WO2023143293A1 - 补体因子b抑制剂的盐型、晶型及其制备方法和应用 - Google Patents

补体因子b抑制剂的盐型、晶型及其制备方法和应用 Download PDF

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WO2023143293A1
WO2023143293A1 PCT/CN2023/072834 CN2023072834W WO2023143293A1 WO 2023143293 A1 WO2023143293 A1 WO 2023143293A1 CN 2023072834 W CN2023072834 W CN 2023072834W WO 2023143293 A1 WO2023143293 A1 WO 2023143293A1
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acid
crystal form
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monohydrochloride
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French (fr)
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栾林波
田勇
姚元山
陈永凯
王朝东
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上海美悦生物科技发展有限公司
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Priority to AU2023210941A priority patent/AU2023210941A1/en
Publication of WO2023143293A1 publication Critical patent/WO2023143293A1/zh

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Definitions

  • the present invention claims the patent application number 202210096073.X submitted to the State Intellectual Property Office of China on January 26, 2022, and the name is "salt form, crystal form and preparation method and application of complement factor B inhibitor" and published in Submitted to the State Intellectual Property Office of China on September 9, 2022, the patent application number is 202211104894.X, and the priority of the previous application entitled “Salt form, crystal form and preparation method and application of complement factor B inhibitor” . The entirety of this prior application is incorporated by reference into the present application.
  • the invention belongs to the field of medicine, and in particular relates to a salt form and a crystal form of a complement factor B inhibitor, a preparation method and an application thereof.
  • Complement is a class of soluble pattern recognition molecules in the immune system that can perform multiple effector functions.
  • complement components exist in the form of inactive zymogens, and a variety of specific and non-specific immunological mechanisms decompose these inactive zymogens to produce active large and small fragments.
  • large fragments usually stay on the surface of pathogens or cells to lyse the latter or accelerate their clearance; small fragments leave the cell surface and mediate various inflammatory reactions.
  • the activation of complement consists of two closely following processes, and thus forms a cascade reaction of complement activation.
  • Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the alternative pathway.
  • the initiation mechanisms and activation sequences of the three complement activation pathways are different, they have a common terminal pathway. Among them, the activation of the alternative pathway does not depend on the antigen-antibody complex.
  • C3b deposited on the cell surface binds to factor B and becomes a state that is easily decomposed by factor D in serum.
  • factor B is decomposed into Ba and Bb ; C3b and Bb then form a complex to become the C3 convertase C3bBb in the alternative pathway; in this process, complement factor B plays an early and central role in the activation of the alternative pathway of the complement cascade.
  • C3b is not only the product that appears after C3 convertase decomposes C3, but also a component of alternative pathway C3 convertase, thus forming a feedback amplification mechanism in which the classical pathway and the alternative pathway influence each other.
  • Current studies have found that various diseases such as hematological, autoimmune, inflammatory, and neurodegeneration are related to the abnormal function of the complement system.
  • Paroxysmal nocturnal hemoglobinuria is a chronic disease with persistent hemolysis. Ultra Rare Blood Disorders (Medicine (Baltimore) 1997, 76(2):63-93).
  • the course of the disease can be manifested by varying degrees of exacerbation of hemolysis (paroxysmal), chronic or recurrent acute intravascular hemolysis or subsequent venous/arterial thrombosis, eventually leading to progressive end-organ damage and death, and most patients often do not Typically, the onset is insidious, the course of the disease is protracted, and the severity of the disease varies.
  • GPI-anchored proteins There are more than ten kinds of proteins on the surface of red blood cells that inhibit the activation of the complement pathway, all of which are anchored on the cell membrane through glycosylated phosphatidylinositol (GPI), collectively referred to as GPI-anchored proteins (AP).
  • GPI glycosylated phosphatidylinositol
  • AP glycosylated phosphatidylinositol
  • CD59 can prevent the incorporation of C9 into the C5b-8 complex, prevent the formation of membrane attack units, and inhibit the terminal attack response of complement. It is currently believed that the typical manifestations of PNH - intravascular hemolysis and thrombosis are due to the lack of CD59.
  • IgAN is the most common form of primary glomerulonephritis, and the disease is characterized by IgA deposits in the mesangium by immunofluorescence. The clinical presentation of the disease is variable and usually presents with recurrent episodes of microscopic or gross hematuria.
  • Existing data indicate that the occurrence of IgAN is related to innate or acquired immune regulation abnormalities. Due to the stimulating effects of viruses, bacteria, and food proteins on the respiratory tract or digestive tract, the synthesis of mucosal IgA1 increases, or the immune complex containing IgA1 is deposited in the mesangium, and activates the alternative pathway of complement, causing glomerular damage.
  • IgA molecules are divided into two subtypes, IgA1 and IgA2, among which IgA1 is the main form in the blood circulation of healthy individuals (accounting for about 85%), and is also the main component of glomerular mesangial deposition in IgAN patients.
  • IgA molecules can exist in two forms, monomer and polymer.
  • the IgA1 molecule has a unique heavy chain hinge region between the first and second constant domains that serves as a domain for attachment of O-linked glycan groups.
  • Recent studies have found that the IgA molecules deposited in the serum of IgAN patients and in the glomerular mesangial region are mainly glycosylation-deficient IgA1 (gd-IgA1). At present, it is believed that the initiation link of the pathogenesis of IgAN is the abnormal production of gd-IgA1 increase.
  • IgAN patients More than 90% of IgAN patients have deposition of complement C3 in the glomerular mesangium. 75%-100% of IgAN patients have co-deposition of properdin, IgA, and C3 in the kidney tissue, and 30%-90% of IgAN patients have co-deposition of complement factor H, IgA, and C3 in the kidney tissue.
  • the levels of markers of the alternative complement pathway in the plasma of IgAN patients are also related to the activity of IgAN (J Nephrol 2013,26(4):708-715). Studies have confirmed that C3a in kidney tissue and urine and C3a receptors in kidney tissue are significantly related to the activity and severity of kidney damage (J clin Immunol 2014,34(2):224-232).
  • IgA can activate the alternative pathway of complement under in vitro conditions.
  • the abnormality of the IgA hinge region does not play a decisive role, but the formation of IgA multimers is the key link (Eur J Immunol 1987,17(3):321-326).
  • deposition of complement C3 in the glomerular mesangium has become an auxiliary diagnostic marker for IgAN.
  • MN membranous nephropathy
  • C3G C3 glomerulonephritis
  • AMD age-related macular degeneration
  • GA geographic atrophy
  • aHUS atypical hemolytic uremic syndrome
  • HUS hemolytic uremic syndrome
  • NMO neuromyelitis
  • liver-like inflammation inflammatory bowel disease
  • dermatomyositis atypical hemolytic uremic syndrome
  • amyotrophic lateral sclerosis myasthenia gravis
  • respiratory diseases and cardiovascular diseases include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome ( aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), liver-like inflammation, inflammatory bowel disease, dermatomyositis, and amyotrophic
  • complement factor B inhibitors used in clinical treatment.
  • oligonucleotide drugs developed by IONIS Pharmaceuticals Inc. as complement factor B (CFB) specific inhibitors to treat, prevent or alleviate diseases associated with dysregulation of the alternative complement pathway (WO2015038939).
  • CFB complement factor B
  • the small molecule complement factor B inhibitor developed by Novartis AG is used to treat age-related macular degeneration (AMD) and other diseases (WO2013164802, WO2013192345, WO2014143638, WO2015009616, WO2015066241), or for the treatment of diseases such as C3G and IgAN (WO2019043609A1).
  • the small molecule complement factor B inhibitor developed by Achillion Pharmaceuticals Inc. is used to treat diseases such as age-related macular degeneration (AMD) (WO2018005552).
  • Inflammatory and immune-related diseases are diverse and difficult to cure; the only drug on the market for PNH diseases is eculizumab, but due to the price, it has brought a heavy burden to patients; at the same time, many patients have been treated with eculizumab Anemia still occurs after zizumab treatment, and many patients still need continuous blood transfusion; in addition, eculizumab needs to be administered intravenously. And some diseases have no specific treatment drugs so far, such as IgAN and so on. There are unmet clinical needs in these areas that require the development of new small molecule drugs for medical treatment.
  • the present invention provides a pharmaceutically acceptable salt of a compound of formula I:
  • the pharmaceutically acceptable salt is the salt formed by the compound of formula I with acid or base, preferably selected from the salts formed by the compound of formula I with acid.
  • the acid may be selected from inorganic or organic acids, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, Pyruvate, Trifluoroacetic Acid, Propionic Acid, Butyric Acid, Hexanoic Acid, Heptanoic Acid, Undecanoic Acid, Lauric Acid, Benzoic Acid, Salicylic Acid, 2-(4-Hydroxybenzoyl)benzoic Acid, Camphoric Acid, Cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, niacin, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid , 2-hydroxyethane
  • inorganic or organic acids
  • the acid may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, One of citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.
  • the base may be selected from inorganic bases such as alkali metal hydroxides or alkaline earth metal hydroxides, preferably from sodium hydroxide or potassium hydroxide.
  • the pharmaceutically acceptable salt of the compound of formula I is selected from its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate One of salt, citrate, L-tartrate and oxalate.
  • the pharmaceutically acceptable salt of the compound of formula I is a salt of the compound of formula I and hydrochloric acid, that is, the hydrochloride of the compound of formula I, preferably the monohydrochloride of the compound of formula I.
  • the molar ratio of the compound of formula I to the acid or base can be independently selected from 1:1, 2:1 or 3:1, Provided that the ion of the compound of formula I in the salt is in charge balance with that of the acid or base.
  • the molar ratio of the compound of formula I to the acid is 1:1;
  • the molar ratio of the compound of formula I and the acid can be 1:1 Or 2:1;
  • the number of ionizable hydrogen atoms in the acid is 3, the molar ratio of the compound of formula I to the acid is 1:1, 2:1 or 3:1.
  • the present invention also provides a preparation method of a pharmaceutically acceptable salt of the compound of formula I, the preparation method comprising reacting the compound of formula I with the acid or base to prepare the pharmaceutically acceptable salt of the compound of formula I.
  • the preparation method comprises reacting the compound of formula I with the acid or base in a solvent to prepare a pharmaceutically acceptable salt of the compound of formula I.
  • said acid or base independently of each other has the definition set out above.
  • the solvent may be selected from alcohols, ketones, esters, ethers, a combination of two or more of the solvents, or a mixture of the above solvents or combinations with water.
  • the alcohols may be selected from alcohols having 1-8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol or two or more thereof combination;
  • the ketones can be selected from ketones with 3-10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone or a combination of two or more thereof ;
  • the esters can be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate or a combination of two or more thereof;
  • the ethers can be linear or branched Alkyl ether or cyclic ether compounds, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran or a
  • the molar ratio of the compound of formula I to the acid or base may be 1:0.8 to 1:1.5, preferably 1:0.9 to 1:1.3, more preferably 1:1.0 to 1: 1.1.
  • the temperature of the reaction in the preparation method, can be selected in a wide range, such as 20°C to 80°C, preferably 30°C to 60°C.
  • the preparation method further includes a step of filtering and/or drying after the reaction, so as to prepare a pharmaceutically acceptable salt of the compound of formula I.
  • the drying temperature in the preparation method, can be selected within a wide range, for example, it can be 20°C-80°C, preferably 30°C-60°C.
  • the drying pressure may be 0-20KPa, preferably 0-10KPa, more preferably 5-10KPa.
  • the present invention also provides crystals, preferably single crystals, of the monohydrochloride salt of the compound of formula I.
  • the unit cell parameters of the single crystal are as follows:
  • the present invention also provides the crystal of the monohydrochloride of the compound of formula I, especially the preparation method of its single crystal, comprising dissolving the monohydrochloride of the compound of formula I in solvent A and then diffusing in the atmosphere of solvent B.
  • the solvent A may be an alcoholic solvent, such as a combination of two or more of methanol and ethanol.
  • the solvent B may be an ester solvent, an ether solvent or a combination of two or more thereof.
  • the ester solvent can be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate or a combination of two or more thereof;
  • the ether solvent can be linear or branched Alkyl ethers, cyclic ether compounds or a combination of two or more thereof, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran or a combination of two or more thereof.
  • the present invention also provides a crystal form of the monohydrochloride salt of the compound of formula I, which is selected from crystal form A, crystal form B, crystal form C, crystal form D or crystal form E described below.
  • a crystal form A of the monohydrochloride of the compound of formula I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 9.66 ⁇ 0.20°, 16.08 ⁇ 0.20°, 23.46 ⁇ 0.20° have characteristic peaks.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 9.66 ⁇ 0.20°, 16.08 ⁇ 0.20°, 18.10 ⁇ 0.20°, 21.30 ⁇ 0.20°, 21.68 ⁇ 0.20° have characteristic peaks.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 9.66 ⁇ 0.20°, 11.62 ⁇ 0.20°, 16.08 ⁇ 0.20°, 18.10 ⁇ 0.20°, 21.30 ⁇ 0.20°, There are characteristic peaks at 21.68 ⁇ 0.20°, 23.40 ⁇ 0.20°, and 25.42 ⁇ 0.20°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 9.66 ⁇ 0.20°, 11.62 ⁇ 0.20°, 16.08 ⁇ 0.20°, 16.84 ⁇ 0.20°, 18.10 ⁇ 0.20°, There are characteristic peaks at 19.64 ⁇ 0.20°, 21.30 ⁇ 0.20°, 21.68 ⁇ 0.20°, 23.40 ⁇ 0.20°, 24.96 ⁇ 0.20°, 25.42 ⁇ 0.20°.
  • the crystal form A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle has the characteristic peaks shown in Table 1, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the crystal form A has a powder X-ray diffraction pattern substantially as shown in FIG. 1 .
  • the crystal form A is an anhydrous monohydrochloride of the compound of formula I.
  • the differential scanning calorimetry (DSC) analysis of the crystalline form A shows that the first endothermic peak appears when heated to a peak temperature of 192.73°C, and the first endothermic peak appears near the peak temperature of 201.78°C. hot peak.
  • the crystal form A has a DSC diagram substantially as shown in FIG. 2 .
  • thermogravimetric analysis (TGA) of the crystal form A shows that it has about 1.41% weight loss.
  • the crystal form A has a TGA diagram substantially as shown in FIG. 3 .
  • the crystal form A is an irregular crystal.
  • the particle size of the crystal form A is no more than 20 ⁇ m.
  • the crystal form A has a PLM spectrum substantially as shown in FIG. 4 .
  • a crystal form B of the monohydrochloride of the compound of formula I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 18.10 ⁇ 0.20°, 19.80 ⁇ 0.20°, 22.10 ⁇ 0.20° have characteristic peaks.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 9.48 ⁇ 0.20°, 15.44 ⁇ 0.20°, 18.10 ⁇ 0.20°, 19.80 ⁇ 0.20°, 22.10 ⁇ 0.20°, There is a characteristic peak at 30.92 ⁇ 0.20°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 9.48 ⁇ 0.20°, 10.78 ⁇ 0.20°, 15.44 ⁇ 0.20°, 18.10 ⁇ 0.20°, 19.18 ⁇ 0.20°, There are characteristic peaks at 19.80 ⁇ 0.20°, 22.10 ⁇ 0.20°, 30.92 ⁇ 0.20°.
  • the crystal form B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle has the characteristic peaks shown in Table 2, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the crystal form B has a powder X-ray diffraction pattern substantially as shown in FIG. 5 .
  • the crystal form B is a hydrate of the monohydrochloride of the compound of formula I, such as a monohydrate of the monohydrochloride of the compound of formula I.
  • the differential scanning calorimetry (DSC) analysis of the crystalline form B shows that the first endothermic peak appears when heated to a peak temperature of 85.87°C, and the second endothermic peak appears near the peak temperature of 197.54°C. Endothermic peak, the peak temperature is around 205.68°C and the first exothermic peak appears.
