WO2022143845A1 - 含氮桥杂环化合物、其制备方法及其在医药上的应用 - Google Patents

含氮桥杂环化合物、其制备方法及其在医药上的应用 Download PDF

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WO2022143845A1
WO2022143845A1 PCT/CN2021/142760 CN2021142760W WO2022143845A1 WO 2022143845 A1 WO2022143845 A1 WO 2022143845A1 CN 2021142760 W CN2021142760 W CN 2021142760W WO 2022143845 A1 WO2022143845 A1 WO 2022143845A1
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group
alkyl
general formula
alkoxy
haloalkyl
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PCT/CN2021/142760
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English (en)
French (fr)
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李心
张志高
董文明
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202180072698.6A priority Critical patent/CN116438170A/zh
Priority to MX2023007853A priority patent/MX2023007853A/es
Priority to EP21912340.3A priority patent/EP4273136A1/en
Priority to AU2021414185A priority patent/AU2021414185A1/en
Priority to CA3203320A priority patent/CA3203320A1/en
Priority to KR1020237025025A priority patent/KR20230128039A/ko
Priority to JP2023564260A priority patent/JP2024504870A/ja
Publication of WO2022143845A1 publication Critical patent/WO2022143845A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a nitrogen-containing bridged heterocyclic compound, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a nitrogen-containing bridged heterocyclic compound represented by the general formula (I), its preparation method, a pharmaceutical composition containing the compound, and its use as a complement factor B (Factor B) inhibitor and its preparation Use in a medicament for the treatment and/or prevention of a disease or disorder mediated by Factor B.
  • Complement is a serum protein that exists in human and vertebrate serum and tissue fluid, is heat-labile, has enzymatic activity after activation, can mediate immune responses and inflammatory responses, and can be activated by antigen-antibody complexes or microorganisms, resulting in Pathogenic microorganisms are lysed or phagocytosed.
  • the complement system is an important regulator of inflammatory responses and tissue damage and consists of more than 20 serum and cell surface proteins.
  • the complement system includes intrinsic components of complement and various regulatory proteins.
  • the intrinsic components of complement include C1-C9, of which C3 has the highest content.
  • Complement regulatory proteins are further divided into two categories: soluble and membrane-bound. Soluble complement regulatory proteins include clusterin, S protein and complement factor H-related proteins.
  • Membrane-bound complement regulatory proteins include membrane cofactor protein (MCP), decay accelerating factor (DAF), complement receptor 1 (complement receptor 1) and the like.
  • MCP membrane cofactor protein
  • DAF decay accelerating factor
  • complement receptor 1 complement receptor 1
  • the complement system also includes some complement fragments and complement receptors, such as C3a receptors, C5a receptors, etc.
  • the complement system is activated through three independent and intersecting pathways, namely the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP), also known as the MBL pathway (mannan-binding pathway). lectin pathway)).
  • C3 convertase is an important component of the first three pathways, generating a series of complement protein fragments and membrane attack complex (MAC) through the complement activation cascade.
  • MAC membrane attack complex
  • C3 convertase cleaves C3 to generate C5 convertase, and then cleaves C5 to generate C5a and C5b.
  • C5b combines with C6, C7, C8, and C9 to form C5b-9 or MAC.
  • the abnormality of the complement pathway can cause the lysis of the body's inherent normal cells and lead to the occurrence of disease.
  • Complement factor B is a thermolabile beta globulin that can be inactivated at 50°C for 30 minutes. It can be cleaved into two fragments Ba and Bb by complement factor D, and Bb and C3b combine to form the C3 convertase of the alternative pathway.
  • Complement factor B is an important component in the alternative complement activation pathway, also known as C3 activator precursor.
  • Complement factor B has a molecular weight of 93 kDa and a concentration of about 3 ⁇ M in human blood. It is mainly synthesized in the liver and is also synthesized in retinal pigment epithelial cells of the eye.
  • Paroxysmal nocturnal hemoglobinuria is an acquired abnormality of hematopoietic stem cells.
  • the acquired somatic PIG-A gene mutation in hematopoietic stem cells results in abnormal synthesis of glycosylphosphatidylinositol, which leads to GPI Loss of a group of membrane proteins anchored to the cell membrane triggers a non-malignant clonal disease.
  • the main clinical manifestations are bone marrow loss of hematopoietic function, thrombosis, acute exacerbation of chronic hemolytic anemia.
  • the etiology of the disease is unknown. Studies have found that the hemolysis of PNH is due to the sensitivity of the patient's red blood cells to complement.
  • PNH erythrocytes lack a complement-regulatory protein called delayed acceleration factor DAF, which acts to inhibit the formation of complement C3 convertase.
  • DAF delayed acceleration factor
  • the Eculizumab antibody drug is very expensive, costing up to $669,000 a year to treat. Moreover, antibody drugs can only control the symptoms of hemolysis, but cannot completely cure PNH. They can only inhibit intravascular hemolysis, but cannot inhibit extravascular hemolysis. There are many drugs currently under development on the entire complement pathway, such as CAP inhibitors upstream of C3: TT30, ACH-4471 (anti-FD) and LNP023 (anti-FB), C3 inhibitors: AMY-101, APL-2 and Anti-C5 agent downstream of C3.
  • LNP023 is an oral small-molecule drug developed by Novartis, and some safety and efficacy reports have been reported in Phase II trials for the treatment of PNH.
  • PNH Proliferative neoplasm originating from a multicenter, open-label, consecutive 2-cohort study of 10 patients (25-79 years old) with PNH and active hemolysis who were treated with eculizumab, all patients were pretreated with LNP023. Red blood cell transfusions are required.
  • Enrolled subjects received LNP023 concomitantly with eculizumab twice daily for at least 13 weeks. The trial found LNP023 to be well tolerated, with no treatment interruptions and no reports of serious adverse events or thromboembolic events.
  • LNP023 showed a 34-81% reduction in LDH in all patients, with normal Hb in all women and Hb >120 g/L in 71% of men. LNP023 was exposed for a mean of 241 days, and no patient required RBC transfusion. At the time of data cutoff, 5 patients had discontinued eculizumab monotherapy and continued LNP023 monotherapy. All LNP023 monotherapy patients maintained hemoglobin levels, did not change any biomarkers of disease activity, and had no symptoms of breakthrough hemolysis.
  • Glomerulopathy includes IgA Nephropathy (IgAN), C3 Glomerulopathy (C3G), Membranous Glomerulonephritis (MGN), etc.
  • IgAN and MGN are the most common, and the incidence of rare kidney diseases, such as C3 glomerulopathy, has also increased in the past decade.
  • the annual incidence of IgAN in the United States is about 185,000.
  • the age of onset is 20-40 years old.
  • the main symptoms are hematuria, fatigue and pain. About 30% of the patients will eventually develop end-stage renal disease (ESRD).
  • ESRD end-stage renal disease
  • Membranous glomerulonephritis affects about 80,000 people in the United States each year, with onset in the 40-60 year old age group, and about 30% of patients will eventually develop ESRD.
  • the annual incidence of C3 glomerulopathy in the United States is about 10,000, and the incidence is mainly adolescents. About 50% of the patients will develop ESRD.
  • Drug therapy is commonly used such as hormones and immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, traditional Chinese medicine triptolide), and others include blood pressure control drugs, diuretics and antiplatelet aggregation drugs , anticoagulants, lipid-lowering drugs, Cordyceps preparations and other kidney-protecting and detoxifying drugs.
  • hormones and immunosuppressants such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, traditional Chinese medicine triptolide
  • others include blood pressure control drugs, diuretics and antiplatelet aggregation drugs , anticoagulants, lipid-lowering drugs, Cordyceps preparations and other kidney-protecting and detoxifying drugs.
  • IgAN is the most common primary glomerular disease worldwide, and its pathological manifestations are local mesangial hyperplasia and matrix increase with diffuse mesangial area IgA protein deposition, often accompanied by IgG, C3 and C5b-9 deposition. Therefore, it is believed that the complement pathway is related to the occurrence and development of IgAN.
  • Two small-molecule drugs targeting the complement pathway are currently in clinical trials.
  • OMS721 is a humanized monoclonal antibody targeting MASP-2 protein developed by Omeros. The MASP-2 protein is an effector enzyme that activates the lectin pathway of the complement system.
  • LNP023 is also in a multi-country, multi-regional Phase II clinical trial for the treatment of IgAN, C3G and MGN.
  • Novartis recently announced that the drug has obtained positive interim clinical results in a phase 2 clinical trial of C3G patients.
  • the effect of maintaining renal function persisted in 7 patients who had been treated for 6 months after enrollment in the long-term extension study.
  • the company will conduct a number of Phase III clinical studies in December this year and early next year.
  • Patent applications that have disclosed Factor B inhibitors include WO2015009616A1, WO2019043609A1, and WO2020016749A2, among others.
  • X is selected from chemical bonds, -CR a R b -, -NR- and -O-;
  • Y is selected from -CR 3a R 3b -, -NR 3c - and -O-;
  • Ring A is aryl or heteroaryl
  • R, Ra and Rb are the same or different and are each independently selected from hydrogen atoms, alkyl groups and haloalkyl groups;
  • Each R 1 is the same or different, and is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein, the alkyl, alkoxy, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl
  • Each R 2 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein, the alkyl, alkoxy, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alky
  • R 3 , R 3a , R 3b and R 3c is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an oxo group, a halogen, a cyano group group, -NR x R y and hydroxyl; wherein, the alkyl group is optionally substituted by one or more cyano groups or amino groups;
  • Each R 4 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 8 R 9 , a hydroxyl group, -C( O)R 10 , -CH 2 C(O)R 10 , -C(O)NR 8 R 9 , -C(O)NHS(O) p R 10 , -S(O) p NHC(O)R 10 , -S(O) p R 10 , -S(O) p NR 8 R 9 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclic , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, halo
  • R 5 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, a hydroxy group, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein Said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxy or more substituents;
  • R 10 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, -OR 11 , alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and hydroxy substituted by a substituent;
  • R 11 is selected from hydrogen atom, alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, cyano, -OR 12 and -C(O)OR 12 ;
  • R 12 is selected from hydrogen atom, alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; wherein, the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and hydroxy;
  • R 6 , R 7 , R x , R y , R 8 and R 9 are the same or different at each occurrence and are each independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, hetero Cyclic, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkane substituted with one or more of the substituents in the group consisting of radical, haloalkoxy, cyano, hydroxyl and hydroxyalkyl;
  • R6 and R7 together with the attached nitrogen atom form a heterocyclyl group
  • Rx and Ry together with the attached nitrogen atom form a heterocyclyl group
  • R8 and R9 together with the attached nitrogen atom form a heterocyclyl group
  • the heterocyclyl groups are the same or different at each occurrence, and each independently is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, substituted with one or more substituents in hydroxy and hydroxyalkyl;
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3, or 4;
  • p 0, 1 or 2.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein
  • X is selected from chemical bonds, -CR a R b -, -NR- and -O-;
  • Y is selected from -CR 3a R 3b -, -NR 3c - and -O-;
  • Ring A is aryl or heteroaryl
  • R, Ra and Rb are the same or different and are each independently selected from hydrogen atoms, alkyl groups and haloalkyl groups;
  • Each R 1 and R 2 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from hal
  • R 3 , R 3a , R 3b and R 3c is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an oxo group, a halogen, a cyano group group, -NR x R y and hydroxyl; wherein, the alkyl group is optionally substituted by one or more cyano groups or amino groups;
  • Each R 4 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 8 R 9 , a hydroxyl group, -C( O)R 10 , -CH 2 C(O)R 10 , -C(O)NR 8 R 9 , -C(O)NHS(O) p R 10 , -S(O) p NHC(O)R 10 , -S(O) p R 10 , -S(O) p NR 8 R 9 , cycloalkyl, heterocyclic, aryl and heteroaryl; wherein, the alkyl, cycloalkyl, heterocyclic , aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, halo
  • R 5 and R 10 are the same or different, and are each independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the said Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and hydroxy substituted by a substituent;
  • R 6 , R 7 , R x , R y , R 8 and R 9 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , substituted by one or more substituents in cyano, hydroxyl and hydroxyalkyl;
  • R6 and R7 together with the attached nitrogen atom form a heterocyclyl group
  • Rx and Ry together with the attached nitrogen atom form a heterocyclyl group
  • R8 and R9 together with the attached nitrogen atom form a heterocyclyl group
  • the heterocyclyl groups are the same or different at each occurrence, and each independently is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, substituted with one or more substituents in hydroxy and hydroxyalkyl;
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3, or 4;
  • p 0, 1 or 2.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein Y is -CR 3a R 3b -, R 3a and R 3b are different and independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; preferably, Y is -CR 3a R 3b -, R 3a is a hydrogen atom, and R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1 -6 haloalkoxy; further preferably, Y is -CR 3a R 3b -, R 3a is a hydrogen atom, and R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane group, C 1-6 alkoxy and
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • Rings A, X, R 1 to R 3 , R 3b , R 4 , m, n, s and t are as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein s is 0 or 1; preferably, s is 0.
  • the compound represented by the general formula (I), the general formula (II) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof of salt:
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • Rings A, X, R 1 , R 3b , R 4 to R 7 , p and t are as defined in general formula (I).
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxy and -C(O)R 10 , R 10 is as defined in general formula (I);
  • R 4 is -C(O)R 10
  • R 10 is as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein R 10 is -OR 11 , R 11 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group; wherein, the C 1-6 alkyl, 3 to 8 The membered cycloalkyl and the 3- to 8-membered heterocyclyl are each independently optionally selected from halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, -OR 12 and -C(O)OR 12 substituted by one or more substituents in, R 12 is a hydrogen atom or a C 1-6 alkyl group;
  • R 10 is -OR 11
  • R 11 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a 3- to 8-membered cycloalkyl group and a 3- to 8-membered heterocyclic group; wherein, the The C 1-6 alkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl groups are each independently optionally substituted by one or more selected from -OR 12 and -C(O)OR 12 substituted by a group, R 12 is a hydrogen atom or a C 1-6 alkyl group;
  • R 10 is selected from hydroxyl
  • R10 is hydroxy
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein each R 4 is the same or different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, -NR 8 R 9 , hydroxyl and -C(O)R 10 ;
  • R 8 and R 9 are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1 -6 Hydroxyalkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from C 1-6 alkoxy, C 1-6 haloalkoxy and cyano ;
  • R 10 is -OR 11 ;
  • R 11 is selected from a hydrogen atom,
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl and -C(O)R 10 ;
  • R 10 is -OR 11 ;
  • R 11 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally selected from -OR 12 and one or more substituents in -C(O)OR 12 are substituted;
  • R 12 is a hydrogen atom or a C 1-6 alkyl group;
  • R 4 is -C(O)R 10
  • R 10 is selected from hydroxyl
  • R 4 is -C(O)R 10 and R 10 is hydroxy.
  • each R 4 is the same or different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, -NR 8 R 9 , hydroxyl and -C(O)R 10 , R 8 , R 9 and R 10 are as defined in general formula (I); preferably, each R 4 is the same or different, and each is independently selected from Hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl and -C(O) R 10 , R 10 is hydroxy; more preferably, R 4 is -C(O)R 10
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof is represented by general formula (IV) A compound or a pharmaceutically acceptable salt thereof:
  • R 10 is selected from hydroxyl, Preferably, R 10 is hydroxyl;
  • t 1 or 2;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • Rings A, X, R 1 , R 3b , R 4 to R 7 and p are as defined in general formula (I).
  • each R 4 is the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkane group, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, -NR 8 R 9 and hydroxyl, R 8 and R 9 is as defined in general formula (I); preferably, each R 4 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy group, C 1-6 haloalkoxy, halogen and hydroxyl; more preferably, R 4 is a hydrogen atom.
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof wherein R 8 and R 9 are the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, wherein the C 1-6 alkyl group is optional Substituted with one or more substituents selected from C 1-6 alkoxy, C 1-6 haloalkoxy and cyano.
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof wherein ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; preferably, ring A is phenyl or pyridyl; more preferably, ring A is phenyl.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein each R 1 is the same or different, and each is independently selected from hydrogen atoms , C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; preferably, R 1 is a hydrogen atom.
  • the compound represented by general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof wherein R 1 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; preferably, R 1 is a hydrogen atom.
  • each R 2 is the same or different, and each is independently selected from hydrogen atoms , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3 to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; preferably, each R 2 is the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and 3 to 6-membered cycloalkyl; more preferably, each R 2 is the same or different, and each is independently selected from a hydrogen atom, methyl, methoxy and cyclopropyl.
  • each R 2 is the same or different, and each is independently selected from hydrogen atoms , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halogen; preferably, each R 2 is the same or different , and each is independently selected from hydrogen atom, C 1-6 alkyl and C 1-6 alkoxy; more preferably, each R 2 is the same or different, and each is independently selected from hydrogen atom, methyl and methoxy base.
  • the compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IV) or a pharmaceutically acceptable salt thereof is the general formula A compound represented by (V) or a pharmaceutically acceptable salt thereof:
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 3b , R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof is rel-(1S,3S,5R) (i.e. cis) or rel-(1R, 3S,5S) (i.e. trans) as a 1:1 mixture of the two enantiomers, or rel-(1S,3S,5R) (i.e. cis) or rel-(1R,3S,5S)( i.e. a mixture of two diastereomers of trans); preferably a 1:1 mixture of two enantiomers of rel-(1S,3S,5R) i.e. ( ⁇ )-rel-(1S , 3S, 5R).
