pharmaceutically acceptable salts, crystalline forms, and methods for preparing nitrogen-containing cross-linked heterocyclic derivatives

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 priority to Chinese patent application 2022107702298, filed on 2022 / 6 / 30. The entire text of the aforementioned Chinese patent application is incorporated herein by reference.

[0002] (Technical field) This disclosure pertains to the pharmaceutical field and relates to pharmaceutically acceptable salts and crystalline forms of nitrogen-containing cross-linked heterocyclic derivatives, and more specifically to pharmaceutically acceptable salts of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid, as well as its crystalline form and method of preparation. [Background technology]

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

[0004] The complement system is a crucial regulator of inflammatory responses and tissue damage, and is composed of more than 20 serum and cell surface proteins. The complement system includes complement-specific components and various regulatory proteins. Complement-specific components include C1-C9, with C3 being the most abundant. Complement regulatory proteins are further divided into two types: soluble and membrane-bound. Soluble complement regulatory proteins include clatherin, S protein, and complement factor H-related proteins. Membrane-bound complement regulatory proteins include membrane cofactor proteins (MCPs), decay-accelerating factors (DAFs), and complement receptor 1. The complement system also includes several complement fragments and complement receptors such as the C3a and C5a receptors.

[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 MBL pathway (mannan-binding lectin pathway)). During the activation process, complement exerts powerful biological effects through a series of positive feedback loops, playing a role in the onset and progression of disease. C3 convertase is a key component of these three pathways, and through the complement activation cascade, it produces a series of complement protein fragments and the membrane attack complex (MAC). C3 convertase cleaves C3 to produce C5 convertase, which then cleaves C5 to produce C5a and C5b. C5b then binds with C6, C7, C8, and C9 to form C5b-9, i.e., the MAC. Abnormalities in the complement pathway lead to the lysis of organism-specific normal cells, resulting in disease development.

[0006] Complement factor B is a non-heat-stable 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, with Bb binding to C3b to form C3 convertase of the complement II pathway. Complement factor B is one of the important components in the complement II pathway activation pathway and is also called a C3 activator precursor. Complement factor B has a molecular weight of 93 kDa, a human blood concentration of approximately 3 μM, and is mainly synthesized in the liver, but has also been found to be synthesized in retinal pigment epithelial cells of the eye.

[0007] Glomerulopathy includes immunoglobulin A nephropathy (IgA nephropathy, abbreviated as IgAN), C3G glomerulopathy (C3G glomerulopathy, abbreviated as C3G), and membranous glomerulonephritis (MGN). Of these, IgAN and MGN are the most common, and the incidence of rare kidney diseases such as C3 glomerulopathy has also increased in the last decade. Research shows that glomerulopathy is closely related to the complement pathway, particularly the complement II pathway. Currently, there is no clinically effective treatment for primary glomerulonephritis. Drug therapy commonly involves hormones and immunosuppressants (e.g., cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and the herbal medicine trypterygium glycoside), as well as blood pressure regulators, diuretics and antiplatelet aggregation agents, anticoagulants, lipid-lowering drugs, and kidney-preserving detoxification agents such as cordyceps preparations.

[0008] IgAN is the most common primary glomerular disease worldwide. Pathologically, it presents with localized mesangial proliferation and matrix increase, accompanied by diffuse IgA protein deposition in the mesangial region, and consistently with IgG, C3, and C5b-9 deposition. Therefore, the complement pathway is thought to be involved in the development and progression of IgAN. Currently, two small molecule drugs targeting the complement pathway are in clinical trials. OMS721 is a humanized monoclonal antibody developed by Omeros that targets the MASP-2 protein. 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, all four IgAN patients who participated in the trial showed significant improvement in their proteinuria index. This drug is currently in Phase III clinical research.

[0009] Currently disclosed patent applications for Factor B inhibitors include WO2015009616A1, WO2019043609A1, and WO2020016749A2, among others. Application WO2022143845 structurally characterizes a series of nitrogen-containing heterocyclic derivatives, including 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid. Furthermore, the application also conducted a biological evaluation of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid (compound I), which showed that the compound has a good inhibitory effect on Factor B enzyme activity.

[0010] The crystalline structure of pharmaceutical active ingredients tends to affect the chemical stability of the drug. Depending on crystallization and storage conditions, the crystalline structure of the compound may change, sometimes leading to the formation of other crystalline forms. Generally, amorphous pharmaceutical products lack a regular crystalline structure and tend to have other defects, such as poor product stability, fine precipitated crystals, difficulty in filtration, tendency to solidify, and poor fluidity. Therefore, in order to improve the various properties of the above-mentioned products, in-depth research is required to find crystalline forms that have high purity and good physical and chemical stability. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] International Publication No. 2015009616A1 [Patent Document 2] International Publication No. 2019043609A1 [Patent Document 3] International Publication No. 2020016749A2 [Overview of the project] [Problems that the invention aims to solve]

[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 disclosure provides a phosphate II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 8.4, 9.5, 10.2, 11.7, 14.7 and 19.1, selectively having characteristic peaks at 6.9, 8.4, 9.5, 10.2, 10.7, 11.7, 14.7, 18.5 and 19.1, and selectively 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 disclosure provides a phosphate III crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 18.5 and 21.3, selectively having characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 21.3 and 24.1, and selectively 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 disclosure provides a phosphate IV crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated at a diffraction angle of 2θ, has characteristic peaks at 6.9, 8.4, 10.3, 11.7, and 14.8.

[0024] In some embodiments, the disclosure provides a phosphate V crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated at a diffraction angle of 2θ, has characteristic peaks at 9.1, 10.2, 11.5, 15.7 and 19.8, and selectively has 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 disclosure provides a crystalline form of p-toluenesulfonate I of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 5.0, 9.4, 10.1, 16.3 and 18.3, selectively having characteristic peaks at 5.0, 9.4, 10.1, 16.3, 18.3, 18.9, 21.2 and 22.9, and selectively having 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 disclosure provides a p-toluenesulfonate II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 4.7, 8.8, 9.3, 10.8, 13.9 and 18.7, and selectively 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 disclosure provides a p-toluenesulfonate III crystalline form of compound I, wherein the powder X-ray diffraction pattern, shown at a diffraction angle of 2θ, has characteristic peaks at 6.8, 7.4, 8.1, 10.1, and 12.7.

[0028] In some embodiments, the disclosure provides a sulfate I crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated at a diffraction angle of 2θ, has characteristic peaks at 7.2, 9.2, 17.1, 20.0, 21.4 and 24.7, and selectively 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 disclosure provides a sulfate II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 9.5, 10.2, 16.6, 21.2 and 25.7, and selectively 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 disclosure provides a sulfate III crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 6.9, 7.6, 9.1, 18.2 and 23.7, and selectively 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 disclosure provides a sulfate IV crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated at a diffraction angle of 2θ, has characteristic peaks at 6.9, 12.5, 16.5, 19.4, 21.2, and 24.0, and selectively 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 disclosure provides a sulfate V crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 7.6, 11.4, 13.5, 17.2, 18.8 and 19.5, and selectively 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 disclosure provides a sulfate VI crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated at a diffraction angle of 2θ, has characteristic peaks at 6.7, 8.8, 14.6, 15.9 and 23.7, and selectively 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 disclosure provides a crystalline form of the hydrochloride salt I of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 5.8, 8.8, 11.6, 20.7, and 23.4, and selectively 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 disclosure provides a hydrochloride salt II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 5.9, 8.8, 10.6, 17.2, 19.3 and 23.9, selectively having 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 selectively having 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 disclosure provides a hydrochloride salt III crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 6.1, 8.8, 10.4, 18.4, 19.9 and 24.6, selectively having characteristic peaks at 6.1, 8.8, 10.4, 12.2, 18.4, 19.9, 22.6, 24.6 and 28.0, and selectively having 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 disclosure provides a IV crystalline form of the hydrochloride salt of compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 5.4, 9.0, 10.8, 20.4, and 21.8, and selectively has characteristic peaks at 5.4, 9.0, 10.8, 19.3, 20.4, 21.8, and 27.3. In some embodiments, the disclosure provides a V crystalline form of the hydrochloride salt of compound I, wherein the powder X-ray diffraction pattern shown at a diffraction angle of 2θ has characteristic peaks at 5.2, 6.7, 7.7, 10.2, and 17.4, and selectively 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 disclosure provides a crystalline form VI of the hydrochloride salt of compound I, wherein the powder X-ray diffraction pattern, indicated by a 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 disclosure provides a fumarate I crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8 and 26.1, selectively having 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 selectively having 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 disclosure provides a fumarate II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle of 2θ, has characteristic peaks at 6.2, 6.6, 8.0, 13.2, 14.0, 20.3 and 24.2, selectively having 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 selectively having 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 disclosure provides a hydrobromide I crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 7.6, 10.6, 16.4, 18.4, 22.6 and 24.0, selectively having 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 selectively having 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 disclosure provides a hydrobromide II crystalline form of compound I, wherein the powder X-ray diffraction pattern, indicated by a diffraction angle 2θ, has characteristic peaks at 7.2, 10.5, 16.5, 22.5, 23.4 and 26.6, selectively having characteristic peaks at 7.2, 10.5, 13.1, 16.5, 18.8, 20.3, 22.5, 23.4 and 26.6, and selectively having 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, in which the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0044] In some embodiments, the present disclosure provides amorphous phosphate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in 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 does not have any distinct characteristic peaks in the range of 3° to 48°.