  • the crystal form B has a DSC diagram substantially as shown in FIG. 6 .
  • thermogravimetric analysis (TGA) of the crystal form B shows a weight loss of about 3.42% at 21.49°C to 120°C, and a weight loss of about 0.49% at 179.88°C to 207.94°C.
  • the crystal form B has a TGA diagram substantially as shown in FIG. 7 .
  • the crystal form B is an irregular crystal.
  • the particle size of the crystal form B is not more than 20 ⁇ m.
  • the crystal form B has a PLM spectrum substantially as shown in FIG. 8 .
  • the crystalline form A is obtained under high humidity conditions to obtain crystalline form B.
  • the high-humidity conditions are preferably at 40° C. and a relative humidity of 75% to 95%.
  • said crystalline form B yields crystalline form A under dry conditions.
  • the drying conditions are preferably under vacuum drying at 40°C.
  • a crystal form C of the monohydrochloride of the compound of formula I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 14.74 ⁇ 0.20°, 17.80 ⁇ 0.20°, 20.08 ⁇ 0.20° , There is a characteristic peak at 21.98 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 14.74 ⁇ 0.20°, 17.80 ⁇ 0.20°, 19.58 ⁇ 0.20°, 20.08 ⁇ 0.20°, 21.98 ⁇ 0.20°, There are characteristic peaks at 22.94 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 14.74 ⁇ 0.20°, 17.80 ⁇ 0.20°, 19.58 ⁇ 0.20°, 20.08 ⁇ 0.20°, 21.98 ⁇ 0.20°, There are characteristic peaks at 22.94 ⁇ 0.20°, 25.92 ⁇ 0.20° and 33.48 ⁇ 0.20°.
  • the crystal form C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle has the characteristic peaks shown in Table 3, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the crystal form C has a powder X-ray diffraction pattern substantially as shown in FIG. 9 .
  • the crystal form C is an anhydrous monohydrochloride of the compound of formula I.
  • the differential scanning calorimetry (DSC) analysis of the crystalline form C shows that the first endothermic peak appears when heated to a peak temperature of 209.93°C, and the first endothermic peak appears near the peak temperature of 215.80°C. exothermic peak.
  • the crystalline form C has a DSC diagram substantially as shown in FIG. 10 .
  • thermogravimetric analysis (TGA) of the crystalline form C shows a weight loss of about 0.29% in the range of 21.62°C to 120°C, and a weight loss of about 0.52% in the range of 173.94°C to 216.60°C.
  • the crystal form C has a TGA diagram substantially as shown in FIG. 11 .
  • the crystal form C is an irregular crystal.
  • the particle size of the crystal form C is no more than 20 ⁇ m.
  • the crystal form C has a PLM spectrum substantially as shown in FIG. 12 .
  • a crystal form D of the monohydrochloride salt of the compound of formula I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 15.74 ⁇ 0.20°, 16.58 ⁇ 0.20°, 21.98 ⁇ 0.20° , There is a characteristic peak at 23.82 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 10.16 ⁇ 0.20°, 11.90 ⁇ 0.20°, 15.74 ⁇ 0.20°, 16.58 ⁇ 0.20°, 19.22 ⁇ 0.20°, There are characteristic peaks at 20.24 ⁇ 0.20°, 21.98 ⁇ 0.20°, and 23.82 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 10.16 ⁇ 0.20°, 11.90 ⁇ 0.20°, 12.60 ⁇ 0.20°, 15.74 ⁇ 0.20°, 16.58 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.80 ⁇ 0.20°, 21.98 ⁇ 0.20°, There are characteristic peaks at 22.66 ⁇ 0.20°, 23.18 ⁇ 0.20°, 23.82 ⁇ 0.20°, 24.94 ⁇ 0.20°, 26.24 ⁇ 0.20°, 26.80 ⁇ 0.20°, 27.50 ⁇ 0.20°.
  • the crystal form D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle has the characteristic peaks shown in Table 4, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the crystal form D has a powder X-ray diffraction pattern substantially as shown in FIG. 13 .
  • the crystal form D is a solvate of the monohydrochloride of the compound of formula I, such as the dichloromethane solvate of the monohydrochloride of the compound of formula I, such as the monohydrochloride of the compound of formula I.
  • Methylene chloride solvate or monodichloromethane solvate.
  • the differential scanning calorimetry (DSC) analysis of the crystalline form D shows that the first exothermic peak appears when heated to a peak temperature of 196.53°C.
  • the crystalline form D has a DSC diagram substantially as shown in FIG. 14 .
  • thermogravimetric analysis (TGA) of the crystalline form D shows a weight loss of about 6.31% in the range of 22.07°C to 120°C.
  • the crystalline form D has a TGA diagram substantially as shown in FIG. 15 .
  • the crystal form D is an irregular crystal.
  • the particle size of the crystal form C is no more than 10 ⁇ m.
  • the crystal form D has a PLM spectrum substantially as shown in FIG. 16 .
  • a crystal form E of the monohydrochloride of the compound of formula I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 9.36 ⁇ 0.20°, 15.22 ⁇ 0.20°, 16.88 ⁇ 0.20° , There is a characteristic peak at 22.10 ⁇ 0.20°.
  • the crystal form E uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 7.20 ⁇ 0.20°, 9.36 ⁇ 0.20°, 15.22 ⁇ 0.20°, 16.88 ⁇ 0.20°, 21.10 ⁇ 0.20°, There are characteristic peaks at 22.10 ⁇ 0.20° and 23.68 ⁇ 0.20°.
  • the crystal form E uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angle is 7.20 ⁇ 0.20°, 9.36 ⁇ 0.20°, 15.22 ⁇ 0.20°, 16.88 ⁇ 0.20°, 18.78 ⁇ 0.20°, There are characteristic peaks at 21.10 ⁇ 0.20°, 22.10 ⁇ 0.20°, 23.68 ⁇ 0.20°, 26.04 ⁇ 0.20°, 27.86 ⁇ 0.20°.
  • the crystal form E uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle has the characteristic peaks shown in Table 5, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the crystal form E has a powder X-ray diffraction pattern substantially as shown in FIG. 17 .
  • the crystal form E is a solvate of the monohydrochloride of the compound of formula I, such as a monoisopropanol solvate of the monohydrochloride of the compound of formula I.
  • the present invention also provides a preparation method of the above crystal form of the compound monohydrochloride of formula I.
  • the first preparation method of crystal form A comprises: dissolving the compound of formula I in an alcoholic solvent, adding HCl in an alcoholic solvent to form a salt, and then adding n-alkane to crystallize to obtain the crystal form A.
  • the alcoholic solvent is selected from ethanol and/or isopropanol, preferably isopropanol.
  • the n-alkane is selected from n-hexane and/or n-heptane, preferably n-heptane.
  • the mass volume ratio of the compound of formula I, alcohol solvent and n-alkane is 1g:(10-30)mL:(10-30)mL, preferably 1g:(15-25)mL:(15-25)mL.
  • the concentration of the solution of HCl in the alcoholic solvent is 1-3 mol/L, for example 2 mol/L.
  • the heating temperature is 45-75°C, preferably 48-60°C.
  • the second preparation method of crystal form A comprises: heating and stirring the monohydrochloride of the compound of formula I in an alcoholic solvent and n-alkane until it dissolves and then crystallizes to obtain the crystal form A.
  • the alcoholic solvent is selected from ethanol and/or isopropanol, preferably isopropanol.
  • the n-alkane is selected from n-hexane and/or n-heptane, preferably n-heptane.
  • the mass volume ratio of the compound monohydrochloride of the formula I, alcohol solvent and normal alkane is 1g: (10-30) mL: (10-30) mL, preferably 1 g: (15-25) mL: (15- 25) mL, for example 1g:20mL:20mL.
  • the heating temperature is 45-75°C, preferably 48-60°C.
  • the preparation method 1 or 2 of the crystal form A further includes the steps of cooling, filtering and drying.
  • the preparation method of the crystal form A comprises: dissolving the compound of formula I in isopropanol, adding HCl in isopropanol solution, after mixing, adding n-heptane and stirring, filtering, After drying, the crystal form A was obtained.
  • the preparation method of the crystal form A comprises: adding the monohydrochloride of the compound of formula I into a mixed solvent of isopropanol and n-heptane, heating and stirring, cooling to normal temperature, filtering, and vacuum drying.
  • the crystalline form A was obtained.
  • the mass volume ratio of the monohydrochloride salt of the compound of formula I, isopropanol and n-heptane is 1g:(10-30)mL:(10-30)mL, for example 1g:20mL:20mL.
  • the preparation method of the crystal form B comprises: placing the crystal form A under high humidity conditions to obtain the crystal form B.
  • the temperature of the high-humidity condition is 30-50° C.
  • the humidity is 60%-98%.
  • the high-humidity condition is preferably at 40° C., with a humidity of 75% to 95%.
  • the preparation method of crystal form C comprises: dissolving the compound of formula I in an alcoholic solvent, and then adding a solution of HCl in an alcoholic solvent to form salt, and then add ether solvent or ester solvent to crystallize to obtain crystal form C.
  • the preparation method of crystal form C comprises: dissolving the compound of formula I in an alcoholic solvent, adding a solution of HCl in an alcoholic solvent, stirring, filtering, and adding an etheric solvent or an ester dropwise to the filtrate solvent, stirred, filtered, and dried to obtain Form C.
  • the alcohol solvent is selected from methanol, ethanol or isopropanol, preferably methanol.
  • the ether solvent is selected from methyl ether, diethyl ether, propyl ether or methyl tert-butyl ether, preferably methyl tert-butyl ether.
  • the ester solvent is selected from ethyl acetate or isopropyl acetate.
  • the mass volume ratio of the compound of formula I, alcohol solvent and ether solvent is 1g: (2-8) mL: (20-40) mL, preferably 1 g: (3-6) mL: (20-30) mL, such as 1g: 4mL: 25mL.
  • the concentration of the solution of HCl in an alcoholic solvent is 1-3mol/L, such as 1.5-2.5mol/L, exemplarily 1.8mol/L; the solution of the compound of formula I and HCl in an alcoholic solvent
  • the mass ratio is 1g: (0.5-1.5)g, such as 1g: (0.8-1.2)g.
  • the preparation method of the crystal form C comprises: after dissolving the compound of formula I in methanol, adding a methanol solution of HCl, stirring, and after filtering, adding methyl tert-butyl ether to the filtrate, filtering , dried to obtain Form C.
  • the preparation method of crystal form D comprises: suspending and stirring the monohydrochloride of the compound of formula I in halogenated alkanes at room temperature for crystallization to obtain crystal form D.
  • the preparation method of crystal form D comprises: adding the monohydrochloride of the compound of formula I to a halogenated alkane, stirring, separating the obtained suspension, drying the separated solid, and the obtained solid is crystal form D .
  • the halogenated alkane is selected from dichloromethane, chloroform or carbon tetrachloride, preferably dichloromethane.
  • the mass volume ratio of the monohydrochloride of the compound of formula I to the haloalkane is 1g:(15-35)mL, preferably 1g:(18-25)mL, for example 1g:20mL.
  • the separation is carried out by a known separation method, preferably by centrifugation.
  • the drying is vacuum drying under reduced pressure under heating conditions, preferably at 40° C. under reduced pressure and vacuum.
  • the preparation method of the crystal form D comprises: adding monohydrochloride of the compound of formula I into dichloromethane, stirring at room temperature, and separating the solid to obtain the crystal form D.
  • the preparation method of the crystal form E comprises: suspending and stirring the monohydrochloride salt of the compound of formula I in an alcohol solvent at room temperature for crystallization to obtain the crystal form E.
  • the monohydrochloride of the compound of formula I is added to an alcoholic solvent, stirred, the obtained suspension is separated, and the separated solid is dried, and the obtained solid is crystal form E.
  • the alcoholic solvent is selected from methanol, ethanol or isopropanol, preferably isopropanol.
  • the mass volume ratio of the monohydrochloride of the compound of formula I to the alcoholic solvent is 1g:(15-35)mL, preferably 1g:(18-25)mL, for example 1g:20mL.
  • the separation is carried out by a known separation method, preferably by centrifugation.
  • the drying is vacuum drying under reduced pressure under heating conditions, preferably at 40° C. under reduced pressure and vacuum.
  • the preparation method of the crystal form E comprises: adding the compound monohydrochloride of formula I into isopropanol, stirring at room temperature, and separating the solid to obtain the crystal form E.
  • the present invention also provides a pharmaceutical composition, comprising a pharmaceutically acceptable salt of the compound of formula I (such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, crystal form At least one of form D, crystal form E), and optional pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable salt of the compound of formula I such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, crystal form At least one of form D, crystal form E
  • the pharmaceutical composition is in the form of a formulation.
  • the present invention also provides a preparation, comprising at least one of the pharmaceutically acceptable salt of the compound of formula I, crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E, and optionally pharmaceutically acceptable excipients.
  • the present invention also provides a pharmaceutically acceptable salt of the compound of formula I as described above (such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E of the hydrochloride salt) ) or at least one of said pharmaceutical compositions in the preparation of medicines for the prevention and/or treatment of complement factor B-mediated diseases or disorders.
  • a pharmaceutically acceptable salt of the compound of formula I as described above such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E of the hydrochloride salt
  • the disease or disorder mediated by complement factor B is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), Membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS ), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, liver-like inflammation, dermatomyositis and muscular atrophy cord sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases.
  • PNH paroxysmal nocturnal hemoglobinuria
  • IgAN primary glomerulonephritis
  • MN Membranous nephropathy
  • C3G C3 glomer
  • the present invention also provides a method for preventing and/or treating diseases related to complement factor B inhibitors, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of the above-mentioned compound I (such as the salt acid salt, such as at least one of the hydrochloride salt of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E) or the pharmaceutical composition.
  • a pharmaceutically acceptable salt of the above-mentioned compound I such as the salt acid salt, such as at least one of the hydrochloride salt of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E
  • the disease or disease associated with complement factor B inhibitors is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN ), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, liver-like inflammation, dermatomyositis, and muscular atrophy sex Diseases such as lateral sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases.
  • PNH paroxysmal nocturnal hemoglobinuria
  • IgAN primary glomerulonephritis
  • MN membranous n
  • the treatment method of the present invention may comprise administering a pharmaceutically acceptable salt of the compound of formula I of the present invention (such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, and crystal form D of the hydrochloride) alone. , crystal form E) or the pharmaceutical composition, and the pharmaceutically acceptable salt of the compound of formula I of the present invention (such as the hydrochloride, such as the crystal form A, crystal form B, crystal form of the hydrochloride C, crystal form D, crystal form E) or one, two or more of said pharmaceutical compositions are administered in combination with one, two or more other chemotherapeutic agents. Administration of multiple drugs can be performed simultaneously or sequentially.
  • a pharmaceutically acceptable salt of the compound of formula I of the present invention such as the hydrochloride, such as the crystal form A, crystal form B, crystal form C, and crystal form D of the hydrochloride
  • the pharmaceutically acceptable salt of the compound of formula I of the present invention such as the hydrochloride, such as the crystal form A, crystal
  • the salts (especially hydrochloride, phosphate, and maleate) of the compound of formula I in the present invention have high stability and high water solubility, and significantly enhance the absorption capacity and bioavailability of oral administration.
  • the crystal form of the hydrochloride salt of the compound of formula I of the present invention has high stability, good solubility and low hygroscopicity, and has good prospects for making medicines.
  • the preparation method of the salt and crystal form of the compound of formula I of the present invention is convenient to operate, easy to control, good in reproducibility, mild in reaction conditions, high in product yield, and beneficial to industrial production.
  • Fig. 1 is the XRPD pattern of monohydrochloride crystal form A of the compound of formula I.
  • Fig. 2 is the DSC spectrum of the monohydrochloride crystal form A of the compound of formula I.
  • Fig. 3 is the TGA pattern of monohydrochloride crystal form A of the compound of formula I.
  • Fig. 4 is the PLM spectrum of the monohydrochloride crystal form A of the compound of formula I.
  • Fig. 5 is the XRPD pattern of the monohydrochloride crystal form B of the compound of formula I.
  • Fig. 6 is the DSC spectrum of the monohydrochloride crystal form B of the compound of formula I.
  • Fig. 7 is the TGA pattern of monohydrochloride crystal form B of the compound of formula I.
