Pharmaceutically acceptable salts, crystal forms of nitrogen-containing crosslinked heterocyclic derivatives, and methods for preparing the same

Abstract

The present disclosure relates to pharmaceutically acceptable salts, crystal forms of nitrogen-containing bridged heterocyclic derivatives, and methods for preparing the same. Specifically, different salt forms, crystal forms of salts, and methods for preparing the same of 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 are provided. The crystal forms of the salts of 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 provided have good stability and are more applicable to clinical treatment.

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application No. 2022107702298, filed on Jun. 30, 2022. The full text of the above Chinese patent application is incorporated herein by reference.

[0002] (Technical Field) The present disclosure belongs to the pharmaceutical field and relates to pharmaceutically acceptable salts and crystalline forms of nitrogen-containing bridged heterocyclic derivatives. Specifically, it relates to pharmaceutically acceptable salts of 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, and their crystalline forms and preparation methods.

Background Art

[0003] Complement is a serum protein present in the sera and tissue fluids of humans and vertebrates. It is heat-labile, exhibits enzymatic activity after activation, can mediate immune responses and inflammatory reactions, is activated by antigen-antibody complexes or microorganisms, and can cause pathogenic microorganisms to be lysed or phagocytosed.

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

[0005] The complement system is activated by three independent and intersecting pathways: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP, also known as the mannan-binding lectin pathway). During the activation process, complement exerts powerful biological effects through a series of positive feedbacks and is involved in the occurrence and progression of diseases. C3 convertase is an important component of the above three pathways and produces a series of complement protein fragments and membrane attack complex (MAC) through the complement activation cascade reaction. C3 convertase cleaves C3 to generate C5 convertase, then cleaves C5 to generate C5a and C5b, and C5b binds to C6, C7, C8, and C9 to form C5b-9, that is, MAC. Abnormalities in the complement pathway can cause lysis of normal cells specific to the organism and lead to the occurrence of diseases.

[0006] Complement factor B is a heat-labile β-globulin that is inactivated at 50°C for 30 minutes. It can be cleaved by complement factor D into two fragments, Ba and Bb, and Bb binds to C3b to form the C3 convertase of the alternative pathway. Complement factor B is one of the important components in the alternative pathway activation of complement and is also called the C3 activator precursor. Complement factor B has a molecular weight of 93 kDa, a human blood concentration of about 3 μM, and is mainly synthesized in the liver, but it has also been found to be synthesized in retinal pigment epithelial cells of the eye.

[0007] Glomerulopathy includes immunoglobulin A nephropathy (abbreviated as IgA Nephropathy, IgAN), C3 glomerulopathy (abbreviated as C3G Glomerulopathy, C3G), membranous glomerulonephritis (abbreviated as 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 10 years. According to research, glomerulopathy is closely related to the complement pathway, especially the complement alternative pathway. Currently, there is a lack of clinically effective treatment methods for primary glomerulonephritis. As drug treatments, hormones and immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and the traditional Chinese medicine tripterygium glycoside) are often used. In addition, it includes blood pressure regulators, diuretics, antiplatelet aggregation drugs, anticoagulants, lipid-lowering drugs, and kidney-protecting and detoxifying drugs such as cordyceps preparations.

[0008] IgAN is the most common primary glomerular disease worldwide. As pathological findings, it is characterized by diffuse IgA protein deposition in the mesangial region, and always accompanied by IgG, C3, and C5b-9 deposition, with local mesangial proliferation and matrix increase. Therefore, the complement pathway is considered to be involved in the occurrence and progression of IgAN. Currently, two small molecule drugs targeting the complement pathway are in 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 II clinical trial of OMS721, the proteinuria indices of the 4 IgAN patients who participated in the trial were all significantly improved. Currently, this drug is in a Phase III clinical study.

[0009] Patent applications for the currently disclosed Factor B inhibitors include WO2015009616A1, WO2019043609A1, and WO2020016749A2, etc. The application WO2022143845 structurally characterizes a series of nitrogen-containing heterocyclic derivatives including 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. Further, as a result of the biological evaluation of 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 (Compound I) in this application, it was shown that the compound has a good inhibitory effect on Factor B enzyme activity.

[0010] The crystal structure of a pharmaceutically active ingredient tends to affect the chemical stability of the drug. Depending on the crystallization conditions and storage conditions, it may change the crystal structure of the compound and may also be accompanied by the formation of other crystal forms. Generally, amorphous pharmaceutical products do not have a regular crystal structure and tend to have other defects such as poor product stability, fine precipitated crystals that are difficult to filter, easy caking, and poor fluidity. Therefore, since it is necessary to improve various properties of the above products, in order to find a crystal form with high purity and good physical and chemical stability, in-depth research must be carried out.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0012] The present disclosure provides salts of Factor B inhibitors, crystal forms of the salts, and methods for their preparation and use.

Means for Solving the Problems

[0013] The present disclosure provides pharmaceutically acceptable salts of Compound I, which is a Factor B inhibitor with the chemical name 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, and the pharmaceutically acceptable salts are selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, mesylate, and hydrobromide.

[0014] In some embodiments, the pharmaceutically acceptable salt of Compound I is 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-fumarate.

[0015] In some embodiments, the pharmaceutically acceptable salt of Compound I is 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-p-toluenesulfonate.

[0016] In some embodiments, the pharmaceutically acceptable salt of Compound I is 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-hydrochloride.

[0017] In some embodiments, the pharmaceutically acceptable salt of Compound I is 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-phosphate.

[0018] The present disclosure provides a method for preparing a pharmaceutically acceptable salt of Compound I, comprising reacting 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 with an acid selected from maleic acid, phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, fumaric acid, tartaric acid, succinic acid, citric acid, malic acid, methanesulfonic acid, and hydrobromic acid.

[0019] In some embodiments, the present disclosure provides a maleate I crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 6.7, 7.6, 8.6, 11.0, 12.1, and 16.2, optionally having characteristic peaks at 6.7, 7.6, 8.1, 8.6, 11.0, 12.1, 16.2, 19.7, and 23.5, and optionally having characteristic peaks at 6.7, 7.6, 8.1, 8.6, 9.3, 11.0, 12.1, 13.5, 16.2, 17.9, 19.7, and 23.5.

[0020] In some embodiments, the present disclosure provides a phosphate I crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 8.4, 10.3, 11.7, 14.8, 19.2, and 21.8, optionally having characteristic peaks at 8.4, 10.3, 11.7, 12.5, 14.8, 19.2, 19.8, 21.8, and 23.9, and optionally having characteristic peaks at 7.0, 8.4, 9.3, 10.3, 11.7, 12.5, 14.8, 17.4, 19.2, 19.8, 21.8, and 23.9.

[0021] In some embodiments, the present disclosure provides a phosphate II crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 8.4, 9.5, 10.2, 11.7, 14.7 and 19.1, optionally having characteristic peaks at 6.9, 8.4, 9.5, 10.2, 10.7, 11.7, 14.7, 18.5 and 19.1, and optionally having characteristic peaks at 6.9, 8.4, 8.8, 9.5, 10.2, 10.7, 11.7, 14.7, 15.7, 18.5, 19.1 and 19.8.

[0022] In some embodiments, the present disclosure provides a phosphate III crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 18.5 and 21.3, optionally having characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 21.3 and 24.1, and optionally having characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 20.8, 21.3, 22.9, 24.1 and 25.3.

[0023] In some embodiments, the present disclosure provides a phosphate IV crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 6.9, 8.4, 10.3, 11.7 and 14.8.

[0024] In some embodiments, the present disclosure provides a phosphate V crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 9.1, 10.2, 11.5, 15.7 and 19.8, optionally having characteristic peaks at 8.6, 9.1, 10.2, 11.5, 15.7, 18.0, 19.8 and 23.5.

[0025] In some embodiments, the present disclosure provides a p-toluenesulfonate I crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at the diffraction angle 2θ has characteristic peaks at 5.0, 9.4, 10.1, 16.3 and 18.3, and optionally has characteristic peaks at 5.0, 9.4, 10.1, 16.3, 18.3, 18.9, 21.2 and 22.9, and optionally has characteristic peaks at 5.0, 9.4, 10.1, 16.0, 16.3, 17.1, 18.3, 18.9, 21.2, 22.9 and 24.0.

[0026] In some embodiments, the present disclosure provides a p-toluenesulfonate II crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at the diffraction angle 2θ has characteristic peaks at 4.7, 8.8, 9.3, 10.8, 13.9 and 18.7, and optionally has characteristic peaks at 4.7, 8.8, 9.3, 9.7, 10.8, 13.9, 17.7 and 18.7.

[0027] In some embodiments, the present disclosure provides a p-toluenesulfonate III crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at the diffraction angle 2θ has characteristic peaks at 6.8, 7.4, 8.1, 10.1 and 12.7.

[0028] In some embodiments, the present disclosure provides a sulfate I crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at the diffraction angle 2θ has characteristic peaks at 7.2, 9.2, 17.1, 20.0, 21.4 and 24.7, and optionally has characteristic peaks at 6.7, 7.2, 9.2, 17.1, 18.7, 20.0, 21.4, 22.9 and 24.7.

[0029] In some embodiments, the present disclosure provides a sulfate II crystal form of Compound I, wherein the powder X-ray diffraction pattern shown at the diffraction angle 2θ has characteristic peaks at 9.5, 10.2, 16.6, 21.2 and 25.7, and optionally has characteristic peaks at 6.3, 8.5, 9.5, 10.2, 16.6, 19.8, 21.2, 23.7 and 25.7.

[0030] In some embodiments, the present disclosure provides a sulfate III crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 6.9, 7.6, 9.1, 18.2 and 23.7, and optionally has characteristic peaks at 6.9, 7.6, 9.1, 17.0, 18.2, 20.7, 23.7 and 24.0.

[0031] In some embodiments, the present disclosure provides a sulfate IV crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 6.9, 12.5, 16.5, 19.4, 21.2 and 24.0, and optionally has characteristic peaks at 6.9, 9.7, 12.5, 16.5, 19.4, 21.2, 24.0 and 25.8.

[0032] In some embodiments, the present disclosure provides a sulfate V crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 7.6, 11.4, 13.5, 17.2, 18.8 and 19.5, and optionally has characteristic peaks at 7.6, 10.0, 11.4, 13.5, 14.0, 17.2, 19.5, 22.5 and 24.6.

[0033] In some embodiments, the present disclosure provides a sulfate VI crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 6.7, 8.8, 14.6, 15.9 and 23.7, and optionally has characteristic peaks at 6.7, 8.8, 10.6, 14.6, 15.9, 19.5, 21.4 and 23.7.

[0034] In some embodiments, the present disclosure provides a hydrochloride I crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 5.8, 8.8, 11.6, 20.7 and 23.4, and optionally has characteristic peaks at 5.8, 8.8, 9.8, 10.5, 11.6, 14.6, 18.4, 20.7 and 23.4.

