Nitrogen-containing bridge heterocyclic compound, preparation method thereof and application of nitrogen-containing bridge heterocyclic compound in medicine

Abstract

The invention relates to a nitrogen-bridge-containing heterocyclic compound, a preparation method thereof and application of the nitrogen-bridge-containing heterocyclic compound in medicine. Specifically, the invention relates to a nitrogen-containing bridge heterocyclic compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the nitrogen-containing bridge heterocyclic compound as a therapeutic agent, especially application of the nitrogen-containing bridge heterocyclic compound as a complement factor B (Factor B) inhibitor and application of the nitrogen-containing bridge heterocyclic compound in preparation of drugs for treating and / or preventing Factor B-mediated diseases or disorders. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180072698.6, application date December 30, 2021, and invention name “Nitrogen-bridged heterocyclic compounds, preparation methods thereof and their application in medicine”. Technical Field

[0002] The present disclosure belongs to the field of medicine, and relates to a nitrogen-bridged heterocyclic compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a nitrogen-bridged heterocyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound thereof, and its use as a complement factor B (Factor B) inhibitor and its use in the preparation of a drug for treating and / or preventing diseases or disorders mediated by Factor B. Background Art

[0003] Complement is a serum protein present in the serum and tissue fluid of humans and vertebrates. It is heat-insensitive and has enzymatic activity after activation. It can mediate immune and inflammatory responses and can be activated by antigen-antibody complexes or microorganisms, leading to the lysis or phagocytosis of pathogenic microorganisms.

[0004] The complement system is an important regulator of inflammatory response and tissue damage, and is composed of more than 20 serum proteins and cell surface proteins. The complement system includes complement intrinsic components and a variety of regulatory proteins. Complement intrinsic components include C1 to C9, among which C3 has the highest content. Complement regulatory proteins are divided into two categories: soluble and membrane-bound. Soluble complement regulatory proteins include clusterin, S protein, and complement factor H-related protein. Membrane-bound complement regulatory proteins include membrane cofactor protein (MCP), decay accelerating factor (DAF), complement receptor 1, etc. In addition, the complement system also includes some complement fragments and complement receptors, such as C3a receptor, C5a receptor, etc.

[0005] The complement system is activated through three independent and overlapping pathways, namely the classical pathway (CP), the alternative pathway (AP) and the lectin pathway (LP, also known as the MBL pathway (mannan-binding lectin pathway)). During the complement activation process, a series of positive feedbacks are used to exert a powerful biological effect and participate in the occurrence and development of diseases. C3 convertase is an important component of the first three pathways. It produces a series of complement protein fragments and membrane attack complexes (MAC) through the complement activation cascade reaction. C3 convertase cleaves C3 to generate C5 convertase, which then cleaves C5 to generate C5a and C5b. C5b combines with C6, C7, C8, and C9 to form C5b-9, namely MAC. Abnormalities in the complement pathway can cause the lysis of the body's inherent normal cells, leading to the occurrence of diseases.

[0006] Complement factor B is a heat-insensitive beta globulin that can be inactivated at 50°C for 30 minutes. It can be cleaved by complement factor D into two fragments, Ba and Bb. Bb combines with C3b to form the C3 convertase of the alternative pathway. Complement factor B is an important component in the complement alternative activation pathway, also known as the C3 activator precursor. The molecular weight of complement factor B is 93kDa, and the concentration in human blood is about 3μM. It is mainly synthesized in the liver and is also found in the retinal pigment epithelial cells of the eye.

[0007] Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell abnormality. Hematopoietic stem cells undergo acquired somatic cell PIG-A gene mutations, resulting in abnormal synthesis of glycosylphosphatidylinositol, leading to the loss of a group of membrane proteins anchored to the cell membrane by GPI, triggering a non-malignant clonal disease. The main clinical manifestations are loss of hematopoietic function of the bone marrow, thrombosis, and acute onset of chronic hemolytic anemia. The cause 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 red blood cells lack a complement regulatory protein called delayed acceleration factor DAF, which inhibits the formation of complement C3 convertase. The global incidence of PNH is 1-9 / million, and the age of onset is mostly 25 to 45 years old. Female patients seem to be slightly more than male patients. About 35% of PNH patients die within five years after diagnosis, and the median survival time after diagnosis is about 10 to 15 years. Although the disease is caused by mutations in autosomal cells and has no genetic tendency, it has an acute onset and cannot be prevented. After the disease occurs, patients experience intravascular hemolysis, which in turn causes serious complications such as thromboembolism and organ failure, causing the patient to lose the ability to work and live, and ultimately leading to death. Previous treatment measures were mainly symptomatic treatment, including red blood cell transfusions to increase hemoglobin, the use of glucocorticoids, etc. Bone marrow transplantation is considered to be curative, but it requires a donor and has a high risk of death. There is a lack of drugs on the market for PNH that can both control hemolysis and reduce the risk of death. At present, in addition to hormone therapy and anticoagulant therapy, the humanized anti-complement C5 monoclonal antibody Eculizumab and its long-acting molecule Ravulizumab are the first choice drugs for the treatment of PNH.

[0008] Eculizumab antibody drug is very expensive, with annual treatment costs of up to $669,000. Moreover, antibody drugs can only control hemolytic symptoms, but cannot completely cure PNH. They can only inhibit intravascular hemolysis, but not extravascular hemolysis. There are many drugs under development in 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 C3 downstream anti-C5 agents.

[0009] LNP023 is an oral small molecule drug developed by Novartis, and some safety and efficacy reports have been reported in the Phase II trial for the treatment of PNH. In a multicenter, open-label, continuous 2-cohort study of 10 patients (25-79 years old) with PNH and active hemolysis (these patients were treated with Eculizumab monoclonal antibody), all patients required red blood cell transfusions before LNP023 treatment. The enrolled subjects received LNP023 twice a day with Eculizumab monoclonal antibody treatment for at least 13 weeks. The trial found that LNP023 was well tolerated, with no reports of treatment interruptions and serious adverse events or thromboembolic events. At week 13, LNP023 showed a 34-81% reduction in LDH in all patients, all females had normal Hb, and 71% of males had Hb>120g / L. LNP023 was exposed to an average of 241 days, and no patient required RBC transfusions. At the time of data cutoff, 5 patients had discontinued eculizumab treatment and continued LNP023 monotherapy. All patients treated with LNP023 monotherapy maintained hemoglobin levels, had no changes in any biomarkers of disease activity, and had no symptoms of breakthrough hemolysis.

[0010] Glomerulopathy includes immunoglobulin A nephropathy (IgANephropathy, referred to as IgAN), C3 glomerulopathy (C3G Glomerulopathy, referred to as C3G), membranous glomerulonephritis (MGN), etc. Among them, 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. Studies have found that glomerulopathy is closely related to the complement pathway, especially the complement bypass pathway. In the United States, the number of cases of IgAN in the United States is about 185,000 per year, with an onset age of 20-40 years old. The main symptoms are hematuria, fatigue and pain. About 30% of patients will eventually develop end-stage renal disease (ESRD). The number of cases of membranous glomerulonephritis in the United States is about 80,000 per year, with an onset age of 40-60 years old, and about 30% of patients will eventually develop ESRD. C3 glomerulopathy occurs in about 10,000 people in the United States each year, mainly in adolescents, and about 50% of patients will develop ESRD. Currently, there is a lack of clinically effective treatment options for primary glomerulonephritis. Drug treatments commonly used include hormones and immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporin A, and the traditional Chinese medicine tripterygium wilfordii polyglycosides). Others include blood pressure control drugs, diuretics and antiplatelet aggregation drugs, anticoagulants, lipid-lowering drugs, cordyceps preparations and other kidney-protecting and detoxifying drugs.

[0011] IgAN is the most common primary glomerular disease in the world. Its pathological manifestations are local mesangial proliferation and matrix increase with diffuse mesangial 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. Currently, there are two small molecule drugs targeting the complement pathway that are undergoing clinical trials. OMS721 is a humanized monoclonal antibody targeting the MASP-2 protein developed by Omeros. The MASP-2 protein is an effector enzyme that activates the lectin pathway of the complement system. At the end of the Phase 2 clinical trial of OMS721, the proteinuria index of the four IgAN patients participating in the trial was significantly improved. This drug is currently undergoing Phase III clinical trials.

[0012] LNP023 is also in Phase II clinical trials in multiple countries and regions for the treatment of IgAN, C3G and MGN. Recently, Novartis announced that the drug has achieved positive interim clinical results in Phase II clinical trials for the treatment of C3G patients. The effect of maintaining renal function was sustained in 7 patients who have been treated for 6 months after entering the long-term extension study. The company will conduct multiple Phase III clinical studies in December this year and early next year.

[0013] Patent applications for Factor B inhibitors that have been disclosed include WO2015009616A1, WO2019043609A1, and WO2020016749A2. Summary of the invention

[0014] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0015]

[0016] in:

[0017] X is selected from chemical bonds, -CR a R b -, -NR-, and -O-;

[0018] Y is selected from -CR 3a R 3b -、-NR 3c - and -O-;

[0019] Ring A is an aryl group or a heteroaryl group;

[0020] R, R a and R b are the same or different and are each independently selected from a hydrogen atom, an alkyl group and a haloalkyl group;

[0021] Each R 1are 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] Each 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0023] Each R 3 , R 3a , R 3b and R 3c are the same or different and are each 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 group, a cyano group, a -NRx R y and hydroxyl; wherein the alkyl group is optionally substituted with one or more cyano groups or amino groups;

[0024] Each R 4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, a cyano group, a -NR 8 R 9 , hydroxyl, -C(O)R 10 、-CH2C(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 group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl;

[0025] R 5 are the same or different at each occurrence and are each independently selected from hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxy;

[0026] R 10 are the same or different at each occurrence and are each independently selected from a hydrogen atom, -OR 11 , alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxyl;

[0027] R 11 is selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, cyano, -OR 12and -C(O)OR 12 is substituted by one or more substituents;

[0028] R 12 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxyl;

[0029] 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, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl and hydroxyalkyl;

[0030] or R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R x and R y Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 8 and R 9 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein each occurrence of the heterocyclic group is the same or different and each is independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

[0031] m is 0, 1 or 2;

[0032] n is 0, 1, 2 or 3;

[0033] s is 0, 1, 2, 3, or 4;

[0034] t is 0, 1, 2, 3 or 4; and

[0035] p is 0, 1 or 2.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0037] X is selected from chemical bonds, -CR a R b -, -NR-, and -O-;

[0038] Y is selected from -CR 3a R 3b -、-NR 3c - and -O-;

[0039] Ring A is an aryl group or a heteroaryl group;

[0040] R, R a and R b are the same or different and are each independently selected from a hydrogen atom, an alkyl group and a haloalkyl group;

[0041] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0042] Each R 3 , R 3a , R 3b and R 3c are the same or different and are each 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 group, a cyano group, a -NR x R y and hydroxyl; wherein the alkyl group is optionally substituted with one or more cyano groups or amino groups;

[0043] Each R 4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, a cyano group, a -NR 8 R 9 , hydroxyl, -C(O)R 10 、-CH2C(O)R10 、-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 group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl;

[0044] 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 alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group and a hydroxyl group;

[0045] 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 heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, a hydroxyl group and a hydroxyalkyl group;

[0046] or R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R x and R y Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 8 and R 9 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein each occurrence of the heterocyclic group is the same or different and each is independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

[0047] m is 0, 1 or 2;

[0048] n is 0, 1, 2 or 3;

[0049] s is 0, 1, 2, 3, or 4;

[0050] t is 0, 1, 2, 3 or 4; and

[0051] p is 0, 1 or 2.

