72 hours under a blue light (AC220V, 450-460 nm, Xuzhou Aijia Electronic Technology Co., Ltd.). After the reaction was completed, the reaction solution was diluted with citric acid aqueous solution (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=40 / 1~10 / 1) to obtain compound 2b (500 mg, yield 84.0%). MS m / z(ESI):436.4[M+1] + .

[0261] Step 3: Synthesis of compound 2c

[0262] Pd / C (150 mg) was added to a THF (15 mL) solution of compound 2b (650 mg, 1.49 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2c (380 mg, yield 84.3%). MS m / z (ESI): 302.2 [M+1] + .

[0263] Step 4: Synthesis of compounds 2d, 2d-P1 and 2d-P2

[0264] At room temperature, sodium acetate borohydride (990 mg, 4.65 mmol) was added to a solution of compound 2c (350 mg, 1.16 mmol) and compound A1 (504 mg, 1.74 mmol) in THF (5 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL×3). The residue was purified by silica gel column chromatography (PE / EA=20 / 1-5 / 1) to obtain compound 2d (420 mg, yield 62.9%). Compound 2d (420 mg) was separated by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IA 250 mm*30 mm 10 um; mobile phase: Hex / EtOH=95-5; flow rate: 25 mL / min] to give compound 2d-P1 (170 mg, yield 40.5%) and compound 2d-P2 (220 mg, yield 52.4%).

[0265] 2d-P1:MS m / z(ESI):575.5[M+1] + . Chiral HPLC: retention time 5.30 min, UV = 230 nm.

[0266] 2d-P2:MS m / z(ESI):575.5[M+1] + . Chiral HPLC: retention time 6.32 min, UV = 230 nm.

[0267] Step 5: Synthesis of compounds 2-P1 and 2-P2

[0268] NaOH (111 mg, 2.79 mmol) was added to a mixture of compound 2d-P1 (160 mg, 0.28 mmol) in methanol / tetrahydrofuran / water (2 mL / 2 mL / 2 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with glacial acetic acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-60%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2-P1 (61.6 mg, yield 48.1%). MS m / z (ESI): 461.1 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.95(d,J=8.4Hz,2H),7.64(d,J=8.0 Hz,2H),7.27-7.23(m,1H),6.65(s,1H),6.51-6.48(m,1H),3.71(s,3H),3.64 -3.50(m,2H),3.37-3.32(m,2H),2.60-2.51(m,2H),2.42(s,3H),2.31-2.23( m,1H),2.11(s,1H),1.87-1.80(m,1H),1.69-1.58(m,2H),1.52-1.46(m,1H).

[0269] NaOH (153 mg, 3.83 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (2.5 mL / 2.5 mL / 2.5 mL) of compound 2d-P2 (220 mg, 0.38 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with glacial acetic acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-60%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2-P2 (129.9 mg, yield 73.8%). MS m / z (ESI): 461.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.95(d,J=8.0Hz,2H),7.64(d,J=7.2Hz,2H),7.27-7.23(m,1H),6.65(s,1H),6.45(s,1H),3.70 (s,3H),3.56-3.50(m,1H),3.28-3.15(m,2H),2.80-2.75(m,1H),2.42(s,3H),2.23-2.00(m,3H),1.81-1.60(m,3H),1.42-1.60(m,2H).

[0270] Example 3 (Compound 3-P1 or 3-P2)

[0271]

[0272] Step 1: Synthesis of compound 3b

[0273] At 0°C, i-PrMgCl.LiCl (104 mL, 135 mmol) was slowly added to a THF (250 mL) solution of compound 3a (25 g, 90.5 mmol). After the mixture was stirred at room temperature for 2 hours, 250 mL of THF was added, the mixture was cooled to -30°C, 4-methoxypyridine (14.8 g, 135 mmmol) and Cbz-Cl (22.9 g, 135 mmmol) were added in sequence, and the reaction mixture was stirred at -30°C for 1 hour. After the reaction was completed, the reaction solution was quenched with water (100 mL), adjusted to pH = 5 with 6N hydrochloric acid, extracted with ethyl acetate (200 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 3b (21.5 g, yield 62.7%). MS m / z (ESI): 380.2 [M+1] + .

[0274] Step 2: Synthesis of compound 3c

[0275] Zinc powder (36 g, 0.55 mol) was added to a solution of compound 3b (21 g, 0.055 mol) in acetic acid (200 mL) at room temperature, and the reaction mixture was stirred at 100 ° C for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (100 mL × 3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 3c (16 g, yield 76.2%). MS m / z (ESI): 382.3 [M+1] + .

[0276] Step 3: Synthesis of compound 3d

[0277] Under nitrogen protection, potassium tert-butoxide solution (7.87 mL, 7.87 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.73 g, 7.87 mmol) in THF and DMSO (20 mL / 20 mL). After the mixture was stirred at room temperature for 1 hour, a solution of compound 3c (2 g, 5.25 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL×3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0~3 / 1) to obtain compound 3d (1.1 g, yield 53.1%). MS m / z(ESI):396.4[M+1] + .

[0278] Step 4: Synthesis of compound 3e

[0279] At room temperature, tri(pentafluorophenyl)borane (3.44 g, 6.72 mmol) was added to a toluene (50 mL) solution of compound 3d (2.41 g, 6.11 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 3e (1.37 g, yield 56.8%). MS m / z (ESI): 396.3 [M+1] + .

[0280] Step 5: Synthesis of compound 3f

[0281] Compound 3e (1.37 g, 3.47 mmol) was added to a solution of (triphenylphosphonium) difluoroacetic acid inner salt (2.47 g, 6.94 mmol) in NMP (15 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 3f (0.75 g, yield 50.0%). MS m / z (ESI): 430.4 [M+1] + .

[0282] Step 6: Synthesis of compound 3g

[0283] At 0°C, TMSI (1.38 g, 6.91 mmol) was added to a dichloromethane (20 mL) solution of compound 3f (593 mg, 1.38 mmol), and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted hydrochloric acid was added to adjust the pH to 4-5, and extracted with petroleum ether (50 mL×2). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with DCM (30 mL×3), and the combined organic phase was concentrated under reduced pressure to obtain compound 3g (0.38 g, yield 94.9%). MS m / z (ESI): 296.3 [M+1] + .

[0284] Step 7: Synthesis of compound 3h

[0285] Sodium acetate borohydride (1.12 g, 5.26 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 3g (388 mg, 1.31 mmol) and compound A1 (532 mg, 1.84 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) was added to the reaction solution, which was washed with saturated sodium bicarbonate solution (10 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~10 / 1) to obtain compound 3h (0.49 g, yield 55.9%). MSm / z(ESI):569.5[M+1] + .

[0286] Step 8: Synthesis of compounds 3i, 3i-P1 and 3i-P2

[0287] At room temperature, Pd / C (220 mg) was added to a methanol (20 mL) solution of compound 3h (440 mg, 0.77 mmol), and the reaction mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1) to obtain a cis-trans mixture (0.19 g), and 190 mg of the cis-trans mixture was further purified by thin layer chromatography on silica gel plates (PE / EA=10 / 1) to obtain compound 3i (130 mg, trans, yield 29.5%). Compound 3i (trans) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IG 250mm*30mm10um; mobile phase: Hex / EtOH / DEA=90-10-0.2; flow rate: 25mL / min] to obtain compound 3i-P1 (55mg, 42.3%) and compound 3i-P2 (50mg, 38.5%)

[0288] 3i-P1:MS m / z(ESI):571.6[M+1] + . Chiral HPLC: retention time 5.90 min, UV = 254 nm.

[0289] 3i-P2:MS m / z(ESI):571.6[M+1] + . Chiral HPLC: retention time 9.42 min, UV = 254 nm.

[0290] Step 9: Synthesis of compounds 3-P1 and 3-P2

[0291] NaOH (38 mg, 0.96 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.5 mL / 0.5 mL / 0.5 mL) of compound 3i-P1 (55 mg, 0.096 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 3-P1 (27.8 mg, yield 63.2%). MS m / z (ESI): 457.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.80(s,1H),7.91(d,J=8.0Hz,1H),7.84(d,J=8.0Hz,1H),7.75(s,1H),7 .25(t,J=2.4Hz,1H),6.65(s,1H),6.50(t,J=2.0Hz,1H),6.31-6.03(m,1H),3.70(s,3H),3.65(d,J =11.2Hz,1H),3.57(d,J=11.6Hz,1H),3.22(d,J=12.0Hz,1H),2.58(d,J=11.2Hz,1H),2.43(s,3H), 2.42(s,3H),2.26(t,J=12.4Hz,1H),2.15-2.01(m,3H),1.67-1.57(m,3H),1.45(d,J=13.6Hz,1H).

[0292] NaOH (35 mg, 0.88 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.5 mL / 0.5 mL / 0.5 mL) of compound 3i-P2 (50 mg, 0.088 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 3-P2 (21.6 mg, yield 54.0%). MS m / z (ESI): 457.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ12.61(br s,1H),10.80(s,1H),7.91(d,J=8.0Hz,1H),7.84(d,J=8.0Hz,1H),7.75(s,1H),7.25(t,J=2.4 Hz,1H),6.65(s,1H),6.50(t,J=2.0Hz,1H),6.31-6.03(m,1H),3.70(s,3H),3.65(d,J=11.2Hz ,1H),3.57(d,J=11.6Hz,1H),3.22(d,J=12.0Hz,1H),2.58(d,J=11.2Hz,1H),2.43(s,3H),2.4 2(s,3H),2.26(t,J=12.4Hz,1H),2.15-2.01(m,3H),1.67-1.57(m,3H),1.45(d,J=13.6Hz,1H).

[0293] Example 4 (Compound 4-P1)

[0294]

[0295] Step 1: Synthesis of compound 4c

[0296] (S)-BINAP (1.10 g, 1.52 mmol) and Rh(Acac)(C2H4)2 (224 mg, 0.87 mmol) were added sequentially to a mixed solution of compound 4a (5 g, 21.65 mmol), compound 4b (12.60 g, 64.95 mmol) and triethylamine (6.60 g, 64.95 mmol) in tert-amyl alcohol and water (80 mL / 8 mL), and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by HPLC (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 4c (4.20 g, yield 51.2%). MS m / z (ESI): 382.3 [M+1] + .