[0035] In some embodiments, the present disclosure provides a hydrochloride II crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 5.9, 8.8, 10.6, 17.2, 19.3 and 23.9, and optionally has characteristic peaks at 5.9, 8.8, 10.6, 13.2, 17.2, 19.3, 21.3, 23.9, 24.4 and 26.1, and optionally has characteristic peaks at 5.9, 8.8, 10.6, 11.9, 13.2, 14.7, 17.2, 19.3, 19.9, 21.3, 23.9, 24.4, 26.1 and 27.4.

[0036] In some embodiments, the present disclosure provides a hydrochloride III crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 6.1, 8.8, 10.4, 18.4, 19.9 and 24.6, and optionally has characteristic peaks at 6.1, 8.8, 10.4, 12.2, 18.4, 19.9, 22.6, 24.6 and 28.0, and optionally has characteristic peaks at 6.1, 8.8, 10.4, 12.2, 14.6, 16.6, 17.8, 18.4, 19.9, 22.6, 24.6, 27.2 and 28.0.

[0037] In some embodiments, the present disclosure provides a hydrochloride IV crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 5.4, 9.0, 10.8, 20.4 and 21.8, and optionally has characteristic peaks at 5.4, 9.0, 10.8, 19.3, 20.4, 21.8 and 27.3. In some embodiments, the present disclosure provides a hydrochloride V crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 5.2, 6.7, 7.7, 10.2 and 17.4, and optionally has characteristic peaks at 5.2, 6.7, 7.7, 10.2, 10.8, 17.4, 20.5 and 24.2.

[0038] In some embodiments, the present disclosure provides a hydrochloride VI crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 5.8, 10.3, 11.7, 17.7, 20.7 and 23.7.

[0039] In some embodiments, the present disclosure provides a fumarate I crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8 and 26.1, and optionally has characteristic peaks at 6.1, 9.6, 10.0, 14.0, 16.7, 17.2, 19.1, 19.6, 25.8 and 26.1, and optionally has characteristic peaks at 6.1, 9.6, 10.0, 10.8, 14.0, 16.7, 17.2, 18.6, 19.1, 19.6, 20.2, 25.8 and 26.1.

[0040] In some embodiments, the present disclosure provides a fumarate II crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 6.2, 6.6, 8.0, 13.2, 14.0, 20.3 and 24.2, and optionally has characteristic peaks at 6.2, 6.6, 8.0, 9.0, 13.2, 14.0, 16.4, 17.1, 19.8, 20.3, 24.2 and 25.3, and optionally has characteristic peaks at 6.2, 6.6, 8.0, 9.0, 12.0, 13.2, 14.0, 16.4, 17.1, 19.3, 19.8, 20.3, 21.9, 22.3, 24.2, 25.3, 25.7 and 28.1.

[0041] In some embodiments, the present disclosure provides a hydrobromide I crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 7.6, 10.6, 16.4, 18.4, 22.6 and 24.0, and optionally has characteristic peaks at 7.6, 10.6, 15.3, 16.4, 18.4, 19.6, 22.6, 24.0, 26.5 and 27.0, and optionally has characteristic peaks at 7.6, 10.6, 15.3, 16.4, 18.4, 19.6, 21.4, 22.6, 24.0, 25.5, 26.5, 27.0 and 28.9.

[0042] In some embodiments, the present disclosure provides a hydrobromide II crystalline form of Compound I, wherein the powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 7.2, 10.5, 16.5, 22.5, 23.4, and 26.6, and optionally has characteristic peaks at 7.2, 10.5, 13.1, 16.5, 18.8, 20.3, 22.5, 23.4, and 26.6, and optionally has characteristic peaks at 7.2, 10.5, 13.1, 16.5, 17.2, 18.8, 20.3, 21.5, 21.9, 22.5, 23.4, and 26.6.

[0043] In some embodiments, the present disclosure provides an amorphous maleate of Compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern has no obvious characteristic peaks within the range of 3° to 48°.

[0044] In some embodiments, the present disclosure provides an amorphous phosphate of Compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern has no obvious characteristic peaks within the range of 3° to 48°.

[0045] In some embodiments, the present disclosure provides an amorphous p-toluenesulfonate of Compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern has no obvious characteristic peaks within the range of 3° to 48°.

[0046] In some embodiments, the present disclosure provides an amorphous sulfate of Compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern has no obvious characteristic peaks within the range of 3° to 48°.

[0047] In some embodiments, the present disclosure provides an amorphous tartrate of Compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern has no obvious characteristic peaks within the range of 3° to 48°.

[0048] In some embodiments, the present disclosure provides a succinate amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0049] In some embodiments, the present disclosure provides a fumarate amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0050] In some embodiments, the present disclosure provides a citrate amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0051] In some embodiments, the present disclosure provides a malate amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0052] In some embodiments, the present disclosure provides a hydrobromide amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0053] In some embodiments, the present disclosure provides a mesylate amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0054] In some embodiments, the present disclosure provides a hydrochloride amorphous of Compound I that has no distinct characteristic peaks within the range of diffraction angle 2θ of 3° to 48° in the powder X-ray diffraction pattern.

[0055] In an alternative embodiment, a crystalline form of a pharmaceutically acceptable salt of Compound I provided by the present disclosure, wherein the error range of the 2θ angle is ±0.2.

[0056] In another aspect, the present disclosure provides a method for preparing the maleate I crystal form of Compound I, comprising: a. dissolving Compound I in acetonitrile, adding a maleic acid solution and slurrying; and b. adding isopropyl ether and crystallizing.

[0057] The present disclosure provides a method for preparing the phosphate I crystal form of Compound I, comprising adding Compound I to a solvent (1) selected from acetonitrile and acetone and phosphoric acid, and stirring to crystallize.

[0058] The present disclosure provides a method for preparing the phosphate II crystal form of Compound I, comprising adding Compound I to a solvent (2) selected from ethyl acetate and acetone and phosphoric acid, and stirring to crystallize.

[0059] The present disclosure provides a method for preparing the phosphate III crystal form of Compound I, comprising adding Compound I to a solvent (3) selected from isopropanol and ethanol and phosphoric acid, and stirring to crystallize.

[0060] The present disclosure provides a method for preparing the phosphate IV crystal form of Compound I, comprising adding Compound I to acetonitrile and phosphoric acid, and stirring to crystallize.

[0061] The present disclosure provides a method for preparing the phosphate V crystal form of Compound I, comprising adding Compound I to ethanol and phosphoric acid, and stirring to crystallize.

[0062] The present disclosure provides a method for preparing the p-toluenesulfonate I crystal form of Compound I, comprising Method 1: adding Compound I to a solvent (4) selected from ethanol, isopropanol and ethyl acetate and p-toluenesulfonic acid, slurrying at room temperature, adding isopropyl ether and stirring to crystallize; and Method 2: adding Compound I to acetonitrile and p-toluenesulfonic acid, and stirring to crystallize.

[0063] The present disclosure provides a method for preparing the p-toluenesulfonate II crystal form of Compound I, which includes adding Compound I to isopropanol and p-toluenesulfonic acid, and stirring to crystallize.

[0064] The present disclosure provides a method for preparing the p-toluenesulfonate III crystal form of Compound I, which includes adding the p-toluenesulfonate II crystal form to methyl tert-butyl ether, and stirring to crystallize.

[0065] The present disclosure provides a method for preparing the sulfate I crystal form of Compound I, which includes adding Compound I to a solvent (5) selected from ethanol and acetonitrile and sulfuric acid, and stirring to crystallize.

[0066] The present disclosure provides a method for preparing the sulfate II crystal form of Compound I, which includes adding Compound I to acetone and sulfuric acid, and stirring to crystallize.

[0067] The present disclosure provides a method for preparing the sulfate III crystal form of Compound I, which includes dissolving Compound I in ethanol, adding sulfuric acid, adding isopropyl ether, and stirring to crystallize.

[0068] The present disclosure provides a method for preparing the sulfate IV crystal form of Compound I, which includes adding Compound I to a solvent (6) selected from isopropanol and acetone and sulfuric acid, and stirring to crystallize.

[0069] The present disclosure provides a method for preparing the sulfate V crystal form of Compound I, which includes adding Compound I to a solvent (7) selected from ethyl acetate and isopropyl acetate and sulfuric acid, and stirring to crystallize.

[0070] The present disclosure provides a method for preparing the sulfate VI crystal form of Compound I, which includes adding the sulfate I crystal form to isopropyl acetate, and stirring to crystallize.

[0071] The present disclosure provides a method for preparing crystalline form I hydrochloride of Compound I, including Method 1: dissolving Compound I in ethanol, adding hydrochloric acid, adding isopropyl ether, stirring, and crystallizing; and Method 2: adding Compound I to isopropyl acetate and hydrochloric acid, stirring, and crystallizing.

[0072] The present disclosure provides a method for preparing crystalline form II hydrochloride of Compound I, including Method 1: dissolving Compound I in ethanol, adding hydrochloric acid, adding isopropyl ether, stirring, and crystallizing; and Method 2: adding Compound I to a solvent (8) selected from isopropanol and acetonitrile and hydrochloric acid, stirring, and crystallizing.

[0073] The present disclosure provides a method for preparing crystalline form III hydrochloride of Compound I, including adding Compound I to a solvent (9) selected from acetone and ethyl acetate and hydrochloric acid, and stirring to crystallize.

[0074] The present disclosure provides a method for preparing crystalline form IV hydrochloride of Compound I, including adding Compound I to a solvent (10) selected from tetrahydrofuran and isopropanol and hydrochloric acid, and stirring to crystallize.

[0075] The present disclosure provides a method for preparing crystalline form V hydrochloride of Compound I, including adding Compound I to acetonitrile and hydrochloric acid, and stirring to crystallize.

[0076] The present disclosure provides a method for preparing crystalline form VI hydrochloride of Compound I, including adding Compound I to isopropanol and hydrochloric acid, and stirring to crystallize.

[0077] The present disclosure provides a method for preparing crystalline form I fumarate of Compound I, including adding Compound I to a solvent (11) selected from acetonitrile and acetone and fumaric acid, and stirring to crystallize.

[0078] The present disclosure provides a method for preparing crystalline form II fumarate of Compound I, including adding Compound I to a methanol / acetonitrile solution and fumaric acid, and volatilizing to crystallize.

[0079] The present disclosure provides a method for preparing the hydrobromide salt I crystal form of Compound I, which includes dissolving Compound I in ethanol, adding hydrobromic acid, adding isopropyl ether, stirring, and crystallizing.

[0080] The present disclosure provides a method for preparing the hydrobromide salt II crystal form of Compound I, which includes adding Compound I to a solvent (12) selected from isopropanol and ethyl acetate and hydrobromic acid, stirring, and crystallizing.

[0081] The present disclosure provides a method for preparing the amorphous maleate salt of Compound I, which includes dissolving Compound I in at least one solvent (13) selected from ethanol, acetone, tetrahydrofuran, and acetonitrile / methanol, isopropanol, and ethyl acetate, adding maleic acid, then adding isopropyl ether, stirring, and crystallizing.

[0082] The present disclosure provides a method for preparing the amorphous phosphate salt of Compound I, which includes Method 1: dissolving Compound I in acetonitrile / methanol and phosphoric acid, slurrying at room temperature, then adding isopropyl ether, stirring, and crystallizing; and Method 2: adding Compound I to a solvent (14) selected from ethanol and tetrahydrofuran and phosphoric acid, stirring, and crystallizing.