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its pharmaceutically acceptable A salt which is a compound represented by the general formula (V") or a pharmaceutically acceptable salt thereof:
  • R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V") A compound or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V-1), or a pharmaceutically acceptable salt thereof:
  • R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V") A compound or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V-2), or a pharmaceutically acceptable salt thereof:
  • R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IV) or a pharmaceutically acceptable salt thereof is the general formula The compound represented by (V') or a pharmaceutically acceptable salt thereof:
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 10 is selected from hydroxyl
  • R 3b , R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof is rel-(1S, 3S, 5R) (ie cis) or rel-(1R) , 3S,5S) (i.e. trans) as a 1:1 mixture of the two enantiomers, or rel-(1S,3S,5R) (i.e. cis) or rel-(1R,3S,5S) A mixture of two diastereomers (i.e. trans); preferably a 1:1 mixture of two enantiomers of rel-(1S,3S,5R) i.e. ( ⁇ )-rel-( 1S, 3S, 5R).
  • the compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IV), the general formula (V') or its pharmaceutically acceptable is a compound represented by the general formula (V'-1) or a pharmaceutically acceptable salt thereof:
  • R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 10 is selected from hydroxyl
  • R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the compound represented by the general formula (I), the general formula (II), the general formula (III), the general formula (IV), the general formula (V') or its pharmaceutically acceptable is a compound represented by the general formula (V'-2) or a pharmaceutically acceptable salt thereof:
  • R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
  • R 2a and R 2b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a halogen, a cyano group, -NR 6 R 7 , hydroxyl, -C(O)R 5 , -CH 2 C(O)R 5 , -OCH 2 C(O)R 5 , -CH 2 NHC(O)R 5 , -C(O)NR 6 R 7 , -S(O) p R 5 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen
  • R 10 is selected from hydroxyl
  • R 5 , R 6 , R 7 and p are as defined in general formula (I).
  • the compound represented by general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are the same or different, and are independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halogen; preferably, R 2a and R 2b are the same or different, and are each independently C 1-6 alkyl or C 1-6 alkoxy; more preferably, R 2a is methoxy and R 2b is methyl.
  • the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V') A compound or a pharmaceutically acceptable salt thereof, wherein R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1- 6 haloalkoxy; preferably, R 3b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; More preferably, R 3b is C 1-6 alkoxy; most preferably, R 3b is ethoxy.
  • the formula (V") general formula (V-1), general formula (V-2), general formula (V'-1), general formula (V'-2)
  • R 3b is C 1-6 alkoxy; preferably, R 3b is ethoxy.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; Y is -CR 3a R 3b -; R 3a and R 3b are different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is 6 to 10-membered aryl or 5 to 10-membered heteroaryl; each R 1 is the same or different, and each is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, and cyano; each R 2 are the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxy, halogen, cyano, amino,
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; Y is -CR 3a R 3b -; R 3a and R 3b are different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is 6 to 10-membered aryl or 5 to 10-membered heteroaryl; each R 1 is the same or different, and each is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, and cyano; each R 2 are the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxy, halogen, cyano, amino,
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; Y is -CR 3a R 3b -; R 3a and R 3b are different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is 6 to 10-membered aryl or 5 to 10-membered heteroaryl; each R 1 is the same or different, and each is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, and cyano; each R 2 are the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkane oxy and halogen; each R 4 is the same or
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; the same for each R 1 or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 is the same or different, and each is independently selected from hydrogen atom, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3- to 8-membered cycloalkane and 3- to 8-membere
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; the same for each R 1 or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 is the same or different, and each is independently selected from hydrogen atom, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3- to 8-membered cycloalkane and 3- to 8-membere
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; R 2a and R 2b are the same or different, and are each independently selected from C 1-6 alkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl; each R 4 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy group, C 1-6 haloalkoxy, halogen
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; R 2a and R 2b are the same or different, and are each independently selected from C 1-6 alkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl; each R 4 is the same or different, and each is independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy group, C 1-6 haloalkoxy, halogen
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein X is a chemical bond; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen and cyano; R 2a and R 2b are the same or different, and are each independently C 1-6 alkyl or C 1-6 alkoxy; each R 4 same or different, and each independently selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , halogen, hydroxy, and -C(O)R 10 ; R 10 is
  • the compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are the same or different, and are independently selected from hydrogen atoms, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3- to 8-membered ring Alkyl and 3- to 8-membered heterocyclic groups; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1 -6 haloalkoxy; R 10 is selected from hydroxyl,
  • the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are the same or different, and are independently selected from hydrogen atoms, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3- to 8-membered cycloalkane group and 3- to 8-membered heterocyclic group; R 3b is selected from hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1- 6 haloalkoxy.
  • the compound represented by the general formula (V") or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are the same or different, and are independently selected from hydrogen atoms, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxyl, 3- to 8-membered ring Alkyl and 3- to 8-membered heterocyclyl; R 3b is C 1-6 alkoxy.
  • the compound represented by general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are the same or different, and each independently selected from C 1-6 alkyl, C 1-6 alkoxy, and 3- to 6-membered cycloalkyl; R 3b is C 1-6 alkoxy.
  • the compound represented by general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof wherein R 2a is selected from C 1-6 alkyl, C 1-6 alkoxy and 3- to 6-membered cycloalkyl, and R 2b is C 1-6 alkyl; R 3b is C 1-6 alkoxy.
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound of general formula (IVA) or a pharmaceutically acceptable salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 10 is alkoxy; preferably, R 10 is C 1-6 alkoxy; more preferably, R 10 is methoxy;
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a compound of general formula (IVB) or a pharmaceutically acceptable salt thereof:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a compound of general formula (VA) or a pharmaceutically acceptable salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 10 is alkoxy; preferably, R 10 is C 1-6 alkoxy; more preferably, R 10 is methoxy;
  • R 2a , R 2b and R 3b are as defined in general formula (V).
  • Another aspect of the present disclosure relates to a compound of general formula (V-1A) or a pharmaceutically acceptable salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 10 is alkoxy; preferably, R 10 is C 1-6 alkoxy; more preferably, R 10 is methoxy;
  • R 2a , R 2b and R 3b are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a compound of general formula (V-2A) or a pharmaceutically acceptable salt thereof:
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 10 is alkoxy; preferably, R 10 is C 1-6 alkoxy; more preferably, R 10 is methoxy;
  • R 2a , R 2b and R 3b are as defined in general formula (V-2).
  • Another aspect of the present disclosure relates to a compound of general formula (V'A) or a pharmaceutically acceptable salt thereof:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V').
  • Another aspect of the present disclosure relates to a compound of general formula (V'-1A) or a pharmaceutically acceptable salt thereof:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V'-1).
  • Another aspect of the present disclosure relates to a compound of general formula (V'-2A) or a pharmaceutically acceptable salt thereof:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V'-2).
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 10 is an alkoxy group (preferably a C 1-6 alkoxy group, more preferably a methoxy group) of the compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof.
  • Deprotection group R w and hydrolysis are carried out reaction to obtain a compound represented by the general formula (IV) in which R 10 is a hydroxyl group or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 10 is an alkoxy group (preferably C 1-6 alkoxy group, more preferably a methoxy group) of the compound represented by the general formula (VA) or a pharmaceutically acceptable salt thereof.
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 10 is an alkoxy group (preferably C 1-6 alkoxy group, more preferably a methoxy group) of the compound represented by the general formula (V-1A) or a pharmaceutically acceptable salt thereof Deprotection R w and Carry out a hydrolysis reaction to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 10 is an alkoxy group (preferably C 1-6 alkoxy group, more preferably a methoxy group) of the compound represented by the general formula (V-2A) or a pharmaceutically acceptable salt thereof Deprotection group R w and Carry out a hydrolysis reaction to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V').
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V'-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V'-2).
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) of the present disclosure , general formula (V"), general formula (V-1), general formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2) and table A compound shown in A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1), general formula Compounds of formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2), and Table A, or a pharmaceutically acceptable salt thereof, or a medicine comprising the same Use of the composition in the preparation of a medicament for inhibiting the activation of the alternative complement pathway, preferably in the preparation of a medicament for inhibiting Factor B.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1), general formula Compounds of formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2), and Table A, or a pharmaceutically acceptable salt thereof, or a medicine comprising the same Use of a composition in the preparation of a medicament for the treatment and/or prevention of a disease or disorder mediated by alternative complement pathway activation; preferably in the preparation of a medicament for the treatment and/or prevention of a disease or disorder mediated by Factor B Use in, wherein said disease or disorder is selected from glomerulopathy (such as glomerulonephritis), hemolytic uremic syndrome (such as Escherichia coli-induced hemolytic uremic syndrome), atypical hemolytic uremic syndrome ( atypical haemolytic uraemic syndrome, aHUS), paroxysmal nocturnal hemoglobinuria
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1), general formula Compounds of formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2), and Table A, or a pharmaceutically acceptable salt thereof, or a medicine comprising the same Use of a composition in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by Factor B, wherein the disease or disorder is an inflammatory disorder.
  • the present disclosure further relates to a method of inhibiting the activation of the alternative complement pathway, preferably a method of inhibiting Factor B, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) ), general formula (IV), general formula (V), general formula (V"), general formula (V-1), general formula (V-2), general formula (V'), general formula (V'- 1), the compound shown in general formula (V'-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of treating and/or preventing a disease or disorder mediated by activation of the alternative complement pathway, preferably a method of treating and/or preventing a disease or disorder mediated by Factor B, comprising administering the A therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1) , general formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2) and compounds shown in Table A or their pharmaceutically acceptable salts or containing pharmaceutical composition.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1) , general formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2) and compounds shown in Table A or their pharmaceutically acceptable salts or containing pharmaceutical composition for use as a medicament.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1) , general formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2) and compounds shown in Table A or their pharmaceutically acceptable salts or containing A pharmaceutical composition for inhibiting alternative complement pathway activation, preferably for inhibiting Factor B.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), general formula (V-1) , general formula (V-2), general formula (V'), general formula (V'-1), general formula (V'-2) and compounds shown in Table A or their pharmaceutically acceptable salts or containing
  • the pharmaceutical composition for treating and/or preventing diseases or disorders mediated by alternative complement pathway activation, preferably for treating and/or preventing diseases or disorders mediated by Factor B.
  • the disease or disorder mediated by the activation of the alternative complement pathway described in the present disclosure is selected from the group consisting of glomerulopathy (eg, glomerulonephritis), hemolytic uremic syndrome (eg, Escherichia coli-induced hemolytic uremic syndrome), atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis (eg, anterior uveal tract) uveitis, posterior and intermediate uveitis), retinitis pigmentosa, macular edema, uveitis due to Behçet syndrome, multifocal choroiditis, Fuku-Koyanagi-Harada syndrome, shotgun Retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoi
  • glomerulopathy eg, glomer
  • the diseases or disorders mediated by Factor B described in the present disclosure are inflammatory disorders.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation.
  • the compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compounds are preferably presented in unit doses or in such a manner that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents. Sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • lower alkyl groups having 1 to 6 carbon atoms 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl And 2,3-dimethylbutyl and so on.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -) and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy group, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring One or more of alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero Cyclooxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 cycloalkyl rings (eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • 3 to 20 cycloalkyl rings eg 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20
  • carbon atoms ie 3 to 20 membered cycloalkyl
  • preferably 3 to 12 carbon atoms ie 3 to 12 membered ring alkyl
  • Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl and cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups .
  • spirocycloalkyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/4 yuan, 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group of rings sharing an adjacent pair of carbon atoms, wherein one or more of the rings may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the number of formed rings it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan , 6 yuan/3
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • ring atoms Preferably there are 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heterocyclic atoms (ie 3 to 12 membered heterocyclyl); further preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1 to 3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (ie, 5 or 6 membered heterocyclyl).
  • 1 to 4 eg 1, 2, 3 and 4
  • 3 to 8 ring atoms eg 3, 4, 5, 6, 7 and 8 of which 1 to 3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocycl
  • Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpho olinyl and homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups .
  • spiroheterocyclyl More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan or 6 yuan/6 yuan unit Spiroheterocyclyl.
  • spiroheterocyclyl include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which an adjacent pair of atoms is shared between rings, one or more rings may contain one or more double bonds, and one or more rings may contain one or more double bonds.
  • the atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • 6 to 14 yuan more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, For example phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably a 5- to 10-membered (eg 5, 6, 7, 8, 9 or 10-membered) heteroaryl, more preferably a 5- or 6-membered heteroaryl, eg furyl, thienyl, pyridyl, pyrrolyl , N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent Residues derived from atoms are "cycloalkylene", “heterocyclylene”, “arylene” and “heteroarylene”.
  • amino protecting group refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (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.
  • hydroxyl protecting group refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound.
  • Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C 1-10 alkyl or aryl) acyl (such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6 to 10-membered aryl) sulfonyl, (C 1-6 alkoxy or 6 to 10-membered Aryloxy)carbonyl, allyl, 2-te
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both and Two configurations.
  • tautomer or tautomeric form refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as “deuterium” or “D”, that position is understood to be at least 1000 times more abundant (i.e., deuterium) than the natural abundance of deuterium, which is 0.015%. at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • C 1-6 alkyl optionally (optionally) substituted by halogen or cyano means that halogen or cyano may, but need not, be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the alkane The case where the group is not substituted by halogen and cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, in admixture with other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the compound represented by the general formula (IV) of the present disclosure or a preparation method of a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • R 10 is an alkoxy group (preferably a C 1-6 alkoxy group, more preferably a methoxy group) of the compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof to remove the protective group under basic conditions R and carry out a hydrolysis reaction to obtain a compound represented by the general formula (IV) in which R 10 is a hydroxyl group or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • the preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • the compound represented by the general formula (IVB) or a pharmaceutically acceptable salt thereof removes the protecting group R s to obtain the compound represented by the general formula (IV) or medicinal salt,
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • t 1 or 2;
  • Rings A, X, R 1 , R 2a , R 2b , R 3b and R 4 are as defined in general formula (IV).
  • the preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • R 10 is an alkoxy (preferably C 1-6 alkoxy, more preferably methoxy) compound represented by the general formula (VA) or a pharmaceutically acceptable salt thereof to remove the protecting group under basic conditions R and carry out a hydrolysis reaction to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V).
  • the preparation method of the compound represented by the general formula (V-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • R 10 is alkoxy (preferably C 1-6 alkoxy, more preferably methoxy) compound represented by general formula (V-1A) or its pharmaceutically acceptable salt is removed under basic conditions Protecting group R and carry out hydrolysis reaction to obtain the compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in the general formula (V-1).
  • the preparation method of the compound represented by the general formula (V-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • R 10 is alkoxy (preferably C 1-6 alkoxy, more preferably methoxy) compound represented by general formula (V-2A) or its pharmaceutically acceptable salt is removed under basic conditions Protecting group R and carry out hydrolysis reaction to obtain the compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof,
  • R w is an amino protecting group; preferably, R w is tert-butoxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butoxycarbonyl;
  • R 2a , R 2b and R 3b are as defined in general formula (V-2).
  • the preparation method of the compound represented by the general formula (V-1) and the general formula (V-2) or the pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
  • the compound represented by the general formula (V") or a pharmaceutically acceptable salt thereof is subjected to chiral preparation and resolution to obtain the compound represented by the general formula (V-1) and the general formula (V-2) or a pharmaceutically acceptable salt thereof;
  • R 2a , R 2b and R 3b are as defined in general formula (V-1) and general formula (V-2).
  • the preparation method of the compound represented by the general formula (V') of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • the compound represented by the general formula (V'A) or a pharmaceutically acceptable salt thereof removes the protecting group R s to obtain the compound represented by the general formula (V').
  • a catalyst preferably tetrakis(triphenylphosphine) palladium
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V').
  • the preparation method of the compound shown in the general formula (V'-1) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • the compound represented by the general formula (V'-1A) or a pharmaceutically acceptable salt thereof removes the protecting group R s to obtain the general formula (V'-1) the compound shown or a pharmaceutically acceptable salt thereof,
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V'-1).
  • the preparation method of the compound represented by the general formula (V'-2) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises the following steps:
  • the compound represented by the general formula (V'-2A) or a pharmaceutically acceptable salt thereof removes the protecting group R s to obtain the general formula (V'-2) the compound shown or a pharmaceutically acceptable salt thereof,
  • R s is a hydroxyl protecting group; preferably, R s is allyl;
  • R 10 is selected from
  • R 2a , R 2b and R 3b are as defined in general formula (V'-2).
  • described base includes organic base and inorganic base
  • described organic base includes but is not limited to triethylamine, N, N-diisopropylethylamine, n-butyllithium, diisopropyl Lithium amide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide , lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably selected from lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.
  • the reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and its mixtures.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane
  • Figure 1 Effects of the compound of Example 1-1 and the positive drug LNP023 on serum iC3b+C3d in passive heymann nephritis rats.
  • Figure 2 and Figure 3 Effects of the compound of Example 1-1 and the positive drug LNP023 on urinary protein/creatinine in passive heymann nephritis rats.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: petroleum ether/ethyl acetate system, E: toluene/acetone system, the volume ratio of the solvent is based on the compound It can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin layer chromatography
  • the relative stereochemistry of these compounds is identified by NMR studies and/or X-ray diffraction. In these cases, the compounds are identified using the prefix "rel” followed by the R/S nomenclature, where R/S only provides relative stereochemical information, not absolute stereochemistry.
  • Compound 1 of the present disclosure (chemical name: ( ⁇ )-rel-4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H -Indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid, structural formula: ), which means that The relative stereochemistry at positions 1, 3 and 5 is 1S,3S,5R or 1R,3R,5S (i.e.
  • the relative stereochemistry at position 5 is also uniquely determined because, due to steric hindrance, 4-carboxyphenyl at position 1 and positions 1, 5-8 are located.
  • the five-membered nitrogen-containing heterocyclic group can only be located on the opposite side of the six-membered nitrogen-containing heterocyclic ring where the 1-5 and 8-positions are located. therefore, In fact, the same compound is a racemate, and Actually the same compound.
