CN117327070A

CN117327070A - Crystal form of nitrogen-bridge-containing heterocyclic derivative and preparation method thereof

Info

Publication number: CN117327070A
Application number: CN202310790225.0A
Authority: CN
Inventors: 杨俊然; 杜振兴; 王捷; 王林; 邵启云; 冯君
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2022-06-30
Filing date: 2023-06-30
Publication date: 2024-01-02

Abstract

The present disclosure relates to crystalline forms of nitrogen-containing bridged heterocyclic derivatives and methods of making the same. In particular, the present disclosure relates to different crystalline forms of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] octane-1-yl) benzoic acid and methods for preparing the same, and the crystalline forms of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] octane-1-yl) benzoic acid provided by the present disclosure possess good stability and can be better used for clinical treatment.

Description

Crystal form of nitrogen-bridge-containing heterocyclic derivative and preparation method thereof

Technical Field

The disclosure belongs to the field of pharmacy, relates to a crystal form of a nitrogen-containing bridged heterocyclic derivative, and in particular relates to a crystal form of 4- ((1S, 3S, 5R) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] octane-1-yl) benzoic acid and a preparation method thereof.

Background

Complement is a serum protein that is found in human and vertebrate serum and tissue fluids, is thermolabile, has enzymatic activity after activation, mediates immune and inflammatory responses, and can be activated by antigen-antibody complexes or microorganisms, resulting in lysis or phagocytosis of pathogenic microorganisms.

The complement system is an important regulator of inflammatory response and tissue injury, consisting of more than 20 serum proteins and cell surface proteins. The complement system includes complement intrinsic components and a variety of regulatory proteins. Complement intrinsic components include C1-C9, with the highest C3 content. Complement regulatory proteins are in turn classified into two classes, soluble and membrane-bound. Soluble complement regulatory proteins include clusterin, S protein, complement factor H related proteins, and the like. Membrane-bound complement regulatory proteins include membrane-assisted proteins (membrane cofactor protein, MCP), decay accelerating factors (decay accelerating factor, DAF), complement receptor 1 (complement receptor 1), and the like. In addition, the complement system includes several complement fragments and complement receptors, such as C3a receptors, C5a receptors, and the like.

The complement system is activated by three pathways, both independent and intersecting, the classical pathway (classical pathway, CP), the alternative pathway (alternative pathway, AP) and the Lectin Pathway (LP), also known as MBL pathway (mannan-binding lectin pathway). The complement activation process exerts a strong biological effect through a series of positive feedback and participates in the occurrence and development of diseases. C3 convertases are important components of the first three pathways, producing a series of complement protein fragments and membrane attack complexes (membrane attack complex, MAC) through the complement activation cascade. C3 convertase cleaves C3 to produce C5 convertase, which then cleaves C5 to produce C5a and C5b, C5b combines with C6, C7, C8, C9 to form C5b-9, the MAC. Abnormalities in the complement pathway can cause lysis of normal cells inherent to the body and thus lead to disease.

Complement Factor B (Factor B) is a thermolabile beta globulin that can be inactivated at 50 ℃ for 30 minutes. It can be cleaved by complement factor D into two fragments Ba, bb, which bind to C3b to form the C3 convertase of the alternative pathway. Complement factor B is an important component of the alternative complement pathway, also known as the C3 activator precursor. Complement factor B has a molecular weight of 93kDa and is synthesized in human blood at a concentration of about 3 μm, mainly in the liver, and is also found in ocular retinal pigment epithelial cells.

Glomerulopathy (Glomerulopathia) includes immunoglobulin A Nephropathy (IgA Nephropathia, igAN), C3 Glomerulopathy (C3G Glomerulopathia, C3G), membranous glomerulonephritis (Membranous Glomerulonephritis, MGN), etc. Of these, igAN and MGN are the most common, and rare kidney diseases, such as C3 glomerulopathy, have increased in incidence in recent decades. The glomerulopathy and complement pathways, in particular the alternative complement pathway, were found to be closely related. At present, the primary glomerulonephritis lacks a clinically effective treatment scheme. The medicines for treating common diseases such as hormone and immunosuppressant (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and tripterygium glycosides), and other medicines including blood pressure controlling medicine, diuretic, anti-platelet aggregation medicine, anticoagulant, lipid lowering medicine, cordyceps preparation, etc.

IgAN is the most common primary glomerular disease worldwide, and the pathology manifests as local mesangial hyperplasia and matrix augmentation with diffuse mesangial IgA protein deposition, and often with IgG, C3 and C5b-9 deposition. The complement pathway is therefore thought to be involved in the development of IgAN. Currently, two small molecule drugs directed to the complement pathway are undergoing clinical trials. OMS721 was a humanized monoclonal antibody developed by omros corporation that targets the MASP-2 protein. MASP-2 protein is an effector enzyme that activates the lectin pathway (lectin pathway) of the complement system. At the end of the OMS721 clinical phase 2 trial, the proteinuria (proteouria) index was significantly improved in all 4 IgAN patients enrolled in the trial. At present, the medicine is being studied in clinical three phases.

Patent applications for which Factor B inhibitors have been disclosed include WO2015009616A1, WO2019043609A1, WO2020016749A2, and the like. A series of nitrogen-containing heterocyclic derivatives are provided in WO2022143845 and are structurally characterized, including 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid (compound I). In addition, the application also carries out biological evaluation on the compound I, and the result shows that the compound has better inhibition effect on the activity of Factor B enzyme.

The crystal structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may lead to a change in the crystal structure of the compound, sometimes accompanied by the generation of other forms of crystal form. Generally, amorphous pharmaceutical products have no regular crystal structure, and often have other defects such as poor product stability, finer crystallization, difficult filtration, easy caking, poor flowability, and the like. Therefore, there is a need to improve the properties of the above products in all aspects, and we need to find the crystal forms with higher purity and good physical and chemical stability.

Disclosure of Invention

The present disclosure provides a crystal form of a Factor B inhibitor, and a preparation method and application thereof.

The present disclosure provides a crystalline form of compound I, which is a Factor B inhibitor having the chemical name 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid, and a preparation method and application thereof.

In some embodiments, the present disclosure provides a form a of compound I having an X-ray powder diffraction pattern with characteristic peaks at 5.2, 7.5, 8.2, 9.3 and 15.4, expressed in terms of diffraction angle 2θ.