[0046] In some embodiments, the present disclosure provides amorphous sulfate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0047] In some embodiments, the present disclosure provides amorphous tartrate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0048] In some embodiments, the present disclosure provides amorphous succinate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0049] In some embodiments, the present disclosure provides an amorphous fumarate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0050] In some embodiments, the present disclosure provides an amorphous citrate of compound I, in which the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0051] In some embodiments, the present disclosure provides an amorphous malate of compound I in which the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0052] In some embodiments, the present disclosure provides amorphous hydrobromide of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0053] In some embodiments, the present disclosure provides an amorphous mesylate of compound I, wherein the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0054] In some embodiments, the present disclosure provides amorphous hydrochloride salts of compound I, in which the diffraction angle 2θ of the powder X-ray diffraction pattern does not have any distinct characteristic peaks in the range of 3° to 48°.

[0055] In a selective embodiment, a crystalline form of a pharmaceutically acceptable salt of compound I provided herein, wherein the error range of the 2θ angle is ±0.2.

[0056] In another embodiment, the present disclosure provides a method for preparing the maleate I crystalline form of compound I, comprising: a. dissolving compound I in acetonitrile and adding a maleic acid solution to form a slurry; and b. adding isopropyl ether and crystallizing the compound.

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

[0058] This disclosure provides a method for preparing the phosphate II crystalline 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 the mixture.

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

[0060] This disclosure provides a method for preparing the phosphate IV crystalline form of compound I, comprising adding compound I to acetonitrile and phosphoric acid, stirring, and crystallizing.

[0061] This disclosure provides a method for preparing the phosphate V crystalline form of compound I, comprising adding compound I to ethanol and phosphoric acid, and stirring to crystallize it.

[0062] This disclosure provides a method for preparing the p-toluenesulfonate I crystalline 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, forming a slurry 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] This disclosure provides a method for preparing the p-toluenesulfonate II crystalline form of compound I, comprising adding compound I to isopropanol and p-toluenesulfonic acid, stirring, and crystallizing.

[0064] This disclosure provides a method for preparing the p-toluenesulfonate III crystalline form of compound I, comprising adding the p-toluenesulfonate II crystalline form to methyl tert-butyl ether and stirring to crystallize it.

[0065] This disclosure provides a method for preparing the sulfate I crystalline form of compound I, comprising adding compound I to a solvent (5) selected from ethanol and acetonitrile and sulfuric acid, and stirring to crystallize the mixture.

[0066] This disclosure provides a method for preparing the sulfate II crystalline form of compound I, comprising adding compound I to acetone and sulfuric acid, stirring, and crystallizing the mixture.

[0067] This disclosure provides a method for preparing the sulfate III crystalline form of compound I, comprising dissolving compound I in ethanol, adding sulfuric acid, adding isopropyl ether, and stirring to crystallize the compound.

[0068] This disclosure provides a method for preparing the sulfate IV crystalline form of compound I, comprising adding compound I to a solvent (6) selected from isopropanol and acetone and sulfuric acid, and stirring to crystallize the mixture.

[0069] This disclosure provides a method for preparing the sulfate V crystalline form of compound I, comprising adding compound I to a solvent (7) selected from ethyl acetate and isopropyl acetate and sulfuric acid, and stirring to crystallize the mixture.

[0070] This disclosure provides a method for preparing the sulfate VI crystalline form of compound I, comprising adding the sulfate I crystalline form to isopropyl acetate and stirring to crystallize it.

[0071] This disclosure provides a method for preparing the hydrochloride salt I crystalline form of compound I, comprising Method 1, in which compound I is dissolved in ethanol, hydrochloric acid is added, isopropyl ether is added and stirred to crystallize, and Method 2, in which compound I is added to isopropyl acetate and hydrochloric acid and stirred to crystallize.

[0072] This disclosure provides a method for preparing the hydrochloride salt II crystalline form of compound I, comprising: Method 1, in which compound I is dissolved in ethanol, hydrochloric acid is added, isopropyl ether is added and stirred to crystallize; and Method 2, in which compound I is added to a solvent (8) selected from isopropanol and acetonitrile and hydrochloric acid, and stirred to crystallize.

[0073] This disclosure provides a method for preparing the hydrochloride salt III crystalline form of compound I, comprising adding compound I to a solvent (9) selected from acetone and ethyl acetate and hydrochloric acid, and stirring to crystallize the mixture.

[0074] This disclosure provides a method for preparing the hydrochloride salt IV crystalline form of compound I, comprising adding compound I to a solvent (10) selected from tetrahydrofuran and isopropanol and hydrochloric acid, and stirring to crystallize the mixture.

[0075] This disclosure provides a method for preparing the hydrochloride salt V crystalline form of compound I, comprising adding compound I to acetonitrile and hydrochloric acid, stirring, and crystallizing.

[0076] This disclosure provides a method for preparing the hydrochloride salt VI crystalline form of compound I, comprising adding compound I to isopropanol and hydrochloric acid, stirring, and crystallizing.

[0077] This disclosure provides a method for preparing the fumarate I crystalline form of compound I, comprising adding compound I to a solvent (11) selected from acetonitrile and acetone and fumaric acid, and stirring to crystallize the mixture.

[0078] This disclosure provides a method for preparing the fumarate II crystalline form of compound I, comprising adding compound I to a methanol / acetonitrile solution and fumaric acid, and allowing it to volatilize and crystallize.

[0079] This disclosure provides a method for preparing the hydrobromide salt I crystalline form of compound I, comprising dissolving compound I in ethanol, adding hydrobromic acid, adding isopropyl ether, and stirring to crystallize the compound.

[0080] This disclosure provides a method for preparing the hydrobromide II crystalline form of compound I, comprising adding compound I to a solvent (12) selected from isopropanol and ethyl acetate and hydrobromic acid, and stirring to crystallize the mixture.

[0081] This disclosure provides a method for preparing an amorphous maleate of compound I, comprising dissolving compound I in a solvent (13) which is at least one selected from ethanol, acetone, tetrahydrofuran, acetonitrile / methanol, isopropanol, and ethyl acetate, and maleic acid, then adding isopropyl ether and stirring to crystallize.

[0082] This disclosure provides a method for preparing an amorphous phosphate of compound I, comprising: Method 1, dissolving compound I in acetonitrile / methanol and phosphoric acid, forming a slurry at room temperature, 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] This disclosure provides a method for preparing an amorphous p-toluenesulfonate of compound I, comprising adding compound I to a solvent (15) which is at least one selected from acetonitrile, acetone, tetrahydrofuran, or acetonitrile / methanol, and p-toluenesulfonic acid, slurring at room temperature, then adding isopropyl ether, stirring, and crystallizing.

[0084] This disclosure provides a method for preparing an amorphous sulfate of compound I, comprising: Method 1, dissolving compound I in acetonitrile / methanol, adding sulfuric acid, forming a slurry at room temperature, then adding isopropyl ether and crystallizing; and Method 2, adding compound I to tetrahydrofuran and sulfuric acid and crystallizing.

[0085] This disclosure provides a method for preparing an amorphous tartrate salt of compound I, comprising: Method 1, dissolving compound I in a solvent (16) selected from ethanol or tetrahydrofuran, adding tartaric acid, forming a slurry at room temperature, and then adding isopropyl ether to crystallize; and Method 2, adding compound I to a solvent (17) selected from acetonitrile or acetone and tartaric acid, and then crystallizing.

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

[0087] This disclosure provides a method for preparing an amorphous fumarate of compound I, comprising: Method 1, in which compound I is dissolved in a solvent (20) selected from ethanol or tetrahydrofuran, fumaric acid is added, the mixture is formed into a slurry at room temperature, and then isopropyl ether is added and crystallized; and Method 2, in which compound I is added to acetone and fumaric acid and crystallized.

[0088] This disclosure provides a method for preparing an amorphous citrate of compound I, comprising dissolving compound I in a solvent (21) which is at least one selected from ethanol, acetonitrile, acetone, or tetrahydrofuran, adding citric acid, forming a slurry at room temperature, and then adding isopropyl ether to crystallize it.