[0083] The present disclosure provides a method for preparing the amorphous p-toluenesulfonate salt of Compound I, which includes adding Compound I to at least one solvent (15) selected from acetonitrile, acetone, tetrahydrofuran, or acetonitrile / methanol and p-toluenesulfonic acid, slurrying at room temperature, then adding isopropyl ether, stirring, and crystallizing.

[0084] The present disclosure provides a method for preparing the amorphous sulfate salt of Compound I, which includes Method 1: dissolving Compound I in acetonitrile / methanol, adding sulfuric acid, slurrying at room temperature, then adding isopropyl ether, and crystallizing; and Method 2: adding Compound I to tetrahydrofuran and sulfuric acid, and crystallizing.

[0085] The present disclosure provides a method for preparing an amorphous tartrate of Compound I, including Method 1: dissolving Compound I in a solvent (16) selected from ethanol or tetrahydrofuran, adding tartaric acid, slurrying at room temperature, then adding isopropyl ether and crystallizing; and Method 2: adding Compound I to a solvent (17) selected from acetonitrile or acetone and tartaric acid and crystallizing.

[0086] The present disclosure provides a method for preparing an amorphous succinate of Compound I, including Method 1: dissolving Compound I in a solvent (18) selected from ethanol or tetrahydrofuran, adding succinic acid, slurrying at room temperature, then adding isopropyl ether and crystallizing; and Method 2: adding Compound I to a solvent (19) selected from acetonitrile or acetone and succinic acid and crystallizing.

[0087] The present disclosure provides a method for preparing an amorphous fumarate of Compound I, including Method 1: dissolving Compound I in a solvent (20) selected from ethanol or tetrahydrofuran, adding fumaric acid, slurrying at room temperature, then adding isopropyl ether and crystallizing; and Method 2: adding Compound I to acetone and fumaric acid and crystallizing.

[0088] The present disclosure provides a method for preparing an amorphous citrate of Compound I, including dissolving Compound I in at least one solvent (21) selected from ethanol, acetonitrile, acetone or tetrahydrofuran, adding citric acid, slurrying at room temperature, then adding isopropyl ether and crystallizing.

[0089] The present disclosure provides a method for preparing an amorphous malate of Compound I, including Method 1: dissolving Compound I in at least one solvent (22) selected from ethanol, acetone or tetrahydrofuran, adding malic acid, slurrying at room temperature, then adding isopropyl ether and crystallizing; and Method 2: adding Compound I to acetonitrile and malic acid and crystallizing.

[0090] The present disclosure provides a method for preparing an amorphous hydrobromide salt of Compound I, which includes dissolving Compound I in a solvent (23) selected from at least one of acetonitrile, acetone, or tetrahydrofuran, adding hydrobromic acid, slurrying at room temperature, then adding isopropyl ether and performing crystallization.

[0091] The present disclosure provides a method for preparing an amorphous methanesulfonate salt of Compound I, which includes dissolving Compound I in a solvent (24) selected from at least one of acetonitrile, acetone, tetrahydrofuran, or ethanol, adding methanesulfonic acid, slurrying at room temperature, then adding isopropyl ether and performing crystallization.

[0092] The present disclosure provides a method for preparing an amorphous hydrochloride salt of Compound I, which includes dissolving Compound I in ethanol, adding hydrochloric acid, slurrying at room temperature, then adding isopropyl ether and performing crystallization.

[0093] In certain embodiments, the method for preparing the crystalline form described in the present disclosure further includes a filtration, washing, or drying step.

[0094] The present disclosure further provides a pharmaceutical composition prepared from a crystalline form of a pharmaceutically acceptable salt of the above Compound I.

[0095] The present disclosure further provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the above Compound I, a crystalline form of a pharmaceutically acceptable salt or a mixture thereof, or a pharmaceutically acceptable salt of Compound I prepared by the above method, a crystalline form of a pharmaceutically acceptable salt, and an optional pharmaceutically acceptable excipient.

[0096] The present disclosure further provides a method for preparing a pharmaceutical composition, which includes mixing a pharmaceutically acceptable salt of the above Compound I, a crystalline form of a pharmaceutically acceptable salt or a mixture thereof, or a pharmaceutically acceptable salt of Compound I prepared by the above method, a crystalline form of a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

[0097] The present disclosure further provides the use of a pharmaceutically acceptable salt of Compound I, a crystalline form of the pharmaceutically acceptable salt or a mixture thereof, or a pharmaceutically acceptable salt prepared by the above method, a crystalline form of the pharmaceutically acceptable salt or a mixture thereof, or the above composition, or a composition prepared by the above method, in the preparation of an agent for inhibiting the activation of the complement alternative pathway.

[0098] The present disclosure further provides the use of a pharmaceutically acceptable salt of Compound I, a crystalline form of the pharmaceutically acceptable salt, or a mixture thereof, or a pharmaceutically acceptable salt prepared by the above method, a crystalline form of the pharmaceutically acceptable salt, or a mixture thereof, or the above composition, in the preparation of a medicament for treating a disease or medical condition, wherein the disease or medical condition is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behçet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada disease, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, undesirable or unwanted complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, post-pump syndrome during balloon angioplasty, cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infection or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and pulmonary infarction, pneumonia, pneumoconiosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitosis, Gerstmann syndrome, pulmonary vasculitis, microscopic immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity, and the disease or medical condition is preferably C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.

[0099] The "2θ or 2θ angle" described in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, the unit is ° or degree, and the error range of each characteristic peak 2θ is ±0.20 (including the case of rounding off numbers exceeding one digit after the decimal point). Specifically, it is -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0100] The "crystallization" or "crystallization" described in the present disclosure includes, but is not limited to, stirring crystallization, slurry crystallization, cooling crystallization, and volatile crystallization.

[0101] The "differential scanning calorimetry or DSC" described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object in order to characterize all physical and chemical changes related to heat effects during the heating or constant temperature of the sample and obtain information on the phase transition of the sample.

[0102] The drying temperature described in the present disclosure is generally 25 to 100 °C, preferably 40 °C to 70 °C, and may be atmospheric drying or vacuum drying.

[0103] The "pharmaceutically acceptable excipient" described in the present disclosure includes, but is not limited to, any auxiliary agent, carrier, flow promoter, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, or emulsifier that has already been approved by the US Food and Drug Administration and is acceptable for use in humans or livestock animals.

Brief Description of the Drawings

[0104]

Figure 1

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Figure 9

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Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

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Figure 24

Figure 25

Figure 26

Embodiments for Carrying Out the Invention

[0105] The present disclosure will be further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0106] Test conditions of the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is indicated in units of 10 -6 (ppm). For the measurement of NMR, a nuclear magnetic resonance apparatus Bruker AVANCE-400 is used, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0107] For the measurement of MS, a mass spectrometer FINNIGAN LCQAd (ESI) (manufacturer: Thermo, model number: Finnigan LCQ advantage MAX) was used.

[0108] For HPLC measurement, an Agilent 1260 DAD high-performance liquid chromatograph (column: Sunfire C18 150×4.6 mm) and a Thermo U3000 high-performance liquid chromatograph (column: Gemini C18 150×4.6 mm) were used.

[0109] XRPD refers to detection by powder X-ray diffraction. For the measurement, a BRUKER D8 type X-ray diffractometer was used. The specific collection information is as follows: Cu anode (40 kV, 40 mA), radiation: monochromatic Cu-Kα radiation (λ = 1.5418 Å). Scanning mode: θ / 2θ, scanning range: 3° to 48 o 。

[0110] DSC refers to differential scanning calorimetry. For the measurement, a METTLER TOLEDO DSC 3+ differential scanning calorimeter was used, with a heating rate of 10 °C / min, from 25 °C to 350 °C, and a purge rate of nitrogen gas of 50 mL / min.

[0111] TGA refers to thermogravimetric analysis. For the detection, a METTLER TOLEDO TGA 2 type thermogravimetric analyzer was used, with a heating rate of 10 °C / min. The specific temperature range refers to the corresponding spectrum, and the purge rate of nitrogen gas is 50 mL / min.

[0112] DVS refers to dynamic vapor sorption. Surface Measurement Systems instrinsic was used. The humidity started at 50% and was investigated in the humidity range of 0% to 95% in 10% steps. The judgment criterion was that the mass change per gradient dM / dT was less than 0.002%, with TMAX of 360 min and two cycles.

[0113] Example 1. Preparation of Compound I (refer to the preparation methods of Examples 1 to 2 in the application with the application number PCT / CN2021 / 142760)

[0114]

Chemical formula

[0115] Step 1 1-(4-Bromophenyl)butane-1,4-diol 1b 4-(4-Bromophenyl)-4-oxobutyric acid methyl ester 1a (5 g, 17.54 mmol, Bide Pharmatech Co., Ltd.) was dissolved in tetrahydrofuran (50 mL). A solution of lithium borohydride in tetrahydrofuran (17 mL, 2 mmol / mL) was added under the condition of 0 °C, and the temperature was naturally raised to room temperature and stirred overnight. The reaction solution was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude title product 1b (4.29 g), which was used directly in the next reaction without purification. MS m / z (ESI): 242.9 [M-H].

[0116] Step 2 4-(4-Bromophenyl)-4-oxobutanal 1c Dimethyl sulfoxide (8.2 g, 104.95 mmol) was dissolved in dichloromethane (50 mL). Oxalyl chloride (8.8 g, 69.33 mmol) was added at -78 °C, and stirring was continued for 10 minutes. Compound 1b (4.29 g, 17.50 mmol) was added, and after 10 minutes, triethylamine (17.7 g, 174.92 mmol) was added. The reaction solution was stirred continuously for 1 hour. The temperature was naturally raised to room temperature, diluted with dichloromethane, the organic phase was washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to obtain the title compound 1c (2.7 g, yield: 64%). MS m / z (ESI): 240.8 [M+1].

[0117] Step 3 1-(4-Bromophenyl)-8-[(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-one 1d 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). 2 M hydrochloric acid (16 mL) and 1,3-acetonedicarboxylic acid (1.96 g, 13.42 mmol) were added at 0 °C, and 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 and 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%). MS m / z (ESI): 399.9 [M+1].

[0118] Step 4 1-(4-Bromophenyl)-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-ol 1e 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 obtain the crude title compound 1e (420 mg, yield: 78.8%). MS m / z (ESI): 401.8 [M+1].

[0119] Step 5 1-(4-Bromophenyl)-3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane 1f Compound 1e was dissolved in dimethylformamide (5 mL), and sodium hydride (83 mg, 2.08 mmol) was added at 0 °C. The reaction mixture was continuously stirred for 1 hour, and iodoethane (325 mg, 2.09 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution, 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 1f (350 mg, yield: 77.9%). MS m / z (ESI): 429.9[M+1].

[0120] Step 6 Methyl 4-(3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoate 1g Compound 1f was dissolved in methanol (4 mL) and dimethylformamide (4 mL), and palladium acetate (54 mg, 240.52 μmol), diphenylphosphoric acid azide (100 mg, 242.46 μmol), and triethylamine (822 mg, 8.12 mmol) were added. The mixture was replaced with carbon monoxide gas three times and stirred at 80 °C overnight. The reaction mixture 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%). MS m / z (ESI): 411.0[M+1].