In some embodiments, the present disclosure provides a form B of compound I having a characteristic peak at 8.2, 9.3, 14.0, 15.7, 17.2 and 18.9, optionally having a characteristic peak at 8.2, 8.8, 9.3, 14.0, 14.6, 15.7, 17.2, 17.8 and 18.9, optionally having a characteristic peak at 8.2, 8.8, 9.3, 9.9, 12.1, 14.0, 14.6, 15.7, 17.2, 17.8 and 18.9, X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

In some embodiments, the present disclosure provides a form C of compound I having an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 5.0, 8.3, 10.4, 12.6, and 17.8.

In some embodiments, the present disclosure provides a D-form of compound I having an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 7.3, 11.2, 14.9, 19.0 and 21.5.

In some embodiments, the present disclosure provides an E-form of compound I having an X-ray powder diffraction pattern with characteristic peaks at 5.1, 6.6, 7.1, 14.3 and 15.1, expressed in terms of diffraction angle 2θ.

In some embodiments, the present disclosure provides an F-form of compound I having an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 6.8, 13.4, 20.5, 23.3, and 24.3.

In some embodiments, the present disclosure provides a form G of compound I having characteristic peaks at 7.0, 10.4, 14.0, 16.8, 19.3 and 21.5, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ; optionally, there are characteristic peaks at 6.4, 7.0, 9.1, 10.4, 14.0, 14.7, 16.8, 19.3 and 21.5; optionally, there are characteristic peaks at 5.0, 6.4, 7.0, 9.1, 10.4, 14.0, 14.7, 16.8, 19.3, 20.1, 21.5 and 24.2.

In some embodiments, the present disclosure provides an H-form of compound I having a characteristic peak at 8.1, 9.3, 14.1, 16.2, 17.9, 18.7, and 23.5, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ; optionally, there are characteristic peaks at 8.1, 9.3, 14.1, 15.6, 16.2, 17.0, 17.9, 18.7, 23.5 and 26.6; optionally, there are characteristic peaks at 8.1, 9.3, 10.3, 11.8, 14.1, 15.6, 16.2, 17.0, 17.9, 18.7, 23.5, 26.0, 26.6 and 27.5.

In some embodiments, the present disclosure provides a form I of compound I having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, optionally with characteristic peaks at 7.0, 8.3, 9.3, 14.0, 16.1, 20.5, and 28.0; optionally, there are characteristic peaks at 7.0, 8.3, 9.3, 14.0, 15.5, 16.1, 18.9, 20.5, 24.1 and 28.0; optionally, there are characteristic peaks at 7.0, 8.3, 9.3, 12.4, 14.0, 15.5, 16.1, 18.3, 18.9, 20.5, 23.6, 24.1 and 28.0.

In some embodiments, the present disclosure provides a J-form of compound I having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, optionally with characteristic peaks at 7.9, 9.3, 14.1, 15.6, 18.9, and 19.9; optionally, there are characteristic peaks at 7.9, 9.3, 12.4, 14.1, 15.6, 17.2, 17.8, 18.9, 19.9, 23.5, 24.0 and 25.3.

In some embodiments, the present disclosure provides an amorphous form of compound I having an X-ray powder diffraction pattern with a diffraction angle 2 theta in the range of 3-48 deg. without distinct characteristic peaks.

In an alternative embodiment, the present disclosure provides a crystalline form of compound I, wherein the error range of the 2Θ angle is ± 0.2.

The present disclosure provides a method for preparing form a of compound I, comprising, method 1: dissolving a compound I in a solvent (1), volatilizing and crystallizing, wherein the solvent (1) is at least one selected from methanol, 10% water/methanol, 7% water/ethanol and acetonitrile/methanol (V/V=1:1); method 2: adding the compound I into a solvent (2), stirring and crystallizing, wherein the solvent (2) is at least one selected from n-heptane, isopropyl ether and isopropyl ether/n-hexane; method 3: adding ethanol into the compound I until the compound I is dissolved, adding water, and stirring for crystallization.

The present disclosure provides a method for preparing form B of compound I, comprising, method 1: adding a compound I into a solvent (3), and stirring for crystallization, wherein the solvent (3) is at least one selected from water, 10% water/isopropanol, 10% water/acetone and acetonitrile; method 2: dissolving the compound I in a solvent (4), adding a solvent (5), and performing volatile crystallization or solvent elution crystallization, wherein the solvent (4) is at least one selected from ethanol, acetone, tetrahydrofuran and tetrahydrofuran/methanol, and the solvent (5) is at least one selected from dichloromethane, n-heptane, water and methyl tertiary butyl ether.

The present disclosure provides a method for preparing form C of compound I, comprising, method 1: dissolving a compound I in a solvent (6), volatilizing and crystallizing, wherein the solvent (6) is at least one selected from ethanol and ethyl acetate/ethanol (V/V=1:1); method 2: adding a compound I into a solvent (7), and stirring for crystallization, wherein the solvent (7) is at least one selected from ethyl acetate, acetonitrile, dichloromethane, 1, 4-dioxane, nitromethane and ethyl acetate/n-heptane (V/V=1:1); method 3: adding isopropanol into the compound I, and carrying out heating and cooling circulation for 2 times at 50-5 ℃ for crystallization; method 4: adding the compound I into a solvent (8) for clearing, adding a solvent (9), and performing volatile crystallization or solvent elution crystallization, wherein the solvent (8) is selected from at least one of methanol, ethanol, tetrahydrofuran, chloroform, acetone and dimethyl sulfoxide, and the solvent (9) is selected from at least one of ethyl acetate and acetonitrile.

The present disclosure provides a method for preparing a D crystal form of compound I, comprising, method 1: adding the compound I into a solvent (10), and stirring for crystallization, wherein the solvent (10) is at least one selected from isopropyl acetate, methyl tertiary butyl ether, methyl isobutyl ketone, toluene, ethanol, methanol, tetrahydrofuran, chloroform, dimethyl sulfoxide and ethyl acetate; method 2: adding a solvent (11) into the compound I for dissolving, adding a solvent (12), stirring and crystallizing, wherein the solvent (11) is at least one selected from ethanol, methanol, tetrahydrofuran, chloroform and dimethyl sulfoxide, and the solvent (12) is at least one selected from methyl tertiary butyl ether and ethyl acetate; .