[0052] In some embodiments of the present disclosure, 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 As defined in general formula (I).

[0053] In some embodiments of the present disclosure, 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 different, and each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Preferably, Y is -CR 3a R 3b -, R 3a is a hydrogen atom, and R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Preferably, Y is -CR 3a R 3b -, R 3a is a hydrogen atom, and R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 More preferably, Y is -CR 3a R 3b -, R 3a is a hydrogen atom, and R 3b C 1-6 Alkoxy; most preferably, Y is -CR 3a R 3b -, R3a is a hydrogen atom, and R 3b It is ethoxy.

[0054] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0055]

[0056] in:

[0057] Ring A, X, R 1 To R 3 , R 3b , R 4 , m, n, s and t are as defined in the general formula (I).

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein s is 0 or 1; preferably, s is 0.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 2.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0064]

[0065] in:

[0066] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0067] Ring A, X, R 1 , R 3b , R 4 To R 7 , p and t are as defined in the general formula (I).

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 As defined in general formula (I);

[0069] Preferably, each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 As defined in general formula (I);

[0070] More preferably, R 4 -C(O)R10 , R 10 As defined in general formula (I).

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 For-OR 11 , R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein said C 1-6 The alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, -OR 12 and -C(O)OR 12 is substituted by one or more substituents, R 12 A hydrogen atom or C 1-6 alkyl;

[0072] Preferably, R 10 For-OR 11 , R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; 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 -C(O)OR 12 is substituted by one or more substituents, R 12 A hydrogen atom or C 1-6 alkyl;

[0073] More preferably, R 10 Selected from hydroxyl,

[0074] Most preferably, R 10 It is hydroxyl.

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, -NR8 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 For-OR 11 ; R 11 Selected from hydrogen atoms, 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 The alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, -OR 12 and -C(O)OR 12 is substituted by one or more substituents; R 12 A hydrogen atom or C 1-6 alkyl;

[0076] Preferably, each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 For-OR 11 ; R 11 Selected from hydrogen atoms, 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 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally selected from -OR 12 and -C(O)OR 12 is substituted by one or more substituents; R 12 A hydrogen atom or C 1-6 alkyl;

[0077] More preferably, R 4 -C(O)R 10 , R10 Selected from hydroxyl,

[0078] Most preferably, R 4 -C(O)R 10 , R 10 It is hydroxyl.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 As defined in general formula (I); preferably, each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 hydroxyl; more preferably, R 4 -C(O)R 10 , R 10 It is hydroxyl.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0081]

[0082] in:

[0083] R 10 Selected from hydroxyl, Preferably, R 10 is hydroxyl group;

[0084] t is 1 or 2;

[0085] R 2a and R2b 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0086] Ring A, X, R 1 , R 3b , R 4 To R 7 and p are as defined in the general formula (I).

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 and hydroxyl, R 8 and R 9 As defined in general formula (I); preferably, each R 4 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 and hydroxy; more preferably, R 4 A hydrogen atom.

[0088] In some embodiments of the present disclosure, the compound represented by the 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 are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 The alkylene group may be substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano.

[0089] In some embodiments of the present disclosure, in the compounds represented by formula (I), formula (II), formula (III), formula (IV), or pharmaceutically acceptable salts thereof, X is a chemical bond.

[0090] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV) or pharmaceutically acceptable salts thereof, wherein ring A is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group; preferably, ring A is a phenyl group or a pyridyl group; more preferably, ring A is a phenyl group.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; preferably, R 1 A hydrogen atom.

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (III) or the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; preferably, R 1 A hydrogen atom.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6haloalkoxy, halogen, cyano, amino, hydroxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; more preferably, each R 2 are the same or different and are each independently selected from a hydrogen atom, a methyl group, a methoxy group and a cyclopropyl group.

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 2 are the same or different and are each independently selected from a hydrogen atom, a 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 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl and C 1-6 Alkoxy; More preferably, each R 2 are the same or different and are each independently selected from a hydrogen atom, a methyl group and a methoxy group.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof:

[0096]

[0097] in:

[0098] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0099] R 3b , R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof is a 1:1 mixture of two enantiomers of rel-(1S,3S,5R) (i.e., cis) or rel-(1R,3S,5S) (i.e., trans), or a mixture of two diastereomers of rel-(1S,3S,5R) (i.e., cis) or rel-(1R,3S,5S) (i.e., trans); preferably, it is a 1:1 mixture of two enantiomers of rel-(1S,3S,5R), i.e., (±)-rel-(1S,3S,5R).

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V") or a pharmaceutically acceptable salt thereof:

[0102]

[0103] in:

[0104] R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0105] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(O)R 5 、-C(O)NR6 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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0106] R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V-1), or a pharmaceutically acceptable salt thereof:

[0108]

[0109] in:

[0110] R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0111] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0112] R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V"), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V-2), or a pharmaceutically acceptable salt thereof:

[0114]

[0115] in:

[0116] R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0117] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0118] R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof:

[0120]

[0121] in:

[0122] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0123] R 10 Selected from hydroxyl,

[0124] R 3b , R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0125] In some embodiments of the present disclosure, the compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof is a 1:1 mixture of two enantiomers of rel-(1S,3S,5R) (i.e., cis) or rel-(1R,3S,5S) (i.e., trans), or a mixture of two diastereomers of rel-(1S,3S,5R) (i.e., cis) or rel-(1R,3S,5S) (i.e., trans); preferably, it is a 1:1 mixture of two enantiomers of rel-(1S,3S,5R), i.e., (±)-rel-(1S,3S,5R).

[0126] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V'-1) or a pharmaceutically acceptable salt thereof:

[0127]

[0128] in:

[0129] R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0130] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0131] R 10 Selected from hydroxyl,

[0132] R 5 , R 6 , R 7 and p are as defined in the general formula (I).

[0133] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V'-2) or a pharmaceutically acceptable salt thereof:

[0134]

[0135] in:

[0136] R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy;

[0137] 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0138] R 10 Selected from hydroxyl,

[0139] R 5, R 6 , R 7 and p are as defined in the general formula (I).

[0140] In some embodiments of the present disclosure, the compounds represented by the 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) or their pharmaceutically acceptable salts, wherein R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, R 2a and R 2b The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl; more preferably, R 2a Selected from C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl, and R 2b C 1-6 Alkyl; most preferably, R 2a is selected from methyl, methoxy and cyclopropyl, and R 2b It is methyl.

[0141] In some embodiments of the present disclosure, the compound represented by the general formula (III) or the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, a 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 The same or different, and each independently is C 1-6 Alkyl or C 1-6 Alkoxy; More preferably, R 2a is a methoxy group, and R 2b It is methyl.

[0142] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V') or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Preferably, R 3b Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 More preferably, R 3b C 1-6 Alkoxy; most preferably, R 3b It is ethoxy.

[0143] In some embodiments of the present disclosure, the compound represented by formula (V"), general formula (V-1), general formula (V-2), general formula (V'-1), general formula (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 3b C 1-6 Alkoxy; preferably, R 3b It is ethoxy.

[0144] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1, 2, 3 or 4; preferably, t is 1 or 2; most preferably, t is 1.

[0145] In some embodiments of the present disclosure, 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 different, and each independently selected from a 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 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 For-OR 11 , R 11 Selected from hydrogen atoms, 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 The alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, -OR 12 and -C(O)OR 12 is substituted by one or more substituents, R 12 A hydrogen atom or C 1-6 alkyl; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0146] In some embodiments of the present disclosure, 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 different, and each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6haloalkoxy; ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; each R 1 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0147] In some embodiments of the present disclosure, 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 different, and each independently selected from a 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 1are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and halogen; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0148] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 For-OR 11 , R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein said C 1-6 The alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, -OR 12 and -C(O)OR 12 is substituted by one or more substituents, R 12 A hydrogen atom or C 1-6 alkyl; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0149] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 are the same or different and are each independently selected from a hydrogen atom, a C1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0150] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 haloalkyl, halogen and cyano; each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and halogen; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; s is 0; m is 1; n is 2; t is 1, 2, 3 or 4.

[0151] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 Selected from hydrogen atoms, 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 a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a C1-6 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 For-OR 11 , R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; 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 -C(O)OR 12 is substituted by one or more substituents, R 12 A hydrogen atom or C 1-6 Alkyl; t is 1 or 2.

[0152] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 Selected from hydrogen atoms, 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 a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; t is 1 or 2.

[0153] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 Selected from hydrogen atoms, 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 a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and halogen; each R 4 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 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, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl is optionally selected from C 1-6 Alkoxy, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; R 10 Selected from hydrogen atoms, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; t is 1 or 2.

[0154] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and cyano; R 2a and R 2b The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 Selected from hydroxyl, t is 1 or 2.

[0155] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C1-6 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 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and cyano; R 2a and R 2b The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 a hydroxyl group; t is 1 or 2.

[0156] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond; R 3b Selected from hydrogen atoms, 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 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and cyano; R 2a and R 2b The same or different, and each independently is C 1-6 Alkyl or C 1-6 Alkoxy; each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 a hydroxyl group; t is 1 or 2.

[0157] In some embodiments of the present disclosure, the compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof, wherein R 2a and R2b are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; R 10 Selected from hydroxyl,

[0158] In some embodiments of the present disclosure, the compound represented by the general formula (V'-1) or the general formula (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b 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 C 1-6 Alkoxy; R 10 Selected from hydroxyl,

[0159] In some embodiments of the present disclosure, 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 each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0160] In some embodiments of the present disclosure, 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 each independently selected from a hydrogen atom, a C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R 3b C 1-6 Alkoxy.

[0161] In some embodiments of the present disclosure, the compound represented by the general formula (V-1) or the general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b 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 C 1-6 Alkoxy.

[0162] In some embodiments of the present disclosure, the compound represented by the general formula (V-1) or the general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein R 2a Selected from C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl, and R 2b C 1-6 Alkyl; R 3b C 1-6 Alkoxy.

[0163] Table A Typical compounds of the present disclosure include, but are not limited to:

[0164]

[0165]

[0166]

[0167]

[0168] Another aspect of the present disclosure relates to a compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof:

[0169]

[0170] in:

[0171] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0172] R10 is an alkoxy group; preferably, R 10 C 1-6 Alkoxy; More preferably, R 10 is methoxy;

[0173] t is 1 or 2;

[0174] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in formula (IV).

[0175] Another aspect of the present disclosure relates to a compound represented by general formula (IVB) or a pharmaceutically acceptable salt thereof:

[0176]

[0177] in:

[0178] R t for

[0179] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0180] t is 1 or 2;

[0181] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in formula (IV).

[0182] Another aspect of the present disclosure relates to a compound represented by the general formula (VA) or a pharmaceutically acceptable salt thereof:

[0183]

[0184] in:

[0185] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0186] R 10 is an alkoxy group; preferably, R 10 C 1-6 Alkoxy; More preferably, R 10 is methoxy;

[0187] R 2a , R2b and R 3b As defined in formula (V).

[0188] Another aspect of the present disclosure relates to a compound represented by the general formula (V-1A) or a pharmaceutically acceptable salt thereof:

[0189]

[0190] in:

[0191] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0192] R 10 is an alkoxy group; preferably, R 10 C 1-6 Alkoxy; More preferably, R 10 is methoxy;

[0193] R 2a , R 2b and R 3b As defined in general formula (V-1).