  • Methyl 4-(4-bromophenyl)-4-oxobutyrate 1a (5 g, 17.54 mmol, Bide Pharmaceutical Technology Co., Ltd.) was dissolved in tetrahydrofuran (50 mL), and lithium borohydride was added at 0°C. A solution of tetrahydrofuran (17 mL, 2 mmol/mL) was naturally warmed to room temperature and stirred overnight. The reaction solution was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was dried and concentrated to give the crude title product 1b (4.29 g), which was used in the next reaction without purification.
  • reaction solution was concentrated, diluted with a small amount of methanol, and then used high performance liquid preparative chromatography (Waters 2545, chromatographic column: Sharpsil-T C18, 250*50mm, 8 ⁇ m; mobile phase A: water (containing 10mmol/L of ammonium bicarbonate) ; mobile phase B: acetonitrile; 18 min gradient: 20%-38%, flow rate: 80 mL/min) purification gave the title compounds 1 (4 mg, yield: 3.86%) and 2 (5 mg, yield: 4.82%).
  • Example 1-1 Example 1-2
  • Chiral HPLC analysis retention time 7.946 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 ⁇ m, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% Diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1 mL/min).
  • Chiral HPLC analysis retention time 12.77 minutes, chiral purity: 98.7% (chromatographic column: CHIRALPAKIG, 5 ⁇ m, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% dimethoxide Ethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1 mL/min).
  • Chiral HPLC analysis retention time 7.946 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 ⁇ m, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% Diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1 mL/min).
  • Chiral HPLC analysis retention time 12.77 minutes, chiral purity: 98.7% (chromatographic column: CHIRALPAKIG, 5 ⁇ m, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% dimethoxide Ethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1 mL/min).
  • D-glucuronic acid 5a (15g, 77.26mmol, Jiangsu Aikang Biomedical R&D Co., Ltd.) was dissolved in N,N-dimethylformamide (150mL), and 1,8-diazabicyclo was added dropwise at room temperature [5.4.0] Undec-7-ene (13 g, 85.39 mmol), stir well. The mixture was cooled in an ice bath for 10 minutes, 3-bromopropene (11.2 g, 92.58 mmol) was added dropwise, the addition was completed, and the mixture was reacted at room temperature for 16 hours.
  • Test Example 1 Inhibitory effect of the disclosed compounds on Factor B enzymatic activity
  • Phosphate buffer (B320, Shanghai Yuanpei Biotechnology Co., Ltd.)
  • Human complement factor B protein needs to form a complex with human complement factor C3 to perform its protease function. Under the hydrolysis of human complement factor D protein, human complement factor B is hydrolyzed into Ba and Bb fragments, and Bb forms with the C3b fragment of human complement factor C3. The complex C3bBb, the C3 convertase, is formed to enable human complement factor B to function as a protease. C3bBb continues to hydrolyze C3 into C3a and C3b fragments, C3b and C3bBb form a complex C3bBbC3b, ie C5 convertase, and the C3a fragment is released.
  • C3a des Arg epitope generated after C3 is cleaved By detecting the C3a des Arg epitope generated after C3 is cleaved, it can be used to evaluate the efficiency of C3 hydrolysis, that is, the C3bBb enzyme activity, so as to evaluate the effect of compounds on C3bBb enzyme. Since C3b is unstable in vitro, Cobra venom factor (hereinafter referred to as CVF) is used instead of C3b to form a complex with human complement factor B, which has the same function as C3b.
  • CVF Cobra venom factor
  • the AA128-2422 amino acid encoding gene of human complement factor B protein (NM_001710.6) was codon-optimized, gene-synthesized, cloned into pcDNA3.4 vector by Nanjing GenScript Biotechnology Co., Ltd. and cloned into HD CHO-S cells. expression and purification.
  • the purified recombinant human complement factor B protein was aliquoted and stored in a -80°C refrigerator.
  • Human complement factor B protein cleavage reaction The recombinant human complement factor D protein was diluted 10 times with PBS (pH 7.4), and stored on ice until use. In the reaction buffer (PBS pH7.4, 10 mM MgCl 2 , 0.05% CHAPS), the final concentration of 300nM recombinant human complement factor D protein, 1 ⁇ M recombinant human complement factor B protein and 1 ⁇ M CVF were added, and after thorough mixing, The reaction was performed in an incubator at 37°C for 3 hours to obtain a complex of CVF and sheared recombinant human complement factor B protein fragment Bb (hereinafter referred to as CVF:Bb).
  • CVF:Bb a complex of CVF and sheared recombinant human complement factor B protein fragment Bb
  • C3 protein cleavage reaction In a 96-well white half-well plate, prepare a 10 ⁇ L reaction system, that is, add CVF:Bb to a final concentration of 2 nM in C3 reaction buffer (PBS pH7.4, 1 mM MgCl 2 , 0.05% CHAPS) , 1 ⁇ L of the above test compound diluted in C3 reaction buffer and DMSO were incubated at room temperature for 1 hour. The final concentrations of the tested compounds were 10000, 2500, 625, 156.25, 39.0625, 9.765625, 2.441406, 0.6103515, 0.152588 nM, respectively.
  • C3 reaction buffer PBS pH7.4, 1 mM MgCl 2 , 0.05% CHAPS
  • Human complement factor C3 was added to the reaction system at a final concentration of 500 nM, mixed well and reacted in an incubator at 37°C for 2 hours.
  • the reaction well containing only 500 nM human complement factor C3 was used as a negative control.
  • C3a des Arg detection wash the plate with 300 ⁇ L/well TBST (0.05% Tween 20) solution for 3 times, add 300 ⁇ L StartingBlock TM T20 (TBS) blocking buffer to each well, incubate at 37°C for 5 minutes; wash with 300 ⁇ L/well PBST solution Plate 3 times, dilute anti-C3a/C3a des Arg antibody [2991] 1:1000 in PBST solution, add 100 ⁇ L to each well, incubate at 37°C for 1 hour; wash the plate 3 times with 300 ⁇ L/well PBST solution, add 100 ⁇ L/well Dilute goat anti-mouse IgG H&L (H&L) (HRP) antibody at 1:5000, add 100 ⁇ L to each well, and incubate at 37°C for 30 minutes; prepare QuantaBlu TM fluorescent peroxidase substrate kit (QuantaBlu TM ) Fluorogenic Peroxidase Substrate Kit) substrate, dilute 1 part Quant
  • Inhibition rate ⁇ 1-(RFU test compound -RFU negative control well )/(RFU blank well- RFU negative control well ) ⁇ 100%
  • Test Example 2 Inhibitory effect of the compounds of the present disclosure on the human complement alternative pathway (Complement Alternative Pathway)
  • PBS Phosphate Buffered Saline
  • B320 B320, Shanghai Yuanpei Biotechnology Co., Ltd.
  • the alternative pathway can be activated by exogenous pathogen molecules such as bacterial cell wall proteins and lipopolysaccharides.
  • a series of complement factors activate the signal cascade through hydrolysis and enzymolysis reactions, and finally C5b, C6, C7, C8 and multiple C9 proteins Membrane attack complexes are formed.
  • the alternative pathway can be activated by zymosan, and the degree of activation of the alternative pathway can be assessed by detecting the formation of the C5b-9 complex.
  • Yeastin can also activate the classical pathway and the lectin pathway.
  • the alternative pathway only requires the participation of magnesium ions.
  • the classical pathway and the lectin pathway were not inhibited. After chelation with EDTA, all three pathways were inhibited. Therefore, the inhibition of the alternative pathway by small-molecule compounds can be assessed by detecting the formation of the C5b-9 complex using zymosan to activate the alternative pathway of complement in human serum in the presence of EGTA chelator.
  • Zymosan A powder was resuspended to 10 mg/mL in TBS solution and activated by heating at 100°C for 2 hours. After activation, centrifuge at 4000 rpm/centrifuge for 30 minutes, discard the supernatant, resuspend in TBS to a 50 mg/mL suspension, and store in a -20°C refrigerator after aliquoting.
  • the activated Zymosan A solution was diluted to 1 mg/mL with carbonic acid buffer (pH 9.5), 100 ⁇ L was added to each well of a 96-well black adsorption plate, and coated overnight at 4°C.
  • Complement pathway activation reaction human serum was diluted 5-fold with PBS solution into a 20% serum solution, and placed on ice for use. 20mM test compound in 100% DMSO was serially diluted with 100% DMSO to 2000, 500, 125, 31.25, 7.8125, 0.488281, 0.12207, 0.030518, 0.007629 ⁇ M, blank wells were 100% DMSO, and then diluted 20-fold in 2X EGTA reaction buffer (4.2 mM HEPES, 0.15 mM CaCl2 , 140 mM NaCl, 4.5 mM MgCl2 , 0.1% gelatin, 20 mM EGTA).
  • serum-EDTA reaction solution For negative control wells, prepare 40 ⁇ L of serum-EDTA reaction solution, namely, 20 ⁇ L of 20% human serum, 4 ⁇ L of the above DMSO diluted in 2X EDTA reaction buffer, and 16 ⁇ L of 2X EDTA reaction buffer, mix well, and incubate at room temperature for 30 minutes.
  • the 96-well black adsorption plate coated with Zymosan A one day in advance was washed three times with 300 ⁇ L/well TBST (0.05% Tween 20) solution, and 25 ⁇ L of serum-EGTA-test compound reaction solution was added to each well, blank control well, serum -EDTA-DMSO reaction solution (negative control well), react at 37°C for 40 minutes.
  • Inhibition rate ⁇ 1-(RFU test compound -RFU negative control well )/(RFU blank well- RFU negative control well ) ⁇ 100%
  • Test Example 3 Therapeutic effect of compounds of the present disclosure on Heymann nephritis in rats
  • male SD rats were selected to establish a Heymann nephritis model induced by sheep anti-rat Fx1A serum, and the therapeutic effects of the positive drug LNP023 (synthesized with reference to Example 26 of WO2015009616A1) and the compound of Example 1-1 on nephritis in male SD rats were evaluated.
  • mice male SD rats for experiments, provided by Weitong Lihua Laboratory Animal Co., Ltd. (production license number: SCXK (Zhe) 2019-0001, animal qualification certificate number: 20210401Abzz0619000322, 180-200g at the time of purchase).
  • Breeding conditions 5 animals/cage, 12/12 hours light/dark cycle adjustment, constant temperature of 23 ⁇ 1°C, humidity of 50-60%, free food and water. After the animals were purchased, the experiment was started after one week of adaptive feeding.
  • Positive drug LNP023 molecular weight 422.5, purity 99.9%.
  • the compound of Example 1-1 molecular weight 448.55, purity 99.9%.
  • Tween 80 Sinopharm Chemical Reagent Co., Ltd., item number 30189828, batch number 20180104.
  • Methylcellulose M450 Sinopharm Chemical Reagent Co., Ltd., item number 69016460, batch number 20170308.
  • Normal goat serum Sangon biotech, batch number GB02FC0260.
  • Sheep anti-rat Fx1A serum PROBETEX, Cat. No. PTX-002S, Lot No. 376-4T.
  • Rat iC3b-ELISA detection kit MYBioSource, Cat. No. MBS 7255121, Lot No. 20210301C.
  • Rat C3d-ELISA detection kit MYBioSource, Cat. No. MBS 7244846, Lot No. 20210301C.
  • Urine/CSF total protein (TPUC) kit Shenzhen Mindray Biomedical, Cat. No. 105-008805-00, Lot No. 147920004.
  • Creatinine kit Shenzhen Mindray Biomedical, item number 105-000457-00, batch number 141120024.
  • Urine microalbumin (MALB) (with calibrator): Shenzhen Mindray Biomedical, item number 105-009325-00, batch number 046020011.
  • Urine trace white protein control product Shenzhen Mindray Biomedical, item number 105-002957-00, batch number 053120008.
  • Urine/cerebrospinal fluid total protein (TPUC) quality control material Shenzhen Mindray Biomedical, item number 105-008841-00, batch number 060520005.
  • Biochemical compound quality control product (quality 1): Shenzhen Mindray Biomedical, item number 105-007316-00, batch number 059320002.
  • Biochemical compound quality control product (quality 2): Shenzhen Mindray Biomedical, item number 105-007317-00, batch number 059419004.
  • Microplate reader manufacturer BMGlabtech, model PHERAstar Fs.
  • Benchtop low-speed centrifuge manufacturer Eppendorf, model 5417R.
  • solvent group 0.5% methylcellulose M450 suspension (containing 0.5% Tween 80); iv: intravenous.
  • Formulation Example 1-1 Compound (10 mg/kg): weighed 300 mg + 1.5 mL of Tween 80 + 298.5 mL of methylcellulose M450.
  • Formulation Example 1-1 Compound (30 mg/kg): weighed 900 mg+1.5 mL Tween 80+298.5 mL methylcellulose M450.
  • Formulation Example 1-1 Compound (90 mg/kg): weighed 2700 mg + 1.5 mL of Tween 80 + 298.5 mL of methylcellulose M450.
  • Example 1-1 group (10mg/kg) , 30mg/kg, 90mg/kg, orally, twice a day).
  • the model group and the administration group were given a single injection of Fx1A serum (5mL/kg) into the tail vein, and the normal group was injected with normal sheep serum through the tail vein.
  • the compound of Example 1-1 (10 mL/kg), the normal group and the model group were given the corresponding solvent by gavage until the end of the 15th day of the experiment.
  • the 2-hour urine was collected on the 2nd, 4th, 6th, 8th, 11th and 14th days to detect urinary creatinine and total protein; the serum on the 15th day was collected for complement activation fragment (C3d+iC3b) analysis.
  • Inhibition rate 100% ⁇ (model group-administration group)/(model group-normal group)
  • #P ⁇ 0.05 means there is a significant difference between the administration group and the model group
  • ##P ⁇ 0.01 means there is a highly significant difference between the administration group and the model group
  • ###P ⁇ 0.001 means the comparison between the administration group and the model group highly significant difference.
  • Figure 1 shows the effects of the compound of Example 1-1 and the positive drug LNP023 on serum iC3b+C3d in passive heymann nephritis rats.
  • the results of serum iC3b+C3d in Figure 1 show that compared with the normal group, the serum iC3b+C3d of the model group rats increased significantly (P ⁇ 0.001); The rat serum iC3b+C3d decreased significantly, the decreasing range was 62.2% (P ⁇ 0.01) and 68.8% (P ⁇ 0.001); compared with the model group, 10 mg/kg, 30 mg/kg, 90 mg/kg
  • the serum iC3b+C3d of the rats in the -1 group decreased significantly, and the decreasing rates were 76.2% (P ⁇ 0.001), 105.5% (P ⁇ 0.001) and 108.7% (P ⁇ 0.001), respectively.
  • FIGS 2 and 3 show that compared with the normal group, the ratio of total urine protein/urine creatinine in the model group continued to increase as time went on, and it started to increase statistically from the 6th day and continued to increase; Compared with the 20mg/kg and 60mg/kg LNP023 groups, the ratio of urine total protein/urine creatinine decreased statistically from the 11th day, and the decrease range on the 14th day was 56.4% (P ⁇ 0.01) and 47.1% (P ⁇ 0.01), respectively.