[0121] Step 7 Methyl 4-(3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoate 1h Compound 1g (225 mg, 549.43 μmol) was dissolved in ethanol (5 mL), and palladium on carbon hydrogenation catalyst (40 mg, 375.87 μmol) was added. The mixture was replaced with hydrogen gas three times and stirred at room temperature for 48 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the organic phase was concentrated under reduced pressure to obtain the crude title compound 1h (130 mg), which was used in the next reaction without purification. MS m / z (ESI): 290.0[M+1].

[0122] Step 8 tert-Butyl 4-(bromomethyl)-5-methoxy-7-methylindole-1-carboxylate 1j Compound tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate 1i (150 mg, 514.86 μmol, synthesized with reference to the preparation method of Intermediate 1-10 in 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 the crude product, compound 1j (183 mg), which was used directly in the next reaction without purification.

[0123] Step 9 tert-Butyl 4-((3-ethoxy-1-(4-(methoxycarbonyl)phenyl)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate 1k 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. After the reaction solution was stirred continuously for 1 hour, a dimethylformamide solution of compound 1j (183 mg, 516.60 μmol) was added, and the reaction solution was stirred continuously for 1 hour, quenched with a saturated aqueous ammonium chloride solution, 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%). MS m / z (ESI): 563.0 [M+1].

[0124] 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 Compound 1k (130 mg, 231.03 μmol) was dissolved in a mixed solution of 6 mL of tetrahydrofuran, methanol, and water (V:V:V = 1:1:1). Lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated, diluted with a small amount of methanol, and then purified by high-speed preparative 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 compound 1 (4 mg, yield: 3.86%) and 2 (5 mg, yield: 4.82%).

[0125] Compound 1: High-speed preparative liquid chromatography: retention time 17.28 min.

[0126] MS m / z (ESI): 449.1 [M+1]. 1H NMR (500 MHz, CD3OD): δ 8.16 - 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 - 1.22 m, 3H).

[0127]

Chemical Structure

[0128] Compound 1 - 1 (Compound I, 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): MS m / z (ESI): 449.1 [M + 1]. Chiral HPLC analysis: retention time 7.946 minutes, chiral purity: 100% (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 and ethanol (20%), flow rate: 1 mL / min).

[0129] 1H NMR (500 MHz, MeOD) δ 8.16 - 8.15 (m, 2H), 7.69 (br, 2H), 7.34 (br, 1H), 6.83 (s, 1H), 6.33 (br, 1H), 4.22 - 4.12 (m, 2H), 4.03 - 4.00 (m, 1H), 3.93 (s, 3H), 3.71 - 3.51 (m, 1H), 3.50 - 3.35 (m, 2H), 3.32 - 2.96 (m, 2H), 2.73 - 2.53 (m, 3H), 2.51 (s, 3H), 2.21 - 2.05 (m, 3H), 1.35 - 1.22 (m, 3H).

[0130] Example 2. Inhibitory effect of Compound I on Factor B enzyme activity I. Experimental materials and equipment 1. Recombinant human complement factor B protein (expressed by Nanjing GenScript Biotech Co., Ltd.) 2. Recombinant human complement factor D protein (1824-SE-010, R&D system) 3. Human complement factor C3 (204885-250UGCN, EMDmillipore) 4. Cobra venom factor (CVF) (A600, Quidel) 5. StartingBlock TM T20 (TBS) blocking buffer (37543, Thermo Fisher) 6. Goat anti-mouse IgG heavy chain + light chain (horseradish peroxidase labeled) (ab205719, Abcam) 7. Anti-C3a / C3a des Arg antibody clone number

[2991] (ab11873, Abcam) 8. QuantaBlu TM Fluorescently labeled peroxidase substrate reagent kit (15169, Thermo Fisher) 9. Amphoteric surfactant (CHAPS) (C3023, Sigma) 10. Magnesium chloride solution (M1028-100ML, Sigma) 11. Sodium carbonate Na2CO3 (10019260, Shanghai Reagent) 12. Sodium bicarbonate NaHCO3 (10018960, Shanghai Reagent) 13. Tween20 (P7949-500ML, Sigma) 14. 20X PBS buffer (B548117-0500, Sangon Biotech) 15. 96-well white half-well plate (66PL96025, Cisbio) 16. 96-well black adsorption plate (437111, Thermo Fisher) 17. Phosphate buffer (B320, Shanghai Yuanpei Biotech Co., Ltd.) 18. Sterile pure water (self-made by Shanghai Hengrui) 19. 96-well combination plate (3795, Corning) 20. Thermostat (Shanghai Yiheng Scientific Instrument Co., Ltd.) 21. Flexstation 3 Plate Reader (Molecular Device)

[0131] II. Experimental Procedures In order to function as a protease, human complement factor B protein needs to form a complex with human complement factor C3. Through the hydrolysis by human complement factor D protein, human complement factor B is hydrolyzed into Ba and Bb fragments. Bb combines with the C3b fragment of human complement factor C3 to form a complex C3bBb, that is, C3 convertase. Only after this complex is formed can human complement factor B function as a protease. C3bBb subsequently hydrolyzes C3 into C3a and C3b fragments. C3b combines with C3bBb to form a complex C3bBbC3b, that is, C5 convertase, and the C3a fragment is released. Detecting the C3a des Arg epitope produced after C3 is cleaved can be used to evaluate the hydrolysis efficiency of C3, that is, the activity of C3bBb enzyme, thereby evaluating the effect of the compound on C3bBb enzyme. Since C3b is unstable in vitro, instead of C3b, cobra venom factor (hereinafter referred to as CVF) is combined with human complement factor B to form a complex, and its function is the same as that of C3b.

[0132] The amino acid coding gene (NM_001710.6) of the AA128 - 2422 fragment of human complement factor B protein was codon-optimized, gene-synthesized, and cloned into the pcDNA3.4 vector by Nanjing GenScript Biotech Co., Ltd., and expressed and purified in HD CHO-S cells. The purified recombinant human complement factor B protein was stored in a -80 °C refrigerator after dispensing.

[0133] Cleavage reaction of human complement factor B protein: Recombinant human complement factor D protein was diluted 10-fold with PBS (pH 7.4) and stored on ice for use. Recombinant human complement factor D protein with a final concentration of 300 nM, 1 μM of recombinant human complement factor B protein and 1 μM of CVF were added to the reaction buffer (PBS pH 7.4, 10 mM of MgCl2, 0.05% of CHAPS), and after mixing well and uniformly, the reaction was carried out in a thermostat at 37 °C for 3 hours to obtain a complex of CVF and the cleaved recombinant human complement factor B protein fragment Bb (hereinafter referred to as CVF:Bb).

[0134] 100 mM of Na2CO3 solution and 100 mM of NaHCO3 were prepared, and the pH value was adjusted to 9.5 with a volume ratio of Na2CO3:NaHCO3 = 3:7 and stored at room temperature for use.

[0135] A 20 mM test compound dissolved in 100% DMSO was diluted to 2000, 500, 125, 31.25, 7.8125, 0.488281, 0.12207, 0.030518, 0.007629 μM with a 100% DMSO series. The blank well was 100% DMSO, and it was further diluted 20-fold with C3 reaction buffer (PBS pH 7.4, 1 mM of MgCl2, 0.05% of CHAPS).

[0136] Shearing reaction of C3 protein: In a 96-well white half-well plate, a 10 μL reaction system was prepared, that is, CVF:Bb with a final concentration of 2 nM in C3 reaction buffer (PBS pH 7.4, 1 mM MgCl2, 0.05% CHAPS), a test compound diluted in 1 μL of the above C3 reaction buffer, and DMSO were added, and incubated at room temperature for 1 hour. The final concentrations of the test compounds were 10000, 2500, 625, 156.25, 39.0625, 9.765625, 2.441406, 0.6103515, 0.152588 nM, respectively. Human complement factor C3 was added to the reaction system at a final concentration of 500 nM, and after uniform mixing, the reaction was carried out in a thermostat at 37 °C for 2 hours. The reaction well containing only 500 nM of human complement factor C3 in the reaction mixture was used as a negative control. 97 μL of carbonate buffer (pH 9.5) was added to a 96-well black adsorption plate, 3 μL of the C3 protein shearing reaction mixture was taken and added to each well, and after uniform mixing, the plate was sealed and incubated at 4 °C overnight.

[0137] Detection of C3a des Arg: The plate was washed 3 times with 300 μL / well of TBST (0.05% Tween 20) solution, 300 μL of StartingBlock TM T20 (TBS) blocking buffer was added, incubated at 37 °C for 5 minutes, the plate was washed 3 times with 300 μL / well of PBST solution, the anti-C3a / C3a des Arg antibody

[2991] was diluted 1:1000 in PBST solution, 100 μL was added to each well, incubated at 37 °C for 1 hour, the plate was washed 3 times with 300 μL / well of PBST solution, the goat anti-mouse IgG H&L (Goat Anti-Mouse IgG H&L) (HRP) antibody was diluted 1:5000 in PBST solution, 100 μL was added to each well, incubated at 37 °C for 30 minutes, QuantaBlu TM fluorescently labeled peroxidase substrate kit (QuantaBlu TM Fluorogenic Peroxidase Substrate Kit) substrate was prepared, 1 part of QuantaBlu TM stable peroxide solution (QuantaBluTM Stable Peroxide Solution) was diluted in 9 parts of QuantaBlu TM substrate solution (QuantaBlu TM Substrate Solution), and the plate was washed 3 times with 300 μL / well of PBST solution. In the final wash, the plate was inverted and dried. 100 μL of substrate was added to each well and incubated at room temperature for 20 minutes. QuantaBlu TM stop solution (QuantaBlu TM Stop Solution) 100 μL was added, and then the fluorescence value was read using a Flexstation. The excitation wavelength Ex was set to 320 nM, the emission wavelength Em was set to 460 nM, and the cutoff was set to 455.

[0138] The inhibition rate was calculated using the following formula: [Equation 1] Inhibition rate = {1 - (RFU 試験化合物 - RFU 陰性対照ウェル ) / (RFU ブランクウェル - RFU 陰性対照ウェル )} × 100% Using Graphpad Prism software, an inhibition curve was plotted based on the concentration of each compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50%, i.e., the IC 50 value, was calculated.

[0139] Conclusion: For compound I, the IC 50 for the inhibitory activity against Factor B enzyme was 1.3 nM, indicating that compound I has excellent inhibitory effects on Factor B enzyme.

[0140] Example 3. Preparation of maleate I crystal form Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of acetonitrile, maleic acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.6 mL of isopropyl ether was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0141] When detected by powder X-ray diffraction, the product was defined as maleate I crystal form, and the XRPD spectrum is shown in Figure 1, and its characteristic peak positions are as shown in Table 1. According to the DSC spectrum, the peak value of the endothermic peak is 156.79 °C. According to the TGA spectrum, the weight decreased by 3.22% from 30 °C to 145 °C.