  • Fig. 8 is the PLM spectrum of the monohydrochloride crystal form B of the compound of formula I.
  • Fig. 9 is the XRPD pattern of the monohydrochloride salt form C of the compound of formula I.
  • Fig. 10 is the DSC spectrum of the monohydrochloride salt form C of the compound of formula I.
  • Fig. 11 is the TGA spectrum of the monohydrochloride crystal form C of the compound of formula I.
  • Fig. 12 is the PLM spectrum of the monohydrochloride crystal form C of the compound of formula I.
  • Fig. 13 is the XRPD pattern of the monohydrochloride salt form D of the compound of formula I.
  • Figure 14 is the DSC spectrum of the monohydrochloride salt form D of the compound of formula I.
  • Fig. 15 is the TGA spectrum of the monohydrochloride crystal form D of the compound of formula I.
  • Fig. 16 is the PLM spectrum of the monohydrochloride crystal form D of the compound of formula I.
  • Figure 17 is the XRPD pattern of the monohydrochloride salt form E of the compound of formula I.
  • Fig. 18 is the XRPD result chart of the monohydrochloride salt form C of the compound of formula I after being placed under accelerated and high temperature conditions for one month.
  • Fig. 19 is an XRPD result chart of the monohydrochloride salt form C of the compound of formula I exposed to high temperature and high humidity for 1 day.
  • Fig. 20 is an XRPD result chart of the monohydrochloride salt form C of the compound of formula I exposed to high temperature and high humidity for 3 days.
  • Fig. 21 is the experimental data (ng/mL) of the blood drug concentration curve in cynomolgus monkeys in the biological example.
  • Fig. 22 is the experimental data of AP activity curve in cynomolgus monkey serum (% relative to 0h) in the biological example.
  • Fig. 23 is the experimental data of Streptococcus-induced rheumatoid arthritis in the biological example.
  • Figure 24 is a single crystal diagram of the monohydrochloride salt of the compound of formula I.
  • the equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters:
  • the radiation source is Cu ⁇ K ⁇ target
  • the minimum operating voltage and current of the light pipe are 40kV and 30mA, respectively.
  • the 2-Theta values of the sample scan range from 2° to 50°.
  • the scanning speed is 5deg/min.
  • the sample is dispersed in the medium (silicone oil), the sample is observed with a 10X eyepiece and a 10X objective lens, and the image is recorded with a camera computer system.
  • the medium silicone oil
  • 40°C/75%RH refers to conditions at 40°C and 75% humidity.
  • 40°C/75%RH-closed refers to airtight storage at 40°C and 75% humidity.
  • 40°C/75%RH-open is placed at 40°C and 75% humidity.
  • 60°C-closed refers to placing it in airtight condition at 60°C.
  • 40°C/75%RH-closed-2wks means that the product should be stored in a sealed environment at 40°C and 75% humidity for 2 weeks.
  • 40°C/75%RH-open-2wks means that it should be kept open for 2 weeks at 40°C and 75% humidity.
  • 60°C-closed-2wks means that it is stored in a sealed environment at 60°C for 2 weeks.
  • Initial refers to the initial state.
  • SGF refers to simulated gastric juice.
  • FaSSIF refers to fasting state simulated intestinal fluid.
  • FeSSIF refers to fed state simulated intestinal fluid.
  • reaction system was diluted by adding anhydrous tetrahydrofuran (500mL) and cooled to -5°C, 4-methoxypyridine (25mL) was added, and benzyl chloroformate (35mL) was slowly added dropwise (maintaining the system temperature below 0°C), After the addition was complete, the reaction was stirred at 0°C for 2 hours, then warmed to room temperature and continued for 16 hours at room temperature.
  • anhydrous tetrahydrofuran 500mL
  • 4-methoxypyridine 25mL
  • benzyl chloroformate 35mL
  • Step ten
  • the compounds of formula I mentioned below are the compounds of formula I prepared by the above method or by repeating the above method.
  • the compound of formula I was prepared in multiple batches. Take 440mg of the compound of formula I, add 5mL of acetone, heat to 40°C and ultrasonically dissolve. Then slowly add 460 ⁇ L of 2 mol/L phosphoric acid methanol solution dropwise. A viscous solid was found, and 5 mL of acetone was added, and stirred at room temperature for 4 hours. After filtering and washing, the filter cake was vacuum-dried at 50°C under reduced pressure to obtain 462 mg of the compound phosphate of formula I with a yield of 87%.
  • the compound of formula I was prepared in multiple batches. Take 400mg of compound of formula I, add 15mL of ethyl acetate, heat to 50°C and dissolve the compound. Then, 109 mg of maleic acid powder was added, and stirred at room temperature for 2 to 3 hours. After filtration, the filter cake was vacuum-dried at 50°C under reduced pressure to obtain 470 mg of the maleate salt of the compound of formula I with a yield of 91%.
  • Embodiment 4 formula I compound monohydrochloride, phosphate, maleate stability test
  • the compound of formula I, the monohydrochloride of the compound of formula I in Example 1, the phosphate of the compound of formula I in Example 2, and the maleate of the compound of formula I in Example 3 were investigated for stability.
  • Stability test conditions 40°C/75%RH-closed, 40°C/75%RH-open, 60°C-closed; Stability test content: changes in related substances and crystal forms.
  • Detection of related substances Weigh approximately 6-7 mg of samples into 10 mL volumetric flasks, add 50% acetonitrile aqueous solution to dissolve and dilute to the mark, and inject 10 ⁇ L of samples.
  • the chromatographic conditions are shown in Table 6.
  • Table 7 shows the stability test results of the compound of formula I and its hydrochloride, phosphate, and maleate salts.
  • Reference substance and linearity Weigh 10 mg of the compound of formula I into a 50 mL volumetric flask, add 50% acetonitrile aqueous solution to dissolve, and dilute to the mark, and prepare two parallel copies. Take the reference substance of the compound of formula I, dilute to 100 ⁇ g/mL, 50 ⁇ g/mL, 10 ⁇ g/mL with 50% acetonitrile aqueous solution, inject 5 ⁇ L, and draw the standard curve.
  • the SPR experiment was performed at 25° C., using PBS buffer supplemented with 0.05% (v/v) P20 and 5% DMSO as the running buffer, and the analytical instrument used was Biacore 8K from GE Healthcare.
  • CM7 chips (GE Healthcare) were activated for 420s with 400 mM EDC and 100 mM NHS at a flow rate of 30 ⁇ L/min.
  • Complement B factor was diluted to 50 ⁇ g/mL with 10 mM sodium acetate (pH 4.0), and then coupled at a flow rate of 10 ⁇ L/min for 1200 s to covalently immobilize complement B factor on the detection chip (protein White curing level is 25000RU); then the detection chip is blocked with 1M ethanolamine hydrochloride at a flow rate of 10 ⁇ L/min for 300s.
  • concentration of the compound to be tested was 500 ⁇ M
  • the binding time was 120 s
  • dissociation time was 300 s.
  • Data analysis was performed using a 1:1 binding model (Biacore Insight Evaluation Software, Version 2.0.15.12933).
  • the inhibitory activity of compounds on human complement factor B was screened by competitive binding experiments using Cy5 fluorescently labeled small molecule inhibitors as probes.
  • Complement factor B and EZ-Link TM Sulfo-NHS-LC-LC-Biotin were incubated on ice at a ratio of 1:2 for 1 hour, and then 1M Tris (pH7.5) was added to terminate the reaction. Then use 2 mL Zeba TM desalt spin column to purify twice to obtain biotin-labeled complement factor B (EZ-LinkTM Sulfo-NHS-LC-Biotin specification).
  • biotin-labeled complement factor B with a final concentration of 10 nM was pre-incubated with different concentrations of compounds in buffer solution for 1 hour at room temperature.
  • Cy5 fluorescent-labeled probe and europium chelate-labeled streptavidin (petroleum ether rkin Elmer, #AD0060) were added at final concentrations of 75 nM and 5 nM, respectively, to initiate the reaction.
  • Kinetic readings were performed on a microplate reader (337nm excitation light, 665nm emission light, 70 ⁇ s time-gated), and time-dependent fluorescence energy transfer (TR-FRET) data was read to determine IC 50 .
  • TR-FRET time-dependent fluorescence energy transfer
  • test compound test concentration was 10 ⁇ M starting, 3-fold dilution, 7 concentration points, and single-hole detection.
  • the test compound was diluted to 1000-fold final concentration solution with DMSO, and then Diluent ( COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) diluted to 5 times the final concentration of the solution.
  • Diluent COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330
  • Transfer 30 ⁇ L to a 96-well plate add 120 ⁇ L of spare serum, and incubate at room temperature for 15 minutes. Add 30 ⁇ L of 5 ⁇ DMSO and 120 ⁇ L of spare serum to the positive control well, and add 30 ⁇ L of 5 ⁇ DMSO and 120 ⁇ L of Diluent to the negative control well.
  • the hemolysis experiment refers to the description of Xuan Yuan et al., Haematologica, (2017) 102:466-475.
  • NHS normal human serum
  • RE rabbit red blood cells
  • GVBO buffer 0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN 3 , pH 7.3, Complement technology
  • GVBO buffer containing 10 mM Mg-EGTA was added to a final concentration of 1 ⁇ 10 8 cells/mL and incubated at 37° C. for 30 minutes.
  • the positive control group (100% lysis) consisted of GVBO buffer containing 10 mM Mg-EGTA with NHS and RE but no test compound; 65° C. for 5 min) and RE but no test compound in GVBO buffer containing 10 mM Mg-EGTA. Samples were centrifuged at 2000 g for 5 min and supernatants were collected. Absorbance at 415 nm (A415) was detected using a microplate reader (Molecular Devices, SpectraMax i3X). IC50 values were calculated by nonlinear regression from percent hemolysis as a function of test compound concentration.
  • Rats SD Rat Liver Microsomes, Cat.No.: LM-DS-02M, RILD Liver Disease Research (Shanghai) Co., Ltd.
  • control compound and the test compound were formulated into 10 mM solutions with DMSO, and then 10 uL was added to 190 uL acetonitrile to prepare a 0.5 mM mother solution.
  • 10 uL was added to 190 uL acetonitrile to prepare a 0.5 mM mother solution.
  • 0.5mM compound stock solution Take 1.5uL of 0.5mM compound stock solution, add 18.75uM of 20mg/mL liver microsomes and 479.75uL of buffer. (The actual preparation amount can be adjusted according to the usage).
  • NADPH reduced coenzyme II
  • the 96-well plate was pre-incubated on a constant temperature microplate shaker (37°C) for 5 minutes, and then 15 ⁇ L of NADPH (10 mg/mL) was added to each well to start the metabolic reaction. After the reaction was carried out for 10, 30, 60, and 90 minutes, 155 ⁇ L of glacial acetonitrile solution (internal standard concentration: 1 ⁇ M) was added to corresponding wells to terminate the reaction. After 90 minutes in the Non-NADPH system, 155 ⁇ L of ice acetonitrile solution (with an internal standard concentration of 1 ⁇ M) was added to terminate the reaction.
  • NADPH NADPH
  • Plasma samples were measured by LC-MS/MS, and the data were calculated by WinNonlin software for kinetic parameters (Tmax, Cmax, T1/2, AUC).
  • the average blood concentration of the compound of formula I is significantly higher than that of the control compound.
  • the blood concentration curve of cynomolgus monkeys is shown in Figure 21, and the inhibition of serum AP activity in cynomolgus monkeys is shown in Figure 22.
  • Figure 22 shows that the compound of formula I can effectively inhibit the serum AP activity of cynomolgus monkeys.
  • the experiment used 6-9 weeks old Lewis female rats (Beijing Weitong Lihua), 6 rats in each group, D1 intraperitoneal injection to give Streptococcus and several other bacterial cell wall peptidoglycan complexes (2-3mg per rat rats), the control compound (15mpk) and the compound of formula I (15mpk) were intragastrically administered every day for 25 days, and the rats were scored for arthritis in different periods. Scoring criteria such as Bottom: Scored according to the different degrees of lesions (redness and swelling) according to the standard of 0-4 points, the highest score of each limb is 4 points, and the highest score of the total limbs of each animal is 16 points.
  • the scoring criteria are as follows: 0 points, no redness and swelling; 1 point, redness and swelling of 1 to 2 interphalangeal joints; 2 points, redness and swelling of 3 to 4 interphalangeal joints; 3 points, redness and swelling of more than 4 interphalangeal joints; 4 points, toe or Severe redness and swelling from fingers to ankle or wrist.
  • Embodiment 6 Preparation method of formula I compound monohydrochloride crystal form A
  • Form A was characterized by XRPD, DSC, TGA and PLM.
  • the crystal form A is anhydrous.
  • the XRPD characteristic peak positions and intensities are shown in Table 1, and the XRPD patterns are shown in Figure 1.
  • DSC showed that the first endothermic peak appeared around the peak temperature of 192.73°C, and the first exothermic peak appeared around the peak temperature of 201.78°C, as shown in Figure 2.
  • TGA showed a weight loss of about 1.41% in the range of 90 °C to 180 °C, as shown in Figure 3.
  • the PLM image shows that the sample is an irregular crystal with a diameter below 20 ⁇ m, as shown in Figure 4.
  • the XRPD pattern of crystal form A is represented by the X-ray powder diffraction pattern in 2 ⁇ angle.
  • the 2 ⁇ angle and relative intensity of the diffraction peaks are shown in Table A, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • Embodiment 7 The preparation method of formula I compound monohydrochloride crystal form B
  • Form A will transform into Form B when placed in the open under accelerated conditions (40°C/75%RH) for 72 hours.
  • the crystal form B is the monohydrate of the monohydrochloride salt of the compound of formula I.
  • Form B was characterized by XRPD, DSC, TGA and PLM.
  • the XRPD characteristic peak positions and intensities are shown in Table 2, and the XRPD patterns are shown in Figure 5.
  • DSC shows that the first endothermic peak appears near the peak temperature of 85.87°C, the second endothermic peak appears near the peak temperature of 197.54°C, and the first exothermic peak appears near the peak temperature of 205.68°C, as shown in Figure 6 .
  • TGA shows a weight loss of about 3.42% in the range of 21.49°C to 120°C, and a weight loss of about 0.49% in the range of 179.88°C to 207.94°C, as shown in FIG. 7 .
  • the PLM image shows that the sample is an irregular crystal with a diameter below 20 ⁇ m, as shown in Figure 8.
  • Embodiment 8 The preparation method of formula I compound monohydrochloride crystal form C
  • Form C is an anhydrous substance, and XRPD, DSC, TGA and PLM were performed on Form C to characterize it.
  • the XRPD characteristic peak positions and intensities are shown in Table 3, and the XRPD patterns are shown in Figure 9.
  • DSC shows that the first endothermic peak appears around the peak temperature of 209.93°C, and the first exothermic peak appears around the peak temperature of 215.80°C, as shown in Figure 10.
  • TGA showed a weight loss of about 0.29% in the range of 21.62°C to 120°C, and a weight loss of about 0.52% in the range of 173.94°C to 216.60°C, as shown in FIG. 11 .
  • the PLM image shows that the sample is an irregular crystal with a diameter below 20 ⁇ m, as shown in Figure 12.
  • Embodiment 9 The preparation method of formula I compound monohydrochloride crystal form D
  • the crystal form D is a dichloromethane solvate (or monodichloromethane solvate) of the monohydrochloride of the compound of formula I.
  • Form D was characterized by XRPD, DSC, TGA and PLM.
  • the XRPD characteristic peak positions and intensities are shown in Table 4, and the XRPD patterns are shown in Figure 13.
  • DSC shows that the first exothermic peak appears near the peak temperature of 196.53°C, as shown in Figure 14.
  • TGA showed a weight loss of about 6.31% in the range of 22.07°C to 120°C, as shown in FIG. 15 .
  • the PLM image shows that the sample is an irregular crystal with a diameter below 10 ⁇ m, as shown in Figure 16.
  • the XRPD pattern of crystal form D is shown in the X-ray powder diffraction pattern represented by 2 ⁇ angle, and the 2 ⁇ angle and relative intensity of the diffraction peak are shown in Table D:
  • Embodiment 10 The preparation method of formula I compound monohydrochloride crystal form E
  • the crystal form E is a monoisopropanol solvate of the monohydrochloride of the compound of formula I.
  • Form E was characterized by XRPD, and the XRPD pattern is shown in FIG. 17 .
  • the XRPD pattern of crystal form E is shown in the X-ray powder diffraction pattern represented by the 2 ⁇ angle, and the 2 ⁇ angle and relative intensity of the diffraction peaks are shown in Table E:
  • Test method for related substances in stability samples Weigh about 6 mg of sample into a 40 mL clean glass bottle, add 10 mL of 50% acetonitrile aqueous solution, dissolve it completely by ultrasonic, inject 10 ⁇ L for related substance test, as shown in Table 15.
  • the XRPD pattern is shown in 18, wherein HCl-salt Form 3-initial (hereinafter referred to as initial) represents the XRPD pattern of the crystal form C prepared in Example 8.
  • test sample was weighed into a vial, add 3mL of medium (water, SGF, FaSSIF, FeSSIF, etc.), stir at 37°C, take an appropriate amount of sample at 1h and 24h respectively, centrifuge at 12000rpm for 10min, and put on The supernatant was diluted with 50% acetonitrile aqueous solution to determine its concentration. Solubility test chromatographic conditions are shown in Table 16.
  • Reference substance and linearity Weigh 10 mg of the compound of formula I into a 50 mL volumetric flask, add 50% acetonitrile aqueous solution to dissolve, and dilute to the mark, and prepare two parallel copies. Take the reference substance, dilute to 100 ⁇ g/mL, 50 ⁇ g/mL, 10 ⁇ g/mL with 50% acetonitrile aqueous solution, inject 5 ⁇ L, and draw the standard curve.