[0089] This disclosure provides a method for preparing an amorphous malate salt of compound I, comprising: Method 1, dissolving compound I in a solvent (22) which is at least one selected from ethanol, acetone, or tetrahydrofuran; adding malic acid; forming a slurry at room temperature; and then adding isopropyl ether and crystallizing; and Method 2, adding compound I to acetonitrile and malic acid and crystallizing.

[0090] This disclosure provides a method for preparing an amorphous hydrobromide salt of compound I, comprising dissolving compound I in a solvent (23) which is at least one selected from acetonitrile, acetone, or tetrahydrofuran, adding hydrobromic acid, forming a slurry at room temperature, and then adding isopropyl ether to crystallize it.

[0091] This disclosure provides a method for preparing an amorphous mesylate of compound I, comprising dissolving compound I in a solvent (24) which is at least one selected from acetonitrile, acetone, tetrahydrofuran, or ethanol, adding methanesulfonic acid, forming a slurry at room temperature, and then adding isopropyl ether to crystallize it.

[0092] This disclosure provides a method for preparing an amorphous hydrochloride salt of compound I, comprising dissolving compound I in ethanol, adding hydrochloric acid, forming a slurry at room temperature, and then adding isopropyl ether and crystallizing it.

[0093] In one embodiment, the method for preparing the crystalline form described herein further includes a filtration, washing, or drying step.

[0094] This disclosure further provides pharmaceutical compositions prepared from crystalline forms of pharmaceutically acceptable salts of compound I.

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

[0096] This disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable salt of compound I, a pharmaceutically acceptable crystalline form of the salt, or a mixture thereof, or a pharmaceutically acceptable salt of compound I prepared by the above method with a pharmaceutically acceptable excipient.

[0097] This disclosure further provides the use of a pharmaceutically acceptable salt of compound I, a pharmaceutically acceptable crystalline form of a pharmaceutically acceptable salt, or a mixture thereof, or a pharmaceutically acceptable salt, a pharmaceutically acceptable crystalline form of a pharmaceutically acceptable salt, or a mixture thereof, or a composition prepared by the above method, or a composition prepared by the above method, in the preparation of agents for inhibiting the activation of the complement II pathway.

[0098] This disclosure further provides the use of a pharmaceutically acceptable salt, pharmaceutically acceptable crystalline form or mixture thereof of compound I, or a pharmaceutically acceptable salt, pharmaceutically acceptable crystalline form or mixture thereof prepared by the above method, or the above composition, in the preparation of a drug for treating a disease or medical condition, wherein the disease or medical condition is glomerulosis, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, or diabetic retinopathy. uveitis, retinitis pigmentosa, macular edema, uveitis due to Behçet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada disease, birdshot retinoretinopathy, sympathetic ophthalmitis, ocular scarring pemphigoid, ocular pemphigus, 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 undesirable complement activation disorder, hemodialysis complications, hyperacute allograft rejection, Xenotransplant rejection, interleukin-2 induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass 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 glomerulonephritis, hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, The following conditions are selected from 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, parasitic diseases, Gerstmann syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, and obesity. Preferably, the above disease or condition is C3 glomerulosis, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.

[0099] In this disclosure, “2θ or 2θ angle” refers to the diffraction angle, where θ is the Bragg angle, the unit is degrees or degrees, and the error range of each characteristic peak 2θ is ±0.20 (including cases where numbers exceeding one decimal place are rounded), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11 The values ​​are -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, and 0.20.

[0100] The terms "crystal precipitation" or "crystallization" as used in this disclosure include, but are not limited to, stirred crystallization, slurry crystallization, cooling crystallization, and volatile crystallization.

[0101] As described in this disclosure, “differential scanning calorimetry or DSC” 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 thermal effects and to obtain information on phase transitions of the sample during heating or constant temperature of the sample.

[0102] The drying temperature described in this disclosure is generally 25 to 100°C, preferably 40 to 70°C, and may be either atmospheric pressure drying or reduced pressure drying.

[0103] The “pharmaceutically acceptable excipients” described herein include, but are not limited to, any excipients, carriers, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have already been approved by the U.S. Food and Drug Administration and are permitted for use in humans or livestock. [Brief explanation of the drawing]

[0104] [Figure 1] This is the XRPD spectrum of the maleate I crystal form of compound I. [Figure 2] This is the XRPD spectrum of the phosphate I crystal form of compound I. [Figure 3] This is the XRPD spectrum of the phosphate II crystal form of compound I. [Figure 4] This is the XRPD spectrum of the phosphate III crystal form of compound I. [Figure 5] This is the XRPD spectrum of the phosphate IV crystal form of compound I. [Figure 6] This is the XRPD spectrum of the phosphate V crystal form of compound I. [Figure 7] This is the XRPD spectrum of the p-toluenesulfonate I crystalline form of compound I. [Figure 8] This is the XRPD spectrum of the p-toluenesulfonate II crystalline form of compound I. [Figure 9] This is the XRPD spectrum of the p-toluenesulfonate III crystalline form of compound I. [Figure 10] This is the XRPD spectrum of the sulfate I crystal form of compound I. [Figure 11] This is the XRPD spectrum of the sulfate II crystal form of compound I. [Figure 12] This is the XRPD spectrum of the sulfate III crystalline form of compound I. [Figure 13] This is the XRPD spectrum of the sulfate IV crystal form of compound I. [Figure 14] This is the XRPD spectrum of the sulfate V crystal form of compound I. [Figure 15] This is the XRPD spectrum of the sulfate VI crystal form of compound I. [Figure 16] This is the XRPD spectrum of the hydrochloride salt I crystal form of compound I. [Figure 17] This is the XRPD spectrum of the hydrochloride salt II crystal form of compound I. [Figure 18] This is the XRPD spectrum of the hydrochloride salt III crystal form of compound I. [Figure 19] This is the XRPD spectrum of the hydrochloride salt IV crystal form of compound I. [Figure 20] This is the XRPD spectrum of the hydrochloride salt V crystal form of compound I. [Figure 21] This is the XRPD spectrum of the hydrochloride salt VI crystal form of compound I. [Figure 22] This is the XRPD spectrum of the fumarate I crystal form of compound I. [Figure 23] This is the XRPD spectrum of the fumarate II crystal form of compound I. [Figure 24] This is the XRPD spectrum of the hydrobromide I crystalline form of compound I. [Figure 25] This is the XRPD spectrum of the hydrobromide II crystalline form of compound I. [Figure 26] This is the XRPD spectrum of the amorphous fumarate of compound I. [Modes for carrying out the invention]

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

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

[0107] A Finnigan LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model number: Finnigan LCQ advantage MAX) was used for the MS measurements.

[0108] For HPLC measurements, the Agilent 1260DAD high-performance liquid chromatograph (with a Sunfire C18 150×4.6mm column) and the Thermo U3000 high-performance liquid chromatograph (with a Gimini C18 150×4.6mm column) were used.

[0109] XRPD refers to detection by powder X-ray diffraction. A BRUKER D8 type X-ray diffractometer was used for the measurement, and the specific collected information is as follows: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation (l=1.5418Å). Scanning method: θ / 2θ, scanning range: 3°~48° o .

[0110] DSC stands for Differential Scanning Calorimetry. The measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10°C / min, a temperature range of 25°C to 350°C, and a nitrogen gas purge rate of 50 mL / min.

[0111] TGA stands for thermogravimetric analysis, and a METTLER TOLEDO TGA 2 thermogravimetric analyzer is used for detection. The heating rate is 10°C / min, the specific temperature range is determined by referring to the corresponding spectrum, and the nitrogen gas purging rate is 50 mL / min.

[0112] DVS stands for Dynamic Moisture Adsorption, and Surface Measurement Systems Instrinsic was used. Humidity was measured starting at 50% and in 10% steps over a humidity range of 0% to 95%. The criteria for evaluation was a mass change dM / dT of less than 0.002% per gradient, with a TMAX of 360 min and two cycles.

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

[0114] [ka]

[0115] Step 1 1-(4-bromophenyl)butane-1,4-diol 1b Methyl 4-(4-bromophenyl)-4-oxobutyrate 1a (5 g, 17.54 mmol, Bi De Pharmaceutical Technology Co., Ltd.) was dissolved in tetrahydrofuran (50 mL), and a solution of lithium borohydride in tetrahydrofuran (17 mL, 2 mmol / mL) was added at 0°C. The mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction mixture was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, title product 1b (4.29 g), which was used directly in the next reaction without purification. MS m / z (ESI): 242.9 [MH].

[0116] Step 2 4-(4-bromophenyl)-4-oxobutyraldehyde 1c Dimethyl sulfoxide (8.2 g, 104.95 mmol) was dissolved in dichloromethane (50 mL), and oxalyl chloride (8.8 g, 69.33 mmol) was added at -78°C. The mixture was stirred 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 mixture was stirred for 1 hour. The mixture was allowed to rise naturally to room temperature, diluted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate aqueous solution, the organic phase was dried, concentrated under reduced pressure, and purified with eluent C by silica gel column chromatography 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 the mixture was stirred 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 mixture was adjusted to a pH of 8-9 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and purified with eluent C by silica gel column chromatography 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-3ol 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 mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain the crude product, 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 stirred for 1 hour, and iodoethane (325 mg, 2.09 mmol) was added. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure, and purified with eluent C by silica gel column chromatography to obtain the title compound 1f (350 mg, yield: 77.9%). MS m / z (ESI): 429.9[M+1].