The present disclosure provides a process for preparing form E of compound I comprising adding compound I to methanol/water (V/v=1:1), stirring to crystallize.

The present disclosure provides a process for the preparation of form F of compound I comprising dissolving compound I in tetrahydrofuran/ethanol (V/v=2:1), and volatilizing to crystallize.

The present disclosure provides a process for preparing form G of compound I comprising adding compound I to methanol/water (V/v=1:1), stirring to crystallize.

The present disclosure provides a process for preparing the H crystalline form of compound I, comprising dissolving compound I in tetrahydrofuran/methanol (V/v=2:1), adding water, stirring for crystallization.

The present disclosure provides a process for preparing form I of compound I comprising dissolving compound I in dichloromethane/methanol (V/v=9:1), discarding the aqueous phase, concentrating the organic phase and crystallizing.

The present disclosure provides a process for preparing form J of compound I comprising heating form I of compound I to 130 ℃. The present disclosure provides a method for the amorphous preparation of compound I, comprising, method 1: dissolving a compound I in a solvent (13), volatilizing and crystallizing, wherein the solvent (13) is at least one selected from acetone, tetrahydrofuran/ethanol (V/V=2:1), N-dimethylformamide and propylene glycol methyl ether; method 2: adding the compound I into a solvent (14) for clearing, adding a solvent (15), volatilizing and crystallizing or eluting a crystal form, wherein the solution (14) is selected from at least one of methanol, tetrahydrofuran and dimethyl sulfoxide, and the solution (15) is selected from at least one of dichloromethane, methyl tertiary butyl ether, ethyl acetate and n-heptane.

In certain embodiments, the methods of making the crystalline forms described in the present disclosure further comprise a filtration, washing, or drying step.

The disclosure also provides pharmaceutical compositions prepared from the aforementioned crystalline forms of compound I.

The present disclosure also provides a pharmaceutical composition comprising a crystalline form of the aforementioned compound I or a mixture thereof, or a crystalline form of the compound I prepared by the aforementioned method, and optionally from a pharmaceutically acceptable excipient.

The present disclosure also provides a method for preparing a pharmaceutical composition comprising the step of mixing the aforementioned crystalline form of compound I or a mixture thereof, or the crystalline form of compound I prepared by the aforementioned method, with a pharmaceutically acceptable excipient.

The disclosure also provides the use of a crystalline form of compound I, or a mixture thereof, or a crystalline form prepared by the foregoing method, or a mixture thereof, or a composition as described above, or a composition prepared by the foregoing method, in the manufacture of a medicament for inhibiting activation of the alternative complement pathway.

The disclosure also provides the use of a crystalline form of compound I, or a mixture thereof, or a crystalline form prepared by the foregoing method, or a mixture thereof, or the foregoing composition, in the manufacture of a medicament for the treatment of a disease or disorder, the disease or condition is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal sleep hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, fu-xiao willow-original field syndrome, shotgun-like retinochoroiditis, sympathogenic ophthalmitis, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, guillain-Barre syndrome, traumatic brain injury, parkinson's disease inappropriate or undesired complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, cloning disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic remodeling, post-infectious disease or sepsis mesenteric artery reperfusion, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, cerebral infarction, renal failure, pulmonary embolism, or renal failure, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, goldmann syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity; the disease or condition is preferably C3 glomerulopathy, immunoglobulin a nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal sleep haemoglobinuria.

The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number of the decimal places exceeding 1 digit is rounded), specifically, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

"crystallization out" or "crystallization out" as described in this disclosure includes, but is not limited to, stirred crystallization, dissolved crystallization, cooled crystallization, and volatilized crystallization.

The term "differential scanning calorimetric analysis or DSC" in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference object during the temperature rising or constant temperature process of the sample, so as to characterize all physical changes and chemical changes related to thermal effects, and obtain phase change information of the sample.

The drying temperature in the present disclosure is generally 25 ℃ to 100 ℃, preferably 40 ℃ to 70 ℃, and can be either normal pressure drying or reduced pressure drying.

The "pharmaceutically acceptable excipients" described in this disclosure include, but are not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

Drawings

Fig. 1 is an XRPD pattern of form a of compound I.

Fig. 2 is an XRPD pattern of form B of compound I.

Fig. 3 is an XRPD pattern of form C of compound I.

Fig. 4 is an XRPD pattern of form D of compound I.

Fig. 5 is an XRPD pattern of form E of compound I.

Fig. 6 is an XRPD pattern of form F of compound I.

Fig. 7 is an XRPD pattern of form G of compound I.

Fig. 8 is an XRPD pattern of form H of compound I.

Fig. 9 is an XRPD pattern of form I of compound I.

Fig. 10 is an XRPD pattern of form J of compound I.

FIG. 11 is an amorphous XRPD pattern for Compound I.

Detailed Description

The present disclosure is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

Test conditions of the instrument used for the experiment:

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR bitShift (delta) by 10 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) as the solvent and Tetramethylsilane (TMS) as the internal standard.

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: thermo, model number Finnigan LCQ advantage MAX).

HPLC was performed using Agilent 1260DAD high pressure liquid chromatography (Sunfire C18X14.6 mm column) and Thermo U3000 high pressure liquid chromatography (Gimini C18X14.6 mm column).

XRPD is X-ray powder diffraction detection: the determination was performed using a BRUKER D8X-ray diffractometer, specifically collecting information: cu anode (40 kv,40 ma), radiation: monochromatic Cu-Ka ray). Scanning mode: : θ/2θ, scan range: 3-48 deg..

DSC is differential scanning calorimeter: the measurement is carried out by adopting a METTLER TOLEDO DSC 3+ differential scanning calorimeter, wherein the heating rate is 10 ℃/min, the temperature is 25-300 ℃ (or 25-350 ℃), and the nitrogen purging speed is 50mL/min.

TGA is thermogravimetric analysis: the detection adopts a METTLER TOLEDO TGA type thermal gravimetric analyzer, the heating rate is 10 ℃/min, the specific temperature range refers to the corresponding map, and the nitrogen purging speed is 50mL/min.