[0194] Another aspect of the present disclosure relates to a compound represented by the general formula (V-2A) or a pharmaceutically acceptable salt thereof:

[0195]

[0196] in:

[0197] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0198] R 10 is an alkoxy group; preferably, R 10 C 1-6 Alkoxy; More preferably, R 10 is methoxy;

[0199] R 2a , R 2b and R 3b As defined in general formula (V-2).

[0200] Another aspect of the present disclosure relates to a compound represented by the general formula (V'A) or a pharmaceutically acceptable salt thereof:

[0201]

[0202] in:

[0203] R t for

[0204] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0205] R 2a , R 2b and R 3b As defined in formula (V').

[0206] Another aspect of the present disclosure relates to a compound represented by general formula (V'-1A) or a pharmaceutically acceptable salt thereof:

[0207]

[0208] in:

[0209] R t for

[0210] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0211] R 2a , R 2b and R 3b As defined in general formula (V'-1).

[0212] Another aspect of the present disclosure relates to a compound represented by the general formula (V'-2A) or a pharmaceutically acceptable salt thereof:

[0213]

[0214] in:

[0215] R t for R s is a hydroxyl protecting group; preferably, R s is allyl;

[0216] R 2a , R 2b and R 3b As defined in general formula (V'-2).

[0217] Table B Typical compounds of the present disclosure include, but are not limited to:

[0218]

[0219]

[0220] 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:

[0221]

[0222] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R w and undergo hydrolysis to obtain R 10 A compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein the compound is a hydroxyl group,

[0223] in:

[0224] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0225] t is 1 or 2;

[0226] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in formula (IV).

[0227] 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:

[0228]

[0229] The compound represented by the general formula (IVB) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R s Obtaining a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0230] and optionally, after resolution, a compound of formula (IV) or a pharmaceutically acceptable salt thereof with a single configuration is obtained.

[0231] in:

[0232] R t for

[0233] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0234] R 10 Selected from

[0235] t is 1 or 2;

[0236] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in formula (IV).

[0237] 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:

[0238]

[0239] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (VA) or its pharmaceutically acceptable salt is deprotected by the removal of the protecting group R w and hydrolyzing to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof,

[0240] in:

[0241] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0242] R 2a , R 2b and R 3b As defined in formula (V).

[0243] 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:

[0244]

[0245] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (V-1A) or a pharmaceutically acceptable salt thereof is deprotected by the removal of the protecting group R w and hydrolyzing to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

[0246] in:

[0247] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0248] R 2a , R 2b and R 3b As defined in general formula (V-1).

[0249] 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:

[0250]

[0251] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (V-2A) or a pharmaceutically acceptable salt thereof is deprotected by the removal of the protecting group R w and hydrolyzing to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

[0252] in:

[0253] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0254] R 2a , R 2b and R 3b As defined in general formula (V-2).

[0255] 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:

[0256]

[0257] The compound represented by the general formula (V'A) or its pharmaceutically acceptable salt is deprotected by the removal of the protecting group R s Obtaining a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof,

[0258] and optionally, after resolution, a compound of formula (V') or a pharmaceutically acceptable salt thereof with a single configuration is obtained.

[0259] in:

[0260] R t for

[0261] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0262] R 10Selected from

[0263] R 2a , R 2b and R 3b As defined in formula (V').

[0264] 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:

[0265]

[0266] The compound represented by the general formula (V'-1A) or its pharmaceutically acceptable salt is deprotected by the removal of the protecting group R s Obtaining a compound represented by the general formula (V'-1) or a pharmaceutically acceptable salt thereof,

[0267] and optionally, after resolution, a compound of general formula (V'-1) or a pharmaceutically acceptable salt thereof with a single configuration is obtained,

[0268] in:

[0269] R t for

[0270] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0271] R 10 Selected from

[0272] R 2a , R 2b and R 3b As defined in general formula (V'-1).

[0273] 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:

[0274]

[0275] The compound represented by the general formula (V'-2A) or its pharmaceutically acceptable salt is deprotected by removing the protecting group R s Obtaining a compound represented by the general formula (V'-2) or a pharmaceutically acceptable salt thereof,

[0276] and optionally, after resolution, a compound of formula (V'-2) or a pharmaceutically acceptable salt thereof with a single configuration is obtained.

[0277] in:

[0278] R t for

[0279] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0280] R 10 Selected from

[0281] R 2a , R 2b and R 3b As defined in general formula (V'-2).

[0282] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure 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 Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0283] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions containing the same in the preparation of drugs for inhibiting activation of the complement alternative pathway, preferably in the preparation of drugs for inhibiting Factor B.

[0284] The present disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by activation of the complement alternative pathway; preferably in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by Factor B, wherein the 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 (such as nephrotic syndrome), syndrome, aHUS), paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis (such as anterior uveitis, posterior uveitis and intermediate uveitis), retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Fuku-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, Postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, postischemic reperfusion disorder, myocardial infarction, balloon angioplasty, post-pump in cardiopulmonary bypass surgery or renal bypass surgery syndrome, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or sepsis, immune complex disorders, autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), immune thrombocytopenia and cold agglutinin syndrome), systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma , chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia (such as allergic pneumonia), fibrosing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodman syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome and obesity; wherein the glomerulopathy is preferably selected from C3 glomerulopathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy (such as primary immunoglobulin A nephropathy) and membranous glomerulonephritis;More preferably, the invention is used in the preparation of a drug for treating and / or preventing C3 glomerulopathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. ;

[0285] The present disclosure further relates to the use of compounds shown in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same in the preparation of drugs for treating and / or preventing diseases or disorders mediated by Factor B, wherein the diseases or disorders are inflammatory disorders.

[0286] The present disclosure further relates to a method for inhibiting activation of the complement alternative pathway, preferably a method for inhibiting Factor B, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0287] The present disclosure further relates to a method for treating and / or preventing a disease or disorder mediated by activation of the complement alternative pathway, preferably a method for treating and / or preventing a disease or disorder mediated by Factor B, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0288] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine.

[0289] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used for inhibiting activation of the complement alternative pathway, preferably for inhibiting Factor B.

[0290] The present disclosure further relates to a compound shown in formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V"), formula (V-1), formula (V-2), formula (V'), formula (V'-1), formula (V'-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing diseases or disorders mediated by activation of the complement alternative pathway, preferably for treating and / or preventing diseases or disorders mediated by Factor B.

[0291] The diseases or disorders mediated by activation of the complement alternative pathway described in the present disclosure (preferably diseases or disorders mediated by Factor B) are selected from glomerulopathy (such as glomerulonephritis), hemolytic uremic syndrome (such as Escherichia coli-induced hemolytic uremic syndrome), atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis (such as anterior uveitis, posterior uveitis and intermediate uveitis), pigmentary retinitis, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, Fuku-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic eye inflammation, ocular cicatricial pemphigoid , ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, complications of hemodialysis, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorder, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, Hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or sepsis, immune complex disorders, autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), immune thrombocytopenia and cold agglutinin syndrome), systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust disease, pulmonary fibrosis The invention relates to a method for treating a glomerulonephritis in a patient with a history of nephropathy, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodman's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome and obesity; wherein the glomerulopathy is preferably selected from C3 glomerulopathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy (such as primary immunoglobulin A nephropathy) and membranous glomerulonephritis; preferably, the disease or disorder is selected from C3 glomerulopathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

[0292] The diseases or disorders mediated by Factor B described in the present disclosure are inflammatory disorders.

[0293] The active compound can be made into a form suitable for administration by any appropriate route, and the composition of the present disclosure is prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can also be formulated into a sustained release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, an emulsion, an injection, a dispersible powder or granules, a suppository, a lozenge or a syrup.

[0294] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0295] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0296] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0297] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0298] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. 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.

[0299] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0300] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, a mineral oil or a mixture thereof. A suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.

[0301] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0302] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0303] The disclosed compounds may 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 will therefore melt in the rectum to release the drug.

[0304] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0305] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0306] Terminology

[0307] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0308] The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6alkyl). 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, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Most preferably, the lower alkyl group has 1 to 6 carbon atoms, non-limiting examples of which 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 and 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0309] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12alkylene), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0310] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and an alkenyl group (i.e., C 2 to 12) carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 The term "alkenyl" refers to an alkylene group or a cycloalkylene group. Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0311] The term "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 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0312] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0313] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0314] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocycles, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). According to the number of spiral atoms shared between rings, spirocycloalkyl is divided into single spiral cycloalkyl or multi-spirocycloalkyl (e.g., double spiral cycloalkyl), preferably single spiral cycloalkyl and double spiral cycloalkyl. 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 yuan / 5 yuan or 6 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0315]

[0316] The term "condensed cycloalkyl" refers to 5 to 20 yuan, a full carbon polycyclic group sharing a pair of adjacent carbon atoms between the rings, wherein one or more rings may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into polycyclic condensed cycloalkyls such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic condensed cycloalkyls, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 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 / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan of bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include:

[0317]

[0318] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, polycyclic bridged cycloalkyls such as bicyclic, tricyclic, and tetracyclic can be divided, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include:

[0319]

[0320] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0321] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0322] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, there are 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclyl); further preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 are heteroatoms (e.g., 1, 2, and 3) (i.e., 3 to 8-membered heterocyclyl); more preferably, there are 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclyl); most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyls include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.

[0323] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group or a multi-spiro heterocyclic group (such as a double spiral heterocyclic group), preferably a single spiral heterocyclic group and a double spiral heterocyclic group. 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 single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0324]

[0325] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein the rings share a pair of adjacent atoms, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, the ring is 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 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 groups. Non-limiting examples of fused heterocyclic groups include:

[0326]

[0327] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

[0328]

[0329] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0330] wait.

[0331] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0332] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0333]

[0334] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0335] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 5-10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan) heteroaryl, more preferably a 5- or 6-yuan heteroaryl, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0336]

[0337] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0338] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0339] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl and p-methoxybenzyl, etc. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.

[0340] The term "hydroxyl protecting group" refers to an easily removable group introduced on a hydroxyl group, which is usually used to block or protect the hydroxyl 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 aromatic) 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-tetrahydropyranyl (THP) and the like.

[0341] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0342] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0343] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0344] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0345] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0346] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0347] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0348] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0349] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0350] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0351] The term "hydroxy" refers to -OH.

[0352] The term "thiol" refers to -SH.

[0353] The term "amino" refers to -NH2.

[0354] The term "cyano" refers to -CN.

[0355] The term "nitro" refers to -NO2.

[0356] The term "oxo" or "oxo" refers to "=0".

[0357] The term "carbonyl" refers to C=O.

[0358] The term "carboxy" refers to -C(O)OH.

[0359] The term "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.

[0360] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0361] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations.

[0362] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0363]

[0364] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0365]

[0366] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0367] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "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. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 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.

[0368] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0369] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each 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 for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0370] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally (optionally) substituted with halogen or cyano" 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0371] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0372] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0373] "Pharmaceutically acceptable salts" refer to salts of the compounds 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 the desired biological activity. Salts may 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 and organic acids.

[0374] With respect to a drug or pharmacologically active agent, 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 a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0375] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0376] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0377] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0378] Synthesis method of the disclosed compound

[0379] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0380] Solution 1

[0381] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0382]

[0383] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof is deprotected under alkaline conditions by removing the protecting group R w and undergo hydrolysis to obtain R 10 A compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein the compound is a hydroxyl group,

[0384] in:

[0385] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0386] t is 1 or 2;

[0387] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in formula (IV).