[0297] Step 2: Synthesis of compound 4d

[0298] Under nitrogen protection, potassium tert-butoxide solution (7.9 mL, 7.88 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.70 g, 7.88 mmol) in THF and DMSO (30 mL / 30 mL). The mixture was stirred at room temperature for 1 hour, and compound 4c (2 g, 5.25 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0~3 / 1) to obtain compound 4d (1.5 g, yield 72.1%). MS m / z(ESI):396.4[M+1] + .

[0299] Step 3: Synthesis of compound 4e

[0300] At room temperature, tri(pentafluorophenyl)borane (2.14 g, 4.18 mmol) was added to a toluene (30 mL) solution of compound 4d (1.50 g, 3.80 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 4e (1.50 g, yield 99.8%). MS m / z (ESI): 396.3 [M+1] + .

[0301] Step 4: Synthesis of compound 4f

[0302] (Triphenylphosphonium) difluoroacetic acid inner salt (2.50 g, 7.08 mmol) was added to a solution of compound 4e (1.40 g, 3.54 mmol) in NMP (15 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 4f (0.63 g, yield 38.7%). MS m / z (ESI): 430.4 [M+1] + .

[0303] Step 5: Synthesis of compound 4g

[0304] At 0°C, TMSI (1.28 g, 6.40 mmol) was added to a dichloromethane (10 mL) solution of compound 4f (550 mg, 1.28 mmol), and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted hydrochloric acid was added to adjust the pH to 4-5, and extracted with petroleum ether (50 mL×2). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with DCM (30 mL×3), and the combined organic phase was concentrated under reduced pressure to obtain compound 4g (0.37 g, yield 97.9%). MS m / z (ESI): 296.2 [M+1] + .

[0305] Step 6: Synthesis of compound 4h

[0306] At room temperature, sodium acetate borohydride (1 g, 4.76 mmol) was added to a tetrahydrofuran (7 mL) solution of compound 4g (350 mg, 1.19 mmol) and compound A1 (517 mg, 1.79 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) was added to the reaction solution, which was washed with saturated sodium bicarbonate solution (10 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 4h (0.52 g, yield 77.2%). MSm / z (ESI): 569.4 [M+1] + .

[0307] Step 7: Synthesis of compounds 4i and 4i-P1

[0308] At room temperature, Pd / C (140 mg) was added to a methanol (20 mL) solution of compound 4h (520 mg, 0.92 mmol), and the reaction mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 4i (0.27 g, yield 51.7%). Compound 4i (270 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IA 250 mm*30 mm 10 um; mobile phase: Hex / IPA=98-2; flow rate: 25 mL / min] to obtain compound 4i-P1 (210 mg, 77.8%). MS m / z (ESI): 571.6 [M+1] +. Chiral HPLC: retention time 7.34 min, UV = 254 nm.

[0309] Step 8: Synthesis of compound 4-P1

[0310] NaOH (132 mg, 3.30 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (2 mL / 2 mL / 2 mL) of compound 4i-P1 (190 mg, 0.33 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 4-P1 (109.30 mg, yield 71.9%). MS m / z (ESI): 457.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.81(d,J=8.0Hz,1H),7.42(d,J=8.4Hz,2H),7.25(t,J =2.4Hz,1H),6.65(s,1H),6.49-6.48(m,1H),6.32-6.02(m,1H),3.71(s,3H),3.62(d,J=12.0Hz ,1H),3.41(d,J=8.4Hz,1H),3.31(d,J=12.0Hz,1H),2.55-2.52(m,4H),2.42(s,3H),2.23(t,J =10.0Hz,1H),2.11-2.00(m,3H),1.85-1.79(m,1H),1.64-1.56(m,2H),1.45(d,J=12.8Hz,1H).

[0311] Example 5 (Compound 5-P1)

[0312]

[0313] Step 1: Synthesis of compound 5c

[0314] (S)-BINAP (526 mg, 1.03 mmol) and Rh(Acac)(C2H4)2 (266 mg, 1.03 mmol) were added to a mixed solution of compound 5a (4 g, 17.31 mmol), compound 5b (10.2 g, 51.94 mmol) and triethylamine (5.15 g, 51.94 mmol) in tert-amyl alcohol and water (160 mL / 16 mL) in sequence, and the reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution, which was washed with water (80 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~3 / 1) to obtain compound 5c (4.50 g, yield 69.2%). MS m / z(ESI):386.3[M+1] + .

[0315] Step 2: Synthesis of compound 5d

[0316] Under nitrogen protection, potassium tert-butoxide solution (8.16 mL, 8.16 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.79 g, 8.16 mmol) in THF and DMSO (40 mL / 40 mL). The mixture was stirred at room temperature for 1 hour, and compound 5c (2.1 g, 5.44 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~5 / 1) to obtain compound 5d (1.90 g, yield 87.5%). MS m / z(ESI):400.3[M+1] + .

[0317] Step 3: Synthesis of compound 5e

[0318] At room temperature, tri(pentafluorophenyl)borane (2.56 g, 5.00 mmol) was added to a toluene (40 mL) solution of compound 5d (2 g, 5.00 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 5e (1.20 g, yield 60.0%). MS m / z (ESI): 400.3 [M+1] + .

[0319] Step 4: Synthesis of compound 5f

[0320] (Triphenylphosphonium) difluoroacetic acid inner salt (2.10 g, 6.01 mmol) was added to a solution of compound 5e (1.2 g, 3.00 mmol) in NMP (15 mL), and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 5f (800 mg, yield 62.0%). MS m / z (ESI): 434.4 [M+1] + .

[0321] Step 5: Synthesis of compound 5g

[0322] At 0°C, TMSI (1.75 g, 8.77 mmol) was added to a dichloromethane (20 mL) solution of compound 5f (760 mg, 1.75 mmol), and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted hydrochloric acid was added to adjust the pH to 4-5, and extracted with petroleum ether (50 mL×2). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with EA (30 mL×3), and the combined ethyl acetate phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5g (450 mg, yield 86.1%). MS m / z (ESI): 300.2[M+1] + .

[0323] Step 6: Synthesis of compound 5h

[0324] At room temperature, sodium acetate borohydride (1.27 g, 6.00 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 5g (450 mg, 1.50 mmol) and compound A1 (652 mg, 2.26 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) was added to the reaction solution, which was washed with saturated sodium bicarbonate solution (15 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~10 / 1) to obtain compound 5h (0.49 g, yield 75.4%). MS m / z(ESI):573.2[M+1] + .

[0325] Step 7: Synthesis of compounds 5i and 5i-P1

[0326] At room temperature, Pd / C (140 mg) was added to a methanol (20 mL) solution of compound 5h (300 mg, 0.69 mmol), and the reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 40-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 5i (0.22 g, yield 73.3%). Compound 5i (220 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IG 250 mm*30 mm 10 um; mobile phase: Hex / IPA=95-5; flow rate: 25 mL / min] to give compound 5i-P1 ​​(160 mg, 72.7%). MS m / z (ESI): 575.6 [M+1] + . Chiral HPLC: retention time 8.83 min, UV = 230 nm.

[0327] Step 8: Synthesis of compound 5-P1

[0328] NaOH (55 mg, 1.40 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.5 mL / 0.5 mL / 0.5 mL) of compound 5i-P1 ​​(80 mg, 0.14 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 5-P1 (45 mg, yield 71.9%). MS m / z (ESI): 461.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): 10.83(s,1H),7.94(t,J=7.6Hz,1H),7.85(d,J=1.2Hz,1H),7.83(d,J=1 .2Hz,1H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.48-6.47(m,1H),6.30-6.00(m,1H),3.82(d,J= 10.8Hz,1H),3.70(s,3H),3.62-3.59(m,1H),3.20-3.18(m,1H),2.67-2.62(m,1H),2.42(s,3H) ,2.33-2.26(m,1H),2.11-1.98(m,3H),1.84-1.81(m,1H),1.78-1.63(m,2H),1.46-1.43(m,1H).

[0329] Example 6 (Compound 6-P1)

[0330]

[0331] Step 1: Synthesis of compound 6c

[0332] (S)-BINAP (0.89 g, 1.21 mmol) and Rh(Acac)(C2H4)2 (179 mg, 0.69 mmol) were added to a mixed solution of compound 6a (4 g, 17.31 mmol), compound 6b (10.30 g, 51.95 mmol) and triethylamine (5.25 g, 51.95 mmol) in tert-amyl alcohol and water (80 mL / 8 mL) in sequence, and the reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution, washed with water (80 mL×3), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=1 / 0~5 / 1) to obtain compound 6c (2.60 g, yield 39.0%). MS m / z(ESI):386.3[M+1] + .

[0333] Step 2: Synthesis of compound 6d

[0334] Under nitrogen protection, potassium tert-butoxide solution (7.08 mL, 7.08 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.56 g, 7.08 mmol) in THF and DMSO (20 mL / 20 mL). The mixture was stirred at room temperature for 1 hour, and compound 6c (2.10 g, 5.45 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 0~5 / 1) to obtain compound 6d (1.00 g, yield 73.4%). MS m / z(ESI):400.3[M+1] + .

[0335] Step 3: Synthesis of compound 6e

[0336] At room temperature, tri(pentafluorophenyl)borane (2.82 g, 5.51 mmol) was added to a toluene (30 mL) solution of compound 6d (2.0 g, 5.00 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound 6e (1.30 g, yield 65.0%). MS m / z (ESI): 400.3 [M+1] + .

[0337] Step 4: Synthesis of compound 6f

[0338] (Triphenylphosphonium) difluoroacetic acid inner salt (2.68 g, 7.51 mmol) was added to a solution of compound 6e (1.50 g, 3.76 mmol) in NMP (20 mL), and the reaction mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 4 / 1) to obtain compound 6f (0.55 g, yield 33.7%). MS m / z (ESI): 434.3 [M+1] + .

[0339] Step 5: Synthesis of compound 6g

[0340] At 0°C, TMSI (1.73 g, 8.65 mmol) was added to a dichloromethane (15 mL) solution of compound 6f (750 mg, 1.73 mmol), and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted hydrochloric acid was added to adjust the pH to 4-5, and petroleum ether (50 mL×2) was used for extraction. The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, EA was extracted (30 mL×3), and the combined ethyl acetate phase was concentrated under reduced pressure to obtain compound 6g (0.50 g, yield 96.5%). MS m / z (ESI): 300.2[M+1] + .