[0142]

Table 1

[0143] Example 4. Preparation of Phosphate I Crystal Form About 8 mg of Compound I was weighed, 0.2 mL of acetonitrile was added, a phosphoric acid solution (2 mol / L, 9.8 μL) was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0144] When detected by powder X-ray diffraction, the product was defined as phosphate I crystal form, and the XRPD spectrum is shown in Figure 2, and its characteristic peak positions are as shown in Table 2. According to the DSC spectrum, the peak value of the endothermic peak is 195.83 °C. According to the TGA spectrum, the weight decreased by 2.80% from 30 °C to 150 °C.

[0145]

Table 2

[0146] Example 5. Preparation of Phosphate I Crystal Form About 8 mg of Compound I was weighed, 0.2 mL of acetone was added, a phosphoric acid solution (2 mol / L, 9.8 μL) was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0147] When detected by powder X-ray diffraction, the product was in phosphate I crystal form.

[0148] Example 6. Preparation of Phosphate II Crystal Form Weighed approximately 8 mg of Compound I, added 0.2 mL of ethyl acetate, added phosphoric acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0149] When detected by powder X-ray diffraction, the product was defined as phosphate II crystal form, the XRPD spectrum is shown in Figure 3, and its characteristic peak positions are as shown in Table 3. When measured by ion chromatography, the content of phosphate ions in it was 17.33%. According to the DSC spectrum, the peak value of the endothermic peak was 146.30 °C. According to the TGA spectrum, the weight decreased by 1.09% from 30 °C to 175 °C.

[0150]

Table 3

[0151] Example 7. Preparation of Phosphate II Crystal Form Weighed approximately 40 mg of Compound I, added 0.75 mL of acetone, added phosphoric acid solution (2 mol / L, 47 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0152] When detected by powder X-ray diffraction, the product was in phosphate II crystal form.

[0153] Example 8. Preparation of Phosphate III Crystal Form Weighed approximately 8 mg of Compound I, added 0.2 mL of isopropanol, added phosphoric acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0154] When detected by powder X-ray diffraction, the product was defined as phosphate III crystal form, and the XRPD spectrum is shown in Figure 4, and its characteristic peak positions are as shown in Table 4. When measured by ion chromatography, the content of phosphate ions therein was 16.72%. According to the DSC spectrum, the peak values of the endothermic peaks were 66.14 °C and 143.48 °C, and the peak value of the exothermic peak was 182.62 °C. According to the TGA spectrum, the weight decreased by 6.16% from 30 °C to 150 °C.

[0155] According to DVS detection, for the sample under normal storage conditions (i.e., 25 °C, 60% RH), the weight increase due to moisture absorption was about 4.77%, under accelerated experiment conditions (i.e., 70% RH), the weight increase due to moisture absorption was 5.44%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption was 7.20%. Also, when the crystal form was re-measured after DVS detection, the crystal form was not converted.

[0156]

Table 4

[0157] Example 9. Preparation of Phosphate IV Crystal Form Weighed about 30 mg of Compound I, dissolved it in 0.5 mL of acetonitrile, heated it to 40 °C, added 8.2 mg of 85% phosphoric acid, cooled it to room temperature, stirred for 16 hours, filtered, collected the filter cake, and dried it under vacuum at 60 °C for 4 hours to obtain the product.

[0158] When detected by powder X-ray diffraction, the product was defined as phosphate IV crystal form, and the XRPD spectrum is shown in Figure 5, and its characteristic peak positions are as shown in Table 5.

[0159]

Table 5

[0160] Example 10. Preparation of Phosphate V Crystal Form Weighed 30 mg of Compound I and dissolved it in 1 mL of ethanol. Heated the solution to 40 °C, added 85% phosphoric acid (8.2 mg, 66.88 μmol), cooled it to room temperature, stirred for 16 hours, filtered, collected the filter cake, and dried it under vacuum at 60 °C for 4 hours to obtain the product.

[0161] As detected by powder X-ray diffraction, the product was defined as the phosphate V crystal form. The XRPD spectrum is shown in Figure 6, and its characteristic peak positions are as shown in Table 6. According to the DSC spectrum, the peak values of the endothermic peaks are 48.64 °C and 223.41 °C, and the peak value of the exothermic peak is 194.80 °C. According to the TGA spectrum, the weight decreased by 2.47% from 30 °C to 100 °C and by 2.76% from 100 °C to 250 °C.

[0162]

Table 6

[0163] Example 11. Preparation of p-Toluenesulfonate I Crystal Form Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of ethanol, added p-toluenesulfonic acid solution (2 mol / L, 9.8 μL), stirred overnight, added 0.8 mL of isopropyl ether, stirred for crystallization, centrifuged, and dried the solid under vacuum to obtain the product.

[0164] As detected by powder X-ray diffraction, the product was defined as the p-toluenesulfonate I crystal form. The XRPD spectrum is shown in Figure 7, and its characteristic peak positions are as shown in Table 7. As measured by ion chromatography, the content of p-toluenesulfonate ions in it is 30.75%. According to the DSC spectrum, the peak values of the endothermic peaks are 57.15 °C and 180.78 °C. According to the TGA spectrum, the weight decreased by 2.07% from 30 °C to 145 °C.

[0165] According to DVS detection, under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 1.22%. Under accelerated experiment conditions (i.e., 70% RH), the weight increase due to moisture absorption is about 1.37%. Under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 1.87%. Also, when the crystal form was re-measured after DVS detection, the crystal form was not converted.

[0166]

Table 7

[0167] Example 12. Preparation of p-Toluenesulfonate I Crystal Form Compound I was weighed and added to a solvent and 2 mol / L p-toluenesulfonic acid solution for crystallization to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 8.

[0168]

Table 8

[0169] Example 13. Preparation of p-Toluenesulfonate II Crystal Form About 938 mg of Compound I was weighed, dissolved in 40 mL of isopropanol, stirred at 40°C until clarified, heated to 60°C, 398 mg of p-toluenesulfonic acid monohydrate was added, stirred for 1 hour, then cooled to room temperature, filtered, and the filter cake was collected and vacuum dried at 60°C for 4 hours to obtain a product.

[0170] When detected by powder X-ray diffraction, the product was defined as p-toluenesulfonate II crystal form, the XRPD spectrum is shown in Figure 8, and its characteristic peak positions are as shown in Table 9. According to the DSC spectrum, the peak values of the endothermic peaks are 104.06°C and 181.38°C, and the peak value of the exothermic peak is 188.49°C. According to the TGA spectrum, the weight decreased by 3.36% from 40°C to 160°C and by 3.84% from 160°C to 270°C.

[0171]

Table 9

[0172] Example 14. Preparation of p-Toluenesulfonate III Crystal Form 15 mg of the p-toluenesulfonate II crystal form compound was dispersed in 1 mL of methyl tert-butyl ether, stirred for 72 hours, filtered to collect the filter cake, and dried under vacuum at 60 °C for 4 hours to obtain the product.

[0173] As detected by powder X-ray diffraction, the product was defined as the p-toluenesulfonate III crystal form, and the XRPD spectrum is shown in Figure 9, and its characteristic peak positions are as shown in Table 10.

[0174]

Table 10

[0175] Example 15. Preparation of Sulfate I Crystal Form Approximately 8 mg of Compound I was weighed, 0.2 mL of acetonitrile was added, a sulfuric acid solution (2 mol / L, 9.8 μL) was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0176] As detected by powder X-ray diffraction, the product was defined as the sulfate I crystal form, and the XRPD spectrum is shown in Figure 10, and its characteristic peak positions are as shown in Table 11. According to the DSC spectrum, the peak values of the endothermic peaks are 52.82 °C and 105.48 °C, and the peak value of the exothermic peak is 190.22 °C. According to the TGA spectrum, the weight decreased by 6.02% from 30 °C to 195 °C.

[0177]

Table 11

[0178] Example 16. Preparation of Sulfate I Crystal Form Weighed about 8 mg of Compound I, added 0.2 mL of ethanol, added sulfuric acid solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0179] As detected by powder X-ray diffraction, the product was defined as sulfate I crystal form.

[0180] Example 17. Preparation of Sulfate II Crystal Form Weighed about 8 mg of Compound I, added 0.2 mL of acetone, added sulfuric acid solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0181] As detected by powder X-ray diffraction, the product was defined as sulfate II crystal form, the XRPD spectrum is shown in Figure 11, and its characteristic peak positions are as shown in Table 12. According to the DSC spectrum, the peak value of the endothermic peak is 64.63 °C, and the peak value of the exothermic peak is 207.53 °C. According to the TGA spectrum, the weight decreased by 6.12% from 30 °C to 180 °C.

[0182]

Table 12

[0183] Example 18. Preparation of Sulfate III Crystal Form Weighed about 40 mg of Compound I, dissolved it in 0.75 mL of ethanol, added sulfuric acid solution (2 mol / L, 47 μL), added 1 mL of isopropyl ether, stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0184] When detected by powder X-ray diffraction, the product was defined as sulfate III crystal form, and the XRPD spectrum is shown in Figure 12, and its characteristic peak positions are as shown in Table 13. When measured by ion chromatography, the sulfate ion content therein was 15.31%. According to the DSC spectrum, the peak values of the endothermic peaks were 76.24 °C and 150.06 °C. According to the TGA spectrum, the weight decreased by 4.31% from 30 °C to 140 °C.

[0185]

Table 13

[0186] Example 19. Preparation of Sulfate IV Crystal Form Weighed about 8 mg of Compound I, added 0.2 mL of isopropanol, added a sulfuric acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0187] When detected by powder X-ray diffraction, the product was defined as sulfate IV crystal form, and the XRPD spectrum is shown in Figure 13, and its characteristic peak positions are as shown in Table 14. When measured by ion chromatography, the sulfate ion content therein was 15.72%. According to the DSC spectrum, the peak values of the endothermic peaks were 68.75 °C and 161.89 °C. According to the TGA spectrum, the weight decreased by 3.74% from 30 °C to 135 °C.

[0188]

Table 14

[0189] Example 20. Preparation of Sulfate IV Crystal Form Weighed about 40 mg of Compound I, added 0.75 mL of acetone, added a sulfuric acid solution (2 mol / L, 47 μL), stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0190] When detected by powder X-ray diffraction, the product is in the form of sulfate IV crystals.

[0191] Example 21. Preparation of Sulfate V Crystal Form Weighed about 8 mg of Compound I, added 0.2 mL of ethyl acetate, added sulfuric acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0192] When detected by powder X-ray diffraction, the product is defined as the sulfate V crystal form. The XRPD spectrum is shown in Figure 14, and its characteristic peak positions are as shown in Table 15. When measured by ion chromatography, the sulfuric acid ion content therein is 11.65%. According to the DSC spectrum, the peak values of the endothermic peaks are 61.82 °C and 153.47 °C. According to the TGA spectrum, the weight decreased by 4.19% from 30 °C to 90 °C and by 6.18% from 90 °C to 195 °C.

[0193]

Table 15

[0194] Example 22. Preparation of Sulfate V Crystal Form Weighed about 500 mg of Compound I and suspended it in 20 mL of isopropyl acetate. While stirring at room temperature, 109 mg of sulfuric acid was added, and the mixture was stirred for 16 hours, filtered, and the filter cake was collected and dried under vacuum at 60 °C for 4 hours to obtain the product.