[0388] Solution 2

[0389] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0390]

[0391] The compound represented by the general formula (IVB) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R in the presence of a catalyst (preferably tetrakis(triphenylphosphine)palladium). s Obtaining a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0392] and optionally undergoing chiral preparation and resolution to obtain a compound of formula (IV) or a pharmaceutically acceptable salt thereof having a single configuration,

[0393] in:

[0394] R t for

[0395] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0396] R 10 Selected from

[0397] t is 1 or 2;

[0398] Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in general formula (IV).

[0399] Option 3

[0400] The present invention discloses a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0401]

[0402] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (VA) or a pharmaceutically acceptable salt thereof is deprotected under alkaline conditions by removing the protecting group R w and hydrolyzing to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof,

[0403] in:

[0404] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0405] R 2a , R 2b and R 3b As defined in formula (V).

[0406] Option 4

[0407] The present invention discloses a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0408]

[0409] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (V-1A) or a pharmaceutically acceptable salt thereof is deprotected under alkaline conditions by removing the protecting group R w and hydrolyzing to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

[0410] in:

[0411] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0412] R 2a , R 2b and R 3b As defined in general formula (V-1).

[0413] Option 5

[0414] The present invention discloses a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0415]

[0416] R 10 is an alkoxy group (preferably C 1-6 The compound represented by the general formula (V-2A) or a pharmaceutically acceptable salt thereof is deprotected under alkaline conditions by removing the protecting group R w and hydrolyzing to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

[0417] in:

[0418] R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl;

[0419] R 2a , R 2b and R 3bAs defined in general formula (V-2).

[0420] Option 6

[0421] The present invention discloses a method for preparing a compound represented by general formula (V-1) and general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0422]

[0423] The compound represented by the general formula (V") or a pharmaceutically acceptable salt thereof is prepared and resolved by chiral separation to obtain the compound represented by the general formula (V-1) and the general formula (V-2) or a pharmaceutically acceptable salt thereof;

[0424] R 2a , R 2b and R 3b As defined in general formula (V-1) and general formula (V-2).

[0425] Option 7

[0426] The present invention discloses a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0427]

[0428] The compound represented by the general formula (V'A) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R in the presence of a catalyst (preferably tetrakis(triphenylphosphine)palladium). s Obtaining a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof,

[0429] and optionally undergoing chiral preparation and resolution to obtain a compound of formula (V') or a pharmaceutically acceptable salt thereof having a single configuration,

[0430] in:

[0431] R t for

[0432] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0433] R 10 Selected from

[0434] R 2a , R 2b and R 3b As defined in formula (V').

[0435] Option 8

[0436] The present invention discloses a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0437]

[0438] The compound represented by the general formula (V'-1A) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R in the presence of a catalyst (preferably tetrakis(triphenylphosphine)palladium) s Obtaining a compound represented by the general formula (V'-1) or a pharmaceutically acceptable salt thereof,

[0439] and optionally undergoing chiral preparation and resolution to obtain a compound of formula (V'-1) or a pharmaceutically acceptable salt thereof having a single configuration,

[0440] in:

[0441] R t for

[0442] R s is a hydroxyl protecting group; preferably, R s is allyl;

[0443] R 10 Selected from

[0444] R 2a , R 2b and R 3b As defined in general formula (V'-1).

[0445] Option 9

[0446] The present invention discloses a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0447]

[0448] The compound represented by the general formula (V'-2A) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R in the presence of a catalyst (preferably tetrakis(triphenylphosphine)palladium) s Obtaining a compound represented by the general formula (V'-2) or a pharmaceutically acceptable salt thereof,

[0449] and optionally undergoing chiral preparation and resolution to obtain a compound of formula (V'-2) of a single configuration or a pharmaceutically acceptable salt thereof,

[0450] in:

[0451] R t for

[0452] R s is a hydroxyl protecting group; preferably, Rs is allyl;

[0453] R 10 Selected from

[0454] R 2a , R 2b and R 3b As defined in general formula (V'-2).

[0455] In the above reaction, the base includes organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, 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.

[0456] The reaction in 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, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0457] Figure 1 : Effects of Example 1-1 compound and positive drug LNP023 on serum iC3b+C3d in rats with passive Heymann nephritis.

[0458] Figure 2 and Figure 3 : Effects of Example 1-1 compound and positive drug LNP023 on urine protein / creatinine in rats with passive Heymann nephritis. DETAILED DESCRIPTION

[0459] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0460] Example

[0461] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0462] MS was measured using Agilent 1200 / 1290DAD-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), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0463] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0464] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0465] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0466] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0467] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0468] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0469] Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0470] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0471] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0472] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0473] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0474] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0475] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0476] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0477] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0478] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0479] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0480] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing solvent system for thin layer chromatography 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 adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0481] When the compounds in the examples contain two or more chiral centers, the relative stereochemistry of these compounds is determined by NMR studies and / or X-ray diffraction. In these cases, the prefix "rel" is used, followed by the R / S nomenclature to identify these compounds, where the R / S only provides relative stereochemical information and does not represent absolute stereochemistry. For example, 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: It means The relative stereochemistry at positions 1, 3 and 5 is 1S, 3S, 5R or 1R, 3R, 5S (i.e., cis, specifically, the five-membered nitrogen-containing heterocyclic group at positions 1, 5-8 and the ethoxy group at position 3 are both located on the same side of the face where the six-membered nitrogen-containing heterocyclic group at positions 1-5 and 8 is located: i.e., facing inward or outward). Since compound 1 is a racemate, a person skilled in the art can undoubtedly determine that compound 1 is two enantiomers. A 1:1 mixture.

[0482] Example 1, Example 2

[0483] (±)-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 1

[0484] (±)-rel-4-((1R,3S,5S)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid 2

[0485]

[0486] Step 1-(4-Bromophenyl)butane-1,4-diol 1b

[0487] Dissolve methyl 4-(4-bromophenyl)-4-oxobutanoate 1a (5 g, 17.54 mmol, Bid Pharmaceutical Technology Co., Ltd.) in tetrahydrofuran (50 mL), add lithium borohydride tetrahydrofuran solution (17 mL, 2 mmol / mL) at 0°C, naturally warm to room temperature, and stir overnight. The reaction solution was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude title product 1b (4.29 g), which was directly used in the next step without purification.

[0488] MS m / z(ESI):242.9[MH].

[0489] Step 2

[0490] 4-(4-Bromophenyl)-4-oxobutyraldehyde 1c

[0491] Dissolve dimethyl sulfoxide (8.2 g, 104.95 mmol) in dichloromethane (50 mL), add oxalyl chloride (8.8 g, 69.33 mmol) at -78 °C, continue stirring for 10 minutes, add compound 1b (4.29 g, 17.50 mmol), and add triethylamine (17.7 g, 174.92 mmol) after 10 minutes. Continue stirring the reaction solution for 1 hour. Naturally warm to room temperature, dilute with dichloromethane, wash the organic phase with saturated sodium bicarbonate aqueous solution, dry the organic phase, concentrate under reduced pressure, and purify by silica gel column chromatography with eluent C to obtain the title compound 1c (2.7 g, yield: 64%).

[0492] MS m / z(ESI):240.8[M+1].

[0493] Step 3

[0494] 1-(4-Bromophenyl)-8-[(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-one 1d

[0495] 4-Methoxybenzylamine (1.61 g, 11.74 mmol, Shaoyuan Technology Co., Ltd.) and sodium acetate (6.43 g, 78.38 mmol) were dissolved in water (7.5 mL), 2M hydrochloric acid (16 mL) and 1,3-acetone dicarboxylic acid (1.96 g, 13.42 mmol) were added at 0°C, stirring was continued for 30 minutes, compound 1c (2.7 g, 11.20 mmol) was added, and after 30 minutes, the mixture was stirred at 40°C for 3 hours. The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to obtain the title compound 1d (580 mg, yield: 12.9%).

[0496] MS m / z(ESI):399.9[M+1].

[0497] Step 4

[0498] 1-(4-Bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-ol 1e

[0499] Compound 1d (530 mg, 1.32 mmol) was dissolved in methanol (5 mL), and sodium borohydride (200 mg, 5.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give the crude title compound 1e (420 mg, yield: 78.8%).

[0500] MS m / z(ESI):401.8[M+1].

[0501] Step 5

[0502] 1-(4-Bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane 1f

[0503] Compound 1e was dissolved in dimethylformamide (5 mL), and sodium hydride (83 mg, 2.08 mmol) was added at 0°C. The reaction solution was stirred for 1 hour, and iodoethane (325 mg, 2.09 mmol) was added. The reaction solution was warmed to room temperature and stirred overnight. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The title compound 1f (350 mg, yield: 77.9%) was purified by silica gel column chromatography with eluent C. MS m / z (ESI): 429.9 [M+1].

[0504] Step 6

[0505] 4-(3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid methyl ester 1g

[0506] Compound 1f was dissolved in methanol (4 mL) and dimethylformamide (4 mL), and palladium acetate (54 mg, 240.52 μmol), diphenylphosphoryl azide (100 mg, 242.46 μmol) and triethylamine (822 mg, 8.12 mmol) were added. Carbon monoxide gas was replaced three times and stirred at 80°C overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to obtain the title compound 1g (225 mg, yield: 67.5%).

[0507] MS m / z(ESI):411.0[M+1].

[0508] Step 7

[0509] Methyl 4-(3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoate 1h

[0510] Dissolve compound 1g (225mg, 549.43μmol) in ethanol (5mL), add palladium carbon hydrogenation catalyst (40mg, 375.87μmol). Replace with hydrogen three times, stir at room temperature for 48 hours under hydrogen atmosphere. Filter the reaction solution, and concentrate the organic phase under reduced pressure to obtain the crude title compound 1h (130mg), which is used directly in the next step without purification.

[0511] MS m / z(ESI):290.0[M+1].

[0512] Step 8

[0513] tert-Butyl 4-(bromomethyl)-5-methoxy-7-methylindole-1-carboxylate 1j

[0514] Compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 1i (150 mg, 514.86 μmol, synthesized by referring to the preparation method of intermediate 1-10 of WO2015009616A1) was dissolved in dichloromethane (2 mL), and carbon tetrabromide (170 mg, 512.62 μmol) and triphenylphosphine (135 mg, 514.71 μmol) were added under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours and directly concentrated to obtain a crude compound 1j (183 mg). The product was directly used in the next step without purification.

[0515] Step 9

[0516] 4-((3-ethoxy-1-(4-(methoxycarbonyl)phenyl)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-methoxy-7-

[0517] Methyl-1H-indole-1-carboxylic acid tert-butyl ester 1k

[0518] Compound 1h (100 mg, 345.5801 μmol) was dissolved in dimethylformamide (2 mL), and sodium hydride (27 mg, 675.07 μmol) was added at 0°C. The reaction solution was stirred for 1 hour, and then a dimethylformamide solution of compound 1j (183 mg, 516.60 μmol) was added, and the reaction solution was stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution, and the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to obtain the title compound 1k (130 mg, yield: 66.8%).

[0519] MS m / z(ESI):563.0[M+1].