[0341] Step 6: Synthesis of compound 6h

[0342] At room temperature, sodium acetate borohydride (1.77 g, 8.35 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 6g (500 mg, 1.67 mmol) and compound A1 (724 mg, 2.51 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, a saturated ammonium chloride solution (30 mL) was added to the reaction solution at 0°C, and EA was extracted (30 mL×3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=1 / 0~10 / 1) to obtain compound 6h (0.65 g, yield 67.9%). MS m / z(ESI):573.2[M+1] + .

[0343] Step 7: Synthesis of compounds 6i and 6i-P1

[0344] At room temperature, Pd / C (140 mg) was added to a methanol (20 mL) solution of compound 6h (500 mg, 0.87 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=1 / 0-5 / 1) to obtain compound 6i (0.44 g, yield 81.2%). Compound 6i (440 mg) was purified by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IE 250mm*30mm 10um; mobile phase: Hex / EtOH=95-5; flow rate: 25 mL / min] to obtain compound 6i-P1 (320 mg, 72.7%). MS m / z (ESI): 575.6 [M+1] + . Chiral HPLC: retention time 9.33 min, UV = 230 nm.

[0345] Step 8: Synthesis of compound 6-P1

[0346] LiOH·H2O (99 mg, 2.35 mmol) was added to a mixed solution of compound 6i-P1 (270 mg, 0.47 mmol) in methanol / tetrahydrofuran / water (5 mL / 5 mL / 5 mL), and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH=6 with 1N dilute hydrochloric acid, extracted with EA (20 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-45%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 6-P1 (201.4 mg, yield 78.7%). MS m / z (ESI): 461.2 [M+1] + . 1 HNMR (400MHz, DMSO-d6): δ13.04(brs,1H),10.83(s,1H),7.84(t,J=8.0Hz,1H),7.47(d,J=12.0Hz,1H),7 .41(d,J=8.0Hz,1H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.49-6.48(m,1H),6.32-6.02(m,1H),3.72(s,3H ),3.68(d,J=12.0Hz,1H),3.59-3.49(m,1H),3.39-3.35(m,1H),2.59-2.52(m,1H),2.42(s,3H),2.35-2. 24(m,1H),2.13-1.91(m,3H),1.83-1.73(m,1H),1.71-1.63(m,1H),1.62-1.51(m,1H),1.50-1.41(m,1H).

[0347] For Examples 7-9, the synthesis method of Example 6 can be referred to, and the compound 6b is replaced with the reaction raw materials in the table to synthesize the corresponding compounds:

[0348]

[0349]

[0350] Synthesis of intermediate compound A2

[0351]

[0352] Step 1: Synthesis of Compound A2-1

[0353] At 0°C, sodium borohydride (392 mg, 10.4 mmol) was added to a methanol (15 mL) solution of compound A1 (1.5 g, 5.18 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched by adding water (10 mL), extracted with dichloromethane (10 mL × 3), and the combined organic phase was washed with a saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10-1 / 2) to obtain compound A2-1 (1.1 g). MS m / z (ESI): 274.05 [M-17] + .

[0354] Step 2: Synthesis of Compound A2

[0355] Add (chloromethylene) dimethylammonium chloride (879 mg, 6.87 mmol) to a dichloromethane (25 mL) solution of compound A2-1 (1.1 g, 3.78 mmol), and stir the reaction mixture at room temperature for 1 hour under nitrogen protection. After the reaction is completed, add saturated sodium bicarbonate (10 mL) solution to the reaction solution, extract with dichloromethane (10 mL × 3), wash the combined organic phase with saturated sodium chloride aqueous solution (10 mL × 2), dry with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain compound A2 (1.23 g, crude product). The crude product is directly used for the next step reaction.

[0356] Synthesis of intermediate compound A3

[0357]

[0358] Step 1: Synthesis of Compound A3-2

[0359] At room temperature, sodium periodate (16.17 g, 75.60 mmol) and ruthenium oxide (0.24 g, 1.80 mmol) were added to a mixed solvent of ethyl acetate (20 mL) and water (20 mL) of compound A3-1 (4.50 g, 18 mmol, synthesis method reference patent WO_2012071509_A2 specification page 163 00418-00419 paragraphs), and the reaction mixture was stirred at room temperature for 40 hours. After the reaction was completed, it was extracted with ethyl acetate (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0-10 / 1) to obtain compound A3-2 (3.40 g). MS m / z (ESI): 208.0 [M+1] + .

[0360] Step 2: Synthesis of Compound A3

[0361] At -78 ° C, potassium bis(trimethylsilyl)amide (1.0M in THF, 16.8mL, 16.77mmol) was slowly added dropwise to a solution of compound A3-2 (3.40g, 12.90mmol) in tetrahydrofuran (35mL). After the reaction mixture was stirred at -78 ° C for 1 hour under nitrogen protection, a solution of N-phenylbis(trifluoromethanesulfonyl)imide (5.99g, 16.77mmol) in tetrahydrofuran (12mL) was added dropwise, and the mixture was continued to stir at -78 ° C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate (30mL), extracted with ethyl acetate (50mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=1 / 0-20 / 1) to obtain compound A3 (5.00g). MS m / z(ESI):359.2[M+1] + .

[0362] Example 10 (Compounds 48-P1, 48-P2)

[0363]

[0364] Step 1: Synthesis of compound 48b

[0365] At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.43 g, 0.59 mmol), cyclopropylboronic acid (1.01 g, 11.96 mmol) and potassium phosphate (2.50 g, 11.96 mmol) were added to a solution of compound 48a (2.00 g, 5.88 mmol) in 1,4-dioxane (40 mL) in sequence, and the reaction mixture was stirred at 100° C. for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0-10 / 1) to obtain compound 48b (1.50 g, crude product). 1 H NMR (400MHz, CDCl3) δ7.70–7.57(m,3H), 3.92–3.88(m,4H), 2.21–2.14(m,1H), 1.08–0.98(m,2H), 0.77–0.72(m,2H).

[0366] Step 2: Synthesis of compound 48c

[0367] Under nitrogen atmosphere, diboric acid pinacol ester (1.98 g, 7.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.16 g, 0.20 mmol), potassium acetate (0.77 g, 7.80 mmol) were added to a mixed solution of compound 48b (1.00 g, 3.90 mmol) in N,N-dimethylformamide (30 mL) in sequence, and the reaction mixture was stirred at 100°C for 48 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 0~97 / 3) to obtain compound 48c (430 mg). 1 H NMR (400MHz, CDCl3) δ7.76(s,2H),7.49(s,1H),3.89(s,3H),2.67–2.62(m,1H),1.37(s,12H),1.26(s,16H),1.02–0.97(m,2H),0.76–0.72(m,2H).

[0368] Step 3: Synthesis of compound 48d

[0369] Under nitrogen atmosphere, compound 48c (450 mg, 1.49 mmol), compound A3 (649.3 mg, 1.64 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (54.5 mg, 0.07 mmol), potassium phosphate (632.2 mg, 2.98 mmol) were added to a mixed solution of 1,4-dioxane and water (20 mL / 2 mL) in sequence. The reaction mixture was stirred at 100 ° C for 48 hours. After the reaction was completed, the reaction solution was diluted with water (150 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0~6 / 1) to obtain compound 48d (440 mg). MS m / z(ESI):422.0[M+1] + .

[0370] Step 4: Synthesis of compound 48e

[0371] Compound 48d (420 mg, 0.99 mmol) was added to a mixed solution of dichloromethane and trifluoroacetic acid (2 mL / 0.2 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), and the pH was adjusted to 8 with a saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0~4 / 1) to obtain compound 48e (300 mg). MS m / z(ESI):322.1[M+1] + .

[0372] Step 5: Synthesis of compound 48f

[0373] At 0°C, sodium borohydride (53.0 mg, 1.40 mmol) was added to a methanol (10 mL) solution of compound 48e (300 mg, 0.93 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0~5 / 1) to obtain compound 48f (210 mg). MS m / z(ESI):324.1[M+1] + .

[0374] Step 6: Synthesis of compounds 48g, 48g-P1 and 48g-P2

[0375] At room temperature, compound 48f (210 mg, 0.65 mmol), cesium carbonate (634.7 mg, 1.95 mmol) and potassium iodide (323.4 mg, 1.95 mmol) were added to a solution of compound A2 (302.7 mg, 0.97 mmol) in N,N-dimethylformamide (10 mL) in sequence, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 4 / 1) to obtain compound 48g (298 mg). Compound 48g (298 mg) was separated by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IG SFC 20mm ID*250mmL, 5μm; mobile phase: CO2 / MeOH (0.1% NH3) = 60 / 40; flow rate: 48mL / min) to give compounds 48g-P1 (125 mg) and 48g-P2 (120 mg).

[0376] 48g-P1:MS m / z(ESI):597.4[M+1] + . Supercritical fluid chromatography SFC: retention time 3.298min, UV=254nm.

[0377] 48g-P2:MS m / z(ESI):597.4[M+1] + . Supercritical fluid chromatography SFC: retention time 5.738min, UV=254nm.

[0378] Step 7: Synthesis of compounds 48-P1 and 48-P2

[0379] Sodium hydroxide (40.2 mg, 1 mmol) was added to a mixture of methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL) of compound 48g-P1 (60 mg, 0.10 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 10-40%) to obtain 48-P1 (13.8 mg). MS m / z (ESI): 483.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.78(s,1H),10.82(s,1H),8.00–7.77(m,2H),7.59(s,1H),7.25(t,J=2.8 Hz,1H),6.65(s,1H),6.45(t,J=2.4Hz,1H),6.27–5.97(m,1H),3.95–3.79(m,1H),3.70(s,3H),3.55 (d,J=11.6Hz,1H),3.19(d,J=11.6Hz,1H),2.82(d,J=12.0Hz,1H),2.41(s,3H),2.20–2.01(m,2H), 1.84–1.68(m,4H),1.62(d,J=12.4Hz,1H),1.27–1.13(m,2H),1.07–0.98(m,2H),0.78–0.57(m,2H).

[0380] Sodium hydroxide (40.1 mg, 1 mmol) was added to a mixture of methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL) of compound 48g-P2 (60 mg, 0.10 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 10-40%) to obtain 48-P2 (20 mg). MS m / z (ESI): 483.20 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),10.82(s,1H),8.00–7.75(m,2H),7.59(s,1H),7. 25(t,J=2.8Hz,1H),6.65(s,1H),6.49–6.40(m,1H),6.27–5.97(m,1H),3.96–3.77(m,1H ),3.70(s,3H),3.55(d,J=11.6Hz,1H),3.19(d,J=11.6Hz,1H),2.82(d,J=11.6Hz,1H),2 .42(s,3H),2.22–2.03(m,2H),1.84–1.61(m,5H),1.23–0.98(m,4H),0.80–0.55(m,2H).