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Abstract

公开了含氮桥杂环化合物、其制备方法及其在医药上的应用。具体而言，公开了一种通式(I)所示的含氮桥杂环化合物，其制备方法，含有该化合物的药物组合物，以及其作为治疗剂的用途，特别是作为补体因子B(Factor B)抑制剂的用途和在制备用于治疗和/或预防由Factor B介导的疾病或障碍的药物中的用途。

Description

含氮桥杂环化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种含氮桥杂环化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的含氮桥杂环化合物，其制备方法，含有其化合物的药物组合物，以及其作为补体因子B(Factor B)抑制剂的用途和在制备用于治疗和/或预防由Factor B介导的疾病或障碍的药物中的用途。
背景技术
补体是一种血清蛋白质，存在于人和脊椎动物血清及组织液中，不耐热，活化后具有酶活性，可介导免疫应答和炎症反应，可被抗原-抗体复合物或微生物所激活，导致病原微生物裂解或被吞噬。
补体系统是炎症反应和组织损伤的重要调节因子，由20多种血清蛋白和细胞表面蛋白组成。补体系统包括补体固有成分和多种调节蛋白。补体固有成分包括C1～C9，其中以C3含量最高。补体调节蛋白又分为可溶性和膜结合两类。可溶性补体调节蛋白包括丛生蛋白、S蛋白和补体因子H相关蛋白等。膜结合补体调节蛋白包括膜辅助蛋白(membrane cofactor protein，MCP)、衰变加速因子(decay accelerating factor，DAF)、补体受体1(complement receptor 1)等。此外，补体系统还包括一些补体片段和补体受体，如C3a受体、C5a受体等。
补体系统通过三条既独立又交叉的途径被激活，即经典途径(classical pathway，CP)、旁路途径(alternative pathway，AP)和凝集素途径(lectin pathway，LP，又称MBL途径(mannan-binding lectin pathway))。补体活化过程中通过一系列的正反馈发挥强大的生物学效应，参与疾病的发生发展过程。C3转化酶是前三条途径的重要成分，通过补体活化级联反应产生一系列补体蛋白片段和膜攻击复合物(membrane attack complex，MAC)。C3转化酶裂解C3生成C5转化酶，随即裂解C5生成C5a和C5b，C5b与C6、C7、C8、C9结合形成C5b-9即MAC。补体途径的异常会造成机体固有正常细胞的裂解从而导致疾病发生。
补体因子B是一种不耐热的β球蛋白，50℃30分钟即可失活。它可被补体因子D裂解为Ba、Bb两个片段，Bb与C3b结合构成旁路途径的C3转化酶。补体因子B是补体旁路活化途径中的一个重要成分，又称C3激活剂前体。补体因子B分子量为93 kDa，人血中浓度约为3μM，主要在肝脏合成，也发现在眼部视网膜色素上皮细胞中有合成。
阵发性睡眠性血红蛋白尿症(paroxysmal nocturnal hemoglobinuria，简称PNH)是一种获得性造血干细胞异常，造血干细胞经获得性体细胞PIG-A基因突变造成糖基磷脂酰肌醇合成异常，导致由GPI锚接在细胞膜上的一组膜蛋白丢失，引发非恶性的克隆性疾病。临床主要表现为骨髓丧失造血功能、血栓、慢性溶血性贫 血急性发作。该病发病原因不详，研究发现PNH的溶血是由于患者的红细胞对补体敏感。PNH红细胞缺乏一种被称为延迟加速因子DAF的补体调控蛋白，这种蛋白的作用为抑制补体C3转化酶的形成。PNH全球发病率为1-9/百万，发病年龄多为25～45岁，女性患者似乎比男性多一点。有大约35％的PNH患者在诊断后五年内死亡，诊断后的中位生存时间约为10到15年。该病虽为常染色体细胞突变后造成无遗传倾向，但起病急骤，无从预防，患者患病后出现血管内溶血，继而引起血栓栓塞和器官衰竭等严重并发症并导致患者丧失工作生活能力，并最终导致死亡。此前的治疗措施主要是对症治疗，包括红细胞输血增加血红蛋白，使用糖皮质激素等，骨髓移植认为能治愈，但需要供体且死亡风险较高。市场上缺乏既能控制溶血又能降低死亡风险的针对PNH的药物。目前除激素治疗和抗凝治疗外，人源型抗补体C5单克隆抗体Eculizumab及其长效分子Ravulizumab是治疗PNH的首选药物。
Eculizumab抗体药物非常昂贵，每年的治疗费用可达669,000美元。而且抗体药只能控制溶血症状，无法彻底治愈PNH，只能抑制血管内溶血，无法抑制血管外溶血。整个补体途径上目前有很多药物在开发中，如C3上游的CAP抑制剂：TT30、ACH-4471(anti-FD)和LNP023(anti-FB)，C3抑制剂：AMY-101、APL-2和C3下游anti-C5剂。
LNP023为诺华公司开发的口服小分子药物，已经有在治疗PNH二期试验中的一些安全性和有效性报道。在一项10例(25-79岁)患有PNH和主动溶血的患者(这些患者接受Eculizumab单抗治疗)参加的多中心、开放标签、连续2-队列研究中，所有患者在LNP023治疗之前都需要输注红细胞。入选的受试者每天两次接受LNP023伴随Eculizumab单抗治疗，时间为至少13周。试验发现LNP023的耐受性良好，没有治疗中断及严重不良事件或血栓栓塞事件的报道。在第13周，LNP023在所有患者中均显示LDH减少34-81％，所有女性Hb均正常，71％的男性Hb>120g/L。LNP023平均暴露241天，无患者需要RBC输血。在数据截止之时，已有5例患者终止了Eculizumab单抗治疗并继续使用LNP023单药治疗。所有LNP023单药治疗的患者保持血红蛋白水平，疾病活动的任何生物标志物均未改变，并且没有突破性溶血的症状。
肾小球病(Glomerulopathy)包括免疫球蛋白A肾病(IgA Nephropathy，简称IgAN)，C3肾小球病(C3G Glomerulopathy，简称C3G)，膜性肾小球肾炎(Membranous Glomerulonephritis，简称MGN)等。其中又以IgAN和MGN最为常见，而罕见肾脏疾病，如C3肾小球病发病率在近十年中也有所增加。研究发现肾小球病和补体途径特别是补体旁路途径密切相关。在美国IgAN在美国每年的发病人数约为18.5万，发病年龄在20-40岁，主要症状是血尿、疲劳和疼痛，大约30％的病人会最终发展为终末期肾病(ESRD)。膜性肾小球肾炎在美国每年的发病人数约为8万，发病年龄在40-60岁，大约30％的病人会最终发展为ESRD。C3 肾小球病在美国每年发病人数大概为1万，发病人群以青少年为主，约有50％的病人会发展成ESRD。目前原发性肾小球肾炎缺乏临床有效治疗方案。药物治疗常用如激素和免疫抑制剂(如环磷酰胺、霉酚酸酯、他克莫司、环孢素A、中药雷公藤多甙)，其他包括控制血压药物、利尿剂及抗血小板聚集药、抗凝药、降脂药、虫草制剂等保肾排毒药。
IgAN是世界范围内最常见的原发性肾小球疾病，病理表现为局部系膜增生和基质增多伴弥漫性系膜区IgA蛋白沉积，并常伴有IgG、C3和C5b-9沉积。因此认为补体途径与IgAN的发生发展有关。目前有两个针对补体途径的小分子药物正在进行临床试验。OMS721是Omeros公司开发的靶向MASP-2蛋白的人源化单克隆抗体。MASP-2蛋白是激活补体系统的凝集素途径(lectin pathway)的效应酶。在OMS721临床2期试验结束时，4名参加试验的IgAN患者的蛋白尿(proteinuria)指数都获得了显著的改善。目前这一药物正在进行临床三期的研究。
LNP023也处于治疗IgAN、C3G和MGN的多国多地区的二期临床试验中。最近诺华公司公布该药在治疗C3G患者的2期临床试验中，获得积极中期临床结果。在入组长期扩展研究后已接受治疗6个月的7例患者中，维持肾功能的效应得以持续。公司将在今年12月和明年初开展多项临床三期研究。
现已公开Factor B抑制剂的专利申请包括WO2015009616A1、WO2019043609A1和WO2020016749A2等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000001
其中：
X选自化学键、-CR aR b-、-NR-和-O-；
Y选自-CR 3aR 3b-、-NR 3c-和-O-；
环A为芳基或杂芳基；
R、R a和R b相同或不同，且各自独立地选自氢原子、烷基和卤代烷基；
各个R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、 杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 3、R 3a、R 3b和R 3c相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、-NR xR y和羟基；其中，所述的烷基任选被一个或多个氰基或氨基所取代；
各个R 4相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氰基、-NR 8R 9、羟基、-C(O)R 10、-CH 2C(O)R 10、-C(O)NR 8R 9、-C(O)NHS(O) pR 10、-S(O) pNHC(O)R 10、-S(O) pR 10、-S(O) pNR 8R 9、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5在每次出现时相同或不同，且各自独立地选自氢原子、羟基、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
R 10在每次出现时相同或不同，且各自独立地选自氢原子、-OR 11、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
R 11选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代；
R 12选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
R 6、R 7、R x、R y、R 8和R 9在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的 烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基和羟烷基中的一个或多个取代基所取代；
或者R 6和R 7与相连的氮原子一起形成杂环基，或者R x和R y与相连的氮原子一起形成杂环基，或者R 8和R 9与相连的氮原子一起形成杂环基，所述的杂环基在每次出现时相同或不同，且各自独立地任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个取代基所取代；
m为0、1或2；
n为0、1、2或3；
s为0、1、2、3或4；
t为0、1、2、3或4；且
p为0、1或2。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
X选自化学键、-CR aR b-、-NR-和-O-；
Y选自-CR 3aR 3b-、-NR 3c-和-O-；
环A为芳基或杂芳基；
R、R a和R b相同或不同，且各自独立地选自氢原子、烷基和卤代烷基；
各个R 1和R 2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 3、R 3a、R 3b和R 3c相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、-NR xR y和羟基；其中，所述的烷基任选被一个或多个氰基或氨基所取代；
各个R 4相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氰基、-NR 8R 9、羟基、-C(O)R 10、-CH 2C(O)R 10、-C(O)NR 8R 9、-C(O)NHS(O) pR 10、-S(O) pNHC(O)R 10、-S(O) pR 10、-S(O) pNR 8R 9、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5和R 10相同或不同，且各自独立地选自氢原子、羟基、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、 芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
R 6、R 7、R x、R y、R 8和R 9相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基和羟烷基中的一个或多个取代基所取代；
或者R 6和R 7与相连的氮原子一起形成杂环基，或者R x和R y与相连的氮原子一起形成杂环基，或者R 8和R 9与相连的氮原子一起形成杂环基，所述的杂环基在每次出现时相同或不同，且各自独立地任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个取代基所取代；
m为0、1或2；
n为0、1、2或3；
s为0、1、2、3或4；
t为0、1、2、3或4；且
p为0、1或2。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Y为-CR 3aR 3b-；R 3a和R 3b如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Y为-CR 3aR 3b-，R 3a和R 3b不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；优选地，Y为-CR 3aR 3b-，R 3a为氢原子，且R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；进一步优选地，Y为-CR 3aR 3b-，R 3a为氢原子，且R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；更优选地，Y为-CR 3aR 3b-，R 3a为氢原子，且R 3b为C 1-6烷氧基；最优选地，Y为-CR 3aR 3b-，R 3a为氢原子，且R 3b为乙氧基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000002
其中：
环A、X、R 1至R 3、R 3b、R 4、m、n、s和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中s为0或1；优选地，s为0。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R 3为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中m为1。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中n为2。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中m为1，且n为2。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000003
其中：
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
环A、X、R 1、R 3b、R 4至R 7、p和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10，R 8、R 9和R 10如通式(I)中所定义；
优选地，各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10，R 10如通式(I)中所定义；
更优选地，R 4为-C(O)R 10，R 10如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物 或其可药用的盐，其中R 10为-OR 11，R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基；其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代，R 12为氢原子或C 1-6烷基；
优选地，R 10为-OR 11，R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基；其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自-OR 12和-C(O)OR 12中的一个或多个取代基所取代，R 12为氢原子或C 1-6烷基；
更优选地，R 10选自羟基、
Figure PCTCN2021142760-appb-000004
Figure PCTCN2021142760-appb-000005
最优选地，R 10为羟基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10为-OR 11；R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基，其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代；R 12为氢原子或C 1-6烷基；
优选地，各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10；R 10为-OR 11；R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基，其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自-OR 12和-C(O)OR 12中的一个或多个取代基所取代；R 12为氢原子或C 1-6烷基；
更优选地，R 4为-C(O)R 10，R 10选自羟基、
Figure PCTCN2021142760-appb-000006
Figure PCTCN2021142760-appb-000007
最优选地，R 4为-C(O)R 10，R 10为羟基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10，R 8、R 9和R 10如通式(I)中所定义；优选地，各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10，R 10为羟基；更优选地，R 4为-C(O)R 10，R 10为羟基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000008
其中：
R 10选自羟基、
Figure PCTCN2021142760-appb-000009
优选地，R 10为羟基；
t为1或2；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
环A、X、R 1、R 3b、R 4至R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其 中各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9和羟基，R 8和R 9如通式(I)中所定义；优选地，各个R 4选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素和羟基；更优选地，R 4为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)所示的化合物或其可药用的盐，其中R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)所示的化合物，或其可药用的盐，其中X为化学键。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选地，环A为苯基或吡啶基；更优选地，环A为苯基。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；优选地，R 1为氢原子。
在本公开一些实施方案中，所述的通式(III)、通式(IV)所示的化合物或其可药用的盐，其中R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；优选地，R 1为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；优选地，各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6烷氧基和3至6元环烷基；更优选地，各个R 2相同或不同，且各自独立地选自氢原子、甲基、甲氧基和环丙基。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基和卤素；优选地，各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6烷氧基；更优选地，各个R 2相同或不同，且各自独立地选自氢原子、甲基和甲氧基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)所示的化合物或其可药用的盐，其为通式(V)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000010
其中：
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3b、R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(V)所示的化合物或其可药用的盐，其为rel-(1S,3S,5R)(即顺式)或rel-(1R,3S,5S)(即反式)的两个对映异构体的1:1的混合物，或者rel-(1S,3S,5R)(即顺式)或rel-(1R,3S,5S)(即反式)的两个非对映异构体的混合物；优选为rel-(1S,3S,5R)的两个对映异构体的1:1的混合物即(±)-rel-(1S,3S,5R)。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)所示的化合物或其可药用的盐，其为通式(V”)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000011
其中：
R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和 杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)所示的化合物或其可药用的盐，其为通式(V-1)所示的化合物，或其可药用的盐：
Figure PCTCN2021142760-appb-000012
其中：
R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)所示的化合物或其可药用的盐，其为通式(V-2)所示的化合物，或其可药用的盐：
Figure PCTCN2021142760-appb-000013
其中：
R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)所示的化合物或其可药用的盐，其为通式(V')所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000014
其中：
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 10选自羟基、
Figure PCTCN2021142760-appb-000015
R 3b、R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(V')所示的化合物或其可药用的盐，其为rel-(1S,3S,5R)(即顺式)或rel-(1R,3S,5S)(即反式)的两个对映异构体的1:1的混合物，或者rel-(1S,3S,5R)(即顺式)或rel-(1R,3S,5S)(即反式)的两个非对映异构体的混合物；优选为rel-(1S,3S,5R)的两个对映异构体的1:1的混合物即(±)-rel-(1S,3S,5R)。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V')所示的化合物或其可药用的盐，其为通式(V'-1)所示的化合物或其可药用的 盐：
Figure PCTCN2021142760-appb-000016
其中：
R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 10选自羟基、
Figure PCTCN2021142760-appb-000017
R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V')所示的化合物或其可药用的盐，其为通式(V'-2)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000018
其中：
R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；
R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、 -OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 10选自羟基、
Figure PCTCN2021142760-appb-000019
R 5、R 6、R 7和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；优选地，R 2a和R 2b相同或不同，且各自独立地选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基；更优选地，R 2a选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基，且R 2b为C 1-6烷基；最优选地，R 2a选自甲基、甲氧基和环丙基，且R 2b为甲基。