[0520] Step 10 (±)-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 1

[0521] (±)-rel-4-((1R,3S,5S)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid 2

[0522] Compound 1k (130 mg, 231.03 μmol) was dissolved in 6 mL of a mixed solution of tetrahydrofuran, methanol and water (V:V:V=1:1:1). Lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. The reaction solution was stirred at 70°C for 3 hours. The reaction solution was concentrated, diluted with a small amount of methanol, and purified by high performance liquid chromatography (Waters 2545, column: Sharpsil-T C18, 250*50 mm, 8 μm; mobile phase A: water (containing 10 mmol / L ammonium bicarbonate); mobile phase B: acetonitrile; 18-minute gradient: 20%-38%, flow rate: 80 mL / min) to obtain the title compounds 1 (4 mg, yield: 3.86%) and 2 (5 mg, yield: 4.82%).

[0523] Compound 1:

[0524] High performance liquid chromatography: retention time 17.28min.

[0525] MS m / z(ESI):449.1[M+1].

[0526] 1 H NMR (500MHz, CD3OD): 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).

[0527] Compound 2:

[0528] High performance liquid preparative chromatography: retention time 14.83min.

[0529] MS m / z(ESI):449.1[M+1].

[0530] 1 H NMR (500MHz, CD3OD): 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).

[0531] Example 1-1, Example 1-2

[0532] 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]

[0533] Octane-1-yl)benzoic acid 1-1

[0534] 4-((1R,3R,5S)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]

[0535] Octane-1-yl)benzoic acid 1-2

[0536]

[0537]

[0538] Compound 1 (100 mg, 222.93 μmol) was purified by chiral preparation (separation conditions: chiral preparation column CHIRALPAKIG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title compounds 1-1 (35 mg, yield: 35%) and 1-2 (33 mg, yield: 33%).

[0539] Compound 1-1:

[0540] MS m / z(ESI):449.1[M+1].

[0541] Chiral HPLC analysis: retention time 7.946 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 μm, 20 mm*250 mm (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).

[0542] 1 H 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),3.9 3(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).

[0543] Compound 1-2:

[0544] MS m / z(ESI):449.1[M+1].

[0545] Chiral HPLC analysis: retention time 12.77 minutes, chiral purity: 98.7% (chromatographic column: CHIRALPAKIG, 5μm, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1mL / min).

[0546] 1 H NMR(500MHz,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),3.9 5(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).

[0547] Example 3

[0548] 4-((1S,3S,5R)-8-((5,7-dimethyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]octane

[0549] -1-yl)benzoic acid 3

[0550]

[0551] First step (±)-rel-(1S,3S)-1-(4-bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-ol 3a

[0552] Compound 1d (22.5 g, 56.21 mmol) was dissolved in tetrahydrofuran (220 mL), and a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (168.86 mL, 168.86 mmol) was added dropwise at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 3 hours. Methanol (100 mL) was added to the reaction mixture to quench the reaction, and the mixture was stirred at room temperature for 1 hour, and ethyl acetate was added. The mixture was washed with 0.5 M hydrochloric acid and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using eluent system C, and then washed with saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 3a (18.7 g, yield: 82.69%).

[0553] MS m / z(ESI):401.9[M+1].

[0554] Step 2 (±)-rel-(1S,3S)-1-(4-bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane 3b

[0555] 3a (18.7 g, 46.48 mmol) was dissolved in tetrahydrofuran (200 mL), sodium hydride (8.91 g, 232.54 mmol, content 60%) was added at 0°C, stirring was continued for 1 hour, 18.62 mL of iodoethane (36.3 g, 232.74 mmol) was added, and the reaction mixture was stirred at 50°C overnight. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to obtain the title compound 3b (13.0 g, yield: 65%). MS m / z (ESI): 429.9 [M+1].

[0556] Step 3

[0557] (1S,3S,5R)-1-(4-bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane 3c

[0558] (1R,3R,5S)-1-(4-bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane 3c'

[0559] Compound 3b was chirally prepared (separation conditions: chiral preparation column Waters SFC 150, DAICEL OJ, mobile phase: supercritical carbon dioxide / methanol = 70 / 30)) and the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 3c (7.2 g, yield: 55.38%) and 3c' (5.8 g, yield: 44.62%).

[0560] Compound 3c:

[0561] MS m / z(ESI):429.9[M+1].

[0562] Chiral HPLC analysis: retention time 7.946 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 μm, 20 mm*250 mm (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).

[0563] Compound 3c':

[0564] MS m / z(ESI):429.9[M+1].

[0565] Chiral HPLC analysis: retention time 12.77 minutes, chiral purity: 98.7% (chromatographic column: CHIRALPAKIG, 5μm, 20mm*250mm (Phenomenex); mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1mL / min).

[0566] Step 4

[0567] Methyl 4-((1S,3S,5R)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoate 3d

[0568] Compound 3c (7.2 g, 16.73 mmol) was dissolved in methanol (40 mL) and N,N-dimethylformamide (40 mL), palladium acetate (1.14 g, 5.08 mmol, Inokai reagent), 1,3-bis(diphenylphosphino)propane (2.08 g, 5.04 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) and triethylamine (17 g, 168.00 mmol) were added, carbon monoxide was replaced three times, and stirred at 80 ° C overnight under a carbon monoxide atmosphere. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 3d (5.9 g, yield: 86.12%). MS m / z (ESI): 410.0 [M+1].

[0569] Step 5

[0570] Methyl 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoate 3e

[0571] Compound 3d (5.9 g, 14.41 mmol) was dissolved in water (30 mL) and acetonitrile (30 mL), cooled to 0°C, and ammonium cerium nitrate (23.7 g, 43.23 mmol, Adamas Reagent Co., Ltd.) was added. The reaction was carried out at room temperature for 1 hour, and ammonium cerium nitrate (16 g, 29.18 mmol) was added, and the reaction was continued at room temperature for 1 hour. A large amount of water was added, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 3e (3.2 g, yield: 76.76%).

[0572] MS m / z(ESI):290.0[M+1].

[0573] Step 6

[0574] 4-Bromo-5,7-dimethyl-1-p-toluenesulfonyl-1H-indole 3g

[0575] 4-Bromo-5,7-dimethyl-1H-indole 3f (1.4 g, 6.25 mmol, Ikon reagent) was dissolved in N,N-dimethylformamide (25 mL), cooled to 0°C, sodium hydride (500 mg, 12.50 mmol, content 60%) was added, and the reaction mixture was stirred for 10 minutes, and p-toluenesulfonyl chloride (1.3 g, 6.82 mmol, Sinopharm reagent) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain 3g of the title compound (1.2 g, yield: 50.78%).

[0576] MS m / z(ESI):377.9[M+1].

[0577] Step 7

[0578] 5,7-Dimethyl-1-p-toluenesulfonyl-1H-indole-4-carboxylic acid methyl ester 3h

[0579] Compound 3g (600 mg, 1.59 mmol) was dissolved in methanol (5 mL) and N,N-dimethylformamide (5 mL), palladium acetate (106.9 mg, 476.15 μmol), 1,3-bis(diphenylphosphino)propane (196.3 mg, 475.94 μmol) and triethylamine (1.61 g, 15.86 mmol) were added, and carbon monoxide was replaced three times. The mixture was stirred at 80°C overnight under a carbon monoxide atmosphere. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 3h (488 mg, yield: 86.08%).

[0580] MS m / z(ESI):357.9[M+1].

[0581] Step 8

[0582] (5,7-Dimethyl-1-p-toluenesulfonyl-1H-indol-4-yl)methanol 3i

[0583] Compound 3h (488 mg, 1.37 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of lithium borohydride (3.06 mmol, 1.53 mL) was added at 0°C. After addition, the mixture was moved to room temperature and stirred overnight. The reaction mixture was cooled to 0°C, and a saturated aqueous solution of ammonium chloride was slowly added dropwise thereto to quench the reaction until no bubbles were generated. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 3i (253 mg, yield: 56.25%).

[0584] MS m / z(ESI):311.9[M-OH].

[0585] Step 9

[0586] Methyl 4-((1S,3S,5R)-8-((5,7-dimethyl-1-toluenesulfonyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoate 3j

[0587] Compound 3i (253 mg, 768.03 μmol) was dissolved in dichloromethane (5.6 mL), cooled to 0 ° C under nitrogen atmosphere, and carbon tetrabromide (255.1 mg, 769.24 μmol, Anergy reagent) and triphenylphosphine (202.4 mg, 771.68 μmol, Sinopharm reagent) were added in sequence. The reaction mixture was stirred at 0 ° C for 1.5 hours. The obtained solution was used for standby. Compound 3e (150.7 mg, 0.52 mmol) was dissolved in N, N-dimethylformamide (4 mL), sodium hydride (43 mg, 1.08 mmol, content 60%) was added at 0 ° C, and stirring was continued for 1 hour. The above solution was added and gradually warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture to quench it, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent System C to give the title compound 3j (67 mg, yield: 21.45%).

[0588] MS m / z(ESI):600.9[M+1].

[0589] Step 10

[0590] 4-((1S,3S,5R)-8-((5,7-dimethyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]octane

[0591] -1-yl)benzoic acid 3

[0592] Compound 3j (67 mg, 111.52 μmol) was dissolved in methanol (1.4 mL) and water (0.3 mL), potassium hydroxide (62.6 mg, 1.12 mmol) was added, and the reaction mixture was stirred at 60°C in a sealed tube overnight. The reaction mixture was cooled to room temperature, the pH of the solution was adjusted to 5-6 with 1M hydrochloric acid, water and ethyl acetate were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved in a small amount of methanol and purified by high performance liquid preparative chromatography (instrument model: Waters Autopurification-SQD2 chromatographic column: Welch XB-C18 30 mm*150 mm; 5 μm; mobile phase 1: pure water (containing 10 mM ammonium bicarbonate); mobile phase 2: acetonitrile; gradient: 25%-95%; flow rate: 30 mL / min) to obtain the title compound 3 (6 mg, yield: 12.44%).

[0593] MS m / z(ESI):433.1[M+1].

[0594] 1 H NMR (500MHz, CD3OD): 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).

[0595] Example 4

[0596] 4-((1S,3S,5R)-8-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]

[0597] Octane-1-yl)benzoic acid 4

[0598]

[0599] first step

[0600] 2-Bromo-4-methyl-5-nitrobenzonitrile 4b

[0601] 2-Bromo-4-methylbenzonitrile 4a (4 g, 20.40 mmol, Bid Pharmaceutical Technology Co., Ltd.) was dissolved in sulfuric acid (6 mL), and a solution of potassium nitrate (2.06 g, 20.40 mmol) dissolved in sulfuric acid (18 mL) was added dropwise under an ice bath. After completion of the addition, the mixture was reacted at 0°C for 1.5 hours. The reaction solution was poured into ice water, stirred, filtered, and the filter cake was washed with ice water and dried to obtain a crude title product 4b (4.9 g), which was directly used in the next step without purification.

[0602] MS m / z(ESI):240.8[M-1].

[0603] Step 2

[0604] 5-Bromo-7-methyl-1H-indole-4-carbonitrile 4c

[0605] Compound 4b (3.9 g, 16.18 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -20°C under a nitrogen atmosphere, and vinylmagnesium bromide (64.76 mL, 64.76 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1.5 hours, cooled to -20°C, quenched with aqueous sodium hydroxide solution, extracted twice with ethyl acetate (100 mL), and the organic phases were combined, washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with eluent B to give the title compound 4c (500 mg, yield: 13.1%).