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Abstract

一种如下式(I)化合物药学上可接受的盐型、晶型及其制备方法和应用.

Description

补体因子B抑制剂的盐型、晶型及其制备方法和应用
本发明要求享有于2022年1月26日向中国国家知识产权局提交的，专利申请号为202210096073.X，名称为“补体因子B抑制剂的盐型、晶型及其制备方法和应用”和于2022年9月9日向中国国家知识产权局提交的，专利申请号为202211104894.X，名称为“补体因子B抑制剂的盐型、晶型及其制备方法和应用”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药领域，具体涉及补体因子B抑制剂的盐型、晶型及其制备方法和应用。
背景技术
补体是免疫系统中一类可溶性模式识别分子，可以行使多种效应功能。在自然条件下，补体成分以无活性的酶原形式存在，多种特异性和非特异性免疫学机制使这些无活性的酶原分解，产生有活性的大片段和小片段。其中，大片段通常停留在病原体或细胞表面，使后者裂解或者加速其清除；小片段离开细胞表面、介导多种炎症反应。补体的激活由两个紧密相随的过程组成，并由此形成补体激活的级联反应。目前已知的补体激活途径主要包括3条：经典途径、凝集素途径、旁路途径。虽然3条补体激活途径的启动机制和激活顺序不同，但是它们具有共同的末端通路。其中，旁路途径的激活不依赖抗原抗体复合物，通常是沉积于细胞表面的C3b与B因子结合，成为易于被血清中D因子分解的状态，在这个过程中B因子被分解成Ba和Bb；然后C3b和Bb组成复合物，成为旁路途径中的C3转化酶C3bBb；在该过程中，补体因子B在补体级联的旁路途径激活中起着早期和核心的作用。这里，C3b既是C3转化酶分解C3之后出现的产物，也是旁路途径C3转化酶的组成部分，由此形成了经典途径和旁路途径相互影响的一种反馈放大机制。当前研究发现血液性、自身免疫性、炎症性和神经变性等多种疾病和补体系统功能异常相关。
阵发性睡眠性血红蛋白尿症(PNH)是一种持续溶血的慢性疾病，病因是由于1个或几个造血干细胞经获得性体细胞PIG-A基因突变造成的非恶性的克隆性疾病，属于超罕见血液疾病 (Medicine(Baltimore)1997,76(2):63-93)。该疾病的病程可表现为不同程度的溶血加重(阵发性)，慢性或反复急性血管内溶血或随后的静脉/动脉血栓形成，最终导致进展性终末器官损伤和死亡，大多数患者常不典型，发病隐袭，病程迁延，病情轻重不一。
红细胞表面有十余种抑制补体通路活化的蛋白，均通过糖基化磷脂酰肌醇(GPI)锚定在其细胞膜上，统称为GPI-锚定蛋白(AP)，目前认为，PNH的发病机制首先是造血干细胞在一定条件下发生突变并产生糖基磷脂酰肌醇(GPI)缺陷的PNH克隆；然后，由于某些因素(现多认为是免疫因素)，发生造血功能损伤或造血功能衰竭，PNH克隆获得增殖优势，超过正常克隆。GPI接连的多种抗原也造成对PNH细胞生物学行为解释的复杂性，其中最重要的是抑制补体通路活化的蛋白C3转化酶衰变加速因子CD55和膜攻击复合物(MAC)抑制因子CD59与PNH在发病机制、临床表现、诊断和治疗方面关系密切(Frontiers in Immunology 2019,10,1157)。CD59可以阻止C9掺入C5b-8复合物中，而阻止膜攻击单位形成，达到抑制补体终末攻击反应的作用。目前认为，PNH的典型表现-血管内溶血和血栓是由于CD59缺乏所致。据报道先天性CD59缺乏症患者，其表现出众多PNH的典型症状，如血管内溶血、血红蛋白尿和静脉血栓等。在PNH患者中，由于GPI合成缺陷导致CD59不能结合到红细胞的细胞膜上，导致其抑制补体通路活化的功能丧失；因此补体通路异常活化的发生并对红细胞进行攻击，导致血管内溶血、血红蛋白尿，以及平滑肌功能障碍等多种临床表现。当前，临床除通过造血干细胞移植重建正常造血功能的治疗方案可治愈PNH外，尚无其它有效的治愈手段。由于造血干细胞移植存在一定风险，并且PNH为良性克隆性疾病，因此控制溶血发作仍然是临床治疗该病的主要策略。目前，仅有依库珠单抗(Eculizumab)被批准用于治疗PNH。然而，许多患者经用依库珠单抗治疗后仍然出现贫血现象，并且许多患者依然需要持续的输血。此外，在用药方式上依库珠单抗需要静脉注射。因此，开发补体途径的新型抑制剂用于PNH的治疗意义重大。
IgAN是一种最常见的原发性肾小球肾炎，该疾病的特点是免疫荧光显示系膜区有IgA沉积。该疾病的临床表现多样，通常表现为反复发作的镜下或者肉眼血尿。现有资料表明，IgAN的发生与先天或者获得性免疫调节异常有关。由于病毒、细菌和食物蛋白等对呼吸道或消化道的刺激作用，黏膜IgA1合成增多，或含IgA1的免疫复合物沉积于系膜区，并激活补体旁路途径，引起肾小球损伤。人类的IgA分子分为IgA1和IgA2这2种亚型，其中IgA1是健康个体血液循环的主要形式(约占85％)，也是IgAN患者肾小球系膜区沉积的主要成分。IgA分子能够以单体和多聚体2种形式存在。IgA1分子在第一和第二恒定区之间具有独特的重链铰链区，可作为O-连接聚糖基团连接位点的结构域。近年研究发现，IgAN患者血清中及肾小球系膜区沉积的IgA分子主要为糖基化缺陷的IgA1(gd-IgA1)。目前认为，IgAN发病机制的启动环节为gd-IgA1产生异常 增多。
超过90％的IgAN患者肾小球系膜区伴有补体C3的沉积。75％-100％的IgAN患者肾组织内存在备解素和IgA、C3的共同沉积，30％-90％的IgAN患者肾组织存在补体因子H、IgA、C3的共同沉积。除肾组织内的沉积外，一些研究还发现IgAN患者的血浆中补体旁路途径的标志物水平也与IgAN的活动度有关(J Nephrol 2013,26(4):708-715)。研究证实，肾组织和尿液中C3a以及肾组织中C3a受体与肾脏损害的活动性和严重程度显著相关(J clin Immunol 2014,34(2):224-232)。另有研究证实，在体外条件下IgA能够激活补体旁路途径。在这一过程中，IgA铰链区异常并不起到决定性的作用，而IgA多聚体的形成则是其关键环节(Eur J Immunol 1987,17(3):321-326)。当前，补体C3沉积于肾小球系膜区已经成为IgAN的一项辅助诊断标志。有研究对163例IgAN患者肾组织进行C3c和C3d免疫荧光检测，结果显示C3c沉积强度高于C3d沉积强度的IgAN患者表现为肾小球滤过率更低、肾小球毛细血管内增生的发生率更高、血尿也更严重，说明肾小球C3c沉积与IgAN的活动性病变有关(Am J Nephrol.2000,20(2):122-128)。当前临床上并没有特效药物治疗IgAN，主要为通用性药物如肾素-血管紧张素抑制剂(ACEI或ARB)、糖皮质激素和各种免疫抑制剂等。此外，这类药物的安全性也是一个不可忽视的问题，例如虽然糖皮质激素有降蛋白尿的作用，但STOP-IgAN试验和TESTING-I试验清楚地证实了糖皮质激素潜在的副作用(IgA nephropathy 2019,95,4,750-756)。
关节炎是一种常见的慢性疾病，由炎症、感染、退化、创伤或其他因素引起的炎性疾病，临床表现为关节的红、肿、热、痛、功能障碍及关节畸形，常会使人感到剧痛、行动受限及身体变形，严重时可致残，影响患者生活质量。研究发现，K/BxN的小鼠血清并不能诱导补体B因子缺陷的小鼠产生关节炎，而野生型小鼠在K/BxN的小鼠血清诱导下产生了关节炎疾病(Immunity,2002,16,157–168)。这表明补体系统在K/BxN的小鼠血清诱导关节炎模型中起着重要的致病作用，而补体B因子是治疗关节炎的潜在靶点。
与补体级联相关的其它疾病还包括膜性肾病(MN)、C3肾小球肾炎(C3G)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、非典型溶血尿毒症综合征(aHUS)、溶血尿毒症综合征(HUS)、血液透析并发症、溶血性贫血或血液透析、神经脊髓炎(NMO)、肝脏类炎症、炎症性肠病、皮肌炎和肌萎缩性侧索硬化、重症肌无力(MG)、呼吸系统疾病和心血管等疾病。
目前，还没有用于临床治疗的补体因子B抑制剂的小分子药物，目前已知的和在研的项目有：IONIS Pharmaceuticals Inc.开发的寡核苷酸类药物作为补体因子B(CFB)特异性抑制剂来治疗、预防或缓解与补体旁路途径失调相关的疾病(WO2015038939)。Novartis AG公司开发的小分子补体因子B抑制剂用于治疗年龄相关性黄斑变性(AMD)等疾病(WO2013164802, WO2013192345,WO2014143638,WO2015009616,WO2015066241)，或用于治疗C3G和IgAN等疾病(WO2019043609A1)。Achillion Pharmaceuticals Inc.开发的小分子补体因子B抑制剂用于治疗年龄相关性黄斑变性(AMD)等疾病(WO2018005552)。
炎症和免疫性相关的疾病具有多样性、难治愈的特点；PNH疾病上市的药物仅有依库珠单抗，但是由于价格，给患者带来了沉重的负担；同时，许多患者经用依库珠单抗治疗后仍然出现贫血现象，并且许多患者依然需要持续的输血；此外，在用药方式上依库珠单抗需要静脉注射。而一些疾病截至目前并没有特效的治疗药物，比如IgAN等。在这些领域有尚未满足的临床需求，需要开发新的小分子药物用于医学治疗。
因此，目前需要开发一种高效、低毒和/或长效的药学上可接受的活性成分，以改善上述技术问题。
发明内容
为了改善上述技术问题，本发明提供一种式Ⅰ化合物药学上可接受的盐：
所述药学上可接受的盐为式Ⅰ化合物与酸或碱形成的盐，优选选自式Ⅰ化合物与酸形成的盐。
根据本发明的实施方案，所述酸可以选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、 柠檬酸、L-酒石酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种。
根据本发明的实施方案，所述碱可以选自无机碱，例如碱金属氢氧化物或碱土金属的氢氧化物，优选选自氢氧化钠或氢氧化钾。
根据本发明优选的实施方案，所述式Ⅰ化合物药学上可接受的盐选自其盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、马来酸盐、柠檬酸盐、L-酒石酸盐和草酸盐中的一种。
根据本发明更优选的实施方案，所述式Ⅰ化合物药学上可接受的盐是式Ⅰ化合物与盐酸形成的盐，即式Ⅰ化合物的盐酸盐，优选为式Ⅰ化合物的单盐酸盐。
根据本发明的实施方案，所述式I化合物药学上可接受的盐中，式I化合物与所述的酸或碱的摩尔比可以独立地选自1:1、2:1或3:1，条件是所述盐中式I化合物的离子与酸或碱的离子电荷平衡。例如，当所述的酸(如盐酸、甲磺酸、对甲苯磺酸)中可电离的氢原子数为1时，式I化合物与所述的酸的摩尔比为1:1；当所述的酸(如硫酸、富马酸、马来酸、柠檬酸、L-酒石酸、草酸)中可电离的氢原子数为2时，式I化合物与所述的酸的摩尔比可以为1:1或2:1；当所述的酸(如磷酸)中可电离的氢原子数为3时，式I化合物与所述的酸的摩尔比为1:1、2:1或3:1。
本发明还提供一种式Ⅰ化合物药学上可接受的盐的制备方法，所述制备方法包括将式Ⅰ化合物与所述酸或碱反应，制备得到式Ⅰ化合物药学上可接受的盐。
根据本发明的实施方案，所述制备方法包括将式Ⅰ化合物与所述酸或碱在溶剂中反应，制备得到式I化合物药学上可接受的盐。
根据本发明的实施方案，所述酸或碱彼此独立地具有上文所述的定义。
根据本发明的实施方案，所述溶剂可以选自醇类、酮类、酯类、醚类，所述溶剂中两种以上的组合，或上述溶剂或组合分别与水的混合物。
根据本发明的实施方案，所述醇类可以选自具有1-8个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其中两种以上的组合；所述酮类可以选自具有3-10个碳原子的酮，例如丙酮、丁酮、戊酮、甲基乙基酮、4-甲基-2-戊酮或其中两种以上的组合；所述酯类可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯或其中两种以上的组合；所述醚类可以为直链或支链烷基醚或环醚类化合物，例如甲基叔丁基醚、四氢呋喃、2-甲基-四氢呋喃或其中两种以上的组合。
根据本发明的实施方案，所述式Ⅰ化合物与所述酸或碱的摩尔比可以为1:0.8～1:1.5，优选为1:0.9～1:1.3，更优选为1:1.0～1:1.1。
根据本发明的实施方案，所述制备方法中，反应的温度可以在较宽的范围内选择，例如为 20℃～80℃，优选为30℃～60℃。
根据本发明的实施方案，所述制备方法还包括反应结束后，进行过滤和/或干燥的步骤，以制备得到式I化合物药学上可接受的盐。
根据本发明的实施方案，所述制备方法中，干燥的温度可以在较宽的范围内选择，例如可以为20℃～80℃，优选为30℃～60℃。
根据本发明的实施方案，所述步制备方法中，干燥的压力可以为0～20KPa，优选为0～10KPa，更优选为5～10KPa。
本发明还提供式I化合物单盐酸盐的晶体，优选单晶。其中，所述单晶的晶胞参数如下：
正交晶系，空间群P212121；