[0381] Intermediates A4-A7 can be synthesized using the method for synthesizing intermediate 48g in Example 10, replacing compound 48c with the reaction raw materials in the table to obtain the corresponding intermediate compounds:

[0382]

[0383]

[0384] Example 11 (Compounds 7-P1, 7-P2)

[0385]

[0386] Step 1: Synthesis of Compound A4-P1 or A4-P2

[0387] Compound A4 (110 mg) was separated by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: DaicelChiralpak AD-10SFC, 20 mm ID*250 mmL, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 75 / 25; flow rate: 85 mL / min) to give compounds A4-P1 (50 mg) and A4-P2 (51 mg).

[0388] Compound A4-P1: MS m / z (ESI): 558.5 [M+1] + . Supercritical fluid chromatography SFC: retention time = 3.500 min, UV = 214 nm.

[0389] Compound A4-P2: MS m / z (ESI): 558.5 [M+1] + . Supercritical fluid chromatography SFC: retention time = 4.282 min, UV = 214 nm.

[0390] Step 2: Synthesis of compound 7-P1 or 7-P2

[0391] Sodium hydroxide (34.6 mg, 0.83 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.3 mL / 0.3 mL / 0.3 mL) of compound A4-P1 (50 mg, 0.09 mmol). The reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 40 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain 7-P1 (23.2 mg). MS m / z (ESI): 444.4 [M+1] + . 1HNMR(400MHz,DMSO-d6)δ10.84(s,1H),8.77(s,1H),8.04(s,2H),7.26(t,J=2 .6Hz,1H),6.64(s,1H),6.48–6.38(m,1H),6.30–5.94(m,1H),3.69(s,3H),3.5 0(d,J=11.6Hz,1H),3.20(d,J=11.6Hz,1H),2.87–2.77(m,1H),2.41(s,3H),2. 04(t,J=11.6Hz,1H),1.83–1.58(m,5H),1.42–1.26(m,1H),1.22–1.09(m,1H).

[0392] Sodium hydroxide (34.6 mg, 0.83 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.3 mL / 0.3 mL / 0.3 mL) of compound A4-P2 (51 mg, 0.09 mmol). The reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 40 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain 7-P2 (22.1 mg). MS m / z (ESI): 444.3 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),8.80(s,1H),8.11–8.02(m,2H),7.26(t, J=2.8Hz,1H),6.64(s,1H),6.45–6.36(m,1H),6.30–5.93(m,1H),3.69(s,3H),3 .50(d,J=11.6Hz,1H),3.20(d,J=12.0Hz,1H),2.88–2.76(m,1H),2.41(s,3H),2 .04(t,J=11.6Hz,1H),1.84–1.57(m,5H),1.40–1.26(m,1H),1.22–1.09(m,1H).

[0393] Example 12 (Compounds 9-P1, 9-P2)

[0394]

[0395] Step 1: Synthesis of compounds A5-P1 and A5-P2

[0396] Compound A5 (140 mg) was purified by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: DaicelChiralpak IG SFC, 20 mm ID*250 mmL, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30; flow rate: 48 mL / min) to give compounds A5-P1 (60 mg), A5-P2 (50 mg)

[0397] A5-P1:MS m / z(ESI):587.4[M+1] + ,SFC: retention time 2.962min, UV=214nm.

[0398] A5-P2:MS m / z(ESI):587.4[M+1] + ,SFC: retention time 3.653min, UV=214nm.

[0399] Step 2: Synthesis of compound 9-P1 or 9-P2

[0400] Sodium hydroxide (40.8 mg, 1.02 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.6 mL / 0.6 mL / 0.6 mL) of compound A5-P1 (60.0 mg, 0.10 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by reverse phase preparation (chromatographic column: Airs Science FlashC18-M Column, 48 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm, 254 nm) to obtain compound 9-P1 (26.6 mg). MS m / z (ESI): 473.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),10.80(s,1H),7.86(d,J=8.0Hz,1H),7.65(d,J=8. 0Hz,1H),7.52(s,1H),7.24(t,J=2.6Hz,1H),6.65(s,1H),6.47–6.42(m,1H),6.26–5.93 (m,1H),3.89(s,3H),3.70(s,3H),3.59(d,J=12.0Hz,1H),3.14(d,J=11.6Hz,1H),2.82– 2.75(m,1H),2.41(s,3H),2.01(t,J=11.4Hz,1H),1.80–1.47(m,6H),1.26–1.05(m,2H).

[0401] Sodium hydroxide (34.0 mg, 0.85 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.5 mL / 0.5 mL / 0.5 mL) of compound A5-P1 (50.0 mg, 0.08 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (chromatographic column: AirsScience Flash C18-M Column, 48 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm, 254 nm) to obtain compound 9-P2 (30.8 mg). MS m / z (ESI): 473.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),10.81(s,1H),7.86(d,J=8.0Hz,1H),7.65(d,J=8. 0Hz,1H),7.52(s,1H),7.24(t,J=2.6Hz,1H),6.65(s,1H),6.48–6.42(m,1H),6.26–5.92 (m,1H),3.89(s,3H),3.70(s,3H),3.59(d,J=12.0Hz,1H),3.14(d,J=12.0Hz,1H),2.82– 2.72(m,1H),2.41(s,3H),2.01(t,J=12.0Hz,1H),1.83–1.41(m,6H),1.27–1.07(m,2H).

[0402] Example 13 (Compounds 37-P1, 37-P2)

[0403]

[0404] Step 1: Synthesis of compound 37a

[0405] At room temperature, trimethylsilyl azide (213.9 mg, 1.86 mmol) and dibutyltin diacetate (325.8 mg, 0.92 mmol) were added to a toluene (10 mL) solution of compound A6 (500 mg, 0.92 mmol), and the reaction mixture was stirred at 90°C for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (chromatographic column: C18 reverse column; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 20-40%) to obtain compound 37a (200 mg). MSm / z(ESI):581.4[M+1] + .

[0406] Step 2: Synthesis of compound 37b

[0407] Compound 37a (200 mg, 0.34 mmol) was added to a mixed solution of TFA and DCM (1 mL / 3 ml), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate (10 mL), extracted with dichloromethane (20 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (chromatographic column: C18 reverse column; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 20-40%) to obtain compound 37 (100 mg).

[0408] Compound 37 (100 mg) was purified by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: DaicelChiralpak IC SFC, 20 mm ID*250 mmL, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 60 / 40; flow rate: 48 mL / min) to obtain compound 37-P1 (26.6 mg) and compound 37-P2 (35.2 mg).

[0409] 37-P1:MS m / z(ESI):575.4[M+1] + , Supercritical fluid chromatography SFC: retention time 4.255min, UV=214nm. MS m / z (ESI): 481.5 [M+1] + . 1H NMR (400MHz, CD3OD) δ8.14(d,J=8.4Hz,1H),8.05(s,1H),7.72(d,J=8.4Hz,1H),7.32(d,J=3. 2Hz,1H),6.77(s,1H),6.36(d,J=2.8Hz,1H),6.01(tt,J=56.2,4.4Hz,1H),4.79(d,J=11.6Hz, 1H),4.42(d,J=12.4Hz,1H),4.19(d,J=12.4Hz,1H),3.77(s,3H),3.60–3.42(m,2H),2.61(s, 3H),2.50(s,3H),2.30–2.11(m,2H),2.09–1.97(m,1H),1.96–1.76(m,3H),1.73–1.58(m,1H).

[0410] 37-P2:MS m / z(ESI):573.3[M+1] + , Supercritical fluid chromatography SFC: retention time 6.458min, UV=214nm. MS m / z (ESI): 481.5 [M+1] + . 1 H NMR (400MHz, CD3OD) δ8.19–7.90(m,2H),7.85–7.66(m,1H),7.27(s,1H),6.74(s,1H),6.38(s,1H),6.17–5.81(m,1H) ,4.53–3.88(m,2H),3.77(s,3H),3.68–3.44(m,2H),2.58(s,3H),2.48(s,3H),2.19–1.98(m,2H),1.92–1.65(m,5H).

[0411] Example 14 (Compounds 39-P1, 39-P2)

[0412]

[0413] Step 1: Synthesis of compounds A7-P1 and A7-P2

[0414] Compound A7 (500 mg) was purified by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, preparative column: Daicel Chiralpak IG SFC 20mm ID*250mmL, 5μm; flow rate: 48ml / min; mobile phase: A: 70% CO2B: 30% methanol [0.1% NH3 (7M solution in MeOH)]) to obtain compound A7-P1 (100 mg) and compound A7-P2 (300 mg).

[0415] A7-P1:MS m / z(ESI):619.2[M+1] + . Chiral HPLC: retention time 2.707 min, UV = 214 nm.

[0416] A7-P2:MS m / z(ESI):619.2[M+1] + . Chiral HPLC: retention time 3.961 min, UV = 214 nm.

[0417] Step 2: Synthesis of compounds 39-P1 and 39-P2

[0418] NaOH (64.6 mg, 1.61 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.5 mL / 0.5 mL / 0.5 mL) of compound A7-P1 (100 mg, 0.16 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-30%) to obtain product 39-P1. (27.5 mg, yield). MS m / z (ESI): 490.9 [M+1] + . Supercritical fluid chromatography SFC: retention time = 2.411 min, UV = 214 nm. 1H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.86(s,1H),7.69–7.59(m,1H),7.54(d,J=1 2.0Hz,1H),7.26(s,1H),6.65(s,1H),6.46(s,1H),6.27–5.96(m,1H),3.69(s,3H), 3.65–3.54(m,1H),3.49–3.39(m,1H),3.25–3.12(m,1H),2.88–2.73(m,1H),2.46– 2.40(m,6H),2.05(s,1H),1.79–1.57(m,5H),1.49–1.41(m,3H),1.32–1.08(m,2H).