在本公开一些实施方案中，所述的通式(III)、通式(IV)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基和卤素；优选地，R 2a和R 2b相同或不同，且各自独立地为C 1-6烷基或C 1-6烷氧基；更优选地，R 2a为甲氧基，且R 2b为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V')所示的化合物或其可药用的盐，其中R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；优选地，R 3b选自C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；更优选地，R 3b为C 1-6烷氧基；最优选地，R 3b为乙氧基。
在本公开一些实施方案中，所述的式(V”)、通式(V-1)、通式(V-2)、通式(V'-1)、通式(V'-2)所示的化合物或其可药用的盐，其中R 3b为C 1-6烷氧基；优选地，R 3b为乙氧基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中t为1、2、3或4；优选地，t为1或2；最优选地，t为1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X为化学键；Y为-CR 3aR 3b-；R 3a和R 3b不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6 烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10为-OR 11，R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基，其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代，R 12为氢原子或C 1-6烷基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X为化学键；Y为-CR 3aR 3b-；R 3a和R 3b不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X为化学键；Y为-CR 3aR 3b-；R 3a和R 3b不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基和卤素；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6 烷氧基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10为-OR 11，R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基；其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代，R 12为氢原子或C 1-6烷基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为6至10元芳基或5至10元杂芳基；各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基和卤素；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、 C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基；s为0；m为1；n为2；t为1、2、3或4。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10为-OR 11，R 11选自氢原子、C 1-6烷基、C 1-6卤代烷基、3至8元环烷基和3至8元杂环基；其中，所述的C 1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自-OR 12和-C(O)OR 12中的一个或多个取代基所取代，R 12为氢原子或C 1-6烷基；t为1或2。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基；t为1或2。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基和卤素；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10；R 8和R 9 相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中，所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基和氰基中的一个或多个取代基所取代；R 10选自氢原子、羟基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基；t为1或2。
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10；R 10选自羟基、
Figure PCTCN2021142760-appb-000020
Figure PCTCN2021142760-appb-000021
t为1或2。
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10；R 10为羟基；t为1或2。
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中X为化学键；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基；环A为苯基或5至6元杂芳基；R 1选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基；R 2a和R 2b相同或不同，且各自独立地为C 1-6烷基或C 1-6烷氧基；各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、羟基和-C(O)R 10；R 10为羟基；t为1或2。
在本公开一些实施方案中，所述的通式(V')所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、 C 1-6烷氧基和C 1-6卤代烷氧基；R 10选自羟基、
Figure PCTCN2021142760-appb-000022
Figure PCTCN2021142760-appb-000023
在本公开一些实施方案中，所述的通式(V'-1)或通式(V'-2)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基；R 3b为C 1-6烷氧基；R 10选自羟基、
Figure PCTCN2021142760-appb-000024
Figure PCTCN2021142760-appb-000025
在本公开一些实施方案中，所述的通式(V)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基。
在本公开一些实施方案中，所述的通式(V”)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基；R 3b为C 1-6烷氧基。
在本公开一些实施方案中，所述的通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中R 2a和R 2b相同或不同，且各自独立地选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基；R 3b为C 1-6烷氧基。
在本公开一些实施方案中，所述的通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中R 2a选自C 1-6烷基、C 1-6烷氧基和3至6元环烷基，且R 2b为C 1-6烷基；R 3b为C 1-6烷氧基。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2021142760-appb-000026
Figure PCTCN2021142760-appb-000027
Figure PCTCN2021142760-appb-000028
Figure PCTCN2021142760-appb-000029
本公开的另一方面涉及通式(IVA)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000030
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 10为烷氧基；优选地，R 10为C 1-6烷氧基；更优选地，R 10为甲氧基；
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
本公开的另一方面涉及通式(IVB)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000031
其中：
R t为
Figure PCTCN2021142760-appb-000032
R s为羟基保护基；优选地，R s为烯丙基；
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
本公开的另一方面涉及通式(VA)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000033
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 10为烷氧基；优选地，R 10为C 1-6烷氧基；更优选地，R 10为甲氧基；
R 2a、R 2b和R 3b如通式(V)中所定义。
本公开的另一方面涉及通式(V-1A)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000034
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 10为烷氧基；优选地，R 10为C 1-6烷氧基；更优选地，R 10为甲氧基；
R 2a、R 2b和R 3b如通式(V-1)中所定义。
本公开的另一方面涉及通式(V-2A)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000035
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 10为烷氧基；优选地，R 10为C 1-6烷氧基；更优选地，R 10为甲氧基；
R 2a、R 2b和R 3b如通式(V-2)中所定义。
本公开的另一方面涉及通式(V'A)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000036
其中：
R t为
Figure PCTCN2021142760-appb-000037
R s为羟基保护基；优选地，R s为烯丙基；
R 2a、R 2b和R 3b如通式(V')中所定义。
本公开的另一方面涉及通式(V'-1A)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000038
其中：
R t为
Figure PCTCN2021142760-appb-000039
R s为羟基保护基；优选地，R s为烯丙基；
R 2a、R 2b和R 3b如通式(V'-1)中所定义。
本公开的另一方面涉及通式(V'-2A)所示的化合物或其可药用的盐：
Figure PCTCN2021142760-appb-000040
其中：
R t为
Figure PCTCN2021142760-appb-000041
R s为羟基保护基；优选地，R s为烯丙基；
R 2a、R 2b和R 3b如通式(V'-2)中所定义。
表B本公开的典型化合物包括但不限于：
Figure PCTCN2021142760-appb-000042
Figure PCTCN2021142760-appb-000043
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000044
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(IVA)所示的化合物或其可药用的盐脱去保护基R w和进行水解反应，得到R 10为羟基的通式(IV)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000045
通式(IVB)所示的化合物或其可药用的盐脱去保护基R s得到通式(IV)所示的化合物或其可药用的盐，
以及任选地经拆分得到单一构型的通式(IV)所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000046
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000047
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
本公开的另一方面涉及一种制备通式(V)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000048
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(VA)所示的化合物或其可药用的盐脱去保护基R w和进行水解反应，得到通式(V)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V)中所定义。
本公开的另一方面涉及一种制备通式(V-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000049
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(V-1A)所示的化合物或其可药用的盐脱去保护基R w和进行水解反应，得到通式(V-1)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w 为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V-1)中所定义。
本公开的另一方面涉及一种制备通式(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000050
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(V-2A)所示的化合物或其可药用的盐脱去保护基R w和进行水解反应，得到通式(V-2)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V-2)中所定义。
本公开的另一方面涉及一种制备通式(V')所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000051
通式(V'A)所示的化合物或其可药用的盐脱去保护基R s得到通式(V')所示的化合物或其可药用的盐，
以及任选地经拆分得到单一构型的通式(V')所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000052
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000053
R 2a、R 2b和R 3b如通式(V')中所定义。
本公开的另一方面涉及一种制备通式(V'-1)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000054
通式(V'-1A)所示的化合物或其可药用的盐脱去保护基R s得到通式(V'-1)所示的化合物或其可药用的盐，
以及任选地经拆分得到单一构型的通式(V'-1)所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000055
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000056
R 2a、R 2b和R 3b如通式(V'-1)中所定义。
本公开的另一方面涉及一种制备通式(V'-2)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2021142760-appb-000057
通式(V'-2A)所示的化合物或其可药用的盐脱去保护基R s得到通式(V'-2)所示的化合物或其可药用的盐，
以及任选地经拆分得到单一构型的通式(V'-2)所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000058
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000059
R 2a、R 2b和R 3b如通式(V'-2)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备用于抑制补体旁路途径活化的药物中的用途，优选在制备用于抑制Factor B的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防由补体旁路途径活化介导的疾病或障碍的药物中的用途；优选在制备用于治疗和/或预防由Factor B介导的疾病或障碍的药物中的用途，其中所述的疾病或障碍选自肾小球病(如肾小球肾炎)、溶血性尿毒综合征(如大肠杆菌诱导的溶血性尿毒综合征)、非典型溶血尿毒综合征(atypical haemolytic uraemic syndrome，aHUS)、阵发性睡眠性血红蛋白尿症、年龄相关性黄斑变性、地图状萎缩、糖尿病性视网膜病变、葡萄膜炎(如前葡萄膜炎、后葡萄膜炎和中间葡萄膜炎)、色素性视网膜炎、黄斑水肿、贝赫切特综合征引起的葡萄膜炎、多灶性脉络膜炎、福-小柳-原田综合征、鸟枪弹样视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮、非动脉炎性缺血性视神经病、手术后炎症、视网膜静脉阻塞、神经病学障碍、多发性硬化、中风、吉-巴综合征、创伤性脑损伤、帕金森病、不适宜的或不希望的补体活化障碍、血液透析并发症、超急性同种异体移植物排斥、异种移植物排斥、IL-2治疗期间白介素-2诱导的毒性、克隆病、成人型呼吸窘迫综合征、心肌炎、缺血后再灌注 病症、心肌梗死、球囊血管成形术、心肺动脉分流手术或肾分流手术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建、感染性疾病或脓毒症后肠系膜动脉再灌注、免疫复合物障碍、自身免疫性疾病(如类风湿性关节炎、系统性红斑狼疮(SLE)、免疫性血小板减少症和冷凝集素综合征)、系统性红斑狼疮性肾炎、增殖性肾炎、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、急性呼吸窘迫综合征(ARDS)、哮喘、慢性阻塞性肺疾病(COPD)、肺气肿、肺栓塞和梗死、肺炎(如过敏性肺炎)、致纤维化粉尘疾病、肺纤维化、哮喘、变态反应、支气管缩窄、寄生虫病、古德曼综合征、肺脉管炎、寡免疫性脉管炎、免疫复合物相关炎症、抗磷脂综合征和肥胖；其中，所述的肾小球病优选选自C3肾小球病(如C3肾小球肾炎)、免疫球蛋白A肾病(如原发性免疫球蛋白A肾病)和膜性肾小球肾炎；更优选在制备用于治疗和/或预防C3肾小球病(如C3肾小球肾炎)、免疫球蛋白A肾病、膜性肾小球肾炎、非典型溶血尿毒综合征和阵发性睡眠性血红蛋白尿症的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防由Factor B介导的疾病或障碍的药物中的用途，其中所述的疾病或障碍为炎性障碍。
本公开进一步涉及一种抑制补体旁路途径活化的方法，优选一种抑制Factor B的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种治疗和/或预防由补体旁路途径活化介导的疾病或障碍的方法，优选一种治疗和/或预防由Factor B介导的疾病或障碍的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用于抑制补体旁路途径活化，优选用于抑制Factor B。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(V)、通式(V”)、通式(V-1)、通式(V-2)、通式(V')、通式(V'-1)、通式(V'-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物，其用于治疗和/或预防由补体旁 路途径活化介导的的疾病或障碍，优选用于治疗和/或预防由Factor B介导的疾病或障碍。
本公开所述的由补体旁路途径活化介导的疾病或障碍(优选由Factor B介导的疾病或障碍)选自肾小球病(如肾小球肾炎)、溶血性尿毒综合征(如大肠杆菌诱导的溶血性尿毒综合征)、非典型溶血尿毒综合征、阵发性睡眠性血红蛋白尿症、年龄相关性黄斑变性、地图状萎缩、糖尿病性视网膜病变、葡萄膜炎(如前葡萄膜炎、后葡萄膜炎和中间葡萄膜炎)、色素性视网膜炎、黄斑水肿、贝赫切特综合征引起的葡萄膜炎、多灶性脉络膜炎、福-小柳-原田综合征、鸟枪弹样视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮、非动脉炎性缺血性视神经病、手术后炎症、视网膜静脉阻塞、神经病学障碍、多发性硬化、中风、吉-巴综合征、创伤性脑损伤、帕金森病、不适宜的或不希望的补体活化障碍、血液透析并发症、超急性同种异体移植物排斥、异种移植物排斥、IL-2治疗期间白介素-2诱导的毒性、克隆病、成人型呼吸窘迫综合征、心肌炎、缺血后再灌注病症、心肌梗死、球囊血管成形术、心肺动脉分流手术或肾分流手术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建、感染性疾病或脓毒症后肠系膜动脉再灌注、免疫复合物障碍、自身免疫性疾病(如类风湿性关节炎、系统性红斑狼疮(SLE)、免疫性血小板减少症和冷凝集素综合征)、系统性红斑狼疮性肾炎、增殖性肾炎、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、急性呼吸窘迫综合征(ARDS)、哮喘、慢性阻塞性肺疾病(COPD)、肺气肿、肺栓塞和梗死、肺炎、致纤维化粉尘疾病、肺纤维化、哮喘、变态反应、支气管缩窄、过敏性肺炎、寄生虫病、古德曼综合征、肺脉管炎、寡免疫性脉管炎、免疫复合物相关炎症、抗磷脂综合征和肥胖；其中，所述的肾小球病优选选自C3肾小球病(如C3肾小球肾炎)、免疫球蛋白A肾病(如原发性免疫球蛋白A肾病)和膜性肾小球肾炎；优选地，所述的疾病或障碍选自C3肾小球病(如C3肾小球肾炎)、免疫球蛋白A肾病、膜性肾小球肾炎、非典型溶血尿毒综合征和阵发性睡眠性血红蛋白尿症。
本公开所述的由Factor B介导的疾病或障碍为炎性障碍。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成持续释放剂型，例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制 剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入甜味剂和矫味剂以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C 1-12烷基)，更优选具有1至6个碳原子的烷基(即C 1-6烷基)。非限制性实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。最优选具有1至6个碳原子的低级烷基，非限制性实施例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基和2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C 1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C 1-12亚烷基)，更优选含有1至6个碳原子的亚烷基(即C 1-6亚烷基)。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基 (-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)和1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基(即C 2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选选自烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选选自烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即3至20元环烷基)，优选具有3至12个碳原子(即3至12元环烷基)，更优选具有3至8个碳原子(即3至8元环烷基)，最优选具有3至6个碳原子(即3至6元环烷基)。单环环烷基的非限制性实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基或多螺环烷基(如双螺环烷基)，优选单螺环烷基和双螺环烷基。更优选3元/5元、 3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/4元、6元/5元或6元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021142760-appb-000060