[0120] Step 6 4-(3-ethoxy-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octan-1-yl)methyl benzoate 1g Compound 1f was dissolved in methanol (4 mL) and dimethylformamide (4 mL), and palladium acetate (54 mg, 240.52 μmol), diphenyl phosphate azide (100 mg, 242.46 μmol), and triethylamine (822 mg, 8.12 mmol) were added. The mixture was purged three times with carbon monoxide gas and stirred overnight at 80°C. The reaction mixture was placed in water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure, and purified with eluent C by silica gel column chromatography to obtain 1 g (225 mg, yield: 67.5%) of the title compound. MS m / z (ESI): 411.0[M+1].

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

[0122] Step 8 4-(bromomethyl)-5-methoxy-7-methylindole-1-carboxylate tert-butyl 1j Compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl 1i (150 mg, 514.86 μmol, synthesized according to the preparation method of intermediates 1-10 of WO2015009616A1) was dissolved in dichloromethane (2 mL), carbon tetrabromide (170 mg, 512.62 μmol) and triphenylphosphine (135 mg, 514.71 μmol) were added under a nitrogen atmosphere, the reaction mixture was stirred at room temperature for 2 hours, and the mixture was directly concentrated to obtain the crude product compound 1j (183 mg), which was used directly in the next reaction without purification.

[0123] Step 9 4-((3-ethoxy-1-(4-(methoxycarbonyl)phenyl)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl 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 stirring the reaction mixture for 1 hour, a dimethylformamide solution of compound 1j (183 mg, 516.60 μmol) was added, and the reaction mixture was stirred for 1 hour. The mixture was quenched with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated under reduced pressure, and purified with eluent C by silica gel column chromatography 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-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid 1 Compound 1k (130 mg, 231.03 μmol) was dissolved in 6 mL of a mixed solution of tetrahydrofuran, methanol, and water (V:V:V = 1:1:1). Lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. The reaction 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-performance 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, gradient: 20%~38% for 18 minutes, flow rate: 80 mL / min) to obtain the title compounds 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] [ka] Compound 1 (100 mg, 222.93 μmol) was purified by chiral preparative separation (separation conditions: chiral preparative 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: 20 mL / min), the corresponding components were collected, concentrated under reduced pressure to obtain the title compounds 1-1 (35 mg, yield: 35%) and 1-2 (33 mg, yield: 33%).

[0128] Compound 1-1 (Compound I, 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-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: 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 1. Materials and equipment for the experiment 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. Starting Block TM T20 (TBS) Blocking Buffer (37543, Thermo Fisher) 6. Goat anti-mouse IgG heavy chain + light chain (labeled with horseradish peroxidase) (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, CSI) 12. Sodium bicarbonate (NaHCO3) (10018960, CSI) 13.Tween20(P7949-500ML, Sigma) 14.20X PBS buffer (B548117-0500, raw material) 15.96-well white half-well plate (66PL96025, Cisbio) 16.96-well black suction plate (437111, Thermo Fisher) 17. Phosphate buffer (B320, Shanghai Yuanpei Biological Technology Co., Ltd.) 18. Sterile pure water (homemade by Shanghai Hengrui) 19.96-well plate (3795, Corning) 20.Thermostatic chamber (Shanghai Yicheng Scientific Instruments Co., Ltd.) 21. Flexstation3 Plate Reader (Molecular Device)

[0131] 2. Experimental Procedure Human complement factor B protein needs to form a complex with human complement factor C3 in order to function as a protease. Hydrolysis of human complement factor D protein hydrolyzes human complement factor B into Ba and Bb fragments. Bb combines with the C3b fragment of human complement factor C3 to form the complex C3bBb, i.e., C3 convertase. Only after this complex is formed can human complement factor B function as a protease. C3bBb then hydrolyzes C3 into C3a and C3b fragments. C3b combines with C3bBb to form the complex C3bBbC3b, i.e., C5 convertase, and the C3a fragment is released. Detecting the C3a des Arg epitope produced after C3 shearing can be used to evaluate the efficiency of C3 hydrolysis, i.e., the C3bBb enzyme activity, thereby evaluating the effect of compounds on the C3bBb enzyme. Since C3b is unstable outside the body, cobra venom factor (CVF) was combined with human complement factor B to form a complex, but its function is the same as C3b.

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

[0133] Shear 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 recombinant human complement factor B protein, and 1 μM CVF were added to the reaction buffer (PBS pH 7.4, 10 mM MgCl2, 0.05% CHAPS). After thoroughly mixing, the mixture was reacted in a 37°C incubator for 3 hours to obtain a complex of CVF and sheared recombinant human complement factor B protein fragment Bb (hereinafter referred to as CVF:Bb).

[0134] A 100 mM Na2CO3 solution and a 100 mM NaHCO3 solution were prepared, and the pH was adjusted to 9.5 with a volume ratio of Na2CO3:NaHCO3 = 3:7. The solutions were then stored at room temperature in preparation 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, and 0.007629 μM using a series of 100% DMSO solutions. The blank wells were 100% DMSO, and the compounds were further diluted 20-fold in C3 reaction buffer (PBS pH 7.4, 1 mM MgCl2, 0.05% CHAPS).

[0136] C3 protein shear reaction: In a 96-well white half-well plate, 10 μL of the reaction system was prepared. Specifically, CVF:Bb with a final concentration of 2 nM, 1 μL of the test compound diluted in the above C3 reaction buffer, and DMSO were added to the C3 reaction buffer (PBS pH 7.4, 1 mM MgCl2, 0.05% CHAPS), and the mixture was 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, and 0.152588 nM, respectively. Human complement factor C3 was added to the reaction system at a final concentration of 500 nM, mixed uniformly, and then reacted in a 37°C incubator for 2 hours. Reaction wells containing only 500 nM human complement factor C3 in the reaction mixture were used as negative controls. 97 μL of carbonate buffer (pH 9.5) was added to a 96-well black adsorption plate, and 3 μL of C3 protein shear reaction mixture was taken and added to each well. After uniform mixing, the plate was sealed and incubated overnight at 4°C.

[0137] C3a des Arg detection: Wash the plate three times with 300 μL / well of TBST (0.05% Tween20) solution, and add 300 μL of StartingBlock to each well. TM Add T20 (TBS) blocking buffer, incubate at 37°C for 5 minutes, wash the plate three times with 300 μL / well PBST solution, dilute anti-C3a / C3a des Arg antibody

[2991] 1:1000 in PBST solution, add 100 μL to each well, incubate at 37°C for 1 hour, wash the plate three times with 300 μL / well PBST solution, dilute goat anti-mouse IgG H&L (HRP) antibody 1:5000 in PBST solution, add 100 μL to each well, incubate at 37°C for 30 minutes, and QuantaBlu TM Fluorescently labeled peroxidase substrate reagent kit (QuantaBlu TM Prepare the substrate using the Fluorogenic Peroxidase Substrate Kit, and add a portion 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 on 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: The IC 50 of compound I for the inhibitory activity against Factor B enzyme was 1.3 nM, and it had an excellent inhibitory effect 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] Powder X-ray diffraction detection revealed the product to be maleate I crystalline form. The XRPD spectrum is shown in Figure 1, and its characteristic peak positions are shown in Table 1. According to the DSC spectrum, the endothermic peak value is 156.79°C. According to the TGA spectrum, the weight decreased by 3.22% between 30°C and 145°C.

[0142] [Table 1]

[0143] Example 4. Preparation of phosphate I crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetonitrile was added, followed by the addition of phosphoric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0144] Powder X-ray diffraction detection revealed the product to be a phosphate I crystalline form. The XRPD spectrum is shown in Figure 2, and its characteristic peak positions are shown in Table 2. According to the DSC spectrum, the endothermic peak value is 195.83°C. According to the TGA spectrum, the weight decreased by 2.80% between 30°C and 150°C.

[0145] [Table 2]

[0146] Example 5. Preparation of phosphate I crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetone was added, followed by the addition of phosphoric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0147] Powder X-ray diffraction detection revealed that the product is a phosphate I crystalline form.

[0148] Example 6. Preparation of phosphate II crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of ethyl acetate was added, and a phosphoric acid ethanol solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0149] Powder X-ray diffraction detection revealed the product to be a phosphate II crystalline form. The XRPD spectrum is shown in Figure 3, and its characteristic peak positions are shown in Table 3. Ion chromatography revealed that the phosphate ion content was 17.33%. According to the DSC spectrum, the endothermic peak value was 146.30°C. TGA spectroscopy showed a weight decrease of 1.09% between 30°C and 175°C.