Z＝4。
本发明还提供所述式I化合物单盐酸盐的晶体，尤其是其单晶的制备方法，包括将式I化合物单盐酸盐溶解于溶剂A然后置于溶剂B的气氛中扩散。
所述溶剂A可以为醇类溶剂，例如甲醇、乙醇等中两种以上的组合。
所述溶剂B可以为酯类溶剂、醚类溶剂或其中两种以上的组合。所述酯类溶剂可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯或其中两种以上的组合；所述醚类溶剂可以为直链或支链烷基醚、环醚类化合物或其中两种以上的组合，例如甲基叔丁基醚、四氢呋喃、2-甲基-四氢呋喃或其中两种以上的组合。
本发明还提供式Ⅰ化合物单盐酸盐的晶体形式，其选自下文所述的晶型A、晶型B、晶型C、晶型D或晶型E。
一种式Ⅰ化合物单盐酸盐的晶型A，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、16.08±0.20°、23.46±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、16.08±0.20°、18.10±0.20°、21.30±0.20°、21.68±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、11.62±0.20°、16.08±0.20°、18.10±0.20°、21.30±0.20°、21.68±0.20°、23.40±0.20°、25.42±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、11.62±0.20°、16.08±0.20°、16.84±0.20°、18.10±0.20°、19.64±0.20°、21.30±0.20°、21.68±0.20°、23.40±0.20°、24.96±0.20°、25.42±0.20°处具有特征峰。
优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1所示的特征峰，其中所述2θ角度的误差范围为±0.20°：
表1晶型A的XRPD解析数据
优选地，所述晶型A具有基本如图1所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型A为式Ⅰ化合物单盐酸盐的无水物。
根据本发明的实施方案，所述晶型A的差示扫描量热法(DSC)分析显示在加热至峰值温度192.73℃附近出现第一个吸热峰，峰值温度201.78℃附近出现第一个放热峰。
优选地，所述晶型A具有基本如图2所示的DSC图。
根据本发明的实施方案，所述晶型A的热重分析(TGA)显示在90℃至180℃区间内具有约 1.41％的失重。
优选地，所述晶型A具有基本如图3所示的TGA图。
根据本发明的实施方案，所述晶型A为不规则形貌晶体。优选地，所述晶型A的粒径不超过20μm。
优选地，所述晶型A具有基本如图4所示的PLM图谱。
一种式Ⅰ化合物单盐酸盐的晶型B，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.10±0.20°、19.80±0.20°、22.10±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.48±0.20°、15.44±0.20°、18.10±0.20°、19.80±0.20°、22.10±0.20°、30.92±0.20°处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.48±0.20°、10.78±0.20°、15.44±0.20°、18.10±0.20°、19.18±0.20°、19.80±0.20°、22.10±0.20°、30.92±0.20°、处具有特征峰。
优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表2所示的特征峰，其中所述2θ角度的误差范围为±0.20°：
表2晶型B的XRPD解析数据
优选地，所述晶型B具有基本如图5所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型B为式Ⅰ化合物单盐酸盐的水合物，如式Ⅰ化合物单盐酸盐的一水合物。
根据本发明的实施方案，所述晶型B的差示扫描量热法(DSC)分析显示在加热至峰值温度85.87℃附近出现第一个吸热峰，峰值温度为197.54℃附近出现第二个吸热峰，峰值温度为205.68℃附近出现第一个放热峰。
优选地，所述晶型B具有基本如图6所示的DSC图。
根据本发明的实施方案，所述晶型B的热重分析(TGA)显示在21.49℃至120℃具有约3.42％的失重，179.88℃至207.94℃具有约0.49％的失重。
优选地，所述晶型B具有基本如图7所示的TGA图。
根据本发明的实施方案，所述晶型B为不规则形貌晶体。优选地，所述晶型B的粒径不超过20μm。
优选地，所述晶型B具有基本如图8所示的PLM图谱。
根据本发明的实施方案，所述晶型A在高湿条件下得到晶型B。所述高湿条件优选在40℃，75％～95％的相对湿度。
根据本发明的实施方案，所述晶型B在干燥条件下得到晶型A。所述干燥条件优选在40℃真空干燥下。
一种式Ⅰ化合物单盐酸盐的晶型C，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、20.08±0.20°、21.98±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、19.58±0.20°、20.08±0.20°、21.98±0.20°、22.94±0.20°、25.92±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、19.58±0.20°、20.08±0.20°、21.98±0.20°、22.94±0.20°、25.92±0.20°、33.48±0.20°处具有特征峰。
优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表3所示的特征峰，其中所述2θ角度的误差范围为±0.20°：
表3晶型C的XRPD解析数据