[0195] Example 23. Preparation of Sulfate VI Crystal Form Weighed 15 mg of the sulfate I crystal form of Compound I and dispersed it in 1 mL of isopropyl acetate, stirred at room temperature for 48 hours, filtered, and the filter cake was collected and dried under vacuum at 60 °C for 4 hours to obtain the product.

[0196] When detected by powder X-ray diffraction, the product is defined as the sulfate VI crystal form. The XRPD spectrum is shown in Figure 15, and its characteristic peak positions are as shown in Table 16.

[0197]

Table 16

[0198] Example 24. Preparation of hydrochloride I crystal form Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of ethanol, added hydrochloric acid solution (2 mol / L, 9.8 μL), stirred overnight, added 1.0 mL of isopropyl ether, stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the product.

[0199] As detected by powder X-ray diffraction, the product was defined as hydrochloride I crystal form, the XRPD spectrum was shown in Figure 16, and its characteristic peak positions were as shown in Table 17. As measured by ion chromatography, the chloride ion content therein was 5.94%. According to the DSC spectrum, the peak value of the exothermic peak was 211.63 °C. According to the TGA spectrum, the weight decreased by 5.62% at 30 °C to 175 °C.

[0200]

Table 17

[0201] Example 25. Preparation of hydrochloride II crystal form Weighed about 8 mg of Compound I, added 0.2 mL of acetonitrile, added hydrochloric acid solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the title product.

[0202] As detected by powder X-ray diffraction, the product was defined as hydrochloride II crystal form, the XRPD spectrum was shown in Figure 17, and its characteristic peak positions were as shown in Table 18. As measured by ion chromatography, the chloride ion content therein was 6.94%. According to the DSC spectrum, the peak value of the endothermic peak was 47.48 °C, and the peak value of the exothermic peak was 221.46 °C. According to the TGA spectrum, the weight decreased by 3.32% at 30 °C to 165 °C.

[0203] According to DVS detection, under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 3.93%. Under accelerated test conditions (i.e., 70% RH), the weight increase due to moisture absorption is about 4.28%. Under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 5.00%. Also, when the crystal form was re-measured after DVS detection, the crystal form was not converted.

[0204]

Table 18

[0205] Example 26. Preparation of hydrochloride II crystal form Compound I was weighed and added to a solvent and 2 mol / L hydrochloric acid solution, and crystallization was carried out to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 19.

[0206]

Table 19

[0207] Example 27. Preparation of hydrochloride III crystal form About 8 mg of Compound I was weighed, 0.2 mL of acetone was added, hydrochloric acid solution (2 mol / L, 9.8 μL) was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0208] When detected by powder X-ray diffraction, the product was defined as hydrochloride III crystal form, the XRPD spectrum is shown in Figure 18, and its characteristic peak positions are as shown in Table 20. When measured by ion chromatography, the chloride ion content therein is 6.68%. According to the DSC spectrum, the peak value of the exothermic peak is 191.78°C, and the peak value of the endothermic peak is 206.27°C. According to the TGA spectrum, the weight decreased by 2.34% at 30°C to 155°C.

[0209] According to DVS detection, under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 2.57%, under accelerated experiment conditions (i.e., 70% RH), the weight increase due to moisture absorption is about 2.96%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 4.57%. Also, when the crystal form was re-measured after DVS detection, the crystal form was not converted.

[0210]

Table 20

[0211] Example 28. Preparation of hydrochloride III crystal form Weighed about 120 mg of Compound I, added 3 mL of ethyl acetate, added hydrochloric acid ethanol solution (2 mol / L, 140 μL), stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0212] When detected by powder X-ray diffraction, the product is in hydrochloride III crystal form.

[0213] Example 29. Preparation of hydrochloride IV crystal form Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of tetrahydrofuran, added hydrochloric acid solution (2 mol / L, 9.8 μL), stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0214] When detected by powder X-ray diffraction, the product is defined as hydrochloride IV crystal form, the XRPD spectrum is shown in Figure 19, and its characteristic peak positions are as shown in Table 21. According to the DSC spectrum, the peak value of the exothermic peak is 208.82°C. According to the TGA spectrum, the weight decreased by 2.60% from 30°C to 160°C.

[0215]

Table 21

[0216] Example 30. Preparation of hydrochloride V crystal form Weighed about 140 mg of Compound I, dissolved it in 5 mL of acetonitrile, added 33 mg of concentrated hydrochloric acid while stirring, stirred for 16 hours, filtered to collect the filter cake, and dried it under vacuum at 60 °C for 4 hours to obtain the product.

[0217] As detected by powder X-ray diffraction, the product was defined as the hydrochloride V crystal form, and the XRPD spectrum is shown in Figure 20, and its characteristic peak positions are as shown in Table 22.

[0218] According to the DSC spectrum, the peak value of the endothermic peak is 63.15 °C, and the peak values of the exothermic peaks are 196.81 °C and 211.82 °C. According to the TGA spectrum, the weight decreased by 4.60% from 30 °C to 170 °C and by 6.81% from 170 °C to 260 °C. According to the DVS data, for the sample, under normal storage conditions (i.e., 25 °C, 60% RH), the weight increase due to moisture absorption was about 6.36%, under accelerated test conditions (i.e., 70% RH), the weight increase due to moisture absorption was about 7.28%, and under extreme conditions (90% RH), the weight increase due to moisture absorption was about 8.32%. According to the XRPD spectrum, the crystal form of the sample did not change before and after DVS.

[0219]

Table 22

[0220] Example 31. Preparation of Hydrochloride VI Crystal Form Weighed about 140 mg of Compound I, dissolved it in 5 mL of isopropanol, added 78 μL of 4 M hydrochloric acid dioxane solution while stirring, stirred for 16 hours, filtered to collect the filter cake, and dried it under vacuum at 60 °C for 4 hours to obtain the product.

[0221] When detected by powder X-ray diffraction, the product was defined as the hydrochloride VI crystal form, and the XRPD spectrum is shown in Figure 21, and its characteristic peak positions are as shown in Table 23. According to the DSC spectrum, the peak values of the exothermic peaks are 104.31 °C, 198.49 °C, and 204.67 °C. According to the TGA spectrum, the weight decreased by 3.22% from 30 °C to 195 °C and by 4.49% from 195 °C to 265 °C. According to the DVS data, the sample had a weight increase of about 3.69% due to moisture absorption under normal storage conditions (i.e., 25 °C, 60% RH), a weight increase of about 4.12% due to moisture absorption under accelerated test conditions (i.e., 70% RH), and a weight increase of about 5.73% due to moisture absorption under extreme conditions (90% RH). According to the XRPD spectrum, the crystal form of the sample did not change before and after DVS.

[0222]

Table 23

[0223] Example 32. Preparation of Fumarate I Crystal Form Weighed about 8 mg of Compound I and about 2.27 mg of fumaric acid, added 0.2 mL of acetonitrile, stirred for crystallization, centrifuged, and dried the solid under vacuum to obtain the product.

[0224] When detected by powder X-ray diffraction, the product was defined as the fumarate I crystal form, and the XRPD spectrum is shown in Figure 22, and its characteristic peak positions are as shown in Table 24. When measured by ion chromatography, the content of fumarate ions in it was 20.34%. According to the DSC spectrum, the peak value of the endothermic peak was 179.08 °C. According to the TGA spectrum, the weight decreased by 1.02% from 30 °C to 150 °C.

[0225] According to DVS detection, under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 0.51%, under accelerated experiment conditions (i.e., 70% RH), the weight increase due to moisture absorption is about 0.60%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 0.82%. Also, when the crystal form was re-measured after DVS detection, the crystal form was not converted.

[0226]

Table 24

[0227] Example 33. Preparation of fumarate I crystal form About 80 mg of Compound I was weighed, added to a methanol solution of fumaric acid (0.33 mol / L, 537 μL), 1.5 mL of acetonitrile was added, stirred for crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0228] When detected by powder X-ray diffraction, the product is fumarate I crystal form.

[0229] Example 34. Preparation of fumarate II crystal form About 8 mg of Compound I and 2.27 mg of fumaric acid were weighed, dissolved in 0.2 mL of methanol / acetonitrile (V / V = 1:8), filtered, and volatilized for crystallization to obtain the product.

[0230] When detected by powder X-ray diffraction, the product is defined as fumarate II crystal form, and the XRPD spectrum is shown in Figure 23, and its characteristic peak positions are as shown in Table 25.

[0231]

Table 25

[0232] Example 35. Preparation of hydrobromide I crystal form Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of ethanol, added hydrobromic acid solution (2 mol / L, 9.8 μL), stirred overnight, added 0.8 mL of isopropyl ether, stirred for crystallization, and after centrifugation, dried the solid under vacuum to obtain the product.

[0233] As detected by powder X-ray diffraction, the product was defined as hydrobromide salt I crystal form, the XRPD spectrum is shown in Figure 24, and its characteristic peak positions are as shown in Table 26. As measured by ion chromatography, the bromine ion content therein was 13.98%. According to the DSC spectrum, the peak value of the exothermic peak was 216.67 °C. According to the TGA spectrum, the weight decreased by 1.24% from 30 °C to 160 °C.

[0234]

Table 26

[0235] Example 36. Preparation of hydrobromide salt II crystal form Weighed about 8 mg of Compound I, added 0.2 mL of isopropanol, added hydrobromic acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, and after centrifugation, dried the solid under vacuum to obtain the title product.

[0236] As detected by powder X-ray diffraction, the product was defined as hydrobromide salt II crystal form, the XRPD spectrum is shown in Figure 25, and its characteristic peak positions are as shown in Table 27. As measured by ion chromatography, the bromine ion content therein was 14.89%. According to the DSC spectrum, the peak value of the exothermic peak was 211.47 °C. According to the TGA spectrum, the weight decreased by 0.77% from 30 °C to 145 °C.

[0237]

Table 27

[0238] Example 37. Preparation of hydrobromide salt II crystal form Weighed about 8 mg of Compound I, added 0.2 mL of ethyl acetate, added hydrobromic acid ethanol solution (2 mol / L, 9.8 μL), stirred for crystallization, centrifuged, and then dried the solid under vacuum to obtain the title product.

[0239] As detected by powder X-ray diffraction, the product is the hydrobromide salt II crystal form.

[0240] Example 38. Preparation of maleate amorphous Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of ethanol, added maleic acid solution (2 mol / L, 9.8 μL), slurried overnight at room temperature, added 0.6 mL of isopropyl ether, stirred for precipitation, centrifuged, and then dried the solid under vacuum to obtain the product.

[0241] As detected by powder X-ray diffraction, the product is maleate amorphous.

[0242] Example 39. Preparation of maleate amorphous Weighed Compound I and added it to a solvent and a solution of 2 mol / L maleic acid for crystallization to obtain the product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 28.

[0243]

Table 28

[0244] Example 40. Preparation of phosphate amorphous Weighed about 8 mg of Compound I, dissolved it in 0.2 mL of ethanol, added phosphoric acid solution (2 mol / L, 9.8 μL), stirred for precipitation, centrifuged, and then dried the solid under vacuum to obtain the product.