[0150] [Table 3]

[0151] Example 7. Preparation of phosphate II crystalline form Approximately 40 mg of compound I was weighed, 0.75 mL of acetone was added, followed by the addition of phosphoric acid solution (2 mol / L, 47 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0152] Powder X-ray diffraction detection revealed that the product is in the phosphate II crystalline form.

[0153] Example 8. Preparation of phosphate III crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of isopropanol was added, and a phosphoric acid ethanol solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0154] Powder X-ray diffraction detection revealed the product to be a phosphate III crystalline form. The XRPD spectrum is shown in Figure 4, and its characteristic peak positions are shown in Table 4. Ion chromatography showed that the phosphate ion content was 16.72%. According to the DSC spectrum, the endothermic peaks were at 66.14°C and 143.48°C, and the heat dissipation peak was at 182.62°C. According to the TGA spectrum, the weight decreased by 6.16% between 30°C and 150°C.

[0155] According to DVS detection, the sample showed a weight increase due to moisture absorption of approximately 4.77% under normal storage conditions (i.e., 25°C, 60%RH), 5.44% under accelerated experimental conditions (i.e., 70%RH), and 7.20% under extreme conditions (i.e., 90%RH). Furthermore, re-measurement of the crystal form after DVS detection showed no transformation of the crystal form.

[0156] [Table 4]

[0157] Example 9. Preparation of phosphate IV crystalline form Approximately 30 mg of compound I was weighed, dissolved in 0.5 mL of acetonitrile, heated to 40°C, 8.2 mg of 85% phosphoric acid was added, cooled to room temperature and stirred for 16 hours, filtered to collect the filtered cake, dried under vacuum at 60°C for 4 hours to obtain the product.

[0158] Powder X-ray diffraction detection revealed that the product is a phosphate IV crystal form. The XRPD spectrum is shown in Figure 5, and its characteristic peak positions are shown in Table 5.

[0159] [Table 5]

[0160] Example 10. Preparation of phosphate V crystalline form 30 mg of compound I was weighed and dissolved in 1 mL of ethanol, the mixture was heated to 40°C, 85% phosphoric acid (8.2 mg, 66.88 μmol) was added, the mixture was cooled to room temperature, stirred for 16 hours, filtered, and the filtered cake was collected. The product was dried under vacuum at 60°C for 4 hours to obtain the product.

[0161] Powder X-ray diffraction detection revealed that the product was defined as a phosphate V crystal form. The XRPD spectrum is shown in Figure 6, and its characteristic peak positions are shown in Table 6. According to the DSC spectrum, the endothermic peaks were at 48.64°C and 223.41°C, and the heat dissipation peak was at 194.80°C. According to the TGA spectrum, the weight decreased by 2.47% between 30°C and 100°C, and by 2.76% between 100°C and 250°C.

[0162] [Table 6]

[0163] Example 11. Preparation of p-toluenesulfonate I crystalline form Approximately 8 mg of compound I was weighed and dissolved in 0.2 mL of ethanol. A solution of p-toluenesulfonic acid (2 mol / L, 9.8 μL) was added, and the mixture was stirred overnight. Then, 0.8 mL of isopropyl ether was added, and the mixture was stirred to induce crystallization. After centrifugation, the solid was dried under vacuum to obtain the product.

[0164] Powder X-ray diffraction detection revealed the product to be p-toluenesulfonate I crystalline form. The XRPD spectrum is shown in Figure 7, and its characteristic peak positions are shown in Table 7. Ion chromatography revealed that the p-toluenesulfonate ion content was 30.75%. According to the DSC spectrum, the endothermic peaks were at 57.15°C and 180.78°C. TGA spectroscopy showed a weight decrease of 2.07% between 30°C and 145°C.

[0165] According to DVS detection, the sample showed a weight increase due to moisture absorption of approximately 1.22% under normal storage conditions (i.e., 25°C, 60%RH), approximately 1.37% under accelerated experimental conditions (i.e., 70%RH), and approximately 1.87% under extreme conditions (i.e., 90%RH). Furthermore, re-measurement of the crystal form after DVS detection showed no transformation of the crystal form.

[0166] [Table 7]

[0167] Example 12. Preparation of p-toluenesulfonate I crystalline form Compound I was weighed and added to a solvent and a 2 mol / L p-toluenesulfonic acid solution, and crystallized to obtain the product. The crystal form was confirmed by powder X-ray diffraction, as shown in Table 8.

[0168] [Table 8]

[0169] Example 13. Preparation of p-toluenesulfonate II crystalline form Approximately 938 mg of compound I was weighed, dissolved in 40 mL of isopropanol, and clarified by stirring at 40°C. The temperature was raised to 60°C, 398 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred for 1 hour. After cooling to room temperature, the mixture was filtered, and the filtered cake was collected. The product was then vacuum-dried at 60°C for 4 hours to obtain the product.

[0170] Powder X-ray diffraction detection revealed that the product was defined as p-toluenesulfonate II crystalline form. The XRPD spectrum is shown in Figure 8, and its characteristic peak positions are shown in Table 9. According to the DSC spectrum, the endothermic peaks were at 104.06°C and 181.38°C, and the heat dissipation peak was at 188.49°C. According to the TGA spectrum, the weight decreased by 3.36% between 40°C and 160°C, and by 3.84% between 160°C and 270°C.

[0171] [Table 9]

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

[0173] Powder X-ray diffraction detection revealed that the product was defined as p-toluenesulfonate III crystalline form. The XRPD spectrum is shown in Figure 9, and its characteristic peak positions are shown in Table 10.

[0174] [Table 10]

[0175] Example 15. Preparation of sulfate I crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetonitrile was added, and sulfuric acid solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0176] Powder X-ray diffraction detection revealed that the product was defined as sulfate I crystalline form. The XRPD spectrum is shown in Figure 10, and its characteristic peak positions are shown in Table 11. According to the DSC spectrum, the endothermic peaks were at 52.82°C and 105.48°C, and the heat dissipation peak was at 190.22°C. According to the TGA spectrum, the weight decreased by 6.02% between 30°C and 195°C.

[0177] [Table 11]

[0178] Example 16. Preparation of sulfate I crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of ethanol was added, followed by sulfuric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0179] Powder X-ray diffraction detection revealed that the product was defined as a sulfate I crystalline form.

[0180] Example 17. Preparation of sulfate II crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetone was added, followed by sulfuric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0181] Powder X-ray diffraction detection revealed that the product was defined as sulfate II crystalline form. The XRPD spectrum is shown in Figure 11, and its characteristic peak positions are shown in Table 12. According to the DSC spectrum, the endothermic peak value was 64.63°C, and the heat dissipation peak value was 207.53°C. According to the TGA spectrum, the weight decreased by 6.12% between 30°C and 180°C.

[0182] [Table 12]

[0183] Example 18. Preparation of sulfate III crystalline form Approximately 40 mg of compound I was weighed, dissolved in 0.75 mL of ethanol, and sulfuric acid solution (2 mol / L, 47 μL) was added. 1 mL of isopropyl ether was added, and the mixture was stirred to induce crystallization. After centrifugation, the solid was dried under vacuum to obtain the product.

[0184] Powder X-ray diffraction detection revealed the product to be sulfate III crystalline form. The XRPD spectrum is shown in Figure 12, and its characteristic peak positions are shown in Table 13. Ion chromatography showed that the sulfate ion content was 15.31%. According to the DSC spectrum, the endothermic peaks were at 76.24°C and 150.06°C. According to the TGA spectrum, the weight decreased by 4.31% between 30°C and 140°C.

[0185] [Table 13]

[0186] Example 19. Preparation of sulfate IV crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of isopropanol was added, and a sulfuric acid ethanol solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0187] Powder X-ray diffraction detection revealed the product to be sulfate IV crystalline form. The XRPD spectrum is shown in Figure 13, and its characteristic peak positions are shown in Table 14. Ion chromatography showed that the sulfate ion content was 15.72%. According to the DSC spectrum, the endothermic peaks were at 68.75°C and 161.89°C. TGA spectroscopy showed a 3.74% weight decrease between 30°C and 135°C.

[0188] [Table 14]

[0189] Example 20. Preparation of sulfate IV crystalline form Approximately 40 mg of compound I was weighed, 0.75 mL of acetone was added, followed by sulfuric acid solution (2 mol / L, 47 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0190] Powder X-ray diffraction detection revealed that the product is in sulfate IV crystalline form.

[0191] Example 21. Preparation of sulfate V crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of ethyl acetate was added, and a sulfuric acid ethanol solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0192] Powder X-ray diffraction detection revealed the product to be a sulfate V crystalline form. The XRPD spectrum is shown in Figure 14, and its characteristic peak positions are shown in Table 15. Ion chromatography showed that the sulfate ion content was 11.65%. According to the DSC spectrum, the endothermic peaks were at 61.82°C and 153.47°C. According to the TGA spectrum, the weight decreased by 4.19% between 30°C and 90°C, and by 6.18% between 90°C and 195°C.