优选地，所述晶型C具有基本如图9所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型C为式Ⅰ化合物单盐酸盐的无水物。
根据本发明的实施方案，所述晶型C的差示扫描量热法(DSC)分析显示在加热至峰值温度为209.93℃附近出现第一个吸热峰，峰值温度215.80℃附近出现第一个放热峰。
优选地，所述晶型C具有基本如图10所示的DSC图。
根据本发明的实施方案，所述晶型C的热重分析(TGA)显示在21.62℃至120℃区间内具有约0.29％的失重，在173.94℃至216.60℃区间内具有约0.52％的失重。
优选地，所述晶型C具有基本如图11所示的TGA图。
根据本发明的实施方案，所述晶型C为不规则形貌晶体。优选地，所述晶型C的粒径不超过20μm。
优选地，所述晶型C具有基本如图12所示的PLM图谱。
一种式Ⅰ化合物单盐酸盐的晶型D，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.74±0.20°、16.58±0.20°、21.98±0.20°、23.82±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.16±0.20°、11.90±0.20°、15.74±0.20°、16.58±0.20°、19.22±0.20°、20.24±0.20°、21.98±0.20°、23.82±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.16±0.20°、11.90±0.20°、12.60±0.20°、15.74±0.20°、16.58±0.20°、19.22±0.20°、19.80±0.20°、21.98±0.20°、 22.66±0.20°、23.18±0.20°、23.82±0.20°、24.94±0.20°、26.24±0.20°、26.80±0.20°、27.50±0.20°处具有特征峰。
优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表4所示的特征峰，其中所述2θ角度的误差范围为±0.20°：
表4晶型D的XRPD解析数据
优选地，所述晶型D具有基本如图13所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型D为式Ⅰ化合物单盐酸盐的溶剂化物，如式Ⅰ化合物单盐酸盐的二氯甲烷溶剂化物，如式Ⅰ化合物单盐酸盐的一二氯甲烷溶剂化物(或称为单二氯甲烷溶剂化物)。
根据本发明的实施方案，所述晶型D的差示扫描量热法(DSC)分析显示在加热至峰值温度196.53℃附近出现第一个放热峰。
优选地，所述晶型D具有基本如图14所示的DSC图。
根据本发明的实施方案，所述晶型D的热重分析(TGA)显示在22.07℃至120℃区间内具有约6.31％的失重。
优选地，所述晶型D具有基本如图15所示的TGA图。
根据本发明的实施方案，所述晶型D为不规则形貌晶体。优选地，所述晶型C的粒径不超过10μm。
优选地，所述晶型D具有基本如图16所示的PLM图谱。
一种式Ⅰ化合物单盐酸盐的晶型E，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.36±0.20°、15.22±0.20°、16.88±0.20°、22.10±0.20°处具有特征峰。
优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.20±0.20°、9.36±0.20°、15.22±0.20°、16.88±0.20°、21.10±0.20°、22.10±0.20°、23.68±0.20°处具有特征峰。
优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.20±0.20°、9.36±0.20°、15.22±0.20°、16.88±0.20°、18.78±0.20°、21.10±0.20°、22.10±0.20°、23.68±0.20°、26.04±0.20°、27.86±0.20°处具有特征峰。
优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表5所示的特征峰，其中所述2θ角度的误差范围为±0.20°：
表5晶型E的XRPD解析数据
优选地，所述晶型E具有基本如图17所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶型E为式Ⅰ化合物单盐酸盐的溶剂化物，如式Ⅰ化合物单盐酸盐的一异丙醇溶剂化物。
本发明还提供式Ⅰ化合物单盐酸盐上述晶型的制备方法。
晶型A的制备方法一，包括：将式Ⅰ化合物溶于醇类溶剂，加入HCl在醇类溶剂中的溶液成盐，再加入正烷烃结晶，得到所述晶型A。
所述醇类溶剂选自乙醇和/或异丙醇，优选为异丙醇。
所述正烷烃选自正己烷和/或正庚烷，优选为正庚烷。
所述式Ⅰ化合物、醇类溶剂和正烷烃的质量体积比为1g：(10-30)mL：(10-30)mL，优选为1g：(15-25)mL：(15-25)mL。
所述HCl在醇类溶剂中的溶液的浓度为1-3mol/L，例如2mol/L。
所述加热的温度为45-75℃，优选48-60℃。
晶型A的制备方法二，包括：将式Ⅰ化合物单盐酸盐在醇类溶剂和正烷烃下加热搅拌至溶清后结晶，得到所述晶型A。
所述醇类溶剂选自乙醇和/或异丙醇，优选为异丙醇。
所述正烷烃选自正己烷和/或正庚烷，优选为正庚烷。
所述式Ⅰ化合物单盐酸盐、醇类溶剂和正烷烃的质量体积比为1g：(10-30)mL：(10-30)mL，优选为1g：(15-25)mL：(15-25)mL，例如1g:20mL:20mL。
所述加热的温度为45-75℃，优选48-60℃。
根据本发明的实施方案，晶型A的制备方法一或二中还包括降温、过滤、干燥的步骤。
根据本发明优选的实施方案，所述晶型A的制备方法包括：将式Ⅰ化合物溶于异丙醇中，加入HCl的异丙醇溶液，混溶后，再加入正庚烷搅拌，过滤，干燥，得到所述晶型A。
根据本发明优选的实施方案，所述晶型A的制备方法包括：将式Ⅰ化合物单盐酸盐加入异丙醇和正庚烷的混合溶剂中，加热搅拌，降温至常温，过滤、真空干燥，得到所述晶型A。
所述式Ⅰ化合物单盐酸盐、异丙醇和正庚烷的质量体积比为1g:(10-30)mL:(10-30)mL，例如1g:20mL:20mL。
晶型B的制备方法，包括：将所述晶型A置于高湿条件下得到晶型B。
根据本发明的实施方案，所述高湿条件的温度为30-50℃，湿度为60％-98％。
所述高湿条件为优选在40℃，75％～95％的湿度。
晶型C的制备方法，包括：将式Ⅰ化合物溶于醇类溶剂，再加入HCl在醇类溶剂中的溶液成 盐，再加入醚类溶剂或酯类溶剂结晶，得到晶型C。
根据本发明的实施方案，晶型C的制备方法包括：将式Ⅰ化合物溶于醇类溶剂，加入HCl在醇类溶剂中的溶液，搅拌，过滤，向滤液中滴加醚类溶剂或酯类溶剂，搅拌，过滤，干燥得到晶型C。
所述醇类溶剂选自甲醇、乙醇或异丙醇，优选为甲醇。
所述醚类溶剂选自甲醚、乙醚、丙醚或甲基叔丁基醚，优选甲基叔丁基醚。
所述酯类溶剂选自乙酸乙酯或乙酸异丙酯。
所述式Ⅰ化合物、醇类溶剂和醚类溶剂的质量体积比为1g：(2-8)mL：(20-40)mL，优选为1g：(3-6)mL：(20-30)mL，例如1g：4mL：25mL。
所述HCl在醇类溶剂中的溶液的浓度为1-3mol/L，例如1.5-2.5mol/L，示例性为1.8mol/L；所述式Ⅰ化合物和HCl在醇类溶剂中的溶液的质量比为1g：(0.5-1.5)g，例如1g：(0.8-1.2)g。
根据本发明优选的实施方案，所述晶型C的制备方法包括：将式Ⅰ化合物溶于甲醇后，加入HCl的甲醇溶液，搅拌，过滤后，向滤液中加入甲基叔丁基醚，过滤，干燥，得到晶型C。
晶型D的制备方法，包括：将式Ⅰ化合物单盐酸盐在卤代烷烃中室温悬浮搅拌结晶，得到晶型D。
根据本发明的实施方案，晶型D的制备方法包括：将式Ⅰ化合物单盐酸盐加入到卤代烷烃，搅拌，所得混悬液进行分离，分离后的固体进行干燥，所得固体为晶型D。
所述卤代烷烃选自二氯甲烷、三氯甲烷或四氯化碳，优选为二氯甲烷。
所述式Ⅰ化合物单盐酸盐与卤代烷烃的质量体积比为1g:(15-35)mL，优选为1g:(18-25)mL，例如为1g:20mL。
所述分离采用已知的分离方式进行分离，优选采用离心的方式进行分离。
所述干燥是在加热的条件下减压真空干燥，优选在40℃下减压真空干燥。
根据本发明优选的实施方案，所述晶型D的制备方法包括：将式Ⅰ化合物单盐酸盐加入到二氯甲烷中，室温搅拌后，分离固体得到晶型D。
晶型E的制备方法，包括：将式Ⅰ化合物单盐酸盐在醇类溶剂中室温悬浮搅拌结晶，得到晶型E。
根据本发明的实施方案，将式Ⅰ化合物单盐酸盐加入到醇类溶剂，搅拌，所得混悬液进行分离，分离后的固体进行干燥，所得固体为晶型E。
所述醇类溶剂选自甲醇、乙醇或异丙醇，优选为异丙醇。
所述式Ⅰ化合物单盐酸盐与醇类溶剂的质量体积比为1g:(15-35)mL，优选为1g:(18-25)mL，例如为1g:20mL。
所述分离采用已知的分离方式进行分离，优选采用离心的方式进行分离。
所述干燥是在加热的条件下减压真空干燥，优选在40℃下减压真空干燥。
根据本发明优选的实施方案，所述晶型E的制备方法包括：将式Ⅰ化合物单盐酸盐加入到异丙醇中，室温搅拌后，分离固体得到晶型E。
本发明还提供一种药物组合物，包含所述式Ⅰ化合物药学上可接受的盐(例如所述盐酸盐，如所述盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E)中的至少一种，以及任选存在的药学上可接受的辅料。优选地，所述药物组合物为制剂形式。
本发明还提供一种制剂，包含所述式Ⅰ化合物药学上可接受的盐、晶型A、晶型B、晶型C、晶型D、晶型E中的至少一种，以及任选存在的药学上可接受的辅料。
本发明还提供如上所述式Ⅰ化合物药学上可接受的盐(例如所述盐酸盐，如所述盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E)或所述药物组合物中的至少一种在制备用于预防和/或治疗补体因子B介导的疾病或病症的药物中的用途。
根据本发明的实施方案，所述补体因子B介导的疾病或病症选自下列中的至少一种：阵发性睡眠性血红蛋白尿症(PNH)、原发性肾小球肾炎(IgAN)、膜性肾病(MN)、C3肾小球肾炎(C3G)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、非典型溶血尿毒症综合征(aHUS)、溶血尿毒症综合征(HUS)、糖尿病性视网膜病变(DR)、血液透析并发症、溶血性贫血或血液透析、神经脊髓炎(NMO)、关节炎、类风湿性关节炎、肝脏类炎症、皮肌炎和肌萎缩性侧索硬化、重症肌无力(MG)、呼吸系统疾病和心血管等疾病。
本发明还提供一种与补体因子B抑制剂相关疾病的预防和/或治疗方法，包括向有此需要的个体施用治疗有效量的如上所述Ⅰ化合物药学上可接受的盐(例如所述盐酸盐，如所述盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E)或所述药物组合物中的至少一种。
根据本发明的实施方案，所述与补体因子B抑制剂相关的疾病或病症选自下列中的至少一种：阵发性睡眠性血红蛋白尿症(PNH)、原发性肾小球肾炎(IgAN)、膜性肾病(MN)、C3肾小球肾炎(C3G)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、非典型溶血尿毒症综合征(aHUS)、溶血尿毒症综合征(HUS)、糖尿病性视网膜病变(DR)、血液透析并发症、溶血性贫血或血液透析、神经脊髓炎(NMO)、关节炎、类风湿性关节炎、肝脏类炎症、皮肌炎和肌萎缩性 侧索硬化、重症肌无力(MG)、呼吸系统疾病和心血管等疾病。
本发明的治疗方法可包括单独给予本发明式Ⅰ化合物药学上可接受的盐(例如所述盐酸盐，如所述盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E)或所述药物组合物，以及将本发明式Ⅰ化合物药学上可接受的盐(例如所述盐酸盐，如所述盐酸盐的晶型A、晶型B、晶型C、晶型D、晶型E)或所述药物组合物的一种、两种或更多种与一种、两种或更多种其它化学治疗剂组合给药。多种药物的给药可以同时或相继进行。
本说明书的上下文中，“以上”、“以下”、“以内”应当被理解为包括本数。作为实例，“至少一种”应当被理解为“一种、两种或更多种”。又如，“两种以上”应当被理解为“两种或更多种”，例如“两种、三种、四种或更多种”。
有益效果
本发明式Ⅰ化合物的盐(尤其是盐酸盐、磷酸盐、马来酸盐)的稳定性高，水溶解度高，显著增强口服给药时的吸收能力和提高生物的利用度。并且，本发明式Ⅰ化合物盐酸盐晶型的稳定性高，溶解度好，吸湿性低，具有良好的成药前景。此外，本发明式Ⅰ化合物的盐及晶型的制备方法操作便捷，容易控制，重现性好，反应条件温和，产品收率高，有利于工业化生产。
附图说明
图1为式Ⅰ化合物单盐酸盐晶型A的XRPD图谱。
图2为式Ⅰ化合物单盐酸盐晶型A的DSC图谱。
图3为式Ⅰ化合物单盐酸盐晶型A的TGA图谱。
图4为式Ⅰ化合物单盐酸盐晶型A的PLM图谱。
图5为式Ⅰ化合物单盐酸盐晶型B的XRPD图谱。
图6为式Ⅰ化合物单盐酸盐晶型B的DSC图谱。
图7为式Ⅰ化合物单盐酸盐晶型B的TGA图谱。
图8为式Ⅰ化合物单盐酸盐晶型B的PLM图谱。
图9为式Ⅰ化合物单盐酸盐晶型C的XRPD图谱。
图10为式Ⅰ化合物单盐酸盐晶型C的DSC图谱。
图11为式Ⅰ化合物单盐酸盐晶型C的TGA图谱。
图12为式Ⅰ化合物单盐酸盐晶型C的PLM图谱。
图13为式Ⅰ化合物单盐酸盐晶型D的XRPD图谱。
图14为式Ⅰ化合物单盐酸盐晶型D的DSC图谱。
图15为式Ⅰ化合物单盐酸盐晶型D的TGA图谱。
图16为式Ⅰ化合物单盐酸盐晶型D的PLM图谱。
图17为式Ⅰ化合物单盐酸盐晶型E的XRPD图谱。
图18为式Ⅰ化合物单盐酸盐晶型C在加速、高温条件下放置1月后的XRPD结果图。
图19为式Ⅰ化合物单盐酸盐晶型C经高温、高湿暴露1天后的XRPD结果图。
图20为式Ⅰ化合物单盐酸盐晶型C经高温、高湿暴露3天后的XRPD结果图。
图21为生物学实施例中的食蟹猴血药浓度曲线实验数据(ng/mL)。
图22为生物学实施例中的食蟹猴血清AP活性曲线实验数据(％相对0h)。
图23为生物学实施例中的链球菌诱导的大鼠类风湿性关节炎的实验数据。
图24为式Ⅰ化合物单盐酸盐的单晶图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实验仪器参数
X-射线粉末衍射(XRPD)
设备为Shimadzu XRD-6000，按以下参数扫描样品：
射线源为Cu～Kα靶
光管的最小操作电压与电流分别为40kV和30mA，
样品扫描范围的2-Theta值从2°到50°。扫描速度为5deg/min。
热重分析(TGA)
称取大约5mg样品于坩埚中，氮气保护，从30℃升温至300℃，升温速率为20℃/min，300℃保持1min。
差示扫描量热仪(DSC)
称取大约1～5mg粉末样品放置在一个封闭的铝坩埚中，坩埚盖上扎一针孔。氮气保护，从30℃升温到300℃进行差示热量扫描，300°℃保持1分钟。升温速率为20℃/min。
偏光显微镜(PLM)
样品分散在介质中(硅油)，使用10X目镜、10X物镜观察样品，用照相机计算机系统记录图像。
动态水分吸附(DVS)
在0％～95％～0％相对湿度(RH)循环下，称取10mg左右的样品在25℃条件下进行吸湿/解吸特性测试，参数如下:
吸湿性分类:
“*”：在25±1℃和80±2％RH条件下(欧洲药典10.0)
“W”:在80％RH时的吸湿增重.
单晶测试仪器和条件
仪器型号：D8Venture
仪器参数：
光源：Mo靶  X射线：Mo-Kα
探测器：CMOS面探测器  分辨率：
电流电压：50kV，1.4mA  曝光时间：10s
面探测器至样品距离：40mm  测试温度：170(2)K
缩略语说明
40℃/75％RH是指在40℃下，75％湿度的条件。
40℃/75％RH-closed是指在在40℃下，75％湿度的条件下密闭放置。
40℃/75％RH-open是在40℃下，75％湿度的条件下敞开放置。
60℃-closed是指在60℃下密闭放置。
40℃/75％RH-closed-2wks是指在40℃下，75％湿度的条件下密闭放置2周。
40℃/75％RH-open-2wks是指在40℃下，75％湿度的条件下敞开放置2周。
60℃-closed-2wks是指在60℃下密闭放置2周。
Initial是指初始状态。
SGF是指模拟胃液。
FaSSIF是指禁食状态模拟肠液。
FeSSIF是指进食状态模拟肠液。
1d是指1天；3d是指3天。
制备例1：式I化合物的制备
式Ⅰ化合物和中间体b的合成的反应式