[0419] NaOH (193.6 mg, 4.84 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL) of compound A7-P2 (300 mg, 0.48 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and purified by Biotage-Flash rapid preparation instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-30%) to obtain product 39-P2 (64.8 mg). MS m / z (ESI): 491.0 [M+1] + . Supercritical fluid chromatography SFC: retention time = 1.984 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6)10.83(s,1H),7.86(s,1H),7.65(t,J=8.8Hz,1H),7.53(d,J=1 2.0Hz,1H),7.26(s,1H),6.65(s,1H),6.46(s,1H),6.27–5.96(m,1H),3.69(s,3H),3 .63–3.56(m,1H),3.46–3.42(m,1H),3.21–3.13(m,1H),2.86–2.76(m,1H),2.45–2.4 0(m,6H),2.16–1.95(m,1H),1.78–1.60(m,5H),1.48–1.40(m,3H),1.30–1.09(m,2H).

[0420] Example 15 (Compound 45-P1)

[0421]

[0422] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (64.5 mg, 0.17 mmol), 1-hydroxybenzotriazole (22.9 mg, 0.17 mmol) and N,N-diisopropylethylamine (43.8 mg, 0.34 mmol) were added to a solution of compound 1-P1 (50 mg, 0.11 mmol) in DMF (1 mL) and amine in tetrahydrofuran (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the residue was purified by reverse column (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-40%; column temperature: 25°C; flow rate: 40 mL / min; wavelength: 214 nm; column pressure: 50 bar) to obtain compound 45-P1 (18.0 mg). MS m / z(ESI):442.20[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),7.93(s,1H),7.87(d,J=8.2Hz,2H),7.59(d,J=8.0Hz,2H),7.3 0(s,1H),7.25(t,J=2.7Hz,1H),6.65(s,1H),6.55–6.47(m,1H),6.17(tt,J=56.2,4.4Hz,1H),3.71(s ,3H),3.62(d,J=11.9Hz,1H),3.47(d,J=8.1Hz,1H),3.31(s,1H),2.60–2.53(m,1H),2.42(s,3H),2.2 5(t,J=11.1Hz,1H),2.12–1.93(m,3H),1.88–1.76(m,1H),1.69–1.52(m,2H),1.46(d,J=13.0Hz,1H).

[0423] Example 16 (Compound 31-P1)

[0424]

[0425] Step 1: Synthesis of compound 31a

[0426] Under nitrogen protection, potassium tert-butoxide solution (6.54 mL, 6.54 mmol) was slowly added to a mixed solution of trimethylsulfoxide iodide (1.44 g, 6.54 mmol) in THF and DMSO (10 mL / 10 mL). After the mixture was stirred at room temperature for 0.5 hours, a solution of compound B1 (2 g, 5.45 mmol) in DMSO (10 mL) was added, and the reaction mixture was stirred at 30°C for 16 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL×3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1~2 / 1) to obtain compound 31a (1.81 g). MS m / z (ESI): 382.4 [M+1] + .

[0427] Step 2: Synthesis of compound 31b

[0428] At room temperature, tri(pentafluorophenyl)borane (1.34 g, 2.62 mmol) was added to a toluene (20 mL) solution of compound 31a (1 g, 2.62 mmol), and the reaction mixture was stirred at 30°C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1-2 / 1) to obtain compound 31b (0.81 g). MS m / z (ESI): 382.2 [M+1] + .

[0429] Step 3: Synthesis of compound 31c

[0430] At room temperature, (triphenylphosphonium) difluoroacetic acid inner salt (1.50 g, 4.20 mmol) was added to a solution of compound 31b (800 mg, 2.10 mmol) in NMP (15 mL), and the reaction mixture was stirred at 40°C for 4 hours. After the reaction was completed, the reaction solution was diluted with an aqueous solution (100 mL), extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with saturated brine (50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=40 / 1-5 / 1) to obtain compound 31c (570 mg). MS m / z (ESI): 416.4 [M+1] + .

[0431] Step 4: Synthesis of compound 31d

[0432] At room temperature, TMSI (1.30 g, 6.51 mmol) was added to a DCM (10 mL) solution of compound 31c (540 mg, 1.30 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH>7 with saturated sodium bicarbonate solution, extracted with DCM (30 mL×3), and the crude product was purified by silica gel column chromatography (DCM / MeOH=50 / 1~10 / 1) to obtain compound 31d (340 mg). MS m / z (ESI): 282.2 [M+1] + .

[0433] Step 5: Synthesis of compound 31f

[0434] At room temperature, compound 31d (150 mg, 0.53 mmol), cesium carbonate (694.9 mg, 2.13 mmol) and potassium iodide (177.0 mg, 1.06 mmol) were added to a solution of compound 31e (314.4 mg, 1.06 mmol, synthesis reference patent WO2023072197A1 specification page 47 synthesis of intermediate compound A8) in N, N-dimethylformamide (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 31f (100 mg). MS m / z (ESI): 539.2 [M+1] + .

[0435] Step 6: Synthesis of compound 31g

[0436] Pd / C (70 mg) was added to a methanol (5 mL) solution of compound 31f (150 mg, 0.28 mmol), and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, washed with ethyl acetate (20 mL), and the combined organic phase was concentrated under reduced pressure to obtain compound 31g (100 mg). The crude product was used directly in the next step without purification. MS m / z (ESI): 541.3 [M+1] + .

[0437] Step 7: Synthesis of compound 31-P1

[0438] Sodium hydroxide (73.8 mg, 1.85 mmol) was added to a mixed solution of compound 31g (100 mg, 0.18 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, concentrated under reduced pressure, and the residue was purified by Biotage-Flash rapid preparation instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 10%-30%) to obtain compound 31-P1 (29.6 mg). MS m / z (ESI): 427.1 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ12.72(s,1H),10.84(s,1H),7.93(d,J=8.0Hz,2H),7.62(d,J=8.4 Hz,2H),7.22(t,J=2.6Hz,1H),6.65(s,1H),6.59–6.50(m,1H),6.32–5.99(m,1H),3.63(d, J=12.4Hz,1H),3.56–3.50(m,1H),3.39–3.37(m,1H),2.47–2.41(m,1H),2.37(s,3H),2.31 –2.21(m,4H),2.12–1.89(m,4H),1.72–1.63(m,1H),1.61–1.52(m,1H),1.51–1.42(m,1H).

[0439] Example 17 (Compounds 52-P1, 52-P2)

[0440]

[0441] Step 1: Synthesis of compound 52b

[0442] [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.50 g, 2.05 mmol) was added to a solution of compound 52a (5 g, 20.57 mmol), pinacol diboron (6.27 g, 24.68 mmol) and potassium acetate (6.05 g, 61.71 mmol) in 1,4-dioxane (100 mL), and the reaction mixture was stirred at 90°C for 16 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution, which was washed with water (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain compound 52b (5 g). MS m / z(ESI):291.3[M+1] + .

[0443] Step 2: Synthesis of Compound 52c

[0444] [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (831.1 mg, 1.13 mmol) was added to a mixed solution of compound 52b (4.94 g, 17.03 mmol), compound A3 (4.50 g, 11.35 mmol) and potassium phosphate (7.23 g, 34.06 mmol) in 1,4-dioxane and water (100 mL / 20 mL), and the reaction mixture was stirred at 90°C for 16 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution, which was washed with water (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain compound 52c (1.5 g). MS m / z(ESI):410.3[M+1] + .

[0445] Step 3: Synthesis of Compound 52d

[0446] Palladium / carbon (10wt%, 750mg) was added to a methanol (50mL) solution of compound 52c (1.50g, 3.65mmol), and the reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=2 / 1) to obtain compound 52d (1.30g). MS m / z (ESI): 414.4 [M+1] + .

[0447] Step 4: Synthesis of compound 52e

[0448] At room temperature, Dess-Martin periodinane (2.66 g, 6.27 mmol) was added to a solution of compound 52d (1.30 g, 3.13 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain compound 52e (1 g). MS m / z(ESI):412.3[M+1] + .

[0449] Step 5: Synthesis of Compound 52f

[0450] At 0°C, diethylaminosulfur trifluoride (1.95 g, 12.12 mmol) was added to a dichloromethane (20 mL) solution of compound 52e (1 g, 2.42 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 52f (1 g, crude product). MS m / z (ESI): 434.2 [M+1] + .

[0451] Step 6: Synthesis of Compound 52g

[0452] At room temperature, trifluoroacetic acid (7 mL) was added to a solution of compound 52f (1 g, 2.30 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 52g (0.50 g). MS m / z (ESI): 334.2 [M+1] + .

[0453] Step 7: Synthesis of compounds 52h, 52h-P1 and 52h-P2

[0454] At room temperature, cesium carbonate (1.76 g, 5.40 mmol), compound 31e (839.1 mg, 2.70 mmol) and potassium iodide (448.2 mg, 2.70 mmol) were added to a DMF (10 mL) solution of compound 52g (450 mg, 1.35 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1) to give compound 52h (200 mg). Compound 52h (200 mg) was purified by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IJ SFC 20 mm ID*250 mmL, 5 μm; mobile phase: A: 80% CO2 B: 20% MeOH [0.1% NH3 (7M solution in MeOH)]; flow rate: 38 ml / min] to obtain compound 52h-P1 (70 mg) and compound 52h-P2 (80 mg)

[0455] 52h-P1:MS m / z(ESI):607.5[M+1] + . Supercritical fluid chromatography SFC: retention time 3.567min, UV=254nm.

[0456] 52h-P2:MS m / z(ESI):607.5[M+1] + . Supercritical fluid chromatography SFC: retention time 4.484min, UV=254nm.

[0457] Step 8: Synthesis of compounds 52-P1 and 52-P2

[0458] Sodium hydroxide (46.1 mg, 1.15 mmol) was added to a mixed solution of compound 52h-P1 (70 mg, 0.11 mmol) in methanol / tetrahydrofuran / water (0.7 mL / 0.7 mL / 0.7 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, and the mixed solution was concentrated under reduced pressure. The residue was purified by reverse phase preparation (chromatographic column: Airs Science Flash C18-M Column, 40 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-40%; flow rate: 50 mL / min; wavelength: 214 nm, 254 nm) to obtain compound 52-P1 (37.1 mg). MS m / z (ESI): 493.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),10.84(s,1H),8.15(s,3H),7.72–7.30(m,1H ),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.43–6.38(m,1H),6.10(tt,J=56.4,4.6Hz, 1H),3.71–3.57(m,4H),3.53–3.42(m,1H),3.20(d,J=5.8Hz,1H),2.79(d,J=11.6H z,1H),2.42(s,3H),2.07(t,J=11.8Hz,1H),1.84–1.58(m,5H),1.37–1.07(m,2H).