DVS is dynamic moisture adsorption: surface Measurement Systems instrinsic, humidity from 50% is adopted, the range of humidity is 0% -95%, the step is 10%, and the judgment standard is that each gradient quality change dM/dT is less than 0.002%, TMAX is 360min, and the two circles are circulated.

Example 1 preparation of Compound I (see the preparation of examples 1-2 of application WO 2022143845)

First step

1- (4-bromophenyl) butane-1, 4-diol 1b

Methyl 4- (4-bromophenyl) -4-oxobutanoate 1a (5 g,17.54mmol, pichia 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 0deg.C, naturally warmed to room temperature, and stirred overnight. The reaction solution was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate. The organic phase was concentrated by drying to give the crude title product 1b (4.29 g) which was used in the next reaction without purification.

MS m/z(ESI):242.9[M-H]。

Second step

4- (4-bromophenyl) -4-oxobutanal 1c

Dimethyl sulfoxide (8.2 g,104.95 mmol) was dissolved in dichloromethane (50 mL), -oxalyl chloride (8.8 g,69.33 mmol) was added at 78deg.C, stirring was continued for 10 min, compound 1b (4.29 g,17.50 mmol) was added, and triethylamine (17.7 g,174.92 mmol) was added after 10 min. The reaction mixture was stirred for 1 hour. Naturally warmed to room temperature, diluted with dichloromethane, the organic phase was washed with saturated aqueous sodium bicarbonate, dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to give the title compound 1C (2.7 g, yield: 64%).

MS m/z(ESI):240.8[M+1]。

Third step

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

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

MS m/z(ESI):399.9[M+1]。

Fourth step

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

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

MS m/z(ESI):401.8[M+1]。

Fifth step

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 0deg.C. The reaction mixture was stirred for 1 hour, and ethyl iodide (325 mg,2.09 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to give the title compound 1f (350 mg, yield: 77.9%).

MS m/z(ESI):429.9[M+1]。

Sixth step

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

Compound 1f was dissolved in methanol (4 mL) and dimethylformamide (4 mL), and palladium acetate (54 mg, 240.52. Mu. Mol), diphenyl azide phosphate (100 mg, 242.46. Mu. Mol) and triethylamine (82 mg,8.12 mmol) were added. Carbon monoxide gas was replaced three times and stirred overnight at 80 ℃. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent C to give the title compound 1g (225 mg, yield: 67.5%).

MS m/z(ESI):411.0[M+1]。

Seventh step

4- (3-ethoxy-8-azabicyclo [3.2.1] oct-1-yl) benzoic acid methyl ester 1h

1g (225 mg, 549.43. Mu. Mol) of the compound was dissolved in ethanol (5 mL) and a palladium on carbon hydrogenation catalyst (40 mg, 375.87. Mu. Mol) was added. The hydrogen was replaced three times and stirred at room temperature for 48 hours under a hydrogen atmosphere. The reaction solution was filtered, and the organic phase was concentrated under reduced pressure to give the crude title compound (130 mg) which was used in the next reaction without purification.

MS m/z(ESI):290.0[M+1]。

Eighth step

4- (bromomethyl) -5-methoxy-7-methylindole-1-carboxylic acid tert-butyl ester 1j

The compound 4- (hydroxymethyl) -5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 1i (150 mg, 514.86. Mu. Mol, synthesized by the method for the preparation of intermediate 1-10, cf. WO2015009616A 1) was dissolved in dichloromethane (2 mL), carbon tetrabromide (170 mg, 512.62. Mu. Mol) and triphenylphosphine (135 mg, 514.71. Mu. Mol) were added under nitrogen atmosphere, the reaction solution was stirred at room temperature for 2 hours, and concentrated directly to give crude compound 1j (183 mg), the product was used directly for the next reaction without purification.

Ninth step

4- ((3-ethoxy-1- (4- (methoxycarbonyl) phenyl) -8-azabicyclo [3.2.1] oct-8-yl) methyl) -5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 1k

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

MS m/z(ESI):563.0[M+1]。

Tenth step (. + -.) -rel-4- ((1S, 3S, 5R) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] octane

-1-yl) benzoic acid 1

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

Compound 1:

high performance liquid chromatography: the retention time was 17.28min.

MS m/z(ESI):449.1[M+1]。 ¹ H NMR(500MHz,CD ₃ OD):δ8.16-8.14(m,2H),7.69(br,2H),7.35-7.34(m,1H),6.84(s,1H),6.34(br,1H),4.20-4.03(m,3H),3.93(s,3H),3.71-3.58(m,1H),3.51-3.34(m,2H),3.32-2.96(m,2H),2.73-2.68(m,3H),2.54(s,3H),2.25-2.04(m,3H),1.25-1.22m,3H)。

Compound 1 (100 mg, 222.93. Mu. Mol) was subjected to chiral preparation (isolation conditions: chiral preparation column CHIRALPAK IG,5 μm,20 mm. Times.250 mm (Phenomex)), mobile phase 1: n-hexane (80%); mobile phase 2: containing 0.1% diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 20mL/min, and the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 1-1 (35 mg, yield: 35%) and 1-2 (33 mg, yield: 33%).

Compound 1-1 (compound I,4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid):

MS m/z (ESI): 449.1[ M+1]. Chiral HPLC analysis: retention time 7.946 min, chiral purity: 100% (column: CHIRALPAK IG,5 μm,20 mm. Times.250 mm (Phenomenex), mobile phase 1: n-hexane (80%); mobile phase 2: 0.1% diethylamine, 0.1% trifluoroacetic acid, ethanol (20%), flow rate: 1 mL/min).