中间体b的制备
在250mL单口瓶中，依次加入二氯甲烷(50mL)、5-甲氧基-7-甲基-1H-吲哚(3g)、Boc酸酐(5.68g)、4-二甲氨基吡啶(227mg)和三乙胺(2.26g)，反应在室温下进行16小时。反应结束后，反应液加入饱和氯化铵溶液(5mL)淬灭，二氯甲烷萃取(20mL)三次，合并的有机相用水洗涤(5mL)，无水硫酸钠干燥并过滤，滤液浓缩，残余物经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到中间体a(4.6g，收率：94％)。MS m/z(ESI):262.0[M+1]。
在250mL单口瓶中，依次加入二氯甲烷(80mL)、N-甲基甲酰苯胺(3.8g)和草酰氯(3.6g)，反应在室温下搅拌3小时。然后将反应温度降至-14℃，加入中间体a(2.5g)，反应体系自然升温到室温并在室温下搅拌1小时。反应结束后，反应液倒入冰水(100mL)中，用二氯甲烷萃取(100mL)三次，合并的有机相用水(10mL)洗涤两次，无水硫酸钠干燥并过滤， 滤液浓缩，残余物经柱层析(石油醚:乙酸乙酯＝20:1)纯化得到中间体b(1.3g，收率：47％)。
MS m/z(ESI):290.0[M+1]。1H NMR(400MHz,CDCl3)δ10.65(s,1H),7.65(d,J＝3.4Hz,1H),7.49(d,J＝3.4Hz,1H),6.76(s,1H),3.98(s,3H),2.70(s,3H),1.65(s,9H)。
式I化合物的制备
第一步：
在3L的三口瓶中，依次加入四氢呋喃(150mL)和4-溴苯腈(50g)，在氮气保护下将异丙基氯化镁氯化锂络合物(1.3M，210mL)缓慢加到反应体系中，反应在室温下进行2小时。然后反应体系加入无水四氢呋喃(500mL)进行稀释并降温至-5℃，加入4-甲氧基吡啶(25mL)，缓慢滴加氯甲酸苄酯(35mL)(维持体系温度在0℃以下)，滴加完毕后反应在0℃搅拌2小时，然后升至室温并在室温下继续反应16小时。反应结束后，加入6M盐酸(150mL)搅拌半小时并加水(1000mL)稀释，用乙酸乙酯(500mL)进行萃取两次，合并的有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥并过滤，滤液浓缩后获得的粗品经柱层析(石油醚:乙酸乙酯＝3:1-1:1)纯化得到化合物1(23g，收率：23％)。
MS m/z(ESI):333.0[M+1]。
第二步：
将第一步二批次制备得到的46g化合物1取出(28g)、锌粉(55g)和乙酸(200mL)依次加入到500mL单口瓶中，反应加热到100℃并在该温度下搅拌16小时。反应结束后过滤，滤液加水(500mL)稀释，用乙酸乙酯(500mL)进行萃取，有机相用饱和碳酸氢钠水溶液(500mL)洗涤两次，饱和食盐水(100mL)洗涤一次，用无水硫酸钠干燥并过滤，滤液减压浓缩获得化合物2(26g，收率：73％)。
MS m/z(ESI):334.8[M+1]。
第三步：
在500mL单口瓶中，依次加入四氢呋喃(100mL)、乙醇(100mL)和化合物2(26g)，然后分批加入硼氢化钠(2g)，反应在室温下进行2小时。反应结束后，将体系降温至0℃，加入饱和氯化铵水溶液(30mL)至不再升温，加水(500mL)稀释，用乙酸乙酯(200mL)萃取两次；合并的有机相用饱和食盐水(500mL)洗涤，用无水硫酸钠干燥并过滤，滤液减压浓缩得到化合物3(25g，收率：76％)。
MS m/z(ESI):336.9[M+1]。
第四步：
将二氯甲烷(200mL)加入到500mL单口瓶中，然后依次加入化合物3(25g)、咪唑(6.6g)和叔丁基二苯基氯硅烷(25g)，室温反应2小时。反应结束后，反应液用水(500mL)洗涤，无水硫酸钠干燥并过滤，滤液减压浓缩，残余物经柱层析(石油醚:乙酸乙酯＝10:1)纯化得到化合物4(5.7g，收率：13％，Rf＝0.55；顺式异构体Rf＝0.50)。
MS m/z(ESI):597.0[M+23]。
第五步：
在250mL单口瓶中，依次加入化合物4(5g)和四丁基氟化铵四氢呋喃溶液(1M，30mL)，反应在室温下进行2小时。反应结束后，加水(100mL)稀释，乙酸乙酯(50mL)萃取三次，合并的有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥并过滤，滤液减压浓缩，残余物经柱层析(石油醚:乙酸乙酯＝3:1-0:1)纯化得到消旋体，该消旋体体经过SFC(Apparatus：SFC Thar prep 80；Column：CHIRALPAK AD-H，250mm×20mm，5μm；Modifier：35％甲醇(0.2％氨水)；柱温：40℃；柱压：60bar；波长：214/254nm；流速：40g/min；Rt＝4.78min)进行手性分离得到化合物5(1.2g，收率：41％)。
MS m/z(ESI):358.8[M+23]。
第六步：
向化合物5(1200mg)的N,N-二甲基甲酰胺(10mL)溶液中，加入咪唑(486mg)和叔丁基二甲基氯硅烷(593mg)，反应在室温搅拌2小时。反应结束后，反应混合物加水(100mL)稀释，用乙酸乙酯(50mL)萃取，有机相用饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥并过滤，过滤液直接浓缩得到化合物6(600mg，收率：90％)。
MS m/z(ESI):472.8[M+23]。
第七步：
室温下将第六步二批次的1.2g化合物6取出化合物6(700mg)加入到二氯甲烷(10mL)中，在氮气保护和-78℃条件下，向反应液中加入环丙基甲醛(110mg)和三氟甲磺酸三甲基硅酯(35mg)，反应体系维持-78℃并搅拌一个小时，然后加入三乙基硅烷(180mg)，反应自然升温至室温并在该温度下继续搅拌16小时。反应结束后，反应液加入饱和碳酸氢钠水溶液(20mL)淬灭，加水(10mL)稀释，用二氯甲烷(10mL)萃取，有机相用水(10mL)洗涤一次，无水硫酸钠干燥并过滤，过滤液浓缩，残余物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到化合物7(400mg，收率：46％)。
MS m/z(ESI):390.9[M+1]。
第八步：
向50mL单口瓶中依次加入化合物7(400mg)、异丙醇(2mL)、水(3mL)，和氢氧化钠(400mg)，反应混合物加热到100℃并在该温度下搅拌16小时。反应结束后，反应液在冰浴下加入稀盐酸(1M)调节pH至5-6，加水(5mL)稀释，用乙酸乙酯(5mL)萃取，有机相用饱和食盐水(5mL)洗涤一次，有机相用无水硫酸钠干燥并过滤，过滤液在45℃浓缩得到化合物8(200mg，收率：33％)。
MS m/z(ESI):431.8[M+23]。
第九步：
将碳酸钾(135mg)和碘甲烷(140mg)加入到化合物8(200mg)的乙腈(5mL)溶液中，反应液加热到50℃并在该温度下搅拌16小时。反应结束后，反应液直接浓缩，残余物经柱层析(石油醚:乙酸乙酯＝3:1)纯化得到化合物9(180mg，收率：40％)。
MS m/z(ESI):445.8[M+23]。
第十步：
向化合物9(180mg)的四氢呋喃(3mL)溶液中加入钯/炭(50mg)，反应液在氢气气氛和室温下进行催化氢化反应2小时。反应结束后，反应液过滤，滤液直接浓缩得到化合物10(120mg，收率：54％)。
MS m/z(ESI):290.0[M+1]。
第十一步：
将化合物10(120mg)加入到中间体b(119mg)的1,2-二氯乙烷(5mL)溶液中，反应在室温下搅拌8小时，然后加入醋酸硼氢化钠(261mg)并在室温下继续搅拌16小时。反应结束后，反应液直接浓缩，残余物经柱层析(二氯甲烷:甲醇＝20:1)纯化得到化合物11(200mg，收率：26％)。
MS m/z(ESI):562.8[M+1]。
第十二步
向50mL单口瓶中，依次加入甲醇(2mL)、水(2mL)、化合物11(200mg)和氢氧化钠(150mg)，反应混合物加热到75℃并在该温度下搅拌3小时。反应结束后，反应液在冰浴下加入稀盐酸(1M)调节pH至7，然后直接减压浓缩并通过Prep-HPLC纯化(色谱柱：Gemini-C18，150x21.2mm，5um；流动相：乙腈-水(0.1％甲酸)；梯度：20-40％)得到式Ⅰ化合物(30.6mg，收率：18％；含0.5当量的甲酸)。
MS m/z(ESI):448.9[M+1]。
1H NMR(400MHz,CD3OD)：δ8.18(d,J＝7.7Hz,2H),7.69(d,J＝7.7Hz,2H),7.32(s,1H), 6.76(s,1H),6.34(s,1H),4.88-4.61(m,1H),4.44-4.07(m,2H),3.95-3.81(m,1H),3.75(s,3H),3.63-3.47(m,1H),3.46-3.33(m,3H),2.50(s,3H),2.35-2.14(m,2H),2.13-1.94(m,2H),1.23-1.04(m,1H),0.58(d,J＝7.2Hz,2H),0.28(d,J＝3.8Hz,2H)。
除非另有说明，否则下文提到的式I化合物均为通过上述方法或重复上述方法制备得到的式I化合物。
实施例1式Ⅰ化合物单盐酸盐的制备方法
式Ⅰ化合物进行多批次制备后，取400mg式Ⅰ化合物，加入8mL的异丙醇，在50℃下加热溶解。然后缓慢滴加460μL的氯化氢异丙醇溶液(浓度为2mol/L)，搅拌半小时，再加入8mL的正庚烷，继续搅拌2小时。过滤，滤饼在50℃减压真空干燥，得到390mg的式Ⅰ化合物单盐酸盐I-1，收率为90％。
取出50mg的式Ⅰ化合物单盐酸盐I-1至4mL的样品瓶中，加入0.5mL的甲醇使化合物溶解。然后将样品敞口置于盛有5mL乙酸乙酯的40mL样品瓶中，40mL样品瓶保持密闭。静置使两种溶剂缓慢扩散得到单晶，单晶结构图见图24。将所述单晶进行测试，得到式Ⅰ化合物单盐酸盐I-1的单晶数据如下：

实施例2式Ⅰ化合物磷酸盐的制备方法
式Ⅰ化合物进行多批次制备，取440mg的式Ⅰ化合物，加入5mL的丙酮，加热至40℃并超声溶解。然后缓慢滴加460μL的2mol/L的磷酸甲醇溶液。发现有粘稠的固体，再加5mL的丙酮，在室温下搅拌4小时。过滤，洗涤，滤饼在50℃减压真空干燥，得到462mg的式Ⅰ化合物磷酸盐，收率为87％。
实施例3式Ⅰ化合物马来酸盐的制备方法
将式Ⅰ化合物进行多批次制备，取400mg的式Ⅰ化合物，加入15mL的乙酸乙酯,加热至50℃并使化合物溶解。然后加入马来酸粉末109mg，室温下搅拌2～3小时。过滤，滤饼在50℃减压真空干燥，得到470mg的式Ⅰ化合物马来酸盐，收率为91％。
实施例4式Ⅰ化合物单盐酸盐、磷酸盐、马来酸盐稳定性测试
对式Ⅰ化合物、实施例1的式Ⅰ化合物单盐酸盐、实施例2的式Ⅰ化合物磷酸盐、实施例3的式Ⅰ化合物马来酸盐进行稳定性考察。
稳定性考察条件：40℃/75％RH-closed,40℃/75％RH-open,60℃-closed；稳定性考察内容：有关物质和晶型变化情况。
有关物质检测：分别称取大约6～7mg的样品于10mL的容量瓶中，加入50％乙腈水溶液溶解并稀释至刻度，进样10μL。色谱条件见表6。
式Ⅰ化合物及其盐酸盐、磷酸盐、马来酸盐稳定性考察实验结果如表7所示。
表6式I化合物及其单盐酸盐、磷酸盐、马来酸盐测试色谱条件

表7式I化合物及其单盐酸盐、磷酸盐、马来酸盐稳定性考察实验结果
从表7的结果可以看出，式Ⅰ化合物及其单盐酸盐、磷酸盐、马来酸盐都很稳定，尤其是式Ⅰ化合物的单盐酸盐的稳定性更为优异。
实施例5式Ⅰ化合物及其盐酸盐、磷酸盐的溶解度测试
考察式Ⅰ化合物、式Ⅰ化合物单盐酸盐、式Ⅰ化合物磷酸盐在水、SGF、FaSSIF、FeSSIF中，37℃条件下的溶解度。
实验方法：称取30mg(水中)或者15mg的样品于4mL的小瓶中，加入3mL的待测介质(水、SGF、FaSSIF、FeSSIF)，于37℃条件下持续搅拌，于1h，24h分别取样0.5mL,12000rpm,离心10min，上清液用50％乙腈水溶液稀释适当倍数后测定其浓度。溶解度测试色谱条件见表8。
对照品与线性：称取10mg的式Ⅰ化合物于50mL的容量瓶中，加入50％乙腈水溶液溶解，并稀释至刻度，平行配制两份。取式Ⅰ化合物的对照品，用50％乙腈水溶液稀释至100μg/mL,50μg/mL,10μg/mL，进样5μL，绘制标准曲线。
式Ⅰ化合物及其盐酸盐、磷酸盐的溶解度测试结果如表9所示。
表8式Ⅰ化合物溶解度测试色谱条件
表9式Ⅰ化合物及其盐酸盐、磷酸盐的溶解度测试结果