[0459] Sodium hydroxide (52.7 mg, 1.32 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.8 mL / 0.8 mL / 0.8 mL) of compound 52h-P2 (80 mg, 0.13 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with acetic acid, and the mixed solution was concentrated under reduced pressure. The residue was purified by reverse phase preparation (chromatographic column: Airs Science Flash C18-M Column, 40 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-40%; flow rate: 50 mL / min; wavelength: 214 nm, 254 nm) to obtain compound 52-P2 (38.1 mg). MS m / z (ESI): 493.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),10.84(s,1H),8.16(s,2H),7.70–7.28(m, 1H),7.26(t,J=2.6Hz,1H),6.65(s,1H),6.42–6.37(m,1H),6.26–5.93(m,1H),3 .72–3.55(m,4H),3.53–3.42(m,1H),3.20(d,J=11.2Hz,1H),2.79(d,J=11.6Hz, 1H), 2.42 (s, 3H), 2.07 (t, J = 11.2Hz, 1H), 1.84–1.58 (m, 5H), 1.37–1.06 (m, 2H).

[0460] Example 18 (Compounds 27-P1, 27-P2)

[0461]

[0462] Step 1: Synthesis of compound 27a

[0463] Compound 1a (1 g, 2.62 mmol) and tri(pentafluorophenyl)borane (1.34 g, 2.62 mmol) were dissolved in 20 mL toluene at room temperature, and the reaction mixture was stirred at 30°C for 16 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to quench, and ethyl acetate was extracted (50 mL×3). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound 27a (0.81 g). MS m / z (ESI): 382.2 [M+1] + .

[0464] Step 2: Synthesis of compound 27b

[0465] Potassium tert-butoxide (5.92 mL, 5.92 mmol) was added to a 30 mL THF solution of compound 27a (1.88 g, 49 mmol) at 0°C, stirred at 0°C for 15 minutes, and then iodomethane (3.5 g, 0.025 mol) was added, and the mixture was stirred at 0°C for 30 minutes. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with EA (50 mL×3), and the combined organic phase was washed with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1~5 / 1) to obtain compound 27b (1.02 g). MS m / z(ESI):396.4[M+1] + .

[0466] Step 3: Synthesis of Compound 27c

[0467] Compound 27b (390 mg, 0.99 mmol) and (triphenylphosphonium) difluoroacetic acid inner salt (1.05 g, 2.96 mmol) were added to 4 mL of NMP solution at room temperature, and the reaction mixture was stirred at 100°C for 24 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with EA (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA=101~3 / 1) to obtain compound 27c (317 mg). MS m / z(ESI):430.3[M+1] + .

[0468] Step 4: Synthesis of compound 27d

[0469] Pd / C (270 mg) was added to a 20 mL THF solution of compound 27c (547 mg, 1.27 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 27d (350 mg, crude product). MS m / z (ESI): 298.3 [M+1] + .

[0470] Step 5: Synthesis of compounds 27e, 27e-P1 and 27e-P2

[0471] Sodium acetate borohydride (500 mg, 2.36 mmol) was added to a solution of compound 27d (175 mg, 0.59 mmol) and compound A1 (256 mg, 0.88 mmol) in 8 mL THF at room temperature, and the reaction mixture was stirred at 40° C. for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL×3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=20 / 1-10 / 1) to give compound 27e (250 mg). Compound 27e (250 mg, trans configuration) was purified by chiral preparation [equipment: Gilson GX-281, column: chiralpark IE 250 mm*30 mm10 um; mobile phase: Hex / EtOH=95 / 5; flow rate: 25 mL / min] to obtain compound 27e-P1 (30 mg) and compound 27e-P2 (190 mg).

[0472] 27e-P1:MS m / z(ESI):571.6[M+1] + . Chiral HPLC: retention time 6.95 min, UV = 254 nm.

[0473] 27e-P2:MS m / z(ESI):571.6[M+1] + . Chiral HPLC: retention time 8.67 min, UV = 254 nm.

[0474] Step 6: Synthesis of compounds 27-P1 and 27-P2

[0475] NaOH (21 mg, 0.53 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (0.3 mL / 0.3 mL / 0.3 mL) of compound 27e-P1 (30 mg, 0.053 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the crude product was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% HCOOH); gradient: 20-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 27-P1 (11.1 mg). MS m / z (ESI): 457.1 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.80(s,1H),7.95(d,J=8.8Hz,2H),7.64(d,J=7.2Hz,2H),7.24(t,2.8 Hz,1H),6.65(s,1H),6.48(q,J=2.0Hz,1H),6.41-6.07(m,1H),3.70(s,3H),3.56(d,J=11.6Hz,1H ),3.42(d,J=16.4Hz,1H),3.22(d,J=16.0Hz,1H),2.57-2.53(m,1H),2.49(s,3H),2.28-2.23(m,1 H), 2.11-2.01 (m, 2H), 1.57 (d, J = 13.6Hz, 1H), 1.45-1.41 (d, 2H), 1.38-1.23 (m, 1H), 0.95 (s, 3H).

[0476] NaOH (112 mg, 2.8 mmol) was added to a mixed solution of methanol / tetrahydrofuran / water (1.6 mL / 1.6 mL / 1.6 mL) of compound 27e-P2 (160 mg, 0.28 mmol), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5 with AcOH, concentrated under reduced pressure, and the crude product was purified by HPLC preparative chromatography (chromatographic column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-45%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 27-P2 (109.5 mg). MS m / z (ESI): 457.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.95(d,J=8.8Hz,2H),7.65(d,J=7.2Hz,2H),7.2 4(t,2.8Hz,1H),6.65(s,1H),6.48(q,J=2.0Hz,1H),6.41-6.07(m,1H),3.72(s,3H),3.54 (d,J=12.0Hz,1H),3.44(d,J=6.8Hz,1H),3.24(d,J=12.0Hz,1H),2.57(d,J=12.0Hz,1H) ,2.41(s,3H),2.24(t,J=11.2Hz,1H),1.77-1.66(m,2H),1.56-1.23(d,4H),1.12(s,3H).

[0477] Biological Examples

[0478] 1. Complement hemolytic activity detection

[0479] Hemolysis experiment is described in Xuan Yuan et al., Haematologica. (2017) 102: 466-475. Before the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit red blood cells (RE) was obtained by titration test. In this experiment, NHS (obtained from healthy volunteers) was added to GVB containing 10 mM Mg-EGTA. 0 The cells were diluted in buffer (0.1% gelatin, 5 mM Vironal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement technology) and incubated with various concentrations of the test compound at 37°C for 15 min. 0 RE (from healthy Japanese white rabbits) was added to the buffer to reach 1×10 8 The final concentration of cells / ml was 100 μg / ml and incubated at 37°C for 30 min. The positive control (100% lysis) consisted of GVB containing 10 mM Mg-EGTA with NHS and RE but without test compound. 0 Buffer composition; negative control (0% lysis) consisted of GVB containing 10 mM Mg-EGTA with inactivated NHS (heated at 56°C for 30 min or 65°C for 5 min) and RE but without test compound 0 Buffer composition. The samples were centrifuged at 2000 g for 5 min and the supernatant was collected. The absorbance at 415 nm (A415) was measured using an ELISA reader (Molecular Devices, SpectraMax i3X). IC 50 The values ​​were calculated by nonlinear regression from the percentage of hemolysis as a function of the concentration of the test compound and the test results are shown in Table 1 .

[0480] Table 1

[0481] Example No. Compound No. <![CDATA[Hemolytic IC 50 (nM)]]> 1 1-P1 80.01 2 2-P1 186 3 3-P1 36.4 4 4-P1 111.7 5 5-P1 90.65 6 6-P1 95.08 7 10-P1 87.79 8 13-P1 135.4 9 14-P1 173.5 10 48-P1 65.97 11 7-P2 96.34 12 9-P1 94.99 13 37-P1 39.73 14 39-P1 121.8 15 45-P1 46.20 16 31-P1 32.50 17 52-P2 87.85 18 27-P1 93.99

[0482] 2. Wieslab complement alternative pathway activation inhibition experiment

[0483] The monkey serum complement alternative pathway activity test was performed using the Wesilab assay kit ( Complement systemAlternative pathway, AP330RUO) for detection. Take out the 96-well plate in the kit as needed, equilibrate at room temperature for 30 minutes, and seal the remaining wells at 4°C; add the positive control (monkey serum before administration) diluted 18 times by Diluent AP in the kit, the negative control (100μL monkey serum before administration, heated in a 56°C water bath for 30 minutes) and the sample to be tested to the well plate, 100μL / well, and 100μL Diluent AP as a blank control. Seal the plate with a transparent sealing film, cover with a lid, incubate at 37°C for 65 minutes, pour out the liquid in the well, add 1X washing buffer, 300μL / well, repeat 3 times, and try to pat the liquid in the well plate dry for the last time. Add 100 μL of conjugate to each well, incubate at room temperature (20-25°C) for 30 minutes, and then repeat the plate washing operation; add substrate solution, 100 μL / well, protect from light, incubate at room temperature (20-25°C) for 30 minutes, and read the OD405 value immediately, or add 5 mM EDTA to terminate the reaction and read the OD405 value within 60 minutes. Calculate the complement activity according to the formula % complement activity = (Sample-NC) / (PC-NC) * 100, and analyze the data.

[0484] 3.TR-FRET binding assay

[0485] Competitive binding experiments using Cy5 fluorescently labeled small molecule inhibitors as probes were used to screen compounds for their inhibitory activity against human complement factor B. Complement factor B and EZ-Link TM After incubation of Sulfo-NHS-LC-LC-Biotin at a ratio of 1:2 on ice for 1 hour, 1M Tris (pH 7.5) was added to terminate the reaction. TM Desalt spin column purification was performed twice to obtain biotin-labeled complement factor B (EZ-LinkTM Sulfo-NHS-LC-Biotin instruction manual). During the experiment, biotin-labeled complement factor B with a final concentration of 10 nM was taken and pre-incubated with different concentrations of compounds in buffer at room temperature for 1 hour. Cy5 fluorescent-labeled probes and europium chelate-labeled streptavidin (PerkinElmer, #AD0060) were added at final concentrations of 75 nM and 5 nM, respectively, to start the reaction. Kinetic readings were performed on an ELISA reader (337 nm excitation light, 665 nm emission light, 70 μs time-gated), and the time-dependent fluorescence energy transfer (TR-FRET) data were read to determine the IC 50 .