¹ H NMR(500MHz,MeOD)δ8.16-8.15(m,2H),7.69(br,2H),7.34(br,1H),6.83(s,1H),6.33(br,1H),4.22-4.12(m,2H),4.03-4.00(m,1H),3.93(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)。

EXAMPLE 2 inhibition of Factor B enzyme Activity by Compound I

1. Experimental material and instrument

1. Recombinant human complement factor B protein (Nanjing Jinsi Biotechnology Co., ltd.)

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

3. Human complement factor C3 (204885-250 UGCN, EMDmilipore)

4. Cobra venom factor (Cobra venom factor, CVF) (A600, quidel)

5.StartingBlock ^TM T20 (TBS) blocking buffer (37543,Thermo Fisher)

6. Goat anti-mouse IgG heavy chain+light chain (horseradish peroxidase label) (ab 205719, abcam)

7. anti-C3 a/C3a des Arg antibody clone number [2991] (ab 11873, abcam)

8.QuantaBlu ^TM Fluorescent peroxidase substrate kit (15169,Thermo Fisher)

9. Amphoteric surfactant (CHAPS) (C3023, sigma)

10. Magnesium chloride solution (M1028-100 ML Sigma)

11. Sodium carbonate Na ₂ CO ₃ (10019260, shanghai test)

12. Sodium bicarbonate NaHCO ₃ (10018960, shanghai test)

13. Tween 20 (P7949-500 ML, sigma)

14.20 XPBS buffer (B548117-0500, industry)

15.96 white half-orifice plate (66PL96025, cisbio)

16.96 hole black adsorption plate (437111,Thermo Fisher)

17. Phosphate buffer (B320, shanghai Yuan-Pe biotechnology Co., ltd.)

18. Sterile pure water (Shanghai Hengrui homemade)

19.96 hole dispensing plate (3795 Corning)

20. Incubator (Shanghai Yiheng scientific instrument limited company)

Flexstation3 microplate reader (Molecular Device)

2. Experimental procedure

The human complement factor B protein needs to form a complex with human complement factor C3 to perform protease function, and under the hydrolysis of human complement factor D protein, human complement factor B is hydrolyzed into Ba and Bb fragments, bb forms a complex C3bBb with the C3B fragment of human complement factor C3, i.e., C3 convertase, and the formation of this complex enables human complement factor B to perform protease function. The C3bBb continues to hydrolyze C3 to C3a and C3b fragments, and C3b forms a complex with C3bBb, C3bBbC3b, i.e., C5 convertase, and the C3a fragment is released. By detecting the C3a des Arg epitope generated after cleavage of C3, the efficiency of C3 hydrolysis, i.e., the activity of the C3bBb enzyme, can be assessed to assess the effect of the compound on the C3bBb enzyme. Since C3B is unstable in vitro, cobra venom factor (Cobra venom factor) (hereinafter CVF) was used instead of C3B to form a complex with human complement factor B, which functions identically to C3B.

The AA128-2422 segment amino acid coding gene (NM_ 001710.6) of human complement factor B protein is subjected to codon optimization, gene synthesis and cloning to pcDNA3.4 vector by Nanjing Jinsri biotechnology limited company, and is expressed and purified in HD CHO-S cells. The purified recombinant human complement factor B protein is packaged and stored in a refrigerator at the temperature of minus 80 ℃.

Human complement factor B protein cleavage reaction: the recombinant human complement factor D protein was diluted 10-fold with PBS (pH 7.4) and stored on ice for use. In reaction buffer (PBS pH7.4, 10mM MgCl) ₂ 0.05% CHAPS) was added to a final concentration of 300nM of recombinant human complement factor D protein, 1 μm of recombinant human complement factor B protein and 1 μm of CVF, and after thoroughly mixing, the mixture was reacted at 37 ℃ in an 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).

Preparation of 100mM Na ₂ CO ₃ Solution and 100mM NaHCO ₃ According to volume ratio Na ₂ CO ₃ ：NaHCO ₃ =3: 7, adjusting the pH value to 9.5, and storing at room temperature for later use.

20mM test compound in 100% DMSO was serially diluted to 2000, 500, 125, 31.25, 7.8125, 0.488281, 0.12207, 0.030518, 0.007629. Mu.M with 100% DMSO and blank wells100% DMSO, further 20-fold diluted in C3 reaction buffer (PBS pH7.4,1mM MgCl) ₂ 0.05% CHAPS).

C3 protein cleavage reaction: in a 96-well white half-well plate, 10. Mu.L of the reaction system was prepared in a C3 reaction buffer (PBS pH7.4,1mM MgCl) ₂ 0.05% CHAPS) was added with a final concentration of 2nM of CVF: bb, 1. Mu.L of the test compound diluted in the C3 reaction buffer and DMSO, were incubated at room temperature for 1 hour. The final concentrations of test compounds were 10000, 2500, 625, 156.25, 39.0625, 9.765625, 2.441406, 0.6103515, 0.152588nM, respectively. Human complement factor C3 was added to the reaction system at a final concentration of 500nM, and after mixing, the mixture was reacted at 37℃for 2 hours in an incubator, and the reaction mixture contained only 500nM human complement factor C3 as a negative control. To a 96-well black plate, 97. Mu.L of carbonic acid buffer (pH 9.5) was added, and 3. Mu. L C3 protein shear reaction mixture was added to each well, and after mixing, the plate was closed and incubated overnight at 4 ℃.

C3a des Arg detection: plates were washed 3 times with 300. Mu.L/well TBST (0.05% Tween 20) solution and 300. Mu.L of LStartingBlock was added to each well ^TM T20 (TBS) blocking buffer, incubated at 37℃for 5 min; plates were washed 3 times with 300. Mu.L/well PBST solution in which anti-C3 a/C3a des Arg antibody [2991 ] was diluted 1:1000]100. Mu.L of each well was added and incubated at 37℃for 1 hour; plates were washed 3 times with 300. Mu.L/well PBST solution in which goat anti-mouse IgG H was diluted 1:5000 &L(Goat Anti-Mouse IgG H&L) (HRP) antibody, 100. Mu.L per well was added and incubated for 30 min at 37 ℃; preparation of QuantaBlu ^TM Fluorescent peroxidase substrate kit (QuantaBlu) ^TM Fluorogenic Peroxidase Substrate Kit) substrate, 1 part QuantaBlu ^TM Stable peroxide solutions (QuantaBlu) ^TM Stable Peroxide Solution) diluted to 9 parts QuantaBlu ^TM Substrate solution (QuantaBlu) ^TM Substrate Solution); washing the plate with 300 mu L/hole PBST solution for 3 times, and buckling the plate to be dry in the last time; 100 mu L of substrate is added to each well, and the mixture is incubated for 20 minutes at room temperature; 100 mu.L QuantaBlu was added to each well ^TM Stop solution (QuantaBlu) ^TM Stop Solution), fluorescence values are read at Flexstation, and excitation light wavelength Ex 320nM and emission light wavelength Em 460nM,Cut off 455 are set.