术语“稠环烷基”指5至20元，环之间共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠环烷基，优选双环或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021142760-appb-000061
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环桥环烷基，优选双环、三环或四环桥环烷基，更优选双环或三环桥环烷基。桥环烷基的非限制性实例包括：
Figure PCTCN2021142760-appb-000062
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2021142760-appb-000063
等；优选
Figure PCTCN2021142760-appb-000064
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其具有3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子 为碳。优选具有3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1至4个(例如1、2、3和4个)是杂原子(即3至12元杂环基)；进一步优选具有3至8个环原子(例如3、4、5、6、7和8个)，其中1至3个是杂原子(例如1、2和3个)(即3至8元杂环基)；更优选具有3至6个环原子，其中1至3个是杂原子(即3至6元杂环基)；最优选具有5或6个环原子，其中1至3个是杂原子(即5或6元杂环基)。单环杂环基的非限制性实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基或多螺杂环基(如双螺杂环基)，优选单螺杂环基和双螺杂环基。更优选3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021142760-appb-000065
术语“稠杂环基”指5至20元，环之间共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环等多环稠杂环基，优选双环或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021142760-appb-000066
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选6至14元，更优选7至10元(例如7、8、9或10元)。根据组成环的数目可 以分为双环、三环、四环等多环桥杂环基，优选双环、三环或四环桥杂环基，更优选双环或三环桥杂环基。桥杂环基的非限制性实例包括：
Figure PCTCN2021142760-appb-000067
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021142760-appb-000068
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021142760-appb-000069
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指包含1至4个杂原子(例如1、2、3和4个)、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选5至10元(例如5、6、7、8、9或10元)杂芳基，更优选5元或6元杂芳基，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基和四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021142760-appb-000070
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“亚环烷基”、“亚杂环基”、“亚芳基”和“亚杂芳基”。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、乙酰基、对甲苯磺酰基(Ts)、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基和硝基中的1至3个取代基所取代。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，通常用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性实例包括：三乙基硅基、三异丙基硅基、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基(如甲氧基甲基(MOM)和乙氧基乙基等)、(C 1-10烷基或芳香基)酰基(如：甲酰基，乙酰基，苯甲酰基、对硝基苯甲酰基等)、(C 1-6烷基或6至10元芳基)磺酰基、(C 1-6烷氧基或6至10元芳基氧基)羰基、烯丙基、2-四氢吡喃基(THP)等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键
Figure PCTCN2021142760-appb-000071
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021142760-appb-000072
可以为
Figure PCTCN2021142760-appb-000073
或者同时包含
Figure PCTCN2021142760-appb-000074
和
Figure PCTCN2021142760-appb-000075
两种构型。
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺的平衡实例如下所示：
Figure PCTCN2021142760-appb-000076
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
Figure PCTCN2021142760-appb-000077
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为 2H(氘，D)、 3H(氚，T)、 11C、 13C、 14C、 15N、 17O、 18O、 32p、 33p、 33S、 34S、 35S、 36S、 18F、 36Cl、 82Br、 123I、 124I、 125I、 129I和 131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
本公开的化合物，当其一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度 比氘的天然丰度大至少6000倍(即至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即至少99.5％的氘掺入)。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选地(任选)被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等参数时，表明该参数可以变化 ±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(IV)所示的化合物，或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000078
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(IVA)所示的化合物或其可药用的盐在碱性条件下脱去保护基R w和进行水解反应，得到R 10为羟基的通式(IV)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
方案二
本公开通式(IV)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000079
通式(IVB)所示的化合物或其可药用的盐在催化剂(优选四(三苯基膦)钯)的存在下脱去保护基R s得到通式(IV)所示的化合物或其可药用的盐，
以及任选地经手性制备拆分得到单一构型的通式(IV)所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000080
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000081
t为1或2；
环A、X、R 1、R 2a、R 2b、R 3b和R 4如通式(IV)中所定义。
方案三
本公开通式(V)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000082
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(VA)所示的化合物或其可药用的盐在碱性条件下脱去保护基R w和进行水解反应，得到通式(V)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V)中所定义。
方案四
本公开通式(V-1)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000083
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(V-1A)所示的化合物或其可药用的盐在碱性条件下脱去保护基R w和进行水解反应，得到通式(V-1)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V-1)中所定义。
方案五
本公开通式(V-2)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000084
R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(V-2A)所示的化合物或其可药用的盐在碱性条件下脱去保护基R w和进行水解反应，得到通式(V-2)所示的化合物或其可药用的盐，
其中：
R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
R 2a、R 2b和R 3b如通式(V-2)中所定义。
方案六
本公开通式(V-1)和通式(V-2)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000085
通式(V”)所示的化合物或其可药用的盐经手性制备拆分得到通式(V-1)和通式(V-2)所示的化合物或其可药用的盐；
R 2a、R 2b和R 3b如通式(V-1)和通式(V-2)中所定义。
方案七
本公开通式(V')所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000086
通式(V'A)所示的化合物或其可药用的盐在催化剂(优选四(三苯基膦)钯)的存在下脱去保护基R s得到通式(V')所示的化合物或其可药用的盐，
以及任选地经手性制备拆分得到单一构型的通式(V')所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000087
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000088
R 2a、R 2b和R 3b如通式(V')中所定义。
方案八
本公开通式(V'-1)所示的化合物或其可药用的盐的制备方法，该方法包括以下 步骤：
Figure PCTCN2021142760-appb-000089
通式(V'-1A)所示的化合物或其可药用的盐在催化剂(优选四(三苯基膦)钯)的存在下脱去保护基R s得到通式(V'-1)所示的化合物或其可药用的盐，
以及任选地经手性制备拆分得到单一构型的通式(V'-1)所示的化合物或其可药用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000090
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000091
R 2a、R 2b和R 3b如通式(V'-1)中所定义。
方案九
本公开通式(V'-2)所示的化合物或其可药用的盐的制备方法，该方法包括以下步骤：
Figure PCTCN2021142760-appb-000092
通式(V'-2A)所示的化合物或其可药用的盐在催化剂(优选四(三苯基膦)钯)的存在下脱去保护基R s得到通式(V'-2)所示的化合物或其可药用的盐，
以及任选地经手性制备拆分得到单一构型的通式(V'-2)所示的化合物或其可药 用的盐，
其中：
R t为
Figure PCTCN2021142760-appb-000093
R s为羟基保护基；优选地，R s为烯丙基；
R 10选自
Figure PCTCN2021142760-appb-000094
R 2a、R 2b和R 3b如通式(V'-2)中所定义。
上述反应中，所述的碱包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、乙酸钠、乙酸钾、乙醇钠、叔丁醇钠和叔丁醇钾；所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾，优选选自氢氧化锂一水合物、氢氧化锂和氢氧化钾。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
附图说明
图1：实施例1-1化合物和阳性药LNP023对被动heymann肾炎大鼠血清iC3b+C3d的影响。
图2和图3：实施例1-1化合物和阳性药LNP023对被动heymann肾炎大鼠尿蛋白/肌酐的影响。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪 (生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱层析色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：正己烷/二氯甲烷体系，D：石油醚/乙酸乙酯体系，E：甲苯/丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例中的化合物含有两个或更多个手性中心时，这些化合物的相对立体化学是通过NMR研究和/或X-射线衍射鉴定的。在这些情况中，使用前缀“rel”、随后使用R/S命名法鉴定这些化合物，此时的R/S仅提供相对立体化学信息，不表 示绝对立体化学。例如，本公开的化合物1(化学名称：(±)-rel-4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸，结构式：
Figure PCTCN2021142760-appb-000095
)，其表示的是
Figure PCTCN2021142760-appb-000096
在1、3和5位的相对立体化学是1S,3S,5R或1R,3R,5S(即顺式，具体地为1、5-8位所在的五元含氮杂环基和3位的乙氧基均位于1-5、8位所在的六元含氮杂环所在面的同侧：即同朝里或者同朝外)，由于化合物1为外消旋体，因此，本领域技术人员可以毫无疑义地确定化合物1为两个对映异构体
Figure PCTCN2021142760-appb-000097
Figure PCTCN2021142760-appb-000098
的1:1的混合物。
此外，本领域技术人员可以毫无疑义地确定，
Figure PCTCN2021142760-appb-000099
在1位和3位的相对立体化学一旦确定，则5位的相对立体化学也是唯一确定的，因为受空间位阻的影响，1位的4-羧基苯基和1、5-8位所在的五元含氮杂环基只能位于1-5、 8位所在的六元含氮杂环所在面的异侧。因此，
Figure PCTCN2021142760-appb-000100
Figure PCTCN2021142760-appb-000101
实际上是同一个化合物即均为外消旋体，而
Figure PCTCN2021142760-appb-000102
实际上是同一个化合物。
实施例1，实施例2
(±)-rel-4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸1
(±)-rel-4-((1R,3S,5S)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸2
Figure PCTCN2021142760-appb-000103
Figure PCTCN2021142760-appb-000104
第一步
1-(4-溴苯基)丁烷-1,4-二醇1b
将4-(4-溴苯基)-4-氧代丁酸甲酯1a(5g，17.54mmol，毕得医药科技有限公司)溶于四氢呋喃(50mL)，在0℃条件下加入硼氢化锂的四氢呋喃溶液(17mL，2mmol/mL)，自然升至室温，搅拌过夜。反应液用饱和硫代硫酸钠溶液淬灭，乙酸乙酯萃取。有机相干燥浓缩得到粗品标题产物1b(4.29g)，不经纯化直接用于下一步反应。
MS m/z(ESI):242.9[M-H]。
第二步
4-(4-溴苯基)-4-氧代丁醛1c
将二甲基亚砜(8.2g，104.95mmol)溶于二氯甲烷(50mL)，-78℃加入草酰氯(8.8g，69.33mmol)，继续搅拌10分钟，加入化合物1b(4.29g，17.50mmol)，10分钟后加入三乙胺(17.7g，174.92mmol)。反应液继续搅拌1小时。自然升至室温，二氯甲烷稀释，有机相用饱和碳酸氢钠水溶液洗涤，干燥有机相，减压浓缩，用硅胶柱层析色谱法以洗脱剂C纯化得到标题化合物1c(2.7g，产率：64％)。
MS m/z(ESI):240.8[M+1]。
第三步
1-(4-溴苯基)-8-[(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷-3-酮1d
将4-甲氧基苄胺(1.61g，11.74mmol，韶远科技有限公司)和乙酸钠(6.43g，78.38mmol)溶于水(7.5mL)，0℃加入2M盐酸(16mL)和1,3-丙酮二羧酸(1.96g，13.42mmol)，继续搅拌30分钟，加入化合物1c(2.7g，11.20mmol)，30分钟后在40℃搅拌3小时。反应液用饱和碳酸氢钠溶液调节pH到8～9，乙酸乙酯萃取。干燥有机相，减压浓缩，用硅胶柱层析色谱法以洗脱剂C纯化得到标题化合物1d(580mg,产率：12.9％)。
MS m/z(ESI):399.9[M+1]。
第四步
1-(4-溴苯基)-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷-3醇1e
将化合物1d(530mg，1.32mmol)溶于甲醇(5mL)，加入硼氢化钠(200mg，5.29mmol)。室温搅拌2小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取。干燥有机相，减压浓缩得到粗品标题化合物1e(420mg，产率：78.8％)。
MS m/z(ESI):401.8[M+1]。
第五步
1-(4-溴苯基)-3-乙氧基-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷1f
将化合物1e溶于二甲基甲酰胺(5mL)，0℃加入氢化钠(83mg，2.08mmol)。反应液继续搅拌1小时，加入碘乙烷(325mg，2.09mmol)。反应液升至室温搅拌过夜。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取，干燥有机相，减压浓缩，用硅胶柱层析色谱法以洗脱剂C纯化得到标题化合物1f(350mg，产率：77.9％)。
MS m/z(ESI):429.9[M+1]。
第六步
4-(3-乙氧基-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯1g
将化合物1f溶于甲醇(4mL)和二甲基甲酰胺(4mL)，加入醋酸钯(54mg，240.52μmol)、叠氮磷酸二苯酯(100mg，242.46μmol)和三乙胺(822mg，8.12mmol)。一氧化碳气体置换三次，80℃搅拌过夜。反应液倒入水中，乙酸乙酯萃取，干燥有机相，减压浓缩，用硅胶柱层析色谱法以洗脱剂C纯化得到标题化合物1g(225mg，产率：67.5％)。
MS m/z(ESI):411.0[M+1]。
第七步
4-(3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯1h
将化合物1g(225mg，549.43μmol)溶于乙醇(5mL)，加入钯碳加氢催化剂(40mg，375.87μmol)。氢气置换三次，在氢气氛围下，室温搅拌48小时。过滤反应液，有机相减压浓缩得到粗品标题化合物1h(130mg)，产物不经纯化直接用于下步反应。
MS m/z(ESI):290.0[M+1]。
第八步
4-(溴甲基)-5-甲氧基-7-甲基吲哚-1-羧酸叔丁酯1j
将化合物4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯1i(150mg，514.86μmol，参照WO2015009616A1的中间体1-10的制备方法合成)溶解于二氯甲烷(2mL)中，氮气氛下加入四溴化碳(170mg，512.62μmol)和三苯基膦(135mg，514.71μmol)，反应液在室温搅拌2小时，直接浓缩得到粗品化合物1j(183mg)，产物不经纯化直接用于下步反应。
第九步
4-((3-乙氧基-1-(4-(甲氧羰基)苯基)-8-氮杂双环[3.2.1]辛烷-8-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯1k
将化合物1h(100mg，345.5801μmol)溶于二甲基甲酰胺(2mL)中，0℃加入氢化钠(27mg，675.07μmol)。反应液继续搅拌1小时，然后加入化合物1j(183mg，516.60μmol)的二甲基甲酰胺溶液，反应液继续搅拌1小时，用饱和氯化铵水溶液淬灭，干燥有机相，减压浓缩，用硅胶柱层析色谱法以洗脱剂C纯化得到标题化合物1k(130mg，产率：66.8％)。
MS m/z(ESI):563.0[M+1]。
第十步
(±)-rel-4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸1
(±)-rel-4-((1R,3S,5S)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸2
将化合物1k(130mg，231.03μmol)溶于6mL四氢呋喃、甲醇和水(V:V:V＝1:1:1)的混合溶液中。加入氢氧化锂一水合物(58mg，1.38mmol)。反应液在70℃搅拌3小时。反应液浓缩，用少量甲醇稀释后，用高效液相制备色谱法(Waters 2545，色谱柱：Sharpsil-T C18，250*50mm，8μm；流动相A：水(含10mmol/L的碳酸氢铵)；流动相B：乙腈；18分钟梯度：20％-38％，流速：80mL/min)纯化，得标题化合物1(4mg，产率：3.86％)和2(5mg，产率：4.82％)。
化合物1：
高效液相制备色谱法：保留时间17.28min。
MS m/z(ESI):449.1[M+1]。
1H NMR(500 MHz,CD 3OD):δ8.16-8.14(m,2H),7.69(br,2H),7.35-7.34(m,1H),6.84(s,1H),6.34(br,1H),4.20-4.03(m,3H),3.93(s,3H),3.71-3.58(m,1H),3.51-3.34(m,2H),3.32-2.96(m,2H),2.73-2.68(m,3H),2.54(s,3H),2.25-2.04(m,3H),1.25-1.22m,3H)。
化合物2：
高效液相制备色谱法：保留时间14.83min。
MS m/z(ESI):449.1[M+1]。
1H NMR(500 MHz,CD 3OD):δ8.16-8.14(m,2H),7.70(br,2H),7.39-7.26(m,1H),6.83(s,1H),6.31(br,1H),4.19-3.92(m,3H),3.87-3.79(m,4H),3.66-3.45(m,2H),3.07-2.58(m,4H),2.50(s,3H),2.38-2.16(m,4H),1.24-1.06(m,3H)。
实施例1-1，实施例1-2
4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸1-1
4-((1R,3R,5S)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸1-2
Figure PCTCN2021142760-appb-000105
将化合物1(100mg，222.93μmol)进行手性制备(分离条件：手性制备柱CHIRALPAK IG，5μm，20mm*250mm(Phenomenex)；流动相1：正己烷(80％)；流动相2：含0.1％二乙胺，0.1％三氟乙酸，乙醇(20％)，流速：20mL/min)纯化，收集其相应组分，减压浓缩，得到标题化合物1-1(35mg，产率：35％)和1-2(33mg，产率：33％)。
化合物1-1：
MS m/z(ESI):449.1[M+1]。
手性HPLC分析：保留时间7.946分钟，手性纯度：100％(色谱柱：CHIRALPAK IG，5μm，20mm*250mm(Phenomenex)；流动相1：正己烷(80％)；流动相2：含0.1％二乙胺，0.1％三氟乙酸，乙醇(20％)，流速：1mL/min)。