[0245] As detected by powder X-ray diffraction, the product is phosphate amorphous.

[0246] Example 41. Preparation of phosphate amorphous Compound I was weighed and added to a solvent and a 2 mol / L phosphoric acid solution, followed by crystallization to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 29.

[0247] [Table 29]

[0248] Example 42. Preparation of p-Toluenesulfonate Amorphous Approximately 8 mg of Compound I was weighed, 0.2 mL of acetonitrile was added, a p-toluenesulfonic acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.6 mL of isopropyl ether was added, stirred for precipitation, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0249] When detected by powder X-ray diffraction, the product was p-toluenesulfonate amorphous.

[0250] Example 43. Preparation of p-Toluenesulfonate Amorphous Compound I was weighed and added to a solvent and a 2 mol / L p-toluenesulfonic acid solution, followed by crystallization to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 30.

[0251] [Table 30]

[0252] Example 44. Preparation of Sulfate Amorphous Approximately 8 mg of Compound I was weighed, dissolved in 0.2 mL of tetrahydrofuran, a sulfuric acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, stirred for precipitation, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0253] When detected by powder X-ray diffraction, the product was sulfate amorphous.

[0254] Example 45. Preparation of Sulfate Amorphous Weigh about 8 mg of Compound I, dissolve it in 0.2 mL of acetonitrile / methanol (V / V = 1:1), add sulfuric acid solution (2 mol / L, 9.8 μL), slurry overnight at room temperature, add 1 mL of isopropyl ether, stir to precipitate, and after centrifugation, dry the solid under vacuum to obtain the product.

[0255] As detected by powder X-ray diffraction, the product is sulfate amorphous.

[0256] Example 46. Preparation of Tartrate Amorphous Weigh about 8 mg of Compound I, add 0.2 mL of acetonitrile, add tartaric acid solution (2 mol / L, 9.8 μL), stir to precipitate, and after centrifugation, dry the solid under vacuum to obtain the product.

[0257] As detected by powder X-ray diffraction, the product is tartrate amorphous.

[0258] Example 47. Preparation of Tartrate Amorphous Weigh Compound I and add it to a solvent and 2 mol / L tartaric acid solution for crystallization to obtain the product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 31.

[0259]

Table 31

[0260] Example 48. Preparation of Succinate Amorphous Weigh about 8 mg of Compound I and about 2.3 mg of succinic acid, add 0.2 mL of acetonitrile, slurry overnight at room temperature, and after centrifugation, dry the solid under vacuum to obtain the product.

[0261] As detected by powder X-ray diffraction, the product is succinate amorphous.

[0262] Example 49. Preparation of Succinate Amorphous Compound I was weighed and added to a solvent and succinic acid, followed by crystallization to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 32.

[0263]

Table 32

[0264] Example 50. Preparation of fumarate amorphous Approximately 8 mg of Compound I and approximately 2.3 mg of fumaric acid were weighed, 0.2 mL of acetone was added, slurried overnight at room temperature, centrifuged, and the solid was dried under vacuum to obtain a product.

[0265] When detected by powder X-ray diffraction, the product was fumarate amorphous and the XRPD spectrum was as shown in Figure 26.

[0266] Example 51. Preparation of fumarate amorphous Compound I was weighed and added to a solvent and fumaric acid, followed by crystallization to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 33.

[0267]

Table 33

[0268] Example 52. Preparation of citrate amorphous Approximately 8 mg of Compound I was weighed, dissolved in 0.2 mL of ethanol, a citric acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.6 mL of isopropyl ether was added, stirred for precipitation, centrifuged, and the solid was dried under vacuum to obtain a product.

[0269] When detected by powder X-ray diffraction, the product was citrate amorphous.

[0270] Example 53. Preparation of citrate amorphous Compound I was weighed and added to a solvent and a 2 mol / L citric acid solution, and crystallization was carried out to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 34.

[0271] [Table 34]

[0272] Example 54. Preparation of malate amorphous About 8 mg of Compound I was weighed, dissolved in 0.2 mL of ethanol, a malic acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.6 mL of isopropyl ether was added, stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0273] When detected by powder X-ray diffraction, the product was malate amorphous.

[0274] Example 55. Preparation of malate amorphous Compound I was weighed and added to a solvent and a 2 mol / L malic acid solution, and crystallization was carried out to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 35.

[0275] [Table 35]

[0276] Example 56. Preparation of hydrobromide amorphous About 8 mg of Compound I was weighed, 0.2 mL of acetonitrile was added, a hydrobromic acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.4 mL of isopropyl ether was added, stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0277] When detected by powder X-ray diffraction, the product was hydrobromide amorphous.

[0278] Example 57. Preparation of hydrobromide amorphous Compound I was weighed and added to a solvent and a 2 mol / L hydrobromic acid solution, and crystallization was carried out to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 36.

[0279] [Table 36]

[0280] Example 58. Preparation of mesylate amorphous Approximately 8 mg of Compound I was weighed, 0.2 mL of acetonitrile was added, a methanesulfonic acid solution (2 mol / L, 9.8 μL) was added, slurried overnight at room temperature, 0.3 mL of isopropyl ether was added, stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain a product.

[0281] When detected by powder X-ray diffraction, the product was mesylate amorphous.

[0282] Example 59. Preparation of mesylate amorphous Compound I was weighed and added to a solvent and a 2 mol / L methanesulfonic acid solution, and crystallization was carried out to obtain a product. When the crystal form was confirmed by powder X-ray diffraction, it was as shown in Table 37.

[0283] [Table 37]

[0284] Example 60. Preparation of hydrochloride amorphous Approximately 8 mg of Compound I was weighed, dissolved in 0.2 mL of ethanol, a hydrochloric acid solution (2 mol / L, 9.8 μL) was added, stirred overnight, 0.8 mL of isopropyl ether was added, stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain the title product.

[0285] When detected by powder X-ray diffraction, the product was hydrochloride amorphous.

[0286] Research on the Stability of Influencing Factors on the Crystal Form of p-Toluenesulfonate I The p-toluenesulfonate I crystal form was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (RH75%, RH92.5%) was investigated respectively, and the sampling investigation period was 30 days.

[0287]

Table 38

[0288] Conclusion: When under the conditions of light irradiation, high temperatures of 40 °C and 60 °C, and high humidities of 75% and 92.5% for 30 days, the p-toluenesulfonate I crystal form has good physical and chemical stability.

[0289] Experimental Example 2. Research on the Stability of Influencing Factors on the Crystal Form of Fumarate I The fumarate I crystal form was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (RH75%, RH92.5%) was investigated respectively, and the sampling investigation period was 30 days.

[0290]

Table 39

[0291] Conclusion: When under the conditions of light irradiation, high temperatures of 40 °C and 60 °C, and high humidities of 75% and 92.5% for 30 days, the fumarate I crystal form has good physical and chemical stability.

[0292] Experimental Example 3. Research on the Stability of Influencing Factors on the Crystal Form of Hydrochloride II The hydrochloride II crystal form was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (RH75%, RH92.5%) was investigated respectively, and the sampling investigation period was 30 days.

[0293]

Table 40

[0294] Conclusion: When exposed to light, high temperatures of 40°C and 60°C, and high humidity of 75% and 92.5% for 30 days, the hydrochloride II crystal form has relatively good physical stability, and the hydrochloride II crystal form has good chemical stability under high humidity conditions.

[0295] Experimental Example 4. Study on the Stability of Influencing Factors on the Hydrochloride III Crystal Form The hydrochloride III crystal form was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperatures (40°C, 60°C), and high humidity (RH75%, RH92.5%) was investigated respectively, and the sampling investigation period was 30 days.

[0296]

Table 41

[0297] Conclusion: When exposed to light, high temperatures of 40°C and 60°C, and high humidity of 75% and 92.5% for 30 days, the hydrochloride III crystal form has relatively good physical stability, and the hydrochloride III crystal form has good chemical stability under high humidity conditions.

[0298] Experimental Example 5. Study on the Stability of Influencing Factors on the Phosphate II Crystal Form The phosphate II crystal form was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperatures (40°C, 60°C), and high humidity (RH75%, RH92.5%) was investigated respectively, and the sampling investigation period was 30 days.

[0299]

Table 42

[0300] Conclusion: Under high humidity conditions, the phosphate II crystal form has good chemical stability, and under high temperature, light irradiation, and high humidity of 75%RH conditions, it has good physical stability.

[0301] Study on the Long-Term Accelerated Stability of p-Toluenesulfonate I Crystal Form The p-toluenesulfonate I crystal form was sealed and placed under the conditions of 25°C / 60%RH and 40°C / 75%RH respectively to investigate its stability.

[0302]

Table 43

[0303] Conclusion: Through the long-term accelerated experiment, when stored under the conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months, it can be seen that the p-toluenesulfonate I crystal form has relatively good physical and chemical stability.

[0304] Experimental Example 7. Study on the Long-Term Accelerated Stability of Fumarate I Crystal Form The fumarate I crystal form was sealed and placed under the conditions of 25°C / 60%RH and 40°C / 75%RH respectively to investigate its stability.

[0305]

Table 44

[0306] Conclusion: Through the long-term accelerated experiment, when stored under the conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months, it can be seen that the fumarate I crystal form has good physical and chemical stability.

[0307] Experimental Example 8. Study on the Long-Term Accelerated Stability of Hydrochloride II Crystal Form The hydrochloride II crystal form was sealed and placed under the conditions of 25°C / 60%RH and 40°C / 75%RH respectively to investigate its stability.

[0308]

Table 45

[0309] Conclusion: Through long-term accelerated experiments, it is found that when exposed to the conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months, the hydrochloride II crystal form has good physical and chemical stability.

[0310] Experimental Example 9. Research on the long-term accelerated stability of hydrochloride III crystal form The hydrochloride III crystal form was sealed and placed under the conditions of 25°C / 60%RH and 40°C / 75%RH respectively to investigate its stability.

[0311]

Table 46

[0312] Conclusion: Through long-term accelerated experiments, it is found that when exposed to the conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months, the hydrochloride III crystal form has good physical and chemical stability.

[0313] Experimental Example 10. Research on the long-term accelerated stability of phosphate II crystal form The phosphate II crystal form was sealed and placed under the conditions of 25°C / 60%RH and 40°C / 75%RH respectively to investigate its stability.

[0314]

Table 47

[0315] Conclusion: Through long-term accelerated experiments, it is found that when exposed to the conditions of 25°C / 60%RH and 40°C / 75%RH for 2 months, the phosphate II crystal form has relatively good physical stability and good long-term chemical stability.

Claims

1. A pharmaceutically acceptable salt of 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, selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, mesylate and hydrobromide. A pharmaceutically acceptable salt of 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.

2. A method for preparing a pharmaceutically acceptable salt of 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 according to claim 1, comprising reacting 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 with an acid selected from maleic acid, phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, fumaric acid, tartaric acid, succinic acid, citric acid, malic acid, methanesulfonic acid and hydrobromic acid. A method for preparing a pharmaceutically acceptable salt of 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 according to claim 1.

3. The pharmaceutically acceptable salt according to claim 1, characterized in that the chemical mixing ratio of the 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 and the acid is 3:1 to 1:2, preferably 2:1 to 1:

1.

4. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 6.7, 7.6, 8.6, 11.0, 12.1 and 16.2, preferably has characteristic peaks at 6.7, 7.6, 8.1, 8.6, 11.0, 12.1, 16.2, 19.7 and 23.5, more preferably has characteristic peaks at 6.7, 7.6, 8.1, 8.6, 9.3, 11.0, 12.1, 13.5, 16.2, 17.9, 19.7 and 23.5, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

1. The maleate I crystal form of 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 according to claim 1.

5. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 8.4, 10.3, 11.7, 14.8, 19.2 and 21.8, preferably has characteristic peaks at 8.4, 10.3, 11.7, 12.5, 14.8, 19.2, 19.8, 21.8 and 23.9, more preferably has characteristic peaks at 7.0, 8.4, 9.3, 10.3, 11.7, 12.5, 14.8, 17.4, 19.2, 19.8, 21.8 and 23.9, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in Figure 2. The phosphate I crystal form of 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 according to claim 1.

6. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 8.4, 9.5, 10.2, 11.7, 14.7 and 19.1, preferably has characteristic peaks at 6.9, 8.4, 9.5, 10.2, 10.7, 11.7, 14.7, 18.5 and 19.1, more preferably has characteristic peaks at 6.9, 8.4, 8.8, 9.5, 10.2, 10.7, 11.7, 14.7, 15.7, 18.5, 19.1 and 19.8, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in Figure 3. The phosphate II crystal form of 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 according to claim 1.

7. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 18.5 and 21.3, preferably has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 21.3 and 24.1, more preferably has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 20.8, 21.3, 22.9, 24.1 and 25.3, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in Figure 4. The phosphate III crystal form of 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 according to claim 1.

8. The powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 6.9, 8.4, 10.3, 11.7 and 14.

8. Preferably, the powder X-ray diffraction pattern shown at diffraction angle 2θ is as shown in Figure 5. The phosphate IV crystal form of 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 according to claim 1.

9. The powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 9.1, 10.2, 11.5, 15.7 and 19.

8. Preferably, it has characteristic peaks at 8.6, 9.1, 10.2, 11.5, 15.7, 18.0, 19.8 and 23.

5. More preferably, the powder X-ray diffraction pattern shown at diffraction angle 2θ is as shown in Figure 6. The phosphate V crystal form of 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 according to claim 1.

10. The powder X-ray diffraction pattern shown at diffraction angle 2θ has characteristic peaks at 5.0, 9.4, 10.1, 16.3 and 18.

3. Preferably, it has characteristic peaks at 5.0, 9.4, 10.1, 16.3, 18.3, 18.9, 21.2 and 22.

9. More preferably, it has characteristic peaks at 5.0, 9.4, 10.1, 16.0, 16.3, 17.1, 18.3, 18.9, 21.2, 22.9 and 24.

0. Most preferably, the powder X-ray diffraction pattern shown at diffraction angle 2θ is as shown in Figure 7. The p-toluenesulfonate I crystal form of 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 according to claim 1.

11. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 4.7, 8.8, 9.3, 10.8, 13.9 and 18.7, preferably has characteristic peaks at 4.7, 8.8, 9.3, 9.7, 10.8, 13.9, 17.7 and 18.7, and more preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

8. The p-toluenesulfonate II crystal form of 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 according to claim 1.

12. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 6.8, 7.4, 8.1, 10.1 and 12.7, and preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

9. The p-toluenesulfonate III crystal form of 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 according to claim 1.

13. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 7.2, 9.2, 17.1, 20.0, 21.4 and 24.7, preferably has characteristic peaks at 6.7, 7.2, 9.2, 17.1, 18.7, 20.0, 21.4, 22.9 and 24.7, and more preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

10. The sulfate I crystal form of 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 according to claim 1.

14. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 9.5, 10.2, 16.6, 21.2 and 25.7, preferably has characteristic peaks at 6.3, 8.5, 9.5, 10.2, 16.6, 19.8, 21.2, 23.7 and 25.7, and more preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

11. The sulfate II crystalline form of 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 according to claim 1.

15. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 6.9, 7.6, 9.1, 18.2 and 23.7, preferably has characteristic peaks at 6.9, 7.6, 9.1, 17.0, 18.2, 20.7, 23.7 and 24.0, and more preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

12. The sulfate III crystalline form of 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 according to claim 1.

16. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 6.9, 12.5, 16.5, 19.4, 21.2 and 24.0, preferably has characteristic peaks at 6.9, 9.7, 12.5, 16.5, 19.4, 21.2, 24.0 and 25.8, and more preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

13. The sulfate IV crystalline form of 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 according to claim 1.

17. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 7.6, 11.4, 13.5, 17.2, 18.8 and 19.5, preferably has characteristic peaks at 7.6, 10.0, 11.4, 13.5, 14.0, 17.2, 19.5, 22.5 and 24.6, and more preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

14. The sulfate V crystalline form of 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 according to claim 1.

18. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 6.7, 8.8, 14.6, 15.9 and 23.7, preferably has characteristic peaks at 6.7, 8.8, 10.6, 14.6, 15.9, 19.5, 21.4 and 23.7, and more preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

15. The sulfate VI crystalline form of 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 according to claim 1.

19. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 5.8, 8.8, 11.6, 20.7 and 23.4, preferably has characteristic peaks at 5.8, 8.8, 9.8, 10.5, 11.6, 14.6, 18.4, 20.7 and 23.4, and more preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

16. The hydrochloride I crystalline form of 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 according to claim 1.

20. The powder X-ray diffraction pattern indicated by the diffraction angle 2θ has characteristic peaks at 5.9, 8.8, 10.6, 17.2, 19.3 and 23.9, preferably has characteristic peaks at 5.9, 8.8, 10.6, 13.2, 17.2, 19.3, 21.3, 23.9, 24.4 and 26.1, more preferably has characteristic peaks at 5.9, 8.8, 10.6, 11.9, 13.2, 14.7, 17.2, 19.3, 19.9, 21.3, 23.9, 24.4, 26.1 and 27.4, and most preferably, the powder X-ray diffraction pattern indicated by the diffraction angle 2θ is as shown in FIG.

17. The hydrochloride II crystalline form of 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 according to claim 1.

21. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 6.1, 8.8, 10.4, 18.4, 19.9 and 24.6, preferably has characteristic peaks at 6.1, 8.8, 10.4, 12.2, 18.4, 19.9, 22.6, 24.6 and 28.0, more preferably has characteristic peaks at 6.1, 8.8, 10.4, 12.2, 14.6, 16.6, 17.8, 18.4, 19.9, 22.6, 24.6, 27.2 and 28.0, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

18. The hydrochloride III crystal form of 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 according to claim 1.

22. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 5.4, 9.0, 10.8, 20.4 and 21.8, preferably has characteristic peaks at 5.4, 9.0, 10.8, 19.3, 20.4, 21.8 and 27.3, more preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

19. The hydrochloride IV crystal form of 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 according to claim 1.

23. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 5.2, 6.7, 7.7, 10.2 and 17.4, preferably has characteristic peaks at 5.2, 6.7, 7.7, 10.2, 10.8, 17.4, 20.5 and 24.2, more preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

20. The hydrochloride V crystal form of 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 according to claim 1.

24. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 5.8, 10.3, 11.7, 17.7, 20.7 and 23.7, preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

21. The hydrochloride VI crystal form of 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 according to claim 1.

25. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8 and 26.1, preferably has characteristic peaks at 6.1, 9.6, 10.0, 14.0, 16.7, 17.2, 19.1, 19.6, 25.8 and 26.1, more preferably has characteristic peaks at 6.1, 9.6, 10.0, 10.8, 14.0, 16.7, 17.2, 18.6, 19.1, 19.6, 20.2, 25.8 and 26.1, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in Figure 22. The fumarate I crystal form of 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 according to claim 1.

26. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 6.2, 6.6, 8.0, 13.2, 14.0, 20.3 and 24.2, preferably has characteristic peaks at 6.2, 6.6, 8.0, 9.0, 13.2, 14.0, 16.4, 17.1, 19.8, 20.3, 24.2 and 25.3, more preferably has characteristic peaks at 6.2, 6.6, 8.0, 9.0, 12.0, 13.2, 14.0, 16.4, 17.1, 19.3, 19.8, 20.3, 21.9, 22.3, 24.2, 25.3, 25.7 and 28.1, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in Figure 23. The fumarate II crystal form of 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 according to claim 1.

27. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 7.6, 10.6, 16.4, 18.4, 22.6 and 24.0, preferably has characteristic peaks at 7.6, 10.6, 15.3, 16.4, 18.4, 19.6, 22.6, 24.0, 26.5 and 27.0, more preferably has characteristic peaks at 7.6, 10.6, 15.3, 16.4, 18.4, 19.6, 21.4, 22.6, 24.0, 25.5, 26.5, 27.0 and 28.9, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

24. The hydrobromide I crystalline form of 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 according to claim 1.

28. The powder X-ray diffraction pattern shown by the diffraction angle 2θ has characteristic peaks at 7.2, 10.5, 16.5, 22.5, 23.4 and 26.6, preferably has characteristic peaks at 7.2, 10.5, 13.1, 16.5, 18.8, 20.3, 22.5, 23.4 and 26.6, more preferably has characteristic peaks at 7.2, 10.5, 13.1, 16.5, 17.2, 18.8, 20.3, 21.5, 21.9, 22.5, 23.4 and 26.6, and most preferably, the powder X-ray diffraction pattern shown by the diffraction angle 2θ is as shown in FIG.

25. The hydrobromide II crystalline form of 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 according to claim 1.

29. The error range of the 2θ angle is ±0.

2. The crystalline form of a pharmaceutically acceptable salt of 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 according to any one of claims 4 to 26.

30. A pharmaceutical composition comprising the following components, namely, i) a pharmaceutically acceptable salt of 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 according to claim 1 or a crystalline form of a pharmaceutically acceptable salt of a compound represented by formula (I) according to any one of claims 4 to 22, and ii) one or more pharmaceutically acceptable excipients, a pharmaceutical composition comprising.

31. A method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable salt of 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 according to claim 1 or a crystalline form of a pharmaceutically acceptable salt of 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 according to any one of claims 4 to 29 with a pharmaceutically acceptable excipient.

32. Use of a pharmaceutically acceptable salt of 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 according to claim 1 or a crystalline form of a pharmaceutically acceptable salt of 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 according to any one of claims 4 to 29, or the composition according to claim 30, in the preparation of an agent for inhibiting the activation of the complement pathway 2, preferably for inhibiting complement factor B.

33. Use of a pharmaceutically acceptable salt of 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 as claimed in claim 1, or a crystalline form of a pharmaceutically acceptable salt of 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 as claimed in any one of claims 4 to 29, or a composition as claimed in claim 30, wherein the disease or medical condition is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis due to Behçet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada disease, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, undesirable or unwanted complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during interleukin-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, 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 infection or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and pulmonary infarction, pneumonia, pneumoconiosis, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitosis, Gerstmann syndrome, pulmonary vasculitis, microscopic immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome and obesity, and wherein the disease or medical condition is preferably C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria

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