The inhibition was calculated using the following formula:

inhibition ratio = {1- (RFU) _{Test compounds} -RFU _{Negative control well} )/(RFU _{Blank hole} -RFU _{Negative control well} )}×100％

Plotting inhibition curves according to the concentrations of the compounds and the corresponding inhibition rates by using Graphpad Prism software, and calculating the concentration of the compound when the inhibition rate reaches 50%, namely IC ₅₀ Values.

Conclusion: IC of Compound I for inhibiting Activity of Factor B enzyme ₅₀ 1.3nM, has good inhibition to Factor B enzyme.

EXAMPLE 3 preparation of form A of the Compound

About 6mg of compound I is weighed, dissolved in 0.02mL of methanol, volatilized and crystallized to obtain a product.

The product was defined as form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 1 and the characteristic peak positions shown in table 1. DSC profile showed that the endothermic peaks were 90.20 ℃ and 174.77 ℃. TGA profile shows a weight loss of 13.18% at 30-150 ℃.

DVS testing showed that the sample had a moisture gain of about 8.87% under normal storage conditions (i.e., 25 ℃, 60% RH); under accelerated experimental conditions (i.e., 70% RH), the hygroscopic gain was about 12.54%; under extreme conditions (i.e., 90% RH), the hygroscopic gain was about 17.46%. And the crystal form is retested after DVS detection, and the crystal form is not transformed.

TABLE 1 peak positions for Compound A crystalline forms

EXAMPLE 4 preparation of Compound A crystalline form

Weighing the compound I, adding a solvent, and crystallizing to obtain a product. The crystalline forms were determined by X-ray powder diffraction detection and are shown in table 2.

Table 2 preparation of form a of compound I

Numbering device	Feed amount and solvent	Crystal form
			1	About 6mg of compound I is weighed, dissolved in 0.03mL of 10% water/methanol, volatilized and crystallized	A
2	Weighing about 6mg of compound I, dissolving in 0.07mL of 7% water/ethanol, volatilizing and crystallizing	A
			3	About 6mg of compound I was weighed, dissolved in 0.02mL of acetonitrile/methanol (V/v=1:1), and volatilized for crystallization	A
4	About 6mg of compound I is weighed, 0.6mL of n-heptane is added, and stirring crystallization is carried out	A
			5	About 6mg of Compound I was weighed, 0.6mL of isopropyl ether was added thereto, and the mixture was stirred for crystallization	A
6	Weighing about 6mg of compound I, dissolving in 0.05mL of ethanol, adding 0.4mL of water, stirring, and crystallizing	A

EXAMPLE 5 preparation of Compound B crystalline form

About 6mg of compound I is weighed, 0.6mL of water is added, stirring crystallization is carried out, and the solid is dried in vacuum after centrifugation, thus obtaining the product.

The product was defined as form B as measured by X-ray powder diffraction, the XRPD pattern shown in figure 2 and the characteristic peak positions shown in table 3. The DSC profile showed an endothermic peak at 188.93 ℃. TGA profile shows a weight loss of 1.89% at 30-155 ℃.

DVS testing showed that the sample had a hygroscopic gain of about 0.46% under normal storage conditions (i.e., 25 ℃, 60% rh); under accelerated experimental conditions (i.e., 70% RH), the hygroscopic gain was about 0.76%; under extreme conditions (i.e., 90% RH), the hygroscopic gain was about 2.48%. And the crystal form is retested after DVS detection, and the crystal form is not transformed.

TABLE 3 peak positions for Compound B crystalline forms

EXAMPLE 6 preparation of Compound B crystalline form

Weighing the compound I, adding a solvent, and crystallizing to obtain a product. The crystal forms were determined by X-ray powder diffraction detection and are shown in table 4.

TABLE 4 preparation of form B of Compound I

EXAMPLE 7 preparation of Compound C form

About 6mg of compound I is weighed, dissolved in 0.4mL of ethanol, volatilized and crystallized to obtain a product.

The product was defined as form C as detected by X-ray powder diffraction, the XRPD pattern shown in figure 3 and the characteristic peak positions shown in table 5. The DSC profile showed an endothermic peak at 151.26 ℃. TGA profile shows a weight loss of 38.38% at 30-190 ℃.

TABLE 5 peak positions of Compound C crystalline forms

EXAMPLE 8 preparation of Compound C Crystal form

Weighing the compound I, adding a solvent, and crystallizing to obtain a product. The crystalline forms were determined by X-ray powder diffraction detection and are shown in table 6.

TABLE 6 preparation of form C of Compound I

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EXAMPLE 9 preparation of crystalline form D of Compound

About 6mg of compound I is weighed, 0.6mL of isopropyl acetate is added, stirring crystallization is carried out, and the solid is dried in vacuum after centrifugation, thus obtaining the product.

The product was defined as form D as measured by X-ray powder diffraction, the XRPD pattern shown in figure 4 and the characteristic peak positions shown in table 7. The DSC profile showed an exothermic peak-to-peak value of 198.86 ℃. TGA spectrum shows that the weight loss is 1.56% at 30-135 ℃; weight loss of 7.87% at 135-215 ℃.

TABLE 7 peak positions of compound D crystalline forms

EXAMPLE 10 preparation of Compound D form

Weighing the compound I, adding a solvent, and crystallizing to obtain a product. The crystal forms were determined by X-ray powder diffraction detection and are shown in table 8.

TABLE 8 preparation of the D forms of Compound I

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EXAMPLE 11 preparation of crystalline form of Compound E

About 6mg of compound I was weighed, 0.2mL of methanol/water (V/v=1:1) was added, stirred for crystallization, and the solid was dried under vacuum after centrifugation to obtain the product.

The product was defined as form E as detected by X-ray powder diffraction, the XRPD pattern shown in figure 5 and the characteristic peak positions shown in table 9. DSC profile showed that the endothermic peaks were 79.92 ℃ and 174.45 ℃. TGA profile shows a weight loss of 5.48% at 30-150 ℃.

TABLE 9 peak positions for Compound E crystalline forms

EXAMPLE 12 preparation of Compound F Crystal form

About 6mg of compound I was weighed, dissolved in 0.4mL of tetrahydrofuran/ethanol (V/v=2:1), and evaporated for crystallization to give a product.