1H NMR(500MHz,MeOD)δ8.16-8.15(m,2H),7.69(br,2H),7.34(br,1H),6.83(s,1H),6.33(br,1H),4.22-4.12(m,2H),4.03-4.00(m,1H),3.93(s,3H),3.71-3.51(m,1H),3.50-3.35(m,2H),3.32-2.96(m,2H),2.73-2.53(m,3H),2.51(s,3H),2.21-2.05(m,3H),1.35-1.22(m,3H)。
化合物1-2：
MS m/z(ESI):449.1[M+1]。
手性HPLC分析：保留时间12.77分钟，手性纯度：98.7％(色谱柱：CHIRALPAKIG，5μm，20mm*250mm(Phenomenex)；流动相1：正己烷(80％)；流动相2：含0.1％二乙胺，0.1％三氟乙酸，乙醇(20％)，流速：1mL/min)。
1H NMR(500 MHz,MeOD)δ8.17-8.16(m,2H),7.71(br,2H),7.35(br,1H),6.85(s,1H),6.34(br,1H),4.23-4.19(m,2H),4.08-4.05(m,1H),3.95(s,3H),3.72-3.59(m,1H),3.51-3.34(m,2H),3.32-2.98(m,2H),2.75-2.60(m,3H),2.54(s,3H),2.27-2.20(m,3H),1.25-1.23(m,3H)。
实施例3
4-((1S,3S,5R)-8-((5,7-二甲基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸3
Figure PCTCN2021142760-appb-000106
Figure PCTCN2021142760-appb-000107
第一步
(±)-rel-(1S,3S)-1-(4-溴苯基)-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷-3-醇3a
将化合物1d(22.5g，56.21mmol)溶于四氢呋喃(220mL)中，氮气氛下，-78℃滴加三仲丁基硼氢化锂的四氢呋喃溶液(168.86mL，168.86mmol)，滴完维持-78℃搅拌3小时。向反应混合物中加入甲醇(100mL)淬灭反应，并移至室温搅拌1小时，加入乙酸乙酯，分别用0.5M盐酸和饱和食盐水洗涤，有机相加入无水硫酸钠干燥，过滤，减压浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化，再用饱和碳酸氢钠水溶液和饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物3a(18.7g，产率：82.69％)。
MS m/z(ESI):401.9[M+1]。
第二步
(±)-rel-(1S,3S)-1-(4-溴苯基)-3-乙氧基-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷3b
将3a(18.7g，46.48mmol)溶于四氢呋喃(200mL)中，0℃加入氢化钠(8.91g，232.54mmol，含量60％)，继续搅拌1小时，加入18.62mL碘乙烷(36.3g，232.74mmol)，反应混合物于50℃搅拌过夜。冷却至室温，加入饱和氯化铵水溶液淬灭反应，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3b(13.0g，产率：65％)。
MS m/z(ESI):429.9[M+1]。
第三步
(1S,3S,5R)-1-(4-溴苯基)-3-乙氧基8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷3c
(1R,3R,5S)-1-(4-溴苯基)-3-乙氧基8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷3c'
将化合物3b进行手性制备(分离条件：手性制备柱Waters SFC 150，DAICEL
Figure PCTCN2021142760-appb-000108
OJ，流动相：超临界二氧化碳/甲醇＝70/30))纯化，收集其相应组分，减压浓缩，得到标题化合物3c(7.2g，收率：55.38％)和3c'(5.8g，收率：44.62％)。
化合物3c：
MS m/z(ESI):429.9[M+1]。
手性HPLC分析：保留时间7.946分钟，手性纯度：100％(色谱柱：CHIRALPAK IG，5μm，20mm*250mm(Phenomenex)；流动相1：正己烷(80％)；流动相2：含0.1％二乙胺，0.1％三氟乙酸，乙醇(20％)，流速：1mL/min)。
化合物3c'：
MS m/z(ESI):429.9[M+1]。
手性HPLC分析：保留时间12.77分钟，手性纯度：98.7％(色谱柱：CHIRALPAKIG，5μm，20mm*250mm(Phenomenex)；流动相1：正己烷(80％)；流动相2：含0.1％二乙胺，0.1％三氟乙酸，乙醇(20％)，流速：1mL/min)。
第四步
4-((1S,3S,5R)-3-乙氧基-8-(4-甲氧基苄基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯3d
将化合物3c(7.2g，16.73mmol)溶于甲醇(40mL)和N,N-二甲基甲酰胺(40mL)中，加入醋酸钯(1.14g，5.08mmol，伊诺凯试剂)、1,3-双(二苯基膦)丙烷(2.08g，5.04mmol，上海韶远试剂有限公司)和三乙胺(17g，168.00mmol)，一氧化碳置换三次，在一氧化碳氛围下，80℃搅拌过夜。反应完成后，将反应液到入水中，用乙酸乙酯萃取，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3d(5.9g，产率：86.12％)。
MS m/z(ESI):410.0[M+1]。
第五步
4-((1S,3S,5R)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯3e
将化合物3d(5.9g，14.41mmol)溶于水(30mL)和乙腈(30mL)中，冷却至0℃，加入硝酸铈铵(23.7g，43.23mmol，阿达玛斯试剂有限公司)。室温反应1小时，再加入硝酸铈铵(16g，29.18mmol)，继续室温反应1小时。加入大量的水，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系A纯化得到标题化合物3e(3.2g，产率：76.76％)。
MS m/z(ESI):290.0[M+1]。
第六步
4-溴-5,7-二甲基-1-对甲苯磺酰基-1H-吲哚3g
将4-溴-5,7-二甲基-1H-吲哚3f(1.4g，6.25mmol，艾康试剂)溶于N,N-二甲基甲酰胺(25mL)中，冷却至0℃，加入氢化钠(500mg，12.50mmol，含量60％)，反应混合物搅拌10分钟后，加入对甲苯磺酰氯(1.3g，6.82mmol，国药试剂)，加完移至室温搅拌过夜。向反应混合物中加入饱和氯化铵水溶液，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3g(1.2g，产率：50.78％)。
MS m/z(ESI):377.9[M+1]。
第七步
5,7-二甲基-1-对甲苯磺酰基-1H-吲哚-4-甲酸甲酯3h
将化合物3g(600mg，1.59mmol)溶于甲醇(5mL)和N,N-二甲基甲酰胺(5mL)中，加入醋酸钯(106.9mg，476.15μmol)，1,3-双(二苯基膦)丙烷(196.3mg，475.94μmol)和三乙胺(1.61g，15.86mmol)，一氧化碳置换三次，在一氧化碳氛围下，80℃搅拌过夜。反应完成后，将反应液到入水中，用乙酸乙酯萃取，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3h(488mg，产率：86.08％)。
MS m/z(ESI):357.9[M+1]。
第八步
(5,7-二甲基-1-对甲苯磺酰基-1H-吲哚-4-基)甲醇3i
将化合物3h(488mg，1.37mmol)溶于四氢呋喃(5mL)中，0℃加入硼氢化锂的四氢呋喃溶液(3.06mmol，1.53mL)，加完移至室温搅拌过夜。将反应混合物冷却至0℃，向其中缓慢滴加饱和氯化铵水溶液淬灭反应，直至无气泡产生，加入乙酸乙酯，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3i(253mg，产率：56.25％)。
MS m/z(ESI):311.9[M-OH]。
第九步
4-((1S,3S,5R)-8-((5,7-二甲基-1-对甲苯磺酰基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯3j
将化合物3i(253mg，768.03μmol)溶解于二氯甲烷(5.6mL)中，氮气氛下，冷却至0℃，依次加入四溴化碳(255.1mg，769.24μmol，安耐吉试剂)和三苯基膦(202.4mg，771.68μmol，国药试剂)，反应混合物于0℃搅拌1.5小时。得到的溶液备用。将化合物3e(150.7mg，0.52mmol)溶于N,N-二甲基甲酰胺(4mL)，0℃加入氢化钠(43mg，1.08mmol，含量60％)，继续搅拌1小时，加入上述溶液，逐渐升至室温搅拌1小时。向反应混合物中加入饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用柱层析色谱法以洗脱剂体系C纯化得到标题化合物3j(67mg，产率：21.45％)。
MS m/z(ESI):600.9[M+1]。
第十步
4-((1S,3S,5R)-8-((5,7-二甲基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸3
将化合物3j(67mg，111.52μmol)溶于甲醇(1.4mL)和水(0.3mL)中，加入氢氧化钾(62.6mg，1.12mmol)，反应混合物于封管内60℃搅拌过夜。反应混合物冷却至室温，用1M盐酸调节溶液pH至5～6，加入水和乙酸乙酯，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残余物用少量甲醇溶解后用高效液相制备色谱法(仪器型号：Waters Autopurification-SQD2色谱柱：Welch XB-C18 30mm*150mm；5μm；流动相1：纯水(含10mM碳酸氢铵)；流动相2：乙腈；梯度：25％-95％；流速：30mL/min)纯化，得到标题化合物3(6mg，产率：12.44％)。
MS m/z(ESI):433.1[M+1]。
1H NMR(500 MHz,CD 3OD):δ8.14(d,2H),7.72-7.74(m,2H),7.33(s,1H),6.86(s,1H),6.51(br,1H),4.60(s,1H),4.08(br,3H),3.73(br,1H),3.32-3.37(m,4H),2.69(br,4H),2.48(s,3H),2.29-2.37(m,4H),1.23(t,3H)。
实施例4
4-((1S,3S,5R)-8-((5-环丙基-7-甲基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸4
Figure PCTCN2021142760-appb-000109
Figure PCTCN2021142760-appb-000110
第一步
2-溴-4-甲基-5-硝基苯腈4b
将2-溴-4-甲基苄腈4a(4g，20.40mmol，毕得医药科技有限公司)溶于硫酸(6mL)中，冰浴下滴加溶于硫酸(18mL)的硝酸钾(2.06g，20.40mmol)溶液，滴完0℃反应1.5小时，反应液倒入冰水中，搅拌，过滤，滤饼用冰水洗涤，干燥，得到粗品标题产物4b(4.9g)，不经纯化直接用于下一步反应。
MS m/z(ESI):240.8[M-1]。
第二步
5-溴-7-甲基-1H-吲哚-4-腈4c
将化合物4b(3.9g，16.18mmol)溶于无水四氢呋喃(30mL)中，氮气氛下，冷至-20℃，滴加乙烯基溴化镁(64.76mL，64.76mmol)，滴完室温反应1.5小时，冷至-20℃，用氢氧化钠水溶液淬灭，用乙酸乙酯(100mL)萃取2次，合并有机相，用饱和碳酸氢钠(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用硅胶柱层析色谱法以洗脱剂B纯化得到标题化合物4c(500mg，产率：13.1％)。
MS m/z(ESI):234.9[M-1]。
第三步
5-溴-7-甲基-1-对甲苯磺酰基-1H-吲哚-4-腈4d
将化合物4c(500mg，2.13mmol)溶于二氯甲烷(10mL)中，加入4-甲苯磺酰氯(609mg，3.19mmol)和苄基三乙基氯化铵(48.5mg，212.93μmol)，再加入氢氧化钠(128mg，3.20mmol)，室温反应过夜。浓缩，残余物用硅胶柱层析色谱法以洗脱剂B纯化得到标题化合物4d(500mg，产率：60.4％)。
MS m/z(ESI):388.9[M-1]。
第四步
5-溴-7-甲基-1-甲苯磺酰基-1H-吲哚-4-甲醛4e
将化合物4d(500mg，1.28mmol)溶于二氯甲烷(5mL)中，-78℃滴加1M二异丁基氢化铝(1.9274mL)，-78℃反应1.5小时，用甲醇淬灭，加入2M盐酸(20mL)，用二氯甲烷(50mL)萃取2次，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残余物用硅胶柱层析色谱法以洗脱剂B纯化得到标题化合物4e(140mg，产率：27.8％)。
MS m/z(ESI):392.0[M-1]。
第五步
5-环丙基-7-甲基-1-甲苯磺酰基-1H-吲哚-4-甲醛4f
将化合物4e(140mg，356.9μmol)溶于甲苯(3mL)和水(1mL)中，加入环丙基三氟硼酸钾(106mg，716.33μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(50mg，107.15μmol)、醋酸钯(16.1mg，71.71μmol)、碳酸铯(698mg，2.14mmol)，氮气氛下，100℃反应2小时，过滤，浓缩，得到粗品标题产物4f(126mg)，不经纯化直接用于下一步反应。
MS m/z(ESI):353.9[M+1]。
第六步
(5-环丙基-7-甲基-1-对甲苯磺酰基-1H-吲哚-4-基)甲醇4g
将化合物4f(126mg，356.50μmol)溶于甲醇(3mL)，0℃加入硼氢化钠(27mg，713.67μmol)，室温反应2小时，加入饱和氯化铵水溶液(10mL)淬灭，用乙酸乙酯(20mL)萃取2次，合并有机相，无水硫酸钠干燥，过滤，浓缩，残余物用硅胶柱层析色谱法以洗脱剂B纯化得到标题化合物4g(126mg，产率：99.4％)。
MS m/z(ESI):354.1[M-1]。
第七步
4-(溴甲基)-5-环丙基-7-甲基-1-对甲苯磺酰基-1H-吲哚4h
将化合物4g(70mg，196.93μmol)溶于二氯甲烷(1mL)中，加入四溴化碳(65.4mg，197.21μmol)，0℃加入三苯基膦(51.7mg，197.11μmol)，保持0℃反应1.5小时，浓缩得到粗品标题产物4h(40mg产率：48.5％)，不经纯化直接用于下一步反应。
第八步
4-((1S,3S,5R)-8-((5-环丙基-7-甲基-1-对甲苯磺酰基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸甲酯4i
将化合物3e(40mg，138.23μmol)溶于N,N-二甲基甲酰胺(1mL)中，0℃加入氢化钠(11mg，287.08μmol，含量60％)，继续搅拌1小时，加入化合物4h(40mg，95.61μmol)溶于N,N-二甲基甲酰胺(1mL)的溶液，室温搅拌1小时，加入饱和氯化铵水溶液(10mL)淬灭，用乙酸乙酯(20mL)萃取2次，合并有机相，用无水硫酸钠干燥。过滤，浓缩得到粗品标题产物4i(59mg)，不经纯化直接用于下一步反应。
MS m/z(ESI):626.9[M+1]。
第九步
4-((1S,3S,5R)-8-((5-环丙基-7-甲基-1H-吲哚-4-基)甲基)-3-乙氧基-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酸4
将化合物4i(59mg，94.13μmol)溶于甲醇(1mL)和水(0.25mL)中，加入氢氧化钾(27mg，481.24μmol)，60℃反应过夜，用2M盐酸溶液调PH至8～9，浓缩，用甲醇稀释，用高效液相制备色谱法(Waters 2545，色谱柱：Sharpsil-T C18，30*150mm，5μm；流动相：水(含10mmol/L的碳酸氢铵)；流动相：乙腈；梯度：36％-43％，流速：30mL/min)纯化，得标题化合物4(20mg，产率：46.3％)。
MS m/z(ESI):459.1[M+1]。
1H NMR(500 MHz,CD 3OD):δ8.08-8.10(d,2H),7.72-7.74(d，2H),7.33(s,1H),6.72(s,1H),6.42-6.55(m，1H),4.03-4.42(m,4H),3.74(s,1H),3.43-3.56(m,2H),3.35(s,2H),2.85(s,1H),2.55-2.75(m,3H),2.47(s,3H),1.99-2.30(m,4H),1.26-1.40(m，3H),1.18-1.25(m,2H)。
实施例5
(2S,3S,4S,5R,6S)-6-((4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸5
Figure PCTCN2021142760-appb-000111
第一步
(2S,3S,4S,5R)-3,4,5,6-四羟基四氢-2H-吡喃-2-羧酸烯丙酯5b
将D-葡萄糖醛酸5a(15g，77.26mmol，江苏艾康生物医药研发有限公司)溶于N,N-二甲基甲酰胺(150mL)中，室温滴加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(13g，85.39mmol)，搅拌均匀。冰浴下冷却10分钟，滴加入3-溴丙烯(11.2g，92.58mmol)，加毕，室温反应16小时。加入1.5mL水淬灭反应，搅拌5分钟，浓缩反应液，残余物用柱层析色谱法以洗脱剂体系E纯化得标题化合物5b(14g，产率：77.4％)。
MS m/z(ESI):235.1[M+1]。
第二步
(2S,3S,4S,5R)-6-((4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸烯丙酯5c
向化合物1-1(5g，11.15mmol)和化合物5b(4.18g，17.85mmol)中加入乙腈(100mL)，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.09g，13.39mmol)，搅拌均匀，反应液中滴入N-甲基吗啡啉(3.95g，39.05mmol)，加毕，室温反应16小时。反应液中加入乙酸(2.68g，44.63mmol)淬灭反应，减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂A纯化得到粗品标题化合物5c(12.3g)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):665.3[M+1]。
第三步
(2S,3S,4S,5R,6S)-6-((4-((1S,3S,5R)-3-乙氧基-8-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-8-氮杂双环[3.2.1]辛烷-1-基)苯甲酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸5
将化合物5c(10.5g，15.80mmol)溶于乙腈(85mL)中，冰浴冷却10分钟，加入四(三苯基膦)钯(3.65g，3.16mmol)和四氢吡咯(1.25g，17.58mmol)，冰浴下反应3小时。加入乙酸(2.85g，47.46mol)淬灭反应，加入15L N,N-二甲基甲酰胺，搅拌5分钟，过滤，滤液减压浓缩，残余物用高效液相制备色谱法(Waters 2545，色谱柱：Welch Xtimate C18，5μm，30mm*150mm；流动相：水(含0.1％甲酸，用氨水调节pH＝4.5)；流动相：乙腈；梯度：15％-35％，流速：30mL/min)纯化，得标题化合物5(2.47g，产率：25.0％)。
MS m/z(ESI):625.2[M+1]。
1H NMR(500 MHz,DMSO-d 6):δ10.84(s,1H),8.26-8.27(d,1H),8.05-8.07(d,2H),7.81-7.83(d,2H),7.28-7.29(t,1H),6.67(s,1H),6.53(s,1H),5.57-5.59(m,1H),3.73-3.75(m,3H),3.69-3.71(d，1H),3.50-3.52(d,1H),3.39-3.43(m,2H),3.21-3.32(m,4H),3.10-3.11(d,1H),2.51(s,3H),2.45(s,1H),2.43(s,3H),2.20-2.24(dd,1H),1.97-2.10(m,5H),1.52-1.53(d,1H),1.24(s,1H),1.14-1.14(m,3H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1：本公开化合物对Factor B酶学活性的抑制作用
一、实验材料及仪器
1.重组人补体因子B蛋白(南京金斯瑞生物科技有限公司表达)
2.重组人补体因子D蛋白(1824-SE-010，R&D system)
3.人补体因子C3(204885-250UGCN，EMDmillipore)
4.眼镜蛇毒因子(Cobra venom factor，CVF)(A600，Quidel)
5.StartingBlock TMT20(TBS)封闭缓冲液(37543，Thermo Fisher)
6.山羊抗鼠IgG重链+轻链(辣根过氧化物酶标记)(ab205719，Abcam)
7.抗C3a/C3a des Arg抗体克隆号[2991](ab11873，Abcam)
8.QuantaBlu TM荧光过氧化物酶底物试剂盒(15169，Thermo Fisher)
9.两性表面活性剂(CHAPS)(C3023，Sigma)
10.氯化镁溶液(M1028-100ML，Sigma)
11.碳酸钠Na 2CO 3(10019260，沪试)
12.碳酸氢钠NaHCO 3(10018960，沪试)
13.吐温20(P7949-500ML，Sigma)
14.20X PBS缓冲液(B548117-0500，生工)
15.96孔白色半孔板(66PL96025,Cisbio)
16.96孔黑色吸附板(437111，Thermo Fisher)
17.磷酸盐缓冲液(B320，上海源培生物科技有限公司)
18.无菌纯水(上海恒瑞自制)
19.96孔配药板(3795，Corning)
20.恒温箱(上海一恒科学仪器有限公司)
21.Flexstation3酶标仪(Molecular Device)
二、实验步骤
人补体因子B蛋白发挥蛋白酶功能需要与人补体因子C3形成复合物，在人补体因子D蛋白的水解下，人补体因子B被水解成Ba和Bb片段，Bb与人补体因子C3的C3b片段形成复合物C3bBb，即C3转化酶，此复合物的形成才可使得人补体因子B发挥蛋白酶功能。C3bBb继续水解C3成C3a和C3b片段，C3b与C3bBb形成复合物C3bBbC3b，即C5转化酶，C3a片段则被释放。通过检测C3被剪切后产生的C3a des Arg表位，可以用来评估C3被水解的效率，即C3bBb酶活性，以此来评估化合物对C3bBb酶的作用。由于C3b在体外不稳定，使用眼镜蛇毒因子(Cobra venom factor)(以下称CVF)代替C3b与人补体因子B形成复合物， 其功能与C3b相同。
人补体因子B蛋白的AA128-2422段氨基酸编码基因(NM_001710.6)由南京金斯瑞生物科技有限公司进行密码子优化、基因合成、克隆至pcDNA3.4载体，并于HD CHO-S细胞内表达、纯化。纯化所得的重组人补体因子B蛋白分装后保存于-80℃冰箱。
人补体因子B蛋白剪切反应：用PBS(pH7.4)将重组人补体因子D蛋白稀释10倍，冰上保存待用。在反应缓冲液中(PBS pH7.4，10mM MgCl 2，0.05％CHAPS)加入终浓度为300nM的重组人补体因子D蛋白，1μM的重组人补体因子B蛋白和1μM的CVF，充分混匀后，于37℃恒温箱反应3小时，获得CVF和剪切后重组人补体因子B蛋白片段Bb复合体(以下称CVF：Bb)。
配制100mM Na 2CO 3溶液和100mM NaHCO 3，按照体积比Na 2CO 3：NaHCO 3＝3：7调整pH值至9.5，室温储存待用。
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、500、125、31.25、7.8125、0.488281、0.12207、0.030518、0.007629μM，空白孔为100％DMSO，再20倍稀释于C3反应缓冲液中(PBS pH7.4，1mM MgCl 2，0.05％CHAPS)中。
C3蛋白剪切反应：在96孔白色半孔板中，配制10μL反应体系，即在C3反应缓冲液(PBS pH7.4，1mM MgCl 2，0.05％CHAPS)中加入终浓度为2nM的CVF：Bb，1μL上述稀释于C3反应缓冲液的受试化合物和DMSO，室温孵育1小时。受试化合物终浓度分别为10000、2500、625、156.25、39.0625、9.765625、2.441406、0.6103515、0.152588nM。将人补体因子C3按终浓度500nM加入到反应体系中，混匀后于37℃恒温箱反应2小时，反应混合物中只含有500nM人补体因子C3的反应孔作为阴性对照。在96孔黑色吸附板中加入97μL碳酸缓冲液(pH9.5)，取3μL C3蛋白剪切反应混合物加入每孔，混匀后封板，4℃孵育过夜。