[0486] 4. Optical surface plasmon resonance (SPR) binding force detection

[0487] The SPR experiment was conducted at 25°C with PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO as the running buffer, and the analytical instrument used was GE Healthcare's Biacore 8K. 400mM EDC and 100mM NHS activated the CM7 chip (GE Healthcare) at a flow rate of 30μL / min for 420s. Complement factor B was diluted to 50μg / mL with 10mM sodium acetate (pH 4.0), and then coupled at a flow rate of 10μL / min for 1200s to covalently fix complement factor B to the detection chip (protein immobilization level was 25000RU); then the detection chip was blocked with 1M ethanolamine hydrochloride at a flow rate of 10μL / min for 300s. The concentration of the test compound was 500μM, the binding time was 120s, and the dissociation time was 300s. The data were analyzed using a 1:1 binding model (Biacore Insight Evalution Software, Version 2.0.15.12933).

[0488] 5. Experimental evaluation of the inhibitory effect of the test substance on the alternative pathway of the human serum complement system

[0489] The test compound was tested at a starting concentration of 10 μM, 3-fold dilution, 8 concentration points, and a final DMSO concentration of 0.1%. Repeated well detection. Take out a Human Serum (Complement Technology, NHS) from the -80°C ultra-low temperature refrigerator, wait for it to completely melt on ice, gently pipette to mix, and use Diluent AP ( COMPLEMENT SYSTEM ALTERNATIVEPATHWAY AP330RUO) was diluted into 1.25x Human Serum working solution, and an appropriate amount of Human Serum was taken out and heated in a 56℃ water bath for 30 minutes to inactivate, and also diluted into 1.25x inactivated working solution as NC control. 25μL of compound working solution and 100μL of 1.25x Human Serum working solution were added to the 96-well plate in sequence, 25μL of 5‰ DMSO and 100μL of 1.25x Human Serum working solution were added to the PC control wells, and 25μL of 5‰ DMSO and 100μL of 1.25x Human Serum inactivated working solution were added to the negative control wells. The mixture was gently mixed on a microplate constant temperature oscillator, and 100μL of the above mixture was taken out after incubation at room temperature for 15 minutes, and gently transferred to the pre-coated (LPS-containing) well plate ( COMPLEMENT SYSTEM ALTERNATIVEPATHWAY AP330RUO provided), take another 100μL Diluent AP as a blank control, avoid bubbles, incubate at 37℃ for 65min; pour out the liquid in the well, add 1X washing buffer, 300μL / well, repeat 4 times, and try to dry the liquid in the well plate for the last time. Add 100μL conjugate to each well, incubate at room temperature (20-25℃) for 30min, and then repeat the plate washing operation; add substrate solution, 100μL / well, avoid light, incubate at room temperature (20-25℃) for 30min, and read the OD405 value immediately, or add 5mM EDTA to stop the reaction and read the OD405 value within 60min. Calculate the complement activity according to the formula %complement activity=(Sample-NC) / (PC-NC)*100, and analyze the data.

[0490] 6. Liver microsome stability test

[0491] (1) Preparation of buffer

[0492] Take a 0.1 M dipotassium hydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid), and then use a 0.1 M dipotassium dihydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid) to adjust the pH to 7.4.

[0493] (2) Microsome source and preparation of working solution

[0494] Microsome Source:

[0495] Mouse: ICR / CD-1 Liver Microsomes, Cat. No.: M00501, Bioreclamation IVT.

[0496] Rat: SD Rat Liver Microsomes, Cat. No.: LM-DS-02M, RILD Reid Liver Disease Research (Shanghai) Co., Ltd.

[0497] Dog: Beagle Dog Liver Microsomes, Cat. No.: M00201, BioreclamationIVT.

[0498] Monkey: Cynomolgus Monkey Liver Microsomes, Cat. No.: LM-SXH-02M, RILD (Shanghai) Liver Disease Research Co., Ltd.

[0499] Human: Pooled Human Liver Microsomes (Mongolian), Cat. No.: LM-R-02M, RILD Reid Liver Disease Research (Shanghai) Co., Ltd.

[0500] Preparation of working fluid

[0501] Prepare a 10mM solution of the test compound with DMSO, then take 10μL and add it to 190μL acetonitrile to prepare a 0.5mM stock solution. Take 1.5μL of the 0.5mM stock solution of the compound, add 18.75uM 20mg / mL liver microsomes and 479.75μL of buffer. (The actual preparation amount can be adjusted according to the usage).

[0502] (3) Experimental process

[0503] Prepare 10 mg / mL NADPH with buffer. Place a 96-well plate on ice, set corresponding wells for each compound at different time points (0, 10, 30, 60, 90 minutes, Non-NADPH), and add 30 μL of working solution to each well. For the 0min well, first add 155 μL of glacial acetonitrile solution (internal standard concentration is 1 μM), mix with a pipette, and then add 15 μL of NADPH (10 mg / mL). Before starting the reaction, pre-incubate the 96-well plate on a thermostatic microplate shaker (37°C) for 5 minutes, and then add 15 μL of NADPH (10 mg / mL) to each well to start the metabolic reaction. After 10, 30, 60, and 90 minutes of reaction, add 155 μL of glacial acetonitrile solution (internal standard concentration is 1 μM) to the corresponding wells to terminate the reaction. After 90 minutes, the Non-NADPH system adds 155 μL of glacial acetonitrile solution (internal standard concentration is 1 μM) to terminate the reaction. After the reaction, the 96-well plate was shaken for 10 minutes using a microplate shaker (600 rpm), and then centrifuged at 4°C and 4000 g for 15 minutes. 50 μL of the supernatant was added to a new 2 mL 96-well plate, and then 300 μL of deionized water was added. The samples were analyzed using an AB SCIEXExion LC-Triple Quad 5500 high performance liquid chromatography-mass spectrometry instrument, and the software used was Analyst 1.6.3.

[0504] 7. Hepatocyte Experiment

[0505] (1) Reagent information

[0506] Williams E Medium: Gibco, Lot No.: 2336217.

[0507] GlutaMAX (100x): Gibco, Lot No.: 22777239.

[0508] Dexamethasone: NICPBP.

[0509] Human-insulin: Gibco, 12585-014.

[0510] FBS:Corning, 35-076-CV.

[0511] DPBS:Gibco,2224922.

[0512] HEPES: Sigma, RNBH8969.

[0513] Isotonic percoll: Cytiva, 10303640.

[0514] (2) Cell sources and preparation of working solution

[0515] Cell source

[0516] Person: BioIVT, Product No.: X008001;

[0517] Monkey: Cynomolgus, RILD, Product No.: HP-SXH-02M;

[0518] Dog: Beagle, TPCS, Product No.: CDH-100BE-SQ;

[0519] Rat: SD, BioIVT, Product No.: M00005;

[0520] Mouse: CD-1, TPCS, Product No.: CMH-100CD-SQ.

[0521] Preparation of working fluid

[0522] The compound was diluted to 10 mM with DMSO and diluted to 100 μM with 50% acetonitrile in water.

[0523] (3) Experimental process

[0524] Preheat the incubation medium and thawing medium at 37°C for 15 min. Take out the hepatocytes from the liquid nitrogen tank, thaw at 37°C, transfer to thawing medium, centrifuge briefly, and transfer to a safety cabinet. AO / PI staining was used to detect the cell number and cell activity, and the incubation medium was diluted to a working concentration of 0.5×10 6 / mL. Add 2μL of compound working solution to 198μL of liver cell solution. After mixing, incubate under 5% CO2 and 37℃. Samples are taken at 0.5, 15, 30, 60, 90 and 120min reaction time points. Take 25μL of reaction solution at each time point and add 150μL of ACN containing internal standard (100nM alprazolam, 200nM caffeine and 100nM tolbutamide) and vortex quench for 5min. All samples are centrifuged at 3,220g for 45min. Take 100μL of supernatant and add 100μL of deionized water to mix.

[0525] LC / MS / MS analysis using Triple Quad TM The analysis was performed using a 5500 high performance liquid chromatography-mass spectrometer, and the software used was Analyst 1.6.3.

[0526] 8. Protein binding rate experiment

[0527] Buffer preparation

[0528] Phosphate buffer: Cat. No.: E607008-0500, BBI.

[0529] (1) Plasma source and working solution preparation

[0530] Plasma source:

[0531] Human plasma was purchased from Wuhan Pure Biotechnology Co., Ltd.

[0532] Animal plasma, collected or from CRO.

[0533] (2) Preparation of working fluid:

[0534] Preparation of compound working solution 1: Pipette 1 μL of compound DMSO stock solution (10 mM) into 99 μL ACN acetonitrile to prepare compound working solution 1 with a concentration of 200 μM. Take an appropriate amount of compound working solution 1 and add it to an appropriate volume of plasma (or serum), mix well to obtain working solution 2 with a final concentration of 1 μM.

[0535] (3) Experimental process

[0536] Insert the equilibrium dialysis system into the corresponding well of the RED Devices plate, add 100 μL of working solution 2 to the red Plasma chamber, add 350 μL of PBS to the Buffer chamber, cover the above equilibrium dialysis reaction plate with a sealing film, and incubate in a constant temperature oscillator at 37°C and 250 rpm for about 4 hours. After the incubation, a certain volume of sample (usually multiples of 25 μL) is transferred from the Buffer Chamber and Plasma Buffer to a centrifuge tube or deep-well plate (stored at -20°C) for later use. Take 25 μL of each of the dialyzed plasma sample and buffer sample and add them to a 96-well plate. Add 25 μL of PBS to the removed plasma sample, add 25 μL of plasma to the buffer sample, add 300 μL of pre-prepared ice-cold precipitant containing internal standard (toluene yellow butyric acid urea, final concentration 1 μM), and shake at 400 rpm for 5 minutes. Preparation of samples at time point T0: Take 25 μL of working solution 2 prepared in 2.2.2 and add it to a 96-well plate, then add 25 μL of PBS and mix well, then add 300 μL of ice-cold precipitant containing internal standard (toluene yellow butyric acid urea), shake at 400 rpm for 5 minutes, and repeat in duplicate. Centrifuge the above precipitated samples at 4°C and 4000 rpm for 15 minutes. Take the supernatant after centrifugation, dilute it 4 times with ultrapure water, load it, and analyze it with AB SCIEX ExionLC-Triple Quad 5500 high performance liquid chromatography-mass spectrometry, and the software used is Analyst 1.6.3.