[0193] [Table 15]

[0194] Example 22. Preparation of sulfate V crystalline form Approximately 500 mg of compound I was weighed and suspended in 20 mL of isopropyl acetate. 109 mg of sulfuric acid was added while stirring at room temperature, and the mixture was stirred for 16 hours. The mixture was then filtered, and the filtered cake was collected. The product was dried under vacuum at 60°C for 4 hours to obtain the final product.

[0195] Example 23. Preparation of sulfate VI crystalline form 15 mg of the crystalline form of compound I sulfate I was weighed and dispersed in 1 mL of isopropyl acetate. The mixture was stirred at room temperature for 48 hours, filtered, and the filtered cake was collected. The product was dried under vacuum at 60°C for 4 hours.

[0196] Powder X-ray diffraction detection revealed that the product was defined as sulfate VI crystalline form. The XRPD spectrum is shown in Figure 15, and its characteristic peak positions are shown in Table 16.

[0197] [Table 16]

[0198] Example 24. Preparation of hydrochloride I crystalline form Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of ethanol, and hydrochloric acid solution (2 mol / L, 9.8 μL) was added. The mixture was stirred overnight, 1.0 mL of isopropyl ether was added, and the mixture was stirred to induce crystallization. After centrifugation, the solid was dried under vacuum to obtain the product.

[0199] Powder X-ray diffraction detection revealed the product to be hydrochloride I crystalline form. The XRPD spectrum is shown in Figure 16, and its characteristic peak positions are shown in Table 17. Ion chromatography showed a chloride ion content of 5.94%. According to the DSC spectrum, the peak value of the heat dissipation peak was 211.63°C. According to the TGA spectrum, the weight decreased by 5.62% between 30°C and 175°C.

[0200] [Table 17]

[0201] Example 25. Preparation of hydrochloride II crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetonitrile was added, followed by hydrochloric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the title product.

[0202] Powder X-ray diffraction detection revealed the product to be hydrochloride salt II crystalline form. The XRPD spectrum is shown in Figure 17, and its characteristic peak positions are shown in Table 18. Ion chromatography revealed a chloride ion content of 6.94%. According to the DSC spectrum, the endothermic peak value was 47.48°C, and the heat dissipation peak value was 221.46°C. According to the TGA spectrum, the weight decreased by 3.32% between 30°C and 165°C.

[0203] According to DVS detection, the sample showed a weight increase due to moisture absorption of approximately 3.93% under normal storage conditions (i.e., 25°C, 60% RH), approximately 4.28% under accelerated experimental conditions (i.e., 70% RH), and approximately 5.00% under extreme conditions (i.e., 90% RH). Furthermore, re-measurement of the crystal form after DVS detection showed no transformation of the crystal form.

[0204] [Table 18]

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

[0206] [Table 19]

[0207] Example 27. Preparation of hydrochloride III crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of acetone was added, followed by hydrochloric acid solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0208] Powder X-ray diffraction detection revealed the product to be hydrochloride salt III crystalline form. The XRPD spectrum is shown in Figure 18, and its characteristic peak positions are shown in Table 20. Ion chromatography revealed a chloride ion content of 6.68%. According to the DSC spectrum, the peak value of the heat dissipation peak was 191.78°C, and the peak value of the endothermic peak was 206.27°C. According to the TGA spectrum, the weight decreased by 2.34% between 30°C and 155°C.

[0209] According to DVS detection, under normal storage conditions (i.e., 25°C, 60% RH), the sample had a weight increase of approximately 2.57% due to moisture absorption. Under accelerated experiment conditions (i.e., 70% RH), the weight increase due to moisture absorption was approximately 2.96%. Under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption was approximately 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, centrifuged, and then dried the solid under vacuum to obtain the product.

[0212] When detected by powder X-ray diffraction, the product was in the 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, centrifuged, and then dried the solid under vacuum to obtain the product.

[0214] When detected by powder X-ray diffraction, the product was defined as the hydrochloride IV crystal form, and 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 was at 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 Approximately 140 mg of compound I was weighed, dissolved in 5 mL of acetonitrile, and 33 mg of concentrated hydrochloric acid was added while stirring. The mixture was stirred for 16 hours, filtered, and the filtered cake was collected. The product was dried under vacuum at 60°C for 4 hours.

[0217] Powder X-ray diffraction detection revealed that the product was defined as a hydrochloride V-crystal form. The XRPD spectrum is shown in Figure 20, and its characteristic peak positions are shown in Table 22.

[0218] According to the DSC spectrum, the endothermic peak value was 63.15°C, and the heat dissipation peak values ​​were 196.81°C and 211.82°C. According to the TGA spectrum, the weight decreased by 4.60% between 30°C and 170°C, and by 6.81% between 170°C and 260°C. According to the DVS data, the sample showed a weight increase due to moisture absorption of approximately 6.36% under normal storage conditions (i.e., 25°C, 60%RH), approximately 7.28% under accelerated testing conditions (i.e., 70%RH), and approximately 8.32% under extreme conditions (90%RH). 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 crystalline form Approximately 140 mg of compound I was weighed and dissolved in 5 mL of isopropanol. 78 μL of 4 M dioxane hydrochloride solution was added while stirring, and the mixture was stirred for 16 hours. The solution was then filtered, and the filtered cake was collected. The product was dried under vacuum at 60°C for 4 hours to obtain the final product.

[0221] Powder X-ray diffraction detection revealed that the product was defined as hydrochloride VI crystal form. The XRPD spectrum is shown in Figure 21, and its characteristic peak positions are shown in Table 23. According to the DSC spectrum, the peak values ​​of the heat dissipation peaks were 104.31°C, 198.49°C, and 204.67°C. According to the TGA spectrum, the weight decreased by 3.22% between 30°C and 195°C, and by 4.49% between 195°C and 265°C. According to the DVS data, the weight increase due to moisture absorption was approximately 3.69% under normal storage conditions (i.e., 25°C, 60%RH), approximately 4.12% under accelerated testing conditions (i.e., 70%RH), and approximately 5.73% 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 crystalline form Approximately 8 mg of compound I and approximately 2.27 mg of fumaric acid were weighed, 0.2 mL of acetonitrile was added, and the mixture was stirred to induce crystallization. After centrifugation, the solid was dried under vacuum to obtain the product.

[0224] Powder X-ray diffraction detection revealed the product to be fumarate I crystalline form. The XRPD spectrum is shown in Figure 22, and its characteristic peak positions are shown in Table 24. Ion chromatography revealed that the fumarate ion content was 20.34%. According to the DSC spectrum, the endothermic peak value was 179.08°C. TGA spectroscopy showed a weight decrease of 1.02% between 30°C and 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 Weighed about 80 mg of Compound I, added it to a methanol solution of fumaric acid (0.33 mol / L, 537 μL), added 1.5 mL of acetonitrile, stirred for crystallization, centrifuged, and dried the solid under vacuum to obtain the product.

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

[0229] Example 34. Preparation of fumarate II crystal form Weighed about 8 mg of Compound I and 2.27 mg of fumaric acid, dissolved them 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 the 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 Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of ethanol, and hydrobromic acid solution (2 mol / L, 9.8 μL) was added. The mixture was stirred overnight, 0.8 mL of isopropyl ether was added, and the mixture was stirred to induce crystallization. After centrifugation, the solid was dried under vacuum to obtain the product.

[0233] Powder X-ray diffraction detection revealed the product to be hydrobromide I crystalline form. The XRPD spectrum is shown in Figure 24, and its characteristic peak positions are shown in Table 26. Ion chromatography showed a bromide ion content of 13.98%. According to the DSC spectrum, the peak value of the heat dissipation peak was 216.67°C. According to the TGA spectrum, the weight decreased by 1.24% between 30°C and 160°C.

[0234] [Table 26]

[0235] Example 36. Preparation of hydrobromide II crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of isopropanol was added, followed by hydrobromic acid ethanol solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the title product.

[0236] Powder X-ray diffraction detection revealed the product to be hydrobromide II crystalline form. The XRPD spectrum is shown in Figure 25, and its characteristic peak positions are shown in Table 27. Ion chromatography revealed a bromide ion content of 14.89%. According to the DSC spectrum, the peak value of the heat dissipation peak was 211.47°C. According to the TGA spectrum, the weight decreased by 0.77% between 30°C and 145°C.

[0237] [Table 27]

[0238] Example 37. Preparation of hydrobromide II crystalline form Approximately 8 mg of compound I was weighed, 0.2 mL of ethyl acetate was added, followed by hydrobromic acid ethanol solution (2 mol / L, 9.8 μL). The mixture was stirred to induce crystallization, and after centrifugation, the solid was dried under vacuum to obtain the title product.