C3a des Arg检测：用300μL/孔TBST(0.05％吐温20)溶液洗板3遍，每孔加入300μL StartingBlock TMT20(TBS)封闭缓冲液，37℃孵育5分钟；用300μL/孔PBST溶液洗板3遍，在PBST溶液中按照1:1000稀释抗-C3a/C3a des Arg抗体[2991]，每孔加入100μL，37℃孵育1小时；用300μL/孔PBST溶液洗板3遍，在PBST溶液中按照1:5000稀释山羊抗鼠IgG H&L(Goat Anti-Mouse IgG H&L)(HRP)抗体，每孔加入100μL，37℃孵育30分钟；配制QuantaBlu TM荧光过氧化物酶底物试剂盒(QuantaBlu TMFluorogenic Peroxidase Substrate Kit)底物，将1份QuantaBlu TM稳定过氧化物溶液(QuantaBlu TMStable Peroxide Solution)稀释到9份QuantaBlu TM底物溶液(QuantaBlu TMSubstrate Solution)中；用300μL/孔PBST溶液洗板3遍，最后一遍将板子扣干；每孔加入100μL底物，室温孵育20分钟；每孔加入100μL QuantaBlu TM终止溶液(QuantaBlu TMStop Solution)后，在Flexstation读取荧光值，设置激发光波长Ex320nM，发射光波长Em 460nM，Cutoff  455。
使用以下公式计算抑制率：
抑制率＝{1-(RFU 受试化合物-RFU 阴性对照孔)/(RFU 空白孔-RFU 阴性对照孔)}×100％
用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值。
表1本公开化合物通过对Factor B酶活性的抑制作用测得的IC 50值
实施例编号 IC 50(nM)
1 4.2
1-1 1.3
1-2 72.2
3 4.9
4 1.6
5 30.0
结论：本公开化合物对Factor B酶活性具有较好的抑制作用。
测试例2：本公开化合物对人补体旁路途径(Complement Alternative Pathway)的抑制作用
一、实验材料及仪器
1.Zymosan A(Z4250，Sigma)
2.人血清
3.StartingBlock TMT20(TBS)封闭缓冲液(37543，Thermo Fisher)
4.山羊抗鼠IgG重链+轻链(辣根过氧化物酶标记)(ab205719，Abcam)
5.抗C5b-9+C5b-8抗体，克隆号[aE11](ab66768，Abcam)
6.QuantaBlu TM荧光过氧化物酶底物试剂盒(15169，Thermo Fisher)
7.明胶，来源于冷水鱼类的皮肤(G7765，Sigma)
8.EDTA(AM9260G，Invitrogen)
9.EGTA(E3889-100G，Sigma)
10.氯化镁溶液(M1028-100ML，Sigma)
11.缓冲液(HEPES)(H3375-250G，Sigma)
12.氯化钙(C5670-500G，Sigma)
13.碳酸钠Na 2CO 3(10019260，沪试)
14.碳酸氢钠NaHCO 3(10018960，沪试)
15.20X TBS(B548105-0500，生工)
16.吐温20(P7949-500ML，Sigma)
17.96孔黑色吸附板(437111，Thermo Fisher)
18.磷酸盐缓冲液(PBS，pH7.4)(B320,上海源培生物科技有限公司)
19.无菌纯水(上海恒瑞自制)
20.96孔配药板(3795，Corning)
21.恒温箱(上海一恒科学仪器有限公司)
22.Flexstation3酶标仪(Molecular Device)
二、实验步骤
补体激活途径主要有3条途径：经典途径，凝集素途径和旁路途径。旁路途径可被细菌胞壁蛋白、脂多糖等外源病菌分子激活，一系列的补体因子通过水解、酶解反应将激活信号级联放大，最终C5b、C6、C7、C8和多个C9蛋白形成膜攻击复合物。旁路途径可通过酵母素激活，通过检测C5b-9复合物的形成可以评估旁路途径的激活程度。酵母素也可以激活经典途径和凝集素途径，由于这两条途径的激活需要镁离子和钙离子共同参与，而旁路途径只需要镁离子参与，因而使用钙离子螯合剂EGTA螯合后，旁路途径不被抑制而经典途径、凝集素途径被抑制。使用EDTA螯合后，三条途径都被抑制。因此，可以在EGTA螯合剂存在的情况下，使用酵母素激活人血清中补体旁路途径，通过检测C5b-9复合物的形成来评估小分子化合物对旁路途径的抑制作用。
Zymosan A粉末用TBS溶液重悬成10mg/mL，于100℃加热2小时活化。活化后4000转/分离心30分钟，弃去上清，用TBS重悬成50mg/mL悬浊液，分装后于-20℃冰箱保存。实验前一天，用碳酸缓冲液(pH9.5)将活化的Zymosan A溶液稀释成1mg/mL，在96孔黑色吸附板中每孔加入100μL，4℃包被过夜。
配制100mM Na 2CO 3溶液和100mM NaHCO 3，按照体积比Na 2CO 3：NaHCO 3＝3：7调整pH值至9.5，室温储存待用。
补体旁路激活反应：用PBS溶液将人血清稀释5倍成20％血清溶液，置于冰上待用。将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、500、125、31.25、7.8125、0.488281、0.12207、0.030518、0.007629μM，空白孔为100％DMSO，再20倍稀释于2X EGTA反应缓冲液(4.2mM HEPES，0.15mMCaCl 2，140mM NaCl，4.5mM MgCl 2，0.1％明胶，20mM EGTA)中。同时将100％DMSO 20倍稀释于2X EDTA反应缓冲液(4.2mM HEPES，0.15mM CaCl 2，140mM NaCl，4.5mM MgCl 2，0.1％明胶，20mM EDTA)中作为阴性对照孔。配制40μL血清-EGTA反应液，即将20μL 20％人血清，4μL上述稀释于2X EGTA反应缓冲液的受试化合物或DMSO，16μL 2X EGTA反应缓冲液混合充分，血清-EGTA-DMSO为空白对照，室温孵育30分钟。阴性对照孔配制40μL血清-EDTA反应液，即将20μL 20％人血清，4μL上述稀释于2X EDTA反应缓冲液的DMSO，16μL 2X EDTA反应缓冲液混合充分，室温孵育30分钟。提前一天包被Zymosan A的96孔黑色吸附板，用300μL/孔TBST(0.05％吐温20)溶液洗板3遍，每孔加入25μL血清-EGTA-受试化合物反应液，空白对照孔，血清-EDTA-DMSO反应液(阴性对照孔)，37℃反应40分钟。用300μL/孔TBST溶液洗板3遍，每孔加入300μL StartingBlock TMT20(TBS)封闭缓冲液，37℃孵育15分钟；用300μL/孔TBST 溶液洗板3遍，在TBST溶液中按照1:5000稀释抗-C5b-9+C5b-8抗体[aE11]，每孔加入100μL，37℃孵育1小时；用300μL/孔TBST溶液洗板3遍，在TBST溶液中按照1:5000稀释山羊抗鼠IgG H&L(HRP)抗体，每孔加入100μL，37℃孵育30分钟；配制QuantaBlu TM荧光过氧化物酶底物试剂盒底物，将1份QuantaBlu TM稳定过氧化物溶液稀释到9份QuantaBlu TM底物溶液中；用300μL/孔TBST溶液洗板3遍，最后一遍将板子扣干；每孔加入100μL底物，室温孵育20分钟；每孔加入100μL QuantaBlu TM终止溶液后，在Flexstation 3读取荧光值，设置激发光波长Ex320nM，发射光波长Em 460nM，Cutoff 455。
使用以下公式计算抑制率：
抑制率＝{1-(RFU 受试化合物-RFU 阴性对照孔)/(RFU 空白孔-RFU 阴性对照孔)}×100％
用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值。
表2本公开化合物通过对人补体旁路途径测得的IC 50值
实施例编号 IC 50(nM)
1 43.2
1-1 27.0
3 49.8
4 50.6
5 74.6
结论：本公开化合物对人补体旁路途径具有较好的抑制作用。
测试例3：本公开化合物对大鼠Heymann肾炎的治疗作用
1摘要
本实验选用雄性SD大鼠建立绵羊抗大鼠Fx1A血清诱导的Heymann肾炎模型，评估阳性药LNP023(参照WO2015009616A1实施例26合成)和实施例1-1化合物对雄性SD大鼠肾炎的治疗作用。
Figure PCTCN2021142760-appb-000112
2实验方法和实验材料
2.1实验动物和饲养条件
实验动物：实验用雄性SD大鼠，由维通利华实验动物有限公司提供(生产许可证编号：SCXK(浙)2019-0001，动物合格证编号：20210401Abzz0619000322， 购入时180-200g)。
饲养条件：5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养1周后开始实验。
2.2实验试剂和仪器
阳性药LNP023：分子量422.5，纯度99.9％。
实施例1-1化合物：分子量448.55，纯度为99.9％。
吐温80：国药集团化学试剂有限公司，货号30189828，批号20180104。
甲基纤维素M450：国药集团化学试剂有限公司，货号69016460，批号20170308。
正常羊血清：Sangon biotech，批号GB02FC0260。
绵羊抗大鼠Fx1A血清：PROBETEX，货号PTX-002S，批号376-4T。
大鼠iC3b-ELISA检测试剂盒：MYBioSource，货号MBS 7255121，批号20210301C。
大鼠C3d-ELISA检测试剂盒：MYBioSource，货号MBS 7244846，批号20210301C。
尿/脑脊液总蛋白(TPUC)试剂盒：深圳迈瑞生物医疗，货号105-008805-00，批号147920004。
肌酐试剂盒：深圳迈瑞生物医疗，货号105-000457-00，批号141120024。
尿微量白蛋白(MALB)(含校准品)：深圳迈瑞生物医疗，货号105-009325-00，批号046020011。
尿微量白蛋白质控品：深圳迈瑞生物医疗，货号105-002957-00，批号053120008。
尿/脑脊液总蛋白(TPUC)质控品：深圳迈瑞生物医疗，货号105-008841-00，批号060520005。
生化复合质控品(质1)：深圳迈瑞生物医疗，货号105-007316-00，批号059320002。
生化复合质控品(质2)：深圳迈瑞生物医疗，货号105-007317-00，批号059419004。
全自动血液生化仪：厂家迈瑞生物医疗，型号SB380。
酶标仪：厂家BMGlabtech，型号PHERAstar Fs。
台式低速离心机：厂家Eppendorf，型号5417R。
电子天平：梅特勒-托利多仪器有限公司，型号AL204。
2.3实验设计和实验方法
2.3.1动物分组
雄性SD大鼠适应性饲养后，根据实验前2天尿液总蛋白和体重分组如下：
Figure PCTCN2021142760-appb-000113
注：溶剂组：0.5％甲基纤维素M450混悬液(含0.5％吐温80)；iv：静脉。
2.3.2药物配制方法
配制阳性药LNP023(20mg/kg)：称600mg+1.5mL吐温80+298.5mL甲基纤维素M450。
配制阳性药LNP023(60mg/kg)：称1800mg+1.5mL吐温80+298.5mL甲基纤维素M450，累计配制3次。
配制实施例1-1化合物(10mg/kg)：称300mg+1.5mL吐温80+298.5mL甲基纤维素M450。
配制实施例1-1化合物(30mg/kg)：称900mg+1.5mL吐温80+298.5mL甲基纤维素M450。
配制实施例1-1化合物(90mg/kg)：称2700mg+1.5mL吐温80+298.5mL甲基纤维素M450。
配制600mL溶剂：3mL吐温80+597mL甲基纤维素M450混匀，累计配制3次。
2.3.3实验方法
雄性SD大鼠按照尿蛋白和体重随机共分为7组：正常组、模型组、LNP023组(20mg/kg、60mg/kg，口服，一天两次)、实施例1-1组(10mg/kg、30mg/kg、90mg/kg，口服，一天两次)。实验第0天，模型组和给药组进行尾静脉单次注射Fx1A血清(5mL/kg)，正常组尾静脉注射正常羊血清，给药组于实验第6天开始 灌胃阳性药LNP023与实施例1-1化合物(10mL/kg)，正常组和模型组灌胃相应溶剂，一直到实验第15天结束。收集第2、4、6、8、11、14天的2小时尿液检测尿肌酐、总蛋白；采集第15天的血清进行补体激活片段(C3d+iC3b)分析。
抑制率＝100％×(模型组-给药组)/(模型组-正常组)
2.4数据表达和统计学处理
实验数据表示为平均数(Mean)±标准误(SEM)。采用Excel软件t检验进行统计比较。将模型组与空白对照组数据进行分析比较，判断是否存在显著数学统计学意义，*P<0.05表示模型组与空白对照组比较具有显著性差异，**P<0.01表示模型组与空白对照组比较具有高度显著性差异，***P<0.001表示模型组与空白对照组比较具有极高度显著性差异。#P<0.05表示给药组与模型组比较具有显著性差异，##P<0.01表示给药组与模型组比较具有高度显著性差异，###P<0.001表示给药组与模型组比较具有极高度显著性差异。
3实验结果
实施例1-1化合物和阳性药LNP023对被动heymann肾炎大鼠血清iC3b+C3d的影响见图1。图1中血清iC3b+C3d结果显示：与正常组相比，模型组大鼠血清iC3b+C3d具有统计学增加(P<0.001)；与模型组相比，20mg/kg、60mg/kg的LNP023组大鼠血清iC3b+C3d明显下降，下降幅度分别为62.2％(P<0.01)和68.8％(P<0.001)；与模型组相比，10mg/kg、30mg/kg、90mg/kg的实施例1-1组大鼠血清iC3b+C3d明显下降，下降幅度分别为76.2％(P<0.001)、105.5％(P<0.001)和108.7％(P<0.001)。
实施例1-1化合物和阳性药LNP023对被动heymann肾炎大鼠尿蛋白/肌酐的影响见图2和图3。图2和图3显示：与正常组相比，随着时间的延长，模型组大鼠尿总蛋白/尿肌酐比值持续增加，第6天开始具有统计学升高并持续增加；与模型组相比，20mg/kg、60mg/kg的LNP023组大鼠尿总蛋白/尿肌酐比值第11天开始具有统计学下降，第14天的下降幅度分别为56.4％(P<0.01)和47.1％(P<0.05)，无明显的剂量依赖关系；10mg/kg、30mg/kg、90mg/kg的实施例1-1组大鼠尿总蛋白/尿肌酐比值明显下降，高剂量第8天开始具有统计学下降，低中剂量组自第11天开始具有统计学下降，三个剂量组第14天的下降幅度分别为48.1％(P<0.05)、70.9％(P<0.001)和77.2％(P<0.001)，有明显的剂量依赖关系。

Claims (21)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2021142760-appb-100001
    其中：
    X选自化学键、-CR aR b-、-NR-和-O-；
    Y选自-CR 3aR 3b-、-NR 3c-和-O-；
    环A为芳基或杂芳基；
    R、R a和R b相同或不同，且各自独立地选自氢原子、烷基和卤代烷基；
    各个R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R 2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R 3、R 3a、R 3b和R 3c相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氧代基、卤素、氰基、-NR xR y和羟基；其中，所述的烷基任选被一个或多个氰基或氨基所取代；
    各个R 4相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氰基、-NR 8R 9、羟基、-C(O)R 10、-CH 2C(O)R 10、-C(O)NR 8R 9、-C(O)NHS(O) pR 10、-S(O) pNHC(O)R 10、-S(O) pR 10、-S(O) pNR 8R 9、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、 羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 5在每次出现时相同或不同，且各自独立地选自氢原子、羟基、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
    R 10在每次出现时相同或不同，且各自独立地选自氢原子、-OR 11、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
    R 11选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、卤代烷基、氰基、-OR 12和-C(O)OR 12中的一个或多个取代基所取代；
    R 12选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代；
    R 6、R 7、R x、R y、R 8和R 9在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、羟基和羟烷基中的一个或多个取代基所取代；
    或者R 6和R 7与相连的氮原子一起形成杂环基，或者R x和R y与相连的氮原子一起形成杂环基，或者R 8和R 9与相连的氮原子一起形成杂环基，所述的杂环基在每次出现时相同或不同，且各自独立地任选被选自卤素、烷基、氧代基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基和羟烷基中的一个或多个取代基所取代；
    m为0、1或2；
    n为0、1、2或3；
    s为0、1、2、3或4；
    t为0、1、2、3或4；且
    p为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其中R 10选自氢原子、羟基、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基和羟基中的一个或多个取代基所取代。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其中Y为-CR 3aR 3b-；R 3a和R 3b如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2021142760-appb-100002
    其中：
    环A、X、R 1至R 3、R 3b、R 4、m、n、s和t如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 3为氢原子。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中m为1，且n为2。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    Figure PCTCN2021142760-appb-100003
    其中：
    R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代 基所取代；
    环A、X、R 1、R 3b、R 4至R 7、p和t如权利要求1中所定义。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、-NR 8R 9、羟基和-C(O)R 10，R 8、R 9和R 10如权利要求1中所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：
    Figure PCTCN2021142760-appb-100004
    其中：R 10选自羟基、
    Figure PCTCN2021142760-appb-100005
    Figure PCTCN2021142760-appb-100006
    优选地，R 10为羟基；
    t为1或2；
    R 2a和R 2b相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烯基、炔基、烷氧基、卤代烷氧基、卤素、氰基、-NR 6R 7、羟基、-C(O)R 5、-CH 2C(O)R 5、-OCH 2C(O)R 5、-CH 2NHC(O)R 5、-C(O)NR 6R 7、-S(O) pR 5、-S(O) pNR 6R 7、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    环A、X、R 1、R 3b、R 4至R 7和p如权利要求1中所定义。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其为X为化学键。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R 1相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、卤素和氰基。
  13. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R 2相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、氨基、羟基、3至8元环烷基和3至8元杂环基。
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 3b选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基和C 1-6卤代烷氧基。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下化合物：
    Figure PCTCN2021142760-appb-100007
    Figure PCTCN2021142760-appb-100008
  16. 一种通式(IVA)所示的化合物或其可药用的盐：
    Figure PCTCN2021142760-appb-100009
    其中：
    R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
    R 10为烷氧基；优选地，R 10为C 1-6烷氧基；更优选地，R 10为甲氧基；
    t为1或2；
    环A、X、R 1、R 2a、R 2b、R 3b和R 4如权利要求9中所定义。
  17. 化合物或其可药用的盐，其选自以下化合物：
    Figure PCTCN2021142760-appb-100010
  18. 一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021142760-appb-100011
    R 10为烷氧基(优选为C 1-6烷氧基，更优选为甲氧基)的通式(IVA)所示的化合物或其可药用的盐脱去保护基R w和进行水解反应，得到R 10为羟基的通式(IV)所示的化合物或其可药用的盐，
    其中：
    R w为氨基保护基；优选地，R w为叔丁氧羰基或对甲苯磺酰基；更优选地，R w为叔丁氧羰基；
    t为1或2；
    环A、X、R 1、R 2a、R 2b、R 3b和R 4如权利要求9中所定义。
  19. 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  20. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于抑制补体旁路途径活化的药物中的用途，优选在制备用于抑制补体因子B的药物中的用途。
  21. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备治疗和/或预防由补体旁路途径活化介导的疾病或障碍的药物中的用途；优选在制备用于治疗和/或预防由补体因子B介导的疾病或障碍的药物中的用途，其中所述的疾病或障碍选自肾小球病、溶血性尿毒综合征、非典型溶血尿毒综合征、阵发性睡眠性血红蛋白尿症、年龄相关性黄斑变性、地图状萎缩、糖尿病性视网膜病变、葡萄膜炎、色素性视网膜炎、黄斑水肿、贝赫切特综合征引起的葡萄膜炎、多灶性脉络膜炎、福-小柳-原田综合征、鸟枪弹样视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮、非动脉炎性缺血性视神经病、手术后炎症、视网膜静脉阻塞、神经病学障碍、多发性硬化、中风、吉-巴综合征、创伤性脑损伤、帕金森病、不适宜的或不希望的补体活化障碍、血液透析并发症、超急性同种异体移植物排斥、异种移植物排斥、IL-2治疗期间白介素-2诱导的毒性、克隆病、成人型呼吸窘迫综合征、心肌炎、缺血后再灌注病症、心肌梗死、球囊血管成形术、心肺动脉分流手术或肾分流手术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建、感染性疾病或脓毒症后肠系膜动脉再灌注、系统性红斑狼疮、系统性红斑狼疮性肾炎、增殖性肾炎、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、急性呼吸窘迫综合征、哮喘、慢性阻塞性肺疾病、肺气肿、肺栓塞和梗死、肺炎、致纤维化粉尘疾病、肺纤维化、哮喘、变态反应、支气管缩窄、寄生虫病、古德曼综合征、肺脉管炎、寡免疫性脉管炎、免疫复合物相关炎症、抗磷脂综合征和肥胖；更优选在制备用于治疗和/或预防C3肾小球病、免疫球蛋白A肾病、膜性肾小球肾炎、非典型溶血尿毒综合征和阵发性睡眠性血红蛋白尿症的药物中的用途。
PCT/CN2021/142760 2020-12-30 2021-12-30 含氮桥杂环化合物、其制备方法及其在医药上的应用 WO2022143845A1 (zh)

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