[0537] 9. Caco-2 permeability test

[0538] (1) Source and preparation of buffer and cell culture medium

[0539] HBSS: Sigma-Aldrich, Cat#: H8264;

[0540] FBS: Gibco, Cat#: 10091148;

[0541] Hepes:Gibco,Cat#:15630106;

[0542] DMEM: Gibco, Cat#: 11995-065;

[0543] Trypsin: Gibco, Cat#: 25200-056;

[0544] DPBS: Gibco, Cat#: 14190-144;

[0545] MEM NEAA: Gibco, Cat#: 11140050;

[0546] Pen Strep: Gibco, Cat#: 15140-122;

[0547] 24-Multiwell insert system: corning, Cat#: 351181;

[0548] 24-Multiwell cell plate: corning, Cat#: 353047.

[0549] Preparation of cell culture medium: Add 50 mL of FBS, 5 mL of Pen Strep and 5 mL of MEM NEAA to DMEM medium (500 mL / bottle). Mix well.

[0550] HBSS (containing Hepes) was prepared for the experiment: 12.5 mL of Hepes was added to 487.5 mL of HBSS and the pH was adjusted to 7.4.

[0551] (2) Cell culture and preparation of working solution

[0552] Aspirate the culture medium in the culture flask with a sterile pipette tip, and then aspirate 10mL of DPBS into the culture flask to rinse it, and repeat the washing with DPBS once. Aspirate 1mL of 0.25% Trypsin, rinse the cells once, then aspirate 2mL of 0.25% Trypsin, gently shake the culture flask, cover it with a lid and place it in an incubator, and perform enzymatic hydrolysis until the cells fall off. Aspirate 8mL of culture medium, mix it with the cells, and aspirate it into a 15mL centrifuge tube, and centrifuge it at 1000rpm for about 5 minutes. Pour out the upper culture medium. Add 10mL of culture medium and mix it by pipetting. Take out about 1mL of enzymatically hydrolyzed cells and put it into a 1.5mL centrifuge tube, take 20μL of cell fluid and mix it with 20μL of trypan blue solution, then take 10μL into the cell counting plate, the cell counter will give data, and write down the data. According to the number of living cells obtained, dilute with DMEM culture medium to 3.2*10 4 / mL, add 400μL cell solution to each well. And gently tap the surroundings. Add 30mL MEM culture medium to the lower layer. Wipe the surroundings of the cell plate with alcohol cotton balls, transfer to the incubator, and culture at 5% CO2, 37℃. The cell plate needs to be replaced every 3-4 days. Use a Millipore resistor meter to measure the cell resistance to determine the cell state. When the resistance is greater than 600Ω, it can be used for the next experiment. Each cell generation, as well as the date of plating, the number of cells are recorded and kept for future reference.

[0553] The compound was diluted to 10 mM with DMSO, and 5 μL of 10 mM compound solution was added to 5 mL HBSS (containing Hepes) to obtain the compound working solution.

[0554] (3) Experimental process

[0555] Preheat HBSS (containing Hepes) to 37°C, detect the resistance of the cell plate and record it, remove the cell plate culture medium, rinse once with HBSS (containing Hepes), add the compound working solution to the Donor end, and add the HBSS (containing Hepes) solution to the Receive end. The cell plate was placed in 5% CO2, 37°C for 10 minutes. Take out 100μL of the Donor end and the Receive end after equilibrium as the sample at 0min. The cell plate was placed in 5% CO2, 37°C for 90 minutes, and the Donor end and the Receive end solution were taken out as the 90min sample. Take 50μL of the 0min sample and the 90min sample, add 300μL of ACN solution (containing 10ng / mL toluene yellow butyric acid as the internal standard), and shake to mix. Centrifuge at 4,000rpm, 4°C for 10 minutes, take 100μL, add 100μL of deionized water, mix well, and analyze. AB SCIEX ExionLC-Triple Quad 5500 high performance liquid chromatography-mass spectrometry was used for analysis, and the software used was Analyst 1.6.3.

[0556] 10. Single-dose PK experiment in mice

[0557] ICR male mice weighing ~25g (Shanghai Bikekeji Biotechnology Co., Ltd.) were fasted overnight, 3 mice in each group, and administered by gavage. The test compound was given at a volume of 10mL / kg. Blood was collected through the eye sockets, 30μL at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000rpm*5min, 4℃, and the supernatant was taken. The samples were frozen in a -80℃ refrigerator until detection. Blood collection time points: before administration, 15min, 30min, 1h, 2h, 4h, 7h, 24h. The animal status was observed at any time after administration. After blood collection at all time points, the animals were euthanized. Plasma samples were measured by LC-MS / MS, and the data were calculated using WinNonlin software for kinetic parameter calculation.

[0558] 11. Single-dose PK experiment in rats

[0559] Experimental methods:

[0560] Wistar han male rats aged 6-9 weeks (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) were used, fasted overnight, 3 rats in each group, and administered by gavage. The test compound was administered at a volume of 10 mL / kg. Blood was collected through the jugular vein, 0.2 mL at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000 rpm*5 min, 4°C, and the supernatant was taken. The samples were frozen in a -80°C refrigerator until detection. Blood collection time points: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h. The state of the animals was observed at any time after administration. After blood collection at all time points, the animals were euthanized. Plasma samples were measured by LC-MS / MS, and the data were calculated using WinNonlin software for kinetic parameter calculation.

[0561] The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims

1. A compound represented by formula (IG) or a pharmaceutically acceptable salt thereof, in: n is 1 or 2; G 1 CR 8 or N; G 2 CR 9 or N; R 8 and R 9 are the same or different and are each independently selected from H, OH, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and 3-8 membered cycloalkyl; R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl; R 2 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl and 3-8 membered cycloalkyl; R 3 and R 4 are the same or different, each independently selected from H, D, halogen and C 1-6 alkyl; R 5 Selected from -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)NHS(O)2R 10 、-S(O)2R 10 、-P(O)(OH)R 11 , -B(OH)2 and 5-membered heteroaryl, wherein the 5-membered heteroaryl may be optionally selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and amino are substituted by one or more substituents; R 6 Selected from H, D, halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from D, halogen, hydroxy, cyano and NR 12 R 13 is substituted by one or more substituents; R 7 Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R 10 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, NH2 and 3-8 membered cycloalkyl; R 11 Selected from H, OH, C 1-6 Alkyl or C 1-6 Haloalkyl; R 12 and R 13 are the same or different and are independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 3-8 membered cycloalkyl; R a and R b are the same or different and are each independently selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and 3-8 membered cycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IG) is a compound represented by formula (I) in: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, G 1 and G 2 As defined in claim 1; Preferably, R 5 Selected from -C(O)OH, -C(O)NHS(O)2R 10 、-S(O)2R 10 、-P(O)(OH)R 11 , -B(OH)2 and 5-membered heteroaryl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein G 1 CR 8 , and G 2 CR 9 Or, G 1 CR 8 , and G 2 N; or G 1 is N, and G 2 CR 9 ; R 8 and R 9 As defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 alkyl.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of formula (II) or formula (II-1) or a pharmaceutically acceptable salt thereof: in: R 1 , R 5 , R 6 , R 7 , R 8 and R 9 As defined in any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-3 Alkoxy or deuterated C 1-3 Alkoxy; preferably, R 1 It is a methoxy group.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -C(O)OH, -C(O)NH2, -C(O)NH(CH3), -C(O)NHSO2R 10 、-S(O)2R 10 , -P(O)(OH)2, -P(O)(OH)(CH3), -B(OH)2, tetrazolyl and R 10 is methyl or NH2; preferably, R 5 It is -COOH.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from H, halogen or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally selected from halogen, hydroxy, cyano and NR 12 R 13 is substituted by one or more substituents; R 12 and R 13 are the same or different and are each independently selected from H or C 1-3 alkyl.

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from H, halogen or C 1-3 Alkyl; preferably, R 7 is H, methyl or ethyl.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are the same or different and are each independently selected from H, OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 haloalkyl and 3-6 membered cycloalkyl; preferably, R 8 and R 9 are the same or different and are each independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy; R 5 is -COOH; R 6 Selected from H, halogen and C 1-3 Alkyl, the C 1-3 Alkyl is optionally selected from halogen, hydroxy, NH2 or NHCH3; R 7 For H.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

14. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the preparation of a medicament for modulating the activity of a complement alternative pathway in a subject, for example, for use in the preparation of a medicament for inhibiting the expression or activity of complement factor B; Preferably, its use in the preparation of a medicament for preventing and / or treating a disease or condition affected by the regulation of the complement alternative pathway, such as its use in the preparation of a medicament for preventing and / or treating a disease mediated by complement factor B; Preferably, the invention relates to a method for preparing a drug for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases or respiratory diseases; More preferably, the invention is used in the preparation of a composition for preventing and / or treating paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, Arthritis, Psoriatic arthritis, Hepatitis, Dermatomyositis and ALS, Liver fibrosis, Myasthenia gravis (MG), Guillain-Barré syndrome (GBS), Neuromyelitis optica spectrum disorder (NMOSD), Uveitis, Retinitis pigmentosa, Macular edema, Behcet's uveitis, Multifocal choroiditis, Vogt-Koyangi-Harada syndrome, Intermediate uveitis, Birdshot retinochoroiditis, Sympathetic ophthalmia, Ocular pemphigoid, Ocular pemphigus, Non-arteritic ischemic optic neuropathy, Postoperative inflammation, Retinal vein occlusion, Glaucoma, Doyne honeycomb retinal dystrophy / Malattia Use of leventinese in drugs for diseases such as Sorsby fundus dystrophy, delayed retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion disorder, myocardial infarction, balloon angioplasty, post-cardiopulmonary bypass or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

16. A compound represented by formula (IGA) or a salt thereof, in, R w is C(O)OR c or P(O)(OR c )R 11 ; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R a , R b , R 11 , n, G 1 and G 2 As defined in claim 1.

17. The compound represented by formula (IGA) or a salt thereof according to claim 16, which is selected from:

18. A method for preparing a compound represented by formula (IG), comprising hydrolyzing and deprotecting a compound represented by formula (IGA) to obtain a compound represented by formula (IG), in, R w is C(O)OR c or P(O)(OR c )R 11 ; R 5 C(O)OH or P(O)(OH)R 11 ; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R a , R b , R 11 , n, G 1 and G 2 As defined in claim 1.

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