[0239] Powder X-ray diffraction detection revealed that the product is in the hydrobromide II crystalline form.

[0240] Example 38. Preparation of amorphous maleate Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of ethanol, and maleic acid solution (2 mol / L, 9.8 μL) was added. The mixture was slurryed overnight at room temperature, 0.6 mL of isopropyl ether was added, and the mixture was stirred to precipitate. After centrifugation, the solid was dried under vacuum to obtain the product.

[0241] Powder X-ray diffraction detection revealed that the product is an amorphous maleate.

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

[0243] [Table 28]

[0244] Example 40. Preparation of amorphous phosphate Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of ethanol, and phosphoric acid solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0245] Powder X-ray diffraction detection revealed that the product is an amorphous phosphate.

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

[0247] [Table 29]

[0248] Example 42. Preparation of amorphous p-toluenesulfonate Approximately 8 mg of compound I was weighed, 0.2 mL of acetonitrile was added, and p-toluenesulfonic acid solution (2 mol / L, 9.8 μL) was added. The mixture was slurryed overnight at room temperature, 0.6 mL of isopropyl ether was added, and the mixture was stirred to precipitate. After centrifugation, the solid was dried under vacuum to obtain the product.

[0249] Powder X-ray diffraction detection revealed that the product is an amorphous p-toluenesulfonate.

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

[0251] [Table 30]

[0252] Example 44. Preparation of amorphous sulfate Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of tetrahydrofuran, and sulfuric acid solution (2 mol / L, 9.8 μL) was added. The mixture was slurryed overnight at room temperature, stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0253] Powder X-ray diffraction detection revealed that the product is an amorphous sulfate.

[0254] Example 45. Preparation of amorphous sulfate Approximately 8 mg of compound I was weighed and dissolved in 0.2 mL of acetonitrile / methanol (V / V=1:1). Sulfuric acid solution (2 mol / L, 9.8 μL) was added, and the mixture was slurryed overnight at room temperature. 1 mL of isopropyl ether was added, and the mixture was stirred to precipitate. After centrifugation, the solid was dried under vacuum to obtain the product.

[0255] Powder X-ray diffraction detection revealed that the product is an amorphous sulfate.

[0256] Example 46. Preparation of amorphous tartrate Approximately 8 mg of compound I was weighed, 0.2 mL of acetonitrile was added, and tartaric acid solution (2 mol / L, 9.8 μL) was added. The mixture was stirred to precipitate, and after centrifugation, the solid was dried under vacuum to obtain the product.

[0257] Powder X-ray diffraction detection revealed that the product is an amorphous tartrate salt.

[0258] Example 47. Preparation of amorphous tartrate Compound I was weighed and added to a solvent and a 2 mol / L tartaric acid solution, and crystallized to obtain the product. The crystal form was confirmed by powder X-ray diffraction, as shown in Table 31.

[0259] [Table 31]

[0260] Example 48. Preparation of amorphous succinate Approximately 8 mg of compound I and approximately 2.3 mg of succinic acid were weighed, 0.2 mL of acetonitrile was added, and the mixture was slurryed overnight at room temperature. After centrifugation, the solid was dried under vacuum to obtain the product.

[0261] Powder X-ray diffraction detection revealed that the product is an amorphous succinate.

[0262] Example 49. Preparation of amorphous succinate Compound I was weighed and added to the solvent and succinic acid, and crystallized to obtain the product. The crystal form was confirmed by powder X-ray diffraction, as shown in Table 32.

[0263] [Table 32]

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

[0265] Powder X-ray diffraction detection revealed that the product is an amorphous fumarate, and the XRPD spectrum is shown in Figure 26.

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

[0267] [Table 33]

[0268] Example 52. Preparation of amorphous citrate Approximately 8 mg of compound I was weighed, dissolved in 0.2 mL of ethanol, and 9.8 μL of citric acid solution (2 mol / L) was added. The mixture was slurryed overnight at room temperature, 0.6 mL of isopropyl ether was added, and the mixture was stirred to precipitate. After centrifugation, the solid was dried under vacuum to obtain the product.

[0269] Powder X-ray diffraction detection revealed that the product is an amorphous citrate.

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

[0271] [Table 34]

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

[0273] Powder X-ray diffraction detection revealed that the product is an amorphous malate salt.

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

[0275] [Table 35]

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

[0277] Powder X-ray diffraction detection revealed that the product is an amorphous hydrobromide salt.

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

[0279] [Table 36]

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

[0281] Powder X-ray diffraction detection revealed that the product is an amorphous mesylate.

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

[0283] [Table 37]

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

[0285] Powder X-ray diffraction detection revealed that the product is an amorphous hydrochloride salt.

[0286] Experimental Example 1. Study on the stability of factors influencing the crystal form of p-toluenesulfonate I. The stability of the p-toluenesulfonate I crystalline form was examined under various conditions: light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%), with a sampling and analysis period of 30 days.

[0287] [Table 38]

[0288] Conclusion: When subjected to light irradiation, high temperatures of 40°C and 60°C, and high humidity of 75% and 92.5% for 30 days, the p-toluenesulfonate I crystalline form exhibits good physical and chemical stability.

[0289] Experimental Example 2. Study on the stability of factors influencing the crystal form of fumarate I. The fumarate I crystalline form was placed flat in an open state, and the stability of the sample was examined under conditions of light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling and examination period was 30 days.

[0290] [Table 39]

[0291] Conclusion: When subjected to light irradiation, high temperatures of 40°C and 60°C, and high humidity of 75% and 92.5% for 30 days, the fumarate I crystalline form exhibits good physical and chemical stability.

[0292] Experimental Example 3. Study on the stability of factors influencing the hydrochloride II crystal form. The hydrochloride salt II crystalline form was placed flat in an open state, and the stability of the sample was examined under conditions of light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling and examination period was 30 days.

[0293] [Table 40]

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

[0295] Experimental Example 4. Study on the stability of factors affecting the crystal form of hydrochloride III. The hydrochloride salt III crystalline form was placed flat in an open state, and the stability of the sample was examined under various conditions: light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling and examination period was 30 days.

[0296] [Table 41]

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

[0298] Experimental Example 5. Study on the stability of factors influencing the phosphate II crystal form. The phosphate II crystalline form was placed flat in an open state, and the stability of the sample was examined under various conditions: light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling and examination period was 30 days.

[0299] [Table 42]

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

[0301] Experimental Example 6. Study on the long-term accelerated stability of the p-toluenesulfonate I crystalline form. The p-toluenesulfonate I crystalline form was sealed, and its stability was investigated under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively.

[0302] [Table 43]

[0303] Conclusion: Long-term accelerated experiments show that the p-toluenesulfonate I crystalline form exhibits relatively good physical and chemical stability when subjected to conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months.

[0304] Experimental Example 7. Study on the long-term accelerated stability of fumarate I crystal form. The fumarate I crystalline form was sealed, and its stability was investigated under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively.

[0305] [Table 44]

[0306] Conclusion: Long-term accelerated experiments show that the fumarate I crystalline form exhibits good physical and chemical stability when subjected to conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months.

[0307] Experimental Example 8. Study on the long-term accelerated stability of the hydrochloride salt II crystal form. The hydrochloride salt II crystalline form was sealed, and its stability was investigated under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively.

[0308] [Table 45]

[0309] Conclusion: Long-term accelerated experiments show that the hydrochloride II crystalline form exhibits good physical and chemical stability when subjected to conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months.

[0310] Experimental Example 9. Study on the long-term accelerated stability of the hydrochloride salt III crystalline form. The hydrochloride salt III crystalline form was sealed, and its stability was investigated under conditions of 25°C / 60%RH and 40°C / 75%RH, respectively.

[0311] [Table 46]

[0312] Conclusion: Long-term accelerated experiments show that the hydrochloride III crystalline form exhibits good physical and chemical stability when subjected to conditions of 25°C / 60%RH and 40°C / 75%RH for 6 months.

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

[0314] [Table 47]

[0315] Conclusion: Long-term accelerated experiments showed that the phosphate II crystalline form exhibited relatively good physical stability and good long-term chemical stability when subjected to conditions of 25°C / 60%RH and 40°C / 75%RH for 2 months.

Claims

1. 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-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid.

2. The process includes the step of reacting 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-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-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

3. The pharmaceutically acceptable salt according to claim 1, characterized in that the chemical mixing ratio of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid to the acid is 3:1 to 1:

2.

4. The pharmaceutically acceptable salt according to claim 3, characterized in that the chemical mixing ratio of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid to the acid is 2:1 to 1:

1.

5. The powder X-ray diffraction pattern, shown at a diffraction angle of 2θ, has characteristic peaks at 6.7, 7.6, 8.6, 11.0, 12.1 and 16.2, for the maleate I crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-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 at a diffraction angle of 2θ has characteristic peaks at 6.7, 7.6, 8.1, 8.6, 11.0, 12.1, 16.2, 19.7 and 23.5, the maleate I crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to Claim 5.