The product was defined as form F as measured by X-ray powder diffraction, the XRPD pattern shown in figure 6 and the characteristic peak positions shown in table 10. DSC profile showed that the endothermic peaks were 83.44 ℃ and 173.43 ℃. TGA profile shows a weight loss of 9.93% at 30 ℃ -170 ℃.

Table 10 peak positions of compound F crystal form

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EXAMPLE 13 preparation of Compound G form

About 130mg of compound I was weighed, 1mL of methanol/water (V/v=1:1) was added, stirred for crystallization, and after centrifugation, the solid was dried in vacuo to give the product.

The product was defined as form G as detected by X-ray powder diffraction, the XRPD pattern shown in figure 7 and the characteristic peak positions shown in table 11. The DSC profile showed an endothermic peak at 176.78 ℃. TGA profile shows a weight loss of 8.40% at 30-150 ℃.

Table 11 peak positions of compound G crystal form

EXAMPLE 14 preparation of Compound H Crystal form

About 120mg of compound I was weighed, dissolved in 0.8mL of tetrahydrofuran/methanol (V/V=2:1), and 4.5mL of pure water was added thereto, followed by stirring for crystallization and suction filtration to obtain a product.

The product was defined as form H as detected by X-ray powder diffraction, the XRPD pattern shown in figure 8 and the characteristic peak positions shown in table 12. DSC profile showed endothermic peaks 70.79 ℃ and 191.42 ℃. TGA profile shows a weight loss of 6.06% at 30 ℃ -155 ℃.

Table 12 peak positions of compound H crystal form

EXAMPLE 15 preparation of Compound I crystalline form

About 46g of wet compound I was weighed, dissolved in about 800mL of methylene chloride/methanol (V/v=9:1), left to stand, the powder was removed from the aqueous phase, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the product.

The XRPD pattern identified as form I by X-ray powder diffraction detection is shown in fig. 9 and the characteristic peak positions are shown in table 13. DSC profile showed endothermic peaks 92.68 ℃ and 176.79 ℃. TGA profile shows a weight loss of 11.94% at 30-150 ℃.

TABLE 13 peak positions of Compound I crystalline forms

EXAMPLE 16 preparation of Compound J Crystal form

Example 15 a sample was heated to 130 c to give the product.

The XRPD pattern identified as form J by X-ray powder diffraction measurement is shown in fig. 10 and the characteristic peak positions are shown in table 14. The DSC profile shows an endothermic peak at 175.50 ℃. TGA profile shows a weight loss of 2.74% at 30 ℃ -145 ℃.

TABLE 14 peak positions for compound J crystalline forms

EXAMPLE 17 amorphous preparation of Compounds

About 6mg of compound I is weighed, dissolved in 0.6mL of acetone, volatilized and crystallized to obtain a product. The product was amorphous as measured by X-ray powder diffraction, and the XRPD pattern is shown in figure 11.

EXAMPLE 18 amorphous preparation of Compounds

Weighing the compound I, adding a solvent, and crystallizing to obtain a product. The crystal forms were determined by X-ray powder diffraction detection and are shown in table 15.

Table 15 preparation of amorphous form of compound I

Experimental example 1 stability study of influencing factors of Compound A Crystal form

The form A of the compound I was left in an open-top state, and stability of the sample under light (4500 Lux), high temperature (40 ℃ C., 60 ℃ C.), and high humidity (RH 75%, RH 92.5%) was examined, respectively, and the sampling examination period was 30 days.

TABLE 16 stability of Compound A Crystal form influencing factors

Conclusion: the influence factor experiment shows that: the physical stability of the free form A crystal form is good under the conditions of high temperature and illumination under the conditions of illumination, high temperature of 40 ℃ and 60 ℃ and high humidity of 75% and 92.5% for 30 days; good chemical stability under high humidity.

Experimental example 2 Long-term accelerated stability study of Compound A Crystal form

The free form A crystal form of the compound is placed under the conditions of 25 ℃/60%RH and 40 ℃/75%RH respectively to examine the stability.

Table 17 long term accelerated stability of compound a crystalline form

Conclusion: the long-term acceleration experiment shows that: the free form A crystal form has good chemical stability under the conditions of 25 ℃/60%RH and 40 ℃/75%RH for 6 months, and has good physical stability under long-term conditions.

Experimental example 3 stability study of influencing factors of Compound B Crystal form

The form B of the compound I was left open and spread, and stability of the sample under light (4500 Lux), high temperature (40 ℃ C., 60 ℃ C.), and high humidity (RH 75%, RH 92.5%) was examined, respectively, and the sampling examination period was 30 days.

Table 18 stability of compound B form factor

Conclusion: the influence factor experiment shows that: the free B crystal form has good physical and chemical stability under the conditions of illumination, high temperature of 40 ℃ and 60 ℃ and high humidity of 75% and 92.5% for 30 days.

Experimental example 4 Long-term accelerated stability study of Compound B Crystal form

The free B crystal form of the compound is placed under the conditions of 25 ℃/60% RH and 40 ℃/75% RH respectively to examine the stability.

Table 19 long term accelerated stability of compound B crystalline form

Conclusion: the long-term acceleration experiment shows that: the free B crystal form has good physical and chemical stability under the conditions of 25 ℃/60%RH and 40 ℃/75%RH for 6 months.

Experimental example 5 influence factor stability study of Compound G Crystal form

The compound I in the form G was left open and spread, and the stability of the sample under light (4500 Lux), high temperature (40 ℃ C., 60 ℃ C.), and high humidity (RH 75%, RH 92.5%) was examined, respectively, with a sampling period of 30 days.

TABLE 20 stability of Compound G Crystal form influencing factors

Conclusion: the influence factor experiment shows that: the physical stability of the free G crystal form is good under the conditions of high humidity and illumination under the conditions of illumination, high temperature of 40 ℃ and 60 ℃ and high humidity of 75% and 92.5% for 30 days; the chemical stability is good under high humidity condition.

Experimental example 6 Long-term accelerated stability study of Compound G Crystal form

The free form G crystal form of the compound is placed under the conditions of 25 ℃/60% RH and 40 ℃/75% RH respectively to examine the stability.