[0606] MS m / z(ESI):234.9[M-1].

[0607] Step 3

[0608] 5-Bromo-7-methyl-1-p-toluenesulfonyl-1H-indole-4-carbonitrile 4d

[0609] Compound 4c (500 mg, 2.13 mmol) was dissolved in dichloromethane (10 mL), 4-toluenesulfonyl chloride (609 mg, 3.19 mmol) and benzyltriethylammonium chloride (48.5 mg, 212.93 μmol) were added, and sodium hydroxide (128 mg, 3.20 mmol) was added, and the mixture was reacted at room temperature overnight. After concentration, the residue was purified by silica gel column chromatography with eluent B to obtain the title compound 4d (500 mg, yield: 60.4%).

[0610] MS m / z(ESI):388.9[M-1].

[0611] Step 4

[0612] 5-Bromo-7-methyl-1-toluenesulfonyl-1H-indole-4-carbaldehyde 4e

[0613] Compound 4d (500 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL), 1 M diisobutylaluminum hydride (1.9274 mL) was added dropwise at -78°C, the reaction was allowed to react for 1.5 hours at -78°C, quenched with methanol, 2 M hydrochloric acid (20 mL) was added, and the mixture was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4e (140 mg, yield: 27.8%).

[0614] MS m / z(ESI):392.0[M-1].

[0615] Step 5

[0616] 5-Cyclopropyl-7-methyl-1-toluenesulfonyl-1H-indole-4-carbaldehyde 4f

[0617] Compound 4e (140 mg, 356.9 μmol) was dissolved in toluene (3 mL) and water (1 mL), and potassium cyclopropyltrifluoroborate (106 mg, 716.33 μmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (50 mg, 107.15 μmol), palladium acetate (16.1 mg, 71.71 μmol), and cesium carbonate (698 mg, 2.14 mmol) were added. The mixture was reacted at 100 ° C for 2 hours under a nitrogen atmosphere, filtered, and concentrated to obtain a crude title product 4f (126 mg), which was directly used in the next step without purification.

[0618] MS m / z(ESI):353.9[M+1].

[0619] Step 6

[0620] (5-Cyclopropyl-7-methyl-1-p-toluenesulfonyl-1H-indol-4-yl)methanol 4g

[0621] Compound 4f (126 mg, 356.50 μmol) was dissolved in methanol (3 mL), sodium borohydride (27 mg, 713.67 μmol) was added at 0°C, the reaction was allowed to react at room temperature for 2 hours, saturated aqueous ammonium chloride solution (10 mL) was added to quench, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4g (126 mg, yield: 99.4%).

[0622] MS m / z(ESI):354.1[M-1].

[0623] Step 7

[0624] 4-(Bromomethyl)-5-cyclopropyl-7-methyl-1-toluenesulfonyl-1H-indole 4h

[0625] Compound 4g (70 mg, 196.93 μmol) was dissolved in dichloromethane (1 mL), carbon tetrabromide (65.4 mg, 197.21 μmol) was added, triphenylphosphine (51.7 mg, 197.11 μmol) was added at 0°C, the reaction was maintained at 0°C for 1.5 hours, and the crude title product 4h was obtained by concentration (40 mg, yield: 48.5%), which was used directly in the next step without purification.

[0626] Step 8

[0627] 4-((1S,3S,5R)-8-((5-cyclopropyl-7-methyl-1-toluenesulfonyl-1H-indol-4-yl)methyl)-3-ethoxy

[0628] -8-Azabicyclo[3.2.1]octan-1-yl)benzoic acid methyl ester 4i

[0629] Compound 3e (40 mg, 138.23 μmol) was dissolved in N, N-dimethylformamide (1 mL), sodium hydride (11 mg, 287.08 μmol, content 60%) was added at 0 ° C, and stirring was continued for 1 hour. A solution of compound 4h (40 mg, 95.61 μmol) dissolved in N, N-dimethylformamide (1 mL) was added, and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (10 mL) was added to quench, and extracted twice with ethyl acetate (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered and concentrated to obtain the crude title product 4i (59 mg), which was directly used in the next step without purification. MS m / z (ESI): 626.9 [M+1].

[0630] Step 9

[0631] 4-((1S,3S,5R)-8-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-3-ethoxy-8-azabicyclo[3.2.1]

[0632] Octane-1-yl)benzoic acid 4

[0633] Compound 4i (59 mg, 94.13 μmol) was dissolved in methanol (1 mL) and water (0.25 mL), potassium hydroxide (27 mg, 481.24 μmol) was added, the mixture was reacted at 60°C overnight, the pH was adjusted to 8-9 with 2M hydrochloric acid solution, concentrated, diluted with methanol, and purified by preparative HPLC (Waters 2545, chromatographic column: Sharpsil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate); mobile phase: acetonitrile; gradient: 36%-43%, flow rate: 30 mL / min) to obtain the title compound 4 (20 mg, yield: 46.3%).

[0634] MS m / z(ESI):459.1[M+1].

[0635] 1 H NMR (500MHz, CD3OD): 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).

[0636] Example 5

[0637] (2S,3S,4S,5R,6S)-6-((4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0638]

[0639]

[0640] first step

[0641] (2S,3S,4S,5R)-3,4,5,6-Tetrahydroxytetrahydro-2H-pyran-2-carboxylic acid allyl ester 5b

[0642] D-glucuronic acid 5a (15 g, 77.26 mmol, Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.) was dissolved in N,N-dimethylformamide (150 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (13 g, 85.39 mmol) was added dropwise at room temperature, and stirred evenly. After cooling in an ice bath for 10 minutes, 3-bromopropylene (11.2 g, 92.58 mmol) was added dropwise, and the reaction was allowed to react at room temperature for 16 hours. 1.5 mL of water was added to quench the reaction, stirred for 5 minutes, and the reaction solution was concentrated. The residue was purified by column chromatography with eluent system E to obtain the title compound 5b (14 g, yield: 77.4%).

[0643] MS m / z(ESI):235.1[M+1].

[0644] Step 2

[0645] (2S,3S,4S,5R)-6-((4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid allyl ester 5c

[0646] Acetonitrile (100 mL) was added to compound 1-1 (5 g, 11.15 mmol) and compound 5b (4.18 g, 17.85 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.09 g, 13.39 mmol) was added, and stirred evenly. N-methylmorpholine (3.95 g, 39.05 mmol) was added dropwise to the reaction solution. After the addition was completed, the reaction was allowed to react at room temperature for 16 hours. Acetic acid (2.68 g, 44.63 mmol) was added to the reaction solution to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to obtain the crude title compound 5c (12.3 g), which was used directly in the next step without purification.

[0647] MS m / z(ESI):665.3[M+1].

[0648] Step 3: (2S,3S,4S,5R,6S)-6-((4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0649] Compound 5c (10.5 g, 15.80 mmol) was dissolved in acetonitrile (85 mL), cooled in an ice bath for 10 minutes, and tetrakis(triphenylphosphine)palladium (3.65 g, 3.16 mmol) and tetrahydropyrrole (1.25 g, 17.58 mmol) were added, and the mixture was reacted in an ice bath for 3 hours. Acetic acid (2.85 g, 47.46 mmol) was added to quench the reaction, and 15 mL of N,N-dimethylformamide was added, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2545, chromatographic column: Welch Xtimate C18, 5 μm, 30 mm*150 mm; mobile phase: water (containing 0.1% formic acid, pH=4.5 adjusted with ammonia water); mobile phase: acetonitrile; gradient: 15%-35%, flow rate: 30 mL / min) to obtain the title compound 5 (2.47 g, yield: 25.0%).

[0650] MS m / z(ESI):625.2[M+1].

[0651] 1 H NMR (500MHz, DMSO-d6): 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),3.5 0-3.52(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).

[0652] Biological evaluation

[0653] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0654] Test Example 1: Inhibitory effect of the disclosed compounds on Factor B enzymatic activity

[0655] 1. Experimental Materials and Instruments

[0656] 1. Recombinant human complement factor B protein (expressed by Nanjing GenScript Biotechnology Co., Ltd.)

[0657] 2. Recombinant human complement factor D protein (1824-SE-010, R&D system)

[0658] 3. Human complement factor C3 (204885-250UGCN, EMDmillipore)

[0659] 4. Cobra venom factor (CVF) (A600, Quidel)

[0660] 5.StartingBlock TM T20 (TBS) blocking buffer (37543, Thermo Fisher)

[0661] 6. Goat anti-mouse IgG heavy chain + light chain (horseradish peroxidase labeled) (ab205719, Abcam)

[0662] 7. Anti-C3a / C3a des Arg antibody clone number

[2991] (ab11873, Abcam)

[0663] 8. QuantaBlu TM Fluorescent peroxidase substrate kit (15169, Thermo Fisher)

[0664] 9. Amphoteric surfactant (CHAPS) (C3023, Sigma)

[0665] 10. Magnesium chloride solution (M1028-100ML, Sigma)

[0666] 11. Sodium carbonate Na2CO3 (10019260, Shanghai trial)

[0667] 12. Sodium bicarbonate NaHCO3 (10018960, Shanghai trial)

[0668] 13. Tween 20 (P7949-500ML, Sigma)

[0669] 14.20X PBS buffer (B548117-0500, Biotech)

[0670] 15.96-well white half-well plate (66PL96025, Cisbio)

[0671] 16.96-well black adsorption plate (437111, Thermo Fisher)

[0672] 17. Phosphate buffer (B320, Shanghai Yuanpei Biotechnology Co., Ltd.)

[0673] 18. Sterile pure water (made by Shanghai Hengrui)

[0674] 19.96-well dispensing plate (3795, Corning)

[0675] 20. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0676] 21.Flexstation3 microplate reader (Molecular Device)

[0677] 2. Experimental steps

[0678] Human complement factor B protein needs to form a complex with human complement factor C3 to play the protease function. Under the hydrolysis of human complement factor D protein, human complement factor B is hydrolyzed into Ba and Bb fragments. Bb forms a complex C3bBb with the C3b fragment of human complement factor C3, i.e., C3 convertase. The formation of this complex allows human complement factor B to play the protease function. C3bBb continues to hydrolyze C3 into C3a and C3b fragments. C3b and C3bBb form a complex C3bBbC3b, i.e., C5 convertase, and the C3a fragment is released. By detecting the C3a des Arg epitope generated after C3 is cleaved, it can be used to evaluate the efficiency of C3 hydrolysis, i.e., C3bBb enzyme activity, so as to evaluate the effect of the compound 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, and its function is the same as C3b.

[0679] The gene encoding the amino acid AA128-2422 of human complement factor B protein (NM_001710.6) was codon-optimized, gene-synthesized, cloned into the pcDNA3.4 vector, and expressed and purified in HD CHO-S cells by Nanjing GenScript Biotechnology Co., Ltd. The purified recombinant human complement factor B protein was stored in a -80°C refrigerator after aliquoting.

[0680] Human complement factor B protein cleavage reaction: dilute the recombinant human complement factor D protein 10 times with PBS (pH 7.4) and store on ice for later use. Add recombinant human complement factor D protein at a final concentration of 300 nM, 1 μM recombinant human complement factor B protein and 1 μM CVF to the reaction buffer (PBS pH 7.4, 10 mM MgCl2, 0.05% CHAPS), mix thoroughly, and react in a 37°C incubator for 3 hours to obtain a complex of CVF and cleaved recombinant human complement factor B protein fragment Bb (hereinafter referred to as CVF:Bb).