7. The powder X-ray diffraction pattern shown at a diffraction angle of 2θ 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, the maleate I crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to Claim 5.

8. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 8.4, 10.3, 11.7, 14.8, 19.2 and 21.

8. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 8.4, 9.5, 10.2, 11.7, 14.7 and 19.

1. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 18.5 and 21.

3. (4) The powder X-ray diffraction pattern of the IV crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 8.4, 10.3, 11.7 and 14.

8. (5) The powder X-ray diffraction pattern of the V crystal, shown at the diffraction angle 2θ, has characteristic peaks at 9.1, 10.2, 11.5, 15.7 and 19.

8. The phosphate phosphate I, II, III, IV, or V crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

9. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal has characteristic peaks at 8.4, 10.3, 11.7, 12.5, 14.8, 19.2, 19.8, 21.8 and 23.9, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 8.4, 9.5, 10.2, 10.7, 11.7, 14.7, 18.5 and 19.

1. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.0, 8.0, 9.8, 11.5, 16.1, 18.0, 18.5, 21.3 and 24.

1. (4) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the V crystal has characteristic peaks at 8.6, 9.1, 10.2, 11.5, 15.7, 18.0, 19.8 and 23.

5. The phosphate phosphate I, II, III, IV, or V crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 8.

10. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, 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. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, 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. The phosphate phosphate I, II, III, IV, or V crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 8.

11. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.0, 9.4, 10.1, 16.3 and 18.

3. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 4.7, 8.8, 9.3, 10.8, 13.9 and 18.

7. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.8, 7.4, 8.1, 10.1 and 12.

7. p-toluenesulfonate I, II, or III crystals of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

12. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal has characteristic peaks at 5.0, 9.4, 10.1, 16.3, 18.3, 18.9, 21.2 and 22.9, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 4.7, 8.8, 9.3, 9.7, 10.8, 13.9, 17.7 and 18.

7. p-toluenesulfonate I, II, or III crystals of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 11.

13. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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. p-toluenesulfonate I, II, or III crystals of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 11.

14. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.2, 9.2, 17.1, 20.0, 21.4 and 24.

7. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 9.5, 10.2, 16.6, 21.2 and 25.

7. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 7.6, 9.1, 18.2 and 23.

7. (4) The powder X-ray diffraction pattern of the IV crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 12.5, 16.5, 19.4, 21.2 and 24.

0. (5) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the V crystal has characteristic peaks at 7.6, 11.4, 13.5, 17.2, 18.8 and 19.

5. (6) The powder X-ray diffraction pattern of the VI crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.7, 8.8, 14.6, 15.9 and 23.

7. Crystal I, II, III, IV, V, or VI of the sulfate of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

15. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal has characteristic peaks at 6.7, 7.2, 9.2, 17.1, 18.7, 20.0, 21.4, 22.9 and 24.7, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.3, 8.5, 9.5, 10.2, 16.6, 19.8, 21.2, 23.7 and 25.

7. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 7.6, 9.1, 17.0, 18.2, 20.7, 23.7 and 24.

0. (4) The powder X-ray diffraction pattern of the IV crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.9, 9.7, 12.5, 16.5, 19.4, 21.2, 24.0 and 25.

8. (5) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the V crystal has characteristic peaks at 7.6, 10.0, 11.4, 13.5, 14.0, 17.2, 19.5, 22.5 and 24.

6. (6) The powder X-ray diffraction pattern of the VI crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.7, 8.8, 10.6, 14.6, 15.9, 19.5, 21.4 and 23.

7. Crystal I, II, III, IV, V, or VI of the sulfate of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 14.

16. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.8, 8.8, 11.6, 20.7 and 23.

4. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.9, 8.8, 10.6, 17.2, 19.3 and 23.

9. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.1, 8.8, 10.4, 18.4, 19.9 and 24.

6. (4) The powder X-ray diffraction pattern of the IV crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.4, 9.0, 10.8, 20.4 and 21.

8. (5) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the V crystal has characteristic peaks at 5.2, 6.7, 7.7, 10.2 and 17.

4. (6) The powder X-ray diffraction pattern of the VI crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.2, 6.7, 7.7, 10.2 and 17.

4. Crystal I, II, III, IV, V, or VI of the hydrochloride salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

17. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal has characteristic peaks at 5.8, 8.8, 9.8, 10.5, 11.6, 14.6, 18.4, 20.7 and 23.4, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, 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. (3) The powder X-ray diffraction pattern of the III crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.1, 8.8, 10.4, 12.2, 18.4, 19.9, 22.6, 24.6 and 28.

0. (4) The powder X-ray diffraction pattern of the IV crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.4, 9.0, 10.8, 19.3, 20.4, 21.8 and 27.

3. (5) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the V crystal has characteristic peaks at 5.2, 6.7, 7.7, 10.2, 10.8, 17.4, 20.5 and 24.

2. (6) The powder X-ray diffraction pattern of the VI crystal, shown at the diffraction angle 2θ, has characteristic peaks at 5.8, 10.3, 11.7, 17.7, 20.7 and 23.

7. Crystal I, II, III, IV, V, or VI of the hydrochloride salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 16.

18. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the II crystal 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, (3) The powder X-ray diffraction pattern of the III crystal, shown at a diffraction angle of 2θ, 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. Crystal I, II, III, IV, V, or VI of the hydrochloride salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 16.

19. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8 and 26.

1. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 6.2, 6.6, 8.0, 13.2, 14.0, 20.3 and 24.

2. The fumarate I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

20. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, 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. The fumarate I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 19.

21. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, 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. The fumarate I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 19.

22. (1) The powder X-ray diffraction pattern of the I crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.6, 10.6, 16.4, 18.4, 22.6 and 24.

0. (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.2, 10.5, 16.5, 22.5, 23.4 and 26.

6. The hydrobromide I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1.

23. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, has characteristic peaks at 7.2, 10.5, 13.1, 16.5, 18.8, 20.3, 22.5, 23.4 and 26.

6. The hydrobromide I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 22.

24. (1) The powder X-ray diffraction pattern shown at the diffraction angle 2θ of the I crystal 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, (2) The powder X-ray diffraction pattern of the II crystal, shown at the diffraction angle 2θ, 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. The hydrobromide I or II crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 22.

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

2. A pharmaceutically acceptable salt crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in any one of claims 5 to 24.

26. 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-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1, ii) A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

27. 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-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in claim 1 with a pharmaceutically acceptable excipient.

28. A pharmaceutically acceptable salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to Claim 1 for inhibiting complement factor B.

29. A pharmaceutically acceptable salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to claim 1 for the treatment of a disease or condition, wherein the disease or condition is glomerulosis, 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 retinoretinopathy, sympathetic ophthalmitis, ocular scarring pemphigoid, ocular pemphigus, 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 Unhealthy complement activation disorders, hemodialysis complications, hyperacute allogeneic transplant rejection, xenotransplant rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infection or sepsis, systemic Selected from: lupus erythematosus, systemic lupus erythematosus nephritis, proliferative glomerulonephritis, hepatic 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, parasitic diseases, Gerstmann syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, and obesity. A pharmaceutically acceptable salt of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid.

30. A pharmaceutical composition comprising the following components, namely, i) A pharmaceutically acceptable salt crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in any one of claims 5 to 24, ii) A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

31. A method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable salt crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid as described in any one of claims 5 to 24 with a pharmaceutically acceptable excipient.

32. A pharmaceutically acceptable salt crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to any one of claims 5 to 24 for inhibiting complement factor B.

33. The composition according to claim 26 for inhibiting complement factor B.

34. A pharmaceutically acceptable salt crystal of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid according to any one of claims 5 to 24 for the treatment of a disease or condition, wherein the disease or condition is glomerulosis, 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 retinoretinopathy, sympathetic ophthalmitis, ocular scarring pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neuropathy, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, undesirable Undesirable or undesirable complement activation disorder, hemodialysis complications, hyperacute allogeneic transplant rejection, xenotransplant rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion injury, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infection or sepsis Selected from systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative glomerulonephritis, hepatic 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, parasitic diseases, Gerstmann syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, and obesity. Crystals of pharmaceutically acceptable salts of 4-((1S,3S,5R)-3-ethoxy-8-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid.

35. A composition according to claim 26 for treating a disease or medical condition, wherein the disease or medical condition is: glomerulosis, 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 retinoretinopathy, sympathetic ophthalmitis, ocular scarring pemphigoid, pemphigus ophthalmos, 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 undesirable complement activation disorder, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, during IL-2 treatment A composition selected from interleukin-2-induced toxicity, 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 glomerulonephritis, hepatic 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, parasitic diseases, Gerstmann syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, and obesity.

Images