Table 21 long term accelerated stability of compound G crystalline forms

Conclusion: the long-term acceleration experiment shows that: the free form G crystal form has good physical and chemical stability under the conditions of 25 ℃/60% RH and 40 ℃/75% RH for 6 months.

Claims

1. Crystalline form a of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ with characteristic peaks at 5.2, 7.5, 8.2, 9.3 and 15.4, preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, as shown in figure 1.

2. Form B of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2θ, preferably at 8.2, 9.3, 14.0, 15.7, 17.2 and 18.9, preferably at 8.2, 8.8, 9.3, 14.0, 14.6, 15.7, 17.2, 17.8 and 18.9, more preferably at 8.2, 8.8, 9.3, 9.9, 12.1, 14.0, 14.6, 15.7, 17.2, 17.8 and 18.9, most preferably an X-ray powder diffraction pattern with diffraction angles 2θ, as shown in fig. 2.

3. A crystalline form C of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ with characteristic peaks at 5.0, 8.3, 10.4, 12.6, and 17.8, preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, as shown in figure 3.

4. A crystalline D form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed as diffraction angle 2Θ angles with characteristic peaks at 7.3, 11.2, 14.9, 19.0, and 21.5, preferably an X-ray powder diffraction pattern expressed as diffraction angle 2Θ angles, as shown in figure 4.

5. Crystalline form E of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 5.1, 6.6, 7.1, 14.3 and 15.1, preferably the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ being as shown in fig. 5.

6. A crystalline form F of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed as diffraction angle 2Θ angles with characteristic peaks at 6.8, 13.4, 20.5, 23.3, and 24.3, preferably an X-ray powder diffraction pattern expressed as diffraction angle 2Θ angles, as shown in figure 6.

7. A crystalline form G of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2Θ, preferably at 6.4, 7.0, 9.1, 10.4, 14.0, 14.7, 16.8, 19.3 and 21.5, more preferably at 5.0, 6.4, 7.0, 9.1, 10.4, 14.0, 14.7, 16.8, 19.3, 20.1, 21.5 and 24.2, and most preferably with characteristic peaks at diffraction angles 2Θ, as shown in figure 7.

8. An H-crystal form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.1, 9.3, 14.1, 16.2, 17.9, 18.7 and 23.5, preferably having characteristic peaks at 8.1, 9.3, 14.1, 15.6, 16.2, 17.0, 17.9, 18.7, 23.5 and 26.6, more preferably having characteristic peaks at 8.1, 9.3, 10.3, 11.8, 14.1, 15.6, 16.2, 17.0, 17.9, 18.7, 23.5, 26.0, 26.6 and 27.5, most preferably having characteristic peaks expressed in terms of diffraction angle 2θ, as shown in figure 8.

9. Form I of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid, having a characteristic peak at 7.0, 8.3, 9.3, 14.0, 16.1, 20.5 and 28.0, preferably at 7.0, 8.3, 9.3, 14.0, 15.5, 16.1, 18.9, 20.5, 24.1 and 28.0, more preferably at 7.0, 8.3, 9.3, 12.4, 14.0, 15.5, 16.1, 18.3, 18.9, 20.5, 23.6, 24.1 and 28.0, most preferably at a diffraction angle 2θ, as shown in figure 9.

10. A crystalline form J of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, having characteristic peaks at 7.9, 9.3, 14.1, 15.6, 18.9, and 19.9, preferably having characteristic peaks at 7.9, 9.3, 12.4, 14.1, 15.6, 17.2, 17.8, 18.9, 19.9, 23.5, 24.0, and 25.3, more preferably having an X-ray powder diffraction pattern expressed in terms of diffraction angle 2Θ, as shown in figure 10.

11. A crystalline form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid according to any one of claims 1-8, wherein the error range of the 2Θ angle is ± 0.2.

12. A process for preparing the crystalline form of any one of claims 1 to 9, selected from any one of the following processes,

the method comprises the following steps:

i) Mixing compound 4- ((1S, 3S, 5R) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] octane-1-yl) benzoic acid with a solvent, stirring for dissolving or heating for dissolving,

ii) devitrification;

or, method two:

ii) adding a second solvent, and crystallizing;

or, method three:

i) The compound 4- ((1S, 3S, 5R) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid is mixed with a solvent,

ii) stirring and pulping, and crystallizing.

13. A pharmaceutical composition comprising the following components:

i) A crystalline form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid of claims 1-9; and

ii) one or more pharmaceutically acceptable excipients.

14. A method of preparing a pharmaceutical composition comprising the steps of: a step of mixing a crystalline form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid according to claims 1-11 with a pharmaceutically acceptable excipient.

15. Use of a crystalline form of 4- ((1 s,3s,5 r) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid according to any one of claims 1-11, or of a composition according to claim 13 in the manufacture of a medicament for inhibiting complement alternative pathway activation, preferably for inhibiting complement factor B.

16. The crystalline form of 4- ((1S, 3S, 5R) -3-ethoxy-8- ((5-methoxy-7-methyl-1H-indol-4-yl) methyl) -8-azabicyclo [3.2.1] oct-1-yl) benzoic acid according to any one of claims 1-11, or the use of a composition according to claim 13 in the preparation of a medicament for the treatment of a disease or disorder, the disease or condition is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal sleep hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choriitis, fu-small willow-original field syndrome, shotgun-elastic retinochoroiditis, sympathogenic ophthalmitis, ocular cicatricial pemphigoid, ocular pemphigus, non-arterial inflammatory ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, guillain-Barre syndrome, traumatic brain injury, parkinson's disease, inappropriate or undesired complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during treatment, crohn's disease, adult respiratory syndrome, pericardial reperfusion disorder, myocardial infarction, balloon-2 shunt, post-operative bypass pump or post-operative arterial bypass, post-arterial bypass pump, multiple sclerosis, hyperacute allograft syndrome, hyperacute allograft rejection, xenograft rejection, and postsurgical inflammatory conditions, hemodialysis, renal ischemia, aortic remodeling, mesenteric artery reperfusion after infectious disease or sepsis, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic disease, goldman syndrome, pulmonary vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity; the disease or condition is preferably C3 glomerulopathy, immunoglobulin a nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal sleep haemoglobinuria.