[0681] Prepare 100 mM Na2CO3 solution and 100 mM NaHCO3, adjust the pH value to 9.5 according to the volume ratio of Na2CO3:NaHCO3=3:7, and store at room temperature until use.

[0682] The 20 mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 500, 125, 31.25, 7.8125, 0.488281, 0.12207, 0.030518, and 0.007629 μM, with the blank wells containing 100% DMSO, and then diluted 20-fold in C3 reaction buffer (PBS pH 7.4, 1 mM MgCl2, 0.05% CHAPS).

[0683] C3 protein cleavage reaction: In a 96-well white half-well plate, prepare a 10 μL reaction system, that is, add CVF:Bb with a final concentration of 2 nM, 1 μL of the test compound diluted in the C3 reaction buffer and DMSO in C3 reaction buffer (PBS pH7.4, 1 mM MgCl2, 0.05% CHAPS), and incubate at room temperature for 1 hour. The final concentrations of the test compounds are 10000, 2500, 625, 156.25, 39.0625, 9.765625, 2.441406, 0.6103515, and 0.152588 nM. Add human complement factor C3 to the reaction system at a final concentration of 500 nM, mix well, and react in a 37°C incubator for 2 hours. The reaction wells containing only 500 nM human complement factor C3 in the reaction mixture are used as negative controls. 97 μL of carbonate buffer (pH 9.5) was added to a 96-well black adsorption plate, and 3 μL of C3 protein shearing reaction mixture was added to each well. After mixing, the plate was sealed and incubated at 4°C overnight.

[0684] C3a des Arg detection: Wash the plate three times with 300 μL / well TBST (0.05% Tween 20) solution, add 300 μL Starting Block to each well TM T20 (TBS) blocking buffer, incubate at 37°C for 5 minutes; wash the plate 3 times with 300 μL / well PBST solution, dilute anti-C3a / C3a des Arg antibody

[2991] in PBST solution at 1:1000, add 100 μL to each well, and incubate at 37°C for 1 hour; wash the plate 3 times with 300 μL / well PBST solution, dilute goat anti-mouse IgG H&L (GoatAnti-Mouse IgG H&L) (HRP) antibody in PBST solution at 1:5000, add 100 μL to each well, and incubate at 37°C for 30 minutes; prepare QuantaBlu TM Fluorescent peroxidase substrate kit (QuantaBlu TMFluorogenic Peroxidase Substrate Kit) substrate, 1 part of QuantaBlu TM Stable peroxide solution (QuantaBlu TM Stable Peroxide Solution) diluted to 9 parts QuantaBlu TM Substrate solution (QuantaBlu TM Substrate Solution); wash the plate three times with 300 μL / well PBST solution, and dry the plate in the last wash; add 100 μL substrate to each well and incubate at room temperature for 20 minutes; add 100 μL QuantaBlu TM Stop solution (QuantaBlu TM After adding Stop Solution), read the fluorescence value on Flexstation, set the excitation wavelength Ex 320nM, emission wavelength Em 460nM, and Cutoff 455.

[0685] The inhibition rate was calculated using the following formula:

[0686] Inhibition rate = {1-(RFU 受试化合物 -RFU 阴性对照孔 ) / (RFU 空白孔 -RFU 阴性对照孔 )}×100%

[0687] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 value.

[0688] Table 1 IC values ​​of the disclosed compounds measured by their inhibitory effects on Factor B enzyme activity 50 value

[0689] Example No. <![CDATA[IC 50 (nM) <!-- 63 -->]]> 1 4.2 1-1 1.3 1-2 72.2 3 4.9 4 1.6 5 30.0

[0690] Conclusion: The disclosed compounds have a good inhibitory effect on Factor B enzyme activity.

[0691] Test Example 2: Inhibitory effect of the disclosed compounds on the human complement alternative pathway

[0692] 1. Experimental Materials and Instruments

[0693] 1. Zymosan A (Z4250, Sigma)

[0694] 2. Human serum

[0695] 3.StartingBlock TM T20 (TBS) blocking buffer (37543, Thermo Fisher)

[0696] 4. Goat anti-mouse IgG heavy chain + light chain (horseradish peroxidase labeled) (ab205719, Abcam)

[0697] 5. Anti-C5b-9+C5b-8 antibody, clone number [aE11] (ab66768, Abcam)

[0698] 6. QuantaBlu TM Fluorescent peroxidase substrate kit (15169, Thermo Fisher)

[0699] 7. Gelatin, derived from the skin of cold-water fish (G7765, Sigma)

[0700] 8.EDTA (AM9260G, Invitrogen)

[0701] 9.EGTA (E3889-100G, Sigma)

[0702] 10. Magnesium chloride solution (M1028-100ML, Sigma)

[0703] 11. Buffer (HEPES) (H3375-250G, Sigma)

[0704] 12. Calcium chloride (C5670-500G, Sigma)

[0705] 13. Sodium carbonate Na2CO3 (10019260, Shanghai trial)

[0706] 14. Sodium bicarbonate NaHCO3 (10018960, Shanghai trial)

[0707] 15.20X TBS (B548105-0500, Biotech)

[0708] 16. Tween 20 (P7949-500ML, Sigma)

[0709] 17.96-well black adsorption plate (437111, Thermo Fisher)

[0710] 18. Phosphate buffered saline (PBS, pH 7.4) (B320, Shanghai Yuanpei Biotechnology Co., Ltd.)

[0711] 19. Sterile pure water (made by Shanghai Hengrui)

[0712] 20.96-well dispensing plate (3795, Corning)

[0713] 21. Constant temperature box (Shanghai Yiheng Scientific Instrument Co., Ltd.)

[0714] 22.Flexstation3 microplate reader (Molecular Device)

[0715] 2. Experimental steps

[0716] There are three main complement activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. The alternative pathway can be activated by exogenous pathogen molecules such as bacterial cell wall proteins and lipopolysaccharides. A series of complement factors amplify the activation signal cascade through hydrolysis and enzymatic reactions, and finally C5b, C6, C7, C8 and multiple C9 proteins form a membrane attack complex. The alternative pathway can be activated by yeast, and the degree of activation of the alternative pathway can be evaluated by detecting the formation of the C5b-9 complex. Yeast can also activate the classical pathway and the lectin pathway. Since the activation of these two pathways requires the participation of magnesium ions and calcium ions, and the alternative pathway only requires the participation of magnesium ions, after chelation with the calcium ion chelator EGTA, the alternative pathway is not inhibited, while the classical pathway and the lectin pathway are inhibited. After chelation with EDTA, all three pathways are inhibited. Therefore, yeast can be used to activate the alternative pathway of complement in human serum in the presence of EGTA chelator, and the inhibitory effect of small molecule compounds on the alternative pathway can be evaluated by detecting the formation of the C5b-9 complex.

[0717] Zymosan A powder was resuspended in TBS solution to 10 mg / mL and activated by heating at 100°C for 2 hours. After activation, centrifugation was performed at 4000 rpm for 30 minutes, the supernatant was discarded, and the suspension was resuspended in TBS to 50 mg / mL, and stored in a refrigerator at -20°C after aliquoting. The day before the experiment, the activated Zymosan A solution was diluted to 1 mg / mL with carbonate buffer (pH 9.5), 100 μL was added to each well of a 96-well black adsorption plate, and coated overnight at 4°C.

[0718] Prepare 100 mM Na2CO3 solution and 100 mM NaHCO3, adjust the pH value to 9.5 according to the volume ratio of Na2CO3:NaHCO3=3:7, and store at room temperature until use.

[0719] Complement alternative pathway activation reaction: Dilute human serum 5-fold with PBS solution to 20% serum solution and place on ice for use. 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 500, 125, 31.25, 7.8125, 0.488281, 0.12207, 0.030518, 0.007629μM, blank wells were 100% DMSO, and then diluted 20-fold in 2XEGTA reaction buffer (4.2mM HEPES, 0.15mM CaCl2, 140mM NaCl, 4.5mM MgCl2, 0.1% gelatin, 20mM EGTA). At the same time, 100% DMSO was diluted 20 times in 2X EDTA reaction buffer (4.2mM HEPES, 0.15mM CaCl2, 140mM NaCl, 4.5mM MgCl2, 0.1% gelatin, 20mM EDTA) as a negative control well. Prepare 40μL serum-EGTA reaction solution, that is, 20μL 20% human serum, 4μL of the test compound or DMSO diluted in 2X EGTA reaction buffer, 16μL 2X EGTA reaction buffer, mix well, serum-EGTA-DMSO as a blank control, and incubate at room temperature for 30 minutes. Prepare 40μL serum-EDTA reaction solution for the negative control well, that is, 20μL 20% human serum, 4μL of the DMSO diluted in 2X EDTA reaction buffer, 16μL 2X EDTA reaction buffer, mix well, and incubate at room temperature for 30 minutes. One day in advance, a 96-well black adsorption plate coated with Zymosan A was washed three times with 300 μL / well TBST (0.05% Tween 20) solution, and 25 μL serum-EGTA-test compound reaction solution, blank control well, serum-EDTA-DMSO reaction solution (negative control well) were added to each well, and reacted at 37°C for 40 minutes. The plate was washed three times with 300 μL / well TBST solution, and 300 μL StartingBlock TM T20 (TBS) blocking buffer, incubate at 37°C for 15 minutes; wash the plate 3 times with 300 μL / well TBST solution, dilute anti-C5b-9+C5b-8 antibody [aE11] at 1:5000 in TBST solution, add 100 μL to each well, and incubate at 37°C for 1 hour; wash the plate 3 times with 300 μL / well TBST solution, dilute goat anti-mouse IgG H&L (HRP) antibody at 1:5000 in TBST solution, add 100 μL to each well, and incubate at 37°C for 30 minutes; prepare QuantaBlu TM Fluorescent Peroxidase Substrate Kit Substrate, 1 part QuantaBlu TM Stabilized peroxide solution diluted to 9 parts QuantaBlu TMSubstrate solution; wash the plate 3 times with 300 μL / well TBST solution, and dry the plate in the last wash; add 100 μL substrate to each well and incubate at room temperature for 20 minutes; add 100 μL QuantaBlu TM After stopping the solution, read the fluorescence value on Flexstation 3, set the excitation wavelength Ex 320nM, emission wavelength Em 460nM, and Cutoff 455.

[0720] The inhibition rate was calculated using the following formula:

[0721] Inhibition rate = {1-(RFU 受试化合物 -RFU 阴性对照孔 ) / (RFU 空白孔 -RFU 阴性对照孔 )}×100%

[0722] The inhibition curve was drawn based on the concentrations of the compounds and the corresponding inhibition rates using Graphpad Prism software, and the concentration of the compound when the inhibition rate reached 50%, i.e., IC 50 value.

[0723] Table 2 IC values ​​of the compounds disclosed herein measured by the human complement alternative pathway 50 value

[0724] Example No. <![CDATA[IC 50 (nM)]]> 1 43.2 1-1 27.0 3 49.8 4 50.6 5 74.6

[0725] Conclusion: The disclosed compounds have a good inhibitory effect on the human complement alternative pathway.

[0726] Test Example 3: Therapeutic effect of the disclosed compound on Heymann nephritis in rats

[0727] 1 Summary

[0728] In this experiment, male SD rats were used 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.

[0729]

[0730] 2 Experimental methods and materials

[0731] 2.1 Experimental animals and housing conditions

[0732] Experimental animals: Male SD rats were provided by Weitonglihua Experimental Animal Co., Ltd. (production license number: SCXK (Zhejiang) 2019-0001, animal certificate number: 20210401Abzz0619000322, 180-200 g when purchased).

[0733] Animals were kept in cages of 5 animals each, with a 12 / 12-hour light / dark cycle, a constant temperature of 23±1°C, and a humidity of 50-60%. Animals were allowed to eat and drink freely. The experiment was started after the animals were adapted for one week.

[0734] 2.2 Experimental reagents and instruments

[0735] Positive drug LNP023: molecular weight 422.5, purity 99.9%.

[0736] Example 1-1 compound: molecular weight 448.55, purity 99.9%.

[0737] Tween 80: Sinopharm Chemical Reagent Co., Ltd., catalog number 30189828, batch number 20180104.

[0738] Methylcellulose M450: Sinopharm Chemical Reagent Co., Ltd., catalog number 69016460, batch number 20170308.

[0739] Normal goat serum: Sangon biotech, batch number GB02FC0260.

[0740] Sheep anti-rat Fx1A serum: PROBETEX, product number PTX-002S, batch number 376-4T.

[0741] Rat iC3b-ELISA detection kit: MYBioSource, catalog number MBS 7255121, batch number 20210301C.

[0742] Rat C3d-ELISA detection kit: MYBioSource, catalog number MBS 7244846, batch number 20210301C.

[0743] Total protein urine / cerebrospinal fluid (TPUC) kit: Shenzhen Mindray Biomedical, catalog number 105-008805-00, batch number 147920004.

[0744] Creatinine test kit: Shenzhen Mindray Bio-Medical, item number 105-000457-00, batch number 141120024.

[0745] Urine microalbumin (MALB) (including calibrator): Shenzhen Mindray Bio-Medical, item number 105-009325-00, batch number 046020011.

[0746] Urine microalbumin control product: Shenzhen Mindray Bio-Medical, item number 105-002957-00, batch number 053120008.

[0747] Urine / cerebrospinal fluid total protein (TPUC) quality control product: Shenzhen Mindray Biomedical, product number 105-008841-00, batch number 060520005.

[0748] Biochemical composite quality control product (quality 1): Shenzhen Mindray Biomedical, item number 105-007316-00, batch number 059320002.

[0749] Biochemical composite quality control product (quality 2): Shenzhen Mindray Biomedical, item number 105-007317-00, batch number 059419004.

[0750] Fully automatic blood biochemical analyzer: manufacturer: Mindray Biomedical, model SB380.

[0751] Microplate reader: manufacturer: BMGlabtech, model: PHERAstar Fs.

[0752] Tabletop low-speed centrifuge: manufacturer: Eppendorf, model 5417R.

[0753] Electronic balance: Mettler-Toledo Instrument Co., Ltd., model AL204.

[0754] 2.3 Experimental design and methods

[0755] 2.3.1 Animal grouping

[0756] After adaptive feeding, male SD rats were divided into the following groups according to urine total protein and body weight 2 days before the experiment:

[0757]

[0758] Note: Solvent group: 0.5% methylcellulose M450 suspension (containing 0.5% Tween 80); iv: intravenous.

[0759] 2.3.2 Drug preparation method

[0760] Preparation of positive drug LNP023 (20 mg / kg): weigh 600 mg + 1.5 mL Tween 80 + 298.5 mL methylcellulose M450.

[0761] Preparation of positive drug LNP023 (60 mg / kg): weigh 1800 mg + 1.5 mL Tween 80 + 298.5 mL methylcellulose M450, prepare 3 times in total.

[0762] Preparation of Example 1-1 compound (10 mg / kg): weigh 300 mg + 1.5 mL Tween 80 + 298.5 mL methylcellulose M450.

[0763] Preparation of Example 1-1 compound (30 mg / kg): weigh 900 mg + 1.5 mL Tween 80 + 298.5 mL methylcellulose M450.

[0764] Preparation of Example 1-1 compound (90 mg / kg): weigh 2700 mg + 1.5 mL Tween 80 + 298.5 mL methylcellulose M450.

[0765] Prepare 600 mL of solvent: 3 mL of Tween 80 + 597 mL of methyl cellulose M450, mix well, and prepare 3 times in total.

[0766] 2.3.3 Experimental methods

[0767] Male SD rats were randomly divided into 7 groups according to urine protein and body weight: normal group, model group, LNP023 group (20 mg / kg, 60 mg / kg, oral, twice a day), Example 1-1 group (10 mg / kg, 30 mg / kg, 90 mg / kg, oral, twice a day). On the 0th day of the experiment, the model group and the drug group were injected with Fx1A serum (5 mL / kg) by tail vein, and the normal group was injected with normal sheep serum by tail vein. The drug group was gavaged with positive drug LNP023 and Example 1-1 compound (10 mL / kg) on ​​the 6th day of the experiment, and the normal group and the model group were gavaged with the corresponding solvent until the end of the experiment on the 15th day. 2-hour urine was collected on the 2nd, 4th, 6th, 8th, 11th, and 14th days to detect urine creatinine and total protein; serum was collected on the 15th day for complement activation fragment (C3d+iC3b) analysis.

[0768] Inhibition rate = 100% × (model group - drug administration group) / (model group - normal group)

[0769] 2.4 Data presentation and statistical processing

[0770] Experimental data are expressed as mean ± standard error (SEM). Statistical comparison was performed using Excel software t test. The data of the model group and the blank control group were analyzed and compared to determine whether there was significant mathematical statistical significance. *P<0.05 indicated that there was a significant difference between the model group and the blank control group, **P<0.01 indicated that there was a highly significant difference between the model group and the blank control group, and ***P<0.001 indicated that there was an extremely highly significant difference between the model group and the blank control group. #P<0.05 indicated that there was a significant difference between the drug administration group and the model group, ##P<0.01 indicated that there was a highly significant difference between the drug administration group and the model group, and ###P<0.001 indicated that there was an extremely highly significant difference between the drug administration group and the model group.

[0771] 3 Experimental results

[0772] Effects of Example 1-1 Compound and positive drug LNP023 on serum iC3b+C3d in rats with passive Heymann nephritis Figure 1 . Figure 1 The results of serum iC3b+C3d showed that compared with the normal group, the serum iC3b+C3d of rats in the model group was statistically increased (P<0.001); compared with the model group, the serum iC3b+C3d of rats in the 20mg / kg and 60mg / kg LNP023 groups was significantly decreased, with decreases of 62.2% (P<0.01) and 68.8% (P<0.001), respectively; compared with the model group, the serum iC3b+C3d of rats in the Example 1-1 groups at 10mg / kg, 30mg / kg, and 90mg / kg was significantly decreased, with decreases of 76.2% (P<0.001), 105.5% (P<0.001), and 108.7% (P<0.001), respectively.

[0773] Effects of Example 1-1 Compound and Positive Drug LNP023 on Urine Protein / Creatinine in Rats with Passive Heymann Nephritis Figure 2 and Figure 3 . Figure 2 and Figure 3The results showed that compared with the normal group, the urine total protein / urine creatinine ratio of the model group rats continued to increase with the extension of time, and began to increase statistically on the 6th day and continued to increase; compared with the model group, the urine total protein / urine creatinine ratio of the rats in the 20mg / kg and 60mg / kg LNP023 groups began to decrease statistically on the 11th day, and the decreases on the 14th day were 56.4% (P<0.01) and 47.1% (P<0.05), respectively, with no obvious dose-dependency; the urine total protein / urine creatinine ratio of the rats in the Example 1-1 group of 10mg / kg, 30mg / kg, and 90mg / kg decreased significantly, and the high dose began to decrease statistically on the 8th day, and the low and medium dose groups began to decrease statistically from the 11th day. The decreases in the three dose groups on the 14th day were 48.1% (P<0.05), 70.9% (P<0.001), and 77.2% (P<0.001), respectively, with an obvious dose-dependency.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: 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 an aryl group or a heteroaryl group; R, R a and R b are the same or different and are each independently selected from a hydrogen atom, an alkyl group and a haloalkyl group; Each R 1 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 3 , R 3a , R 3b and R 3c are the same or different and are each 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 group, a cyano group, a -NR x R y and hydroxyl; wherein the alkyl group is optionally substituted with one or more cyano groups or amino groups; Each R 4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, a cyano group, a -NR 8 R 9 , hydroxyl, -C(O)R 10 、-CH2C(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 group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; R 5 are the same or different at each occurrence and are each independently selected from hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxy; R 10 are the same or different at each occurrence and are each independently selected from a hydrogen atom, -OR 11 , alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxyl; R 11 is selected from hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, cyano, -OR 12 and -C(O)OR 12 is substituted by one or more substituents; R 12 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxyl; 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, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl and hydroxyalkyl; or R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R x and R y Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, or R 8 and R 9 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein each occurrence of the heterocyclic group is the same or different and each is independently optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; m is 0, 1 or 2; n is 0, 1, 2 or 3; s is 0, 1, 2, 3, or 4; t is 0, 1, 2, 3 or 4; and p is 0, 1 or 2.

2. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein, The alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano and hydroxy.

3. The compound represented by the general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Y is -CR 3a R 3b -; R 3a and R 3b As defined in claim 1.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in: Ring A, X, R 1 To R 3 , R 3b , R 4 , m, n, s and t are as defined in claim 1.

5. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 A hydrogen atom. 6 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 1 and n is 2.

7. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof: in: 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring A, X, R 1 , R 3b , R 4 To R 7 , p and t are as defined in claim 1.

8. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R 4 are the same or different and are each independently selected from a hydrogen atom, a 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 As defined in claim 1.

9. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof: in: R 10 Selected from hydroxyl, Preferably, R 10 is hydroxyl group; t is 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 group, a cyano group, a -NR 6 R 7 , hydroxyl, -C(O)R 5 、-CH2C(O)R 5 、-OCH2C(O)R 5 、-CH2NHC(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 substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring A, X, R 1 , R 3b , R 4 To R 7 and p is as defined in claim 1. 10 . The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 , wherein X is a chemical bond.

11. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group.

12. A compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and cyano.

13. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein each R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen, cyano, amino, hydroxy, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl.

14. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 3b Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

15. A compound represented by general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

16. A compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof: in: R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl; R 10 is an alkoxy group; preferably, R 10 C 1-6 Alkoxy; More preferably, R 10 is methoxy; t is 1 or 2; Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in claim 9.

17. A compound or a pharmaceutically acceptable salt thereof selected from the following compounds:

18. 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 C 1-6 The compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof is deprotected by removing the protecting group R w and undergo hydrolysis to obtain R 10 A compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein the compound is a hydroxyl group, in: R w is an amino protecting group; preferably, R w is tert-butyloxycarbonyl or p-toluenesulfonyl; more preferably, R w is tert-butyloxycarbonyl; t is 1 or 2; Ring A, X, R 1 , R 2a , R 2b , R 3b and R 4 As defined in claim 9.

19. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting activation of the complement alternative pathway, preferably in the preparation of a medicament for inhibiting complement factor B.

21. Use of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by activation of the complement alternative pathway; preferably in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by complement factor B, wherein the disease or disorder is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, map atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behcet's syndrome, multifocal choroiditis, Fuku-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, complications of hemodialysis, hyperacute allogeneic Allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorder, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration The invention relates to a method for treating and / or preventing pulmonary embolism, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodman syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome and obesity; more preferably, the method is used for preparing a medicament for treating and / or preventing C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

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