从表9可以看出，式Ⅰ化合物成盐后，水中的溶解度提高。
对照化合物
向50mL单口瓶中加入甲醇(3mL)、水(1mL)、中间体1(160mg)和氢氧化钠(230mg)。反应在室温下进行16小时。反应结束后，加入水(10mL)稀释，用稀盐酸溶液(1M)调节pH＝7-8，减压除去溶剂(水浴：45℃)，残余物经高压液相制备色谱(色谱柱：Gemini-C18，150x 21.2mm，5um；流动相：乙腈-水(0.1％甲酸)；梯度：15-30％)纯化得到对照化合物(29mg，收率：24％)。MS m/z(ESI):423.1[M+1].1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝8.4Hz,2H),7.67(d,J＝8.4Hz,2H),7.33(t,J＝2.8Hz,1H),6.78(s,1H),6.35(s,1H),4.82–4.67(m,1H),4.40–4.17(m,2H),3.90–3.81(m,1H),3.77(s,3H),3.62(q,J＝6.8Hz,2H),3.57–3.50(m,1H),3.45–3.35(m,1H),2.52(s,3H),2.32–2.22(m,2H),2.14–1.96(m,2H),1.32(t,J＝6.8Hz,3H).
生物学实施例1
1.光学表面等离子共振(SPR)结合力检测
SPR实验在25℃条件下，以补充有0.05％(v/v)P20和5％DMSO的PBS缓冲液作为运行缓冲液，采用的分析仪器为GE Healthcare的Biacore 8K。400mM EDC和100mM NHS以30μL/min的流速活化CM7芯片(GE Healthcare)420s。补体B因子用10mM醋酸钠(pH 4.0)稀释到50μg/mL，然后以10μL/min的流速偶联1200s，使补体B因子共价固定到检测芯片上(蛋 白固化水平为25000RU)；然后检测芯片用1M盐酸乙醇胺以10μL/min的流速作用300s进行芯片封闭。待测化合物浓度为500μM，结合时间120s,解离时间300s。数据分析采用的是1:1binding结合模型进行分析(Biacore Insight Evalution Software,Version2.0.15.12933)。
实验结果：
实验结果如表10所示。在500μM浓度下，式I化合物和靶蛋白具有更显著的结合能力，显著优于对照化合物，显示式I化合物与靶蛋白有较好的结合能力。
2.TR-FRET结合力检测
以Cy5荧光标记的小分子抑制剂作为探针的竞争性结合实验来筛选化合物对人补体因子B的抑制活性。补体因子B与EZ-LinkTM Sulfo-NHS-LC-LC-Biotin以1:2比例在冰上孵育1小时后加入1M Tris(pH7.5)终止反应。随后用2mL ZebaTM desalt spin column纯化两次获得生物素标记的补体因子B(EZ-LinkTM Sulfo-NHS-LC-Biotin说明书)。实验时，取终浓度为10nM生物素标记的补体因子B与不同浓度的化合物在缓冲液中室温预孵育1小时。加入终浓度分别为75nM和5nM的Cy5荧光标记的探针和铕螯合物标记的链霉亲和素(石油醚rkin Elmer,#AD0060)，启动反应。在酶标仪上(337nm激发光，665nm发射光，70μs time-gated)进行动力学读数，读取时间依赖的荧光能量转移(TR-FRET)的数据，确定IC50。
3.补体系统水解C3活性检测
受试化合物测试浓度为10μM起始，3倍稀释，7个浓度点，单孔检测。在96孔板用DMSO将受试化合物稀释成1000倍终浓度的溶液，再用Diluent(COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330)稀释成5倍终浓度的溶液。转移30μL到96孔板中，加入120μL的备用血清，室温孵育15分钟。阳性对照孔加30μL的5‰DMSO和120μL的备用血清，阴性对照孔加30μL的5‰DMSO和120μL的Diluent。(3)取100μL加入反应板中，37℃孵育60分钟。弃去孔中液体，每孔用300μL洗涤液洗涤3次。每孔加入100μL Conjugate(COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330)，室温孵育30分钟。去孔中液体，每孔用300μL洗涤液洗涤3次。然后每孔加入100μL底物，室温孵育30分钟。使用酶标仪(Perkin Elmer，EnSight)检测，读取OD405值。
4.补体溶血活性检测
溶血实验参考文献Xuan Yuan等,Haematologica,(2017)102:466-475的描述，在实验之前，实现兔红细胞(RE)的100％裂解所需的正常人血清(NHS)的最佳浓度通过滴定测试获得。在该实验中，NHS在含10mM Mg-EGTA的GVB0缓冲液(0.1％明胶，5mM Veronal，145mM NaCl，0.025％NaN3，pH 7.3，Complement technology)中稀释并与各种浓度梯度的测试化合物在37℃孵育15分钟。新悬浮在含10mM Mg-EGTA的GVB0缓冲液中的RE(取自健康日本大耳白兔)添加达到1×108细胞/mL的终浓度且在37℃下孵育30分钟。阳性对照组(100％裂解)由具有NHS和RE但没有测试化合物的含10mM Mg-EGTA的GVB0缓冲液组成；阴性对照组(0％裂解)由具有灭活的NHS(56℃加热30分钟或65℃加热5分钟)和RE但没有测试化合物的含10mM Mg-EGTA的GVB0缓冲液组成。样品以2000g离心5分钟后收集上清液。415nm的吸光度(A415)使用酶标仪(Molecular Devices，SpectraMax i3X)检测。IC50值通过非线性回归从作为测试化合物浓度的函数的溶血百分比计算。
实验结果：
实验结果如表11所示，其中式I化合物对人血清中补体B因子的抑制活性显著优于对照化合物，显示本发明化合物能较好的抑制人血清中补体B因子活性，阻止其对兔红细胞的攻击而产生的溶血。
5.肝微粒体稳定性实验
(1)缓冲液的配制
取0.1M的磷酸氢二钾蒸馏水溶液(含1mM的乙二胺四乙酸)，然后用0.1M的磷酸二氢钾蒸馏水溶液(含1mM的乙二胺四乙酸)调节pH至7.4。
(2)微粒体来源和工作液的配制
微粒体来源：
大鼠：SD Rat Liver Microsomes，Cat.No.:LM-DS-02M，RILD瑞德肝脏疾病研究(上海)有限公司。
猴子：Cynomolgus Monkey Liver Microsomes，Cat.No.:LM-SXH-02M，RILD瑞德肝脏疾 病研究(上海)有限公司。
人：Pooled Human Liver Microsomes(Mongolian)，Cat.No.:LM-R-02M，RILD瑞德肝脏疾病研究(上海)有限公司。
工作液的配制
将对照化合物和测试化合物分别用DMSO配成10mM的溶液，然后取10uL加入到190uL乙腈中配制程0.5mM的母液。取1.5uL的0.5mM的化合物母液、加18.75uM的20mg/mL肝微粒体和479.75uL的缓冲液。(实际配制量可根据使用情况进行调整)。
(3)实验过程
用缓冲液配制10mg/mL的还原型辅酶II(NADPH)。取一块96孔板置于冰上，每个化合物设置不同时间点的对应孔(0，10，30，60，90分钟，Non-NADPH)，每孔加入30μL工作液。对于0min孔先加155μL冰乙腈溶液(内标浓度为1μM)、用移液枪混匀后加入15μL的NADPH(10mg/mL)。反应启动前，96孔板在恒温微孔板震荡仪上(37℃)预孵育5分钟，然后每孔加入15μL NADPH(10mg/mL)启动代谢反应。反应进行10、30、60、90分钟后在对应孔中分别加入155μL冰乙腈溶液(内标浓度为1μM)终止反应。Non-NADPH体系在90分钟后，加入155μL冰乙腈溶液(内标浓度为1μM)终止反应。反应结束后，96孔板用微孔板震荡仪(600rpm)震荡10分钟，然后在4℃和4000g下离心15分钟，取上清50μL加到一新的2mL的96孔板中，再加入300μL去离子水，用AB SCIEX ExionLC-Triple Quad 5500高效液相色谱-质谱联用仪分析，软件采用的是Analyst 1.6.3。测试结果见表12。
实验结果：数据显示，式I化合物具有显著的肝微粒体稳定性。
6.大鼠单次灌胃给药PK实验
实验方法：
采用6-9周龄Wistar han雄性大鼠(上海西普尔-必凯实验动物有限公司)，过夜禁食，每组3只，灌胃给药，分别给予对照化合物、式I化合物各3mg/kg，给药体积10mL/kg，通过颈静脉采血，每时间点0.2mL，EDTA-K2抗凝，立即在4000rpm*5min，4℃条件下离心，取 上清，样品冻存于-80℃冰箱直至检测。采血时间点：给药前，5min，15min，30min，1h，2h，4h,7h,24h。给药后随时观察动物状态，完成所有时间点血液采集后，对动物进行安乐死。血浆样品采用LC-MS/MS进行测定，数据采用WinNonlin软件进行动力学参数计算(Tmax，Cmax，T1/2，AUC)。
实验结果：
测试结果见表13。
7.食蟹猴单次灌胃给药PK/PD实验
实验方法：
采用食蟹猴，每组3只给予对照化合物3mpk、对照化合物30mpk、式I化合物3mpk、式I化合物30mpk，灌胃给药，不同时间点采血，用于药物浓分析和补体活性检测，血浆化合物浓度采用LC-MS/MS进行测定，血清补体活性采用wieslab assay(Svar Life Science AB,COMPL AP330RUO)试剂盒进行检测，其中Normal Human Serum(Complement Technology，NHS)。
实验结果：
在所检测的浓度和时间范围内，同等剂量下，式I化合物的血药浓度平均值明显高于对照化合物。食蟹猴血药浓度曲线见图21，食蟹猴血清AP活性抑制见图22。图22表明式I化合物能够有效的抑制食蟹猴血清AP活性。
8.链球菌诱导的大鼠类风湿性关节炎(RA)模型
实验方法：
实验采用6-9周龄Lewis雌性大鼠(北京维通利华)，每组6只大鼠，D1腹腔注射给予链球菌及其他几种细菌的细胞壁肽聚糖复合物(2-3mg每只大鼠),每天灌胃给药对照化合物(15mpk)和式I化合物(15mpk)，持续25天，在不同时期对大鼠进行关节炎评分。评分标准如 下：根据病变的不同程度(红肿)按照0-4分的标准进行评分，每个肢体的最高评分为4分，每只动物四肢总和最高评分为16分。评分标准如下：0分，无红肿；1分，1～2个指间关节红肿；2分，3～4个指间关节红肿；3分，4个以上指间关节红肿；4分，脚趾或手指到踝关节或腕关节严重红肿。
实验结果：
实验结果见图23，数据表明式I化合物能够改善关节炎评分，且其效果显著优于对照化合物，证明式I化合物能够更有效地改善链球菌诱导的大鼠类风湿性关节炎。
实施例6式Ⅰ化合物单盐酸盐晶型A的制备方法
取400mg式Ⅰ化合物，加入8mL的异丙醇，在50℃下加热溶解。然后缓慢滴加460μL的氯化氢异丙醇溶液(浓度为2mol/L)，搅拌半小时，再加入8mL的正庚烷，继续搅拌2小时。过滤，滤饼在50℃减压真空干燥，得到390mg的式Ⅰ化合物单盐酸盐晶型A，收率为90％。
对晶型A进行XRPD、DSC、TGA和PLM表征。
所述晶型A为无水物。XRPD特征峰位置和强度如表1，XRPD图谱如图1所示。
DSC显示在加热至峰值温度192.73℃附近出现第一个吸热峰，峰值温度201.78℃附近出现第一个放热峰，如图2所示。
TGA显示在90℃至180℃区间内具有约1.41％的失重，如图3所示。
PLM图显示样品为20μm以下的不规则形貌晶体，如图4所示。
晶型A的XRPD图谱其以2θ角度表示的X-射线粉末衍射图中，衍射峰的2θ角度及相对强度如表A所示，其中所述2θ角度的误差范围为±0.20°：
表A晶型A的XRPD解析数据

实施例7式Ⅰ化合物单盐酸盐晶型B的制备方法
晶型A在加速条件下(40℃/75％RH)敞口放置72h，会转变成晶型B。该晶型B为式Ⅰ化合物单盐酸盐的一水合物。
对晶型B进行XRPD、DSC、TGA和PLM表征。
XRPD特征峰位置和强度如表2，XRPD图谱如图5所示。
DSC显示在加热至峰值温度85.87℃附近出现第一个吸热峰，峰值温度197.54℃附近出现第二个吸热峰，峰值温度为205.68℃附近出现第一个放热峰，如图6所示。
TGA显示在21.49℃至120℃区间内具有约3.42％的失重，179.88℃至207.94℃区间内具有约0.49％的失重，如图7所示。
PLM图显示样品为20μm以下的不规则形貌晶体，如图8所示。
晶型B的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，衍射峰的2θ角度及相对强度如表B所示，其中所述2θ角度的误差范围为±0.20°：
表B晶型B的XRPD解析数据
实施例8式Ⅰ化合物单盐酸盐晶型C的制备方法
将式Ⅰ化合物(3.15g)加到三口烧瓶中，加入甲醇(12.6mL)搅拌，完全溶解。在常温下滴加1.8N HCl的甲醇溶液(3.05g)，搅拌10分钟后过滤。将滤液加入到三口烧瓶中，在常温下滴加甲基叔丁基醚(78.75mL)，搅拌2小时，过滤，滤饼干燥得到晶型C(3.06g)，收率为90％。
晶型C为无水物，对晶型C进行XRPD、DSC、TGA和PLM表征。
XRPD特征峰位置和强度如表3，XRPD图谱如图9所示。
DSC显示在加热至峰值温度209.93℃附近出现第一个吸热峰，峰值温度215.80℃附近出现第一个放热峰，如图10所示。
TGA显示在21.62℃至120℃区间内具有约0.29％的失重，在173.94℃至216.60℃区间内具有约0.52％的失重，如图11所示。
PLM图显示样品为20μm以下的不规则形貌晶体，如图12所示。
晶型C的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，衍射峰的2θ角度及相对强度如表C所示：
表C晶型C的XRPD解析数据
实施例9式Ⅰ化合物单盐酸盐晶型D的制备方法
取400mg式Ⅰ化合物单盐酸盐，加入8mL二氯甲烷，在常温下搅拌24小时。所得混悬液采用离心进行分离，固体在40℃下减压真空干燥，所述固体为晶型D。
所述晶型D为式Ⅰ化合物单盐酸盐的一二氯甲烷溶剂化物(或称为单二氯甲烷溶剂化物)。
对晶型D进行XRPD、DSC、TGA和PLM表征。
XRPD特征峰位置和强度如表4，XRPD图谱如图13所示。
DSC显示在加热至峰值温度196.53℃附近出现第一个放热峰，如图14所示。
TGA显示在22.07℃至120℃区间内具有约6.31％的失重，如图15所示。
PLM图显示样品为10μm以下的不规则形貌晶体，如图16所示。
晶型D的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，衍射峰的2θ角度及相对强度如表D所示：
表D晶型D的XRPD解析数据
实施例10式Ⅰ化合物单盐酸盐晶型E的制备方法
取400mg式Ⅰ化合物单盐酸盐，加入8mL异丙醇，在常温下搅拌72小时。所得混悬液采用离心进行分离，固体在40℃下减压真空干燥，所述固体为晶型E。
所述晶型E为式Ⅰ化合物单盐酸盐的一异丙醇溶剂化物。
对晶型E进行XRPD表征，XRPD图谱如图17所示。
晶型E的XRPD图谱其以2θ角表示的X-射线粉末衍射图中，衍射峰的2θ角度及相对强度如表E所示：
表E晶型E的XRPD解析数据

实施例11式Ⅰ化合物单盐酸盐晶型C的稳定性考察
将式Ⅰ化合物单盐酸盐晶型C放置在40℃/75％RH-closed(密闭)，40℃/75％RH-open(敞口)，60℃-open(敞口)条件下,于1个月时取出，对其晶型的稳定性进行考察。
色谱条件测试如表14所示。
稳定性样品有关物质检测方法：称取大约6mg的样品于40mL的洁净玻璃瓶中，加入10mL的50％乙腈水溶液，超声使完全溶解，进样10μL进行有关物质测试，如表15所示。XRPD图如18所示，其中HCl-salt Form 3-initial(下称initial)代表实施例8制备的晶型C的XRPD图。
表14色谱条件测试
表15式Ⅰ化合物单盐酸盐晶型C的稳定性测试结果(1M)
注：1M代表放置1个月。
从以上数据可以看出，式Ⅰ化合物单盐酸盐晶型C在40℃/75％RH，60℃放置1月，其化学稳定性良好。另外，从图18可见，式Ⅰ化合物单盐酸盐晶型C的晶型未发生变化。
实施例12高温、高湿对晶型C的影响
将式Ⅰ化合物单盐酸盐晶型C敞口放置于60℃、80％RH、92.5％RH条件下，评估晶型是否发生明显变化。分别于1d、3d取样测试其XRPD。XRPD如图19、20所示。
从图19、图20可以看出，式Ⅰ化合物单盐酸盐晶型C在高温、高湿的条件下暴露1天和3天后，晶型C都未发生变化。
实施例13式Ⅰ化合物、晶型A和B的混合物、晶型C的溶解度测试
称取适量的受试样品于小瓶中，加入3mL的介质(水、SGF、FaSSIF、FeSSIF等)，于37℃下，进行搅拌，分别于1h、24h取适量样品，12000rpm，离心10min，上清液用50％乙腈水溶液稀释适当倍数后测定其浓度。溶解度测试色谱条件见表16。
对照品与线性：称取10mg的式Ⅰ化合物于50mL的容量瓶中，加入50％乙腈水溶液溶解，并稀释至刻度，平行配制两份。取对照品，用50％乙腈水溶液稀释至100μg/mL,50μg/mL,10μg/mL，进样5μL，绘制标准曲线。
测试结果示于表17。
表16式Ⅰ化合物单盐酸盐溶解度测试色谱条件

表17式Ⅰ化合物、晶型A和B的混合物、晶型C的溶解度结果(37℃)
注：在pH6.8、pH7.4中的pH值经过了氢氧化钠溶液调节，因此最终pH值与初始值接近。
从上述实验结果可以看出，晶型C相比晶型A和B的混合物，在水中的溶解度降低。
以上对本发明示例性的实施方式进行了说明。但是，本申请的保护范围不拘囿于上述示例性的实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书限定的保护范围之内。

Claims (11)

  1. 一种式Ⅰ化合物药学上可接受的盐：
    所述药学上可接受的盐为式Ⅰ化合物与酸或碱形成的盐；
    所述酸选自盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸、甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸中的一种；优选选自盐酸、氢溴酸、硫酸、磷酸、硝酸、甲磺酸、对甲苯磺酸、富马酸、马来酸、柠檬酸、L-酒石酸、草酸、甲酸、乙酸、三氟乙酸、月桂酸、苯甲酸和苯磺酸中的一种；
    所述碱选自碱金属氢氧化物或碱土金属的氢氧化物，优选选自氢氧化钠或氢氧化钾；
    优选地，所述式Ⅰ化合物药学上可接受的盐选自其盐酸盐、硫酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐、富马酸盐、马来酸盐、柠檬酸盐、L-酒石酸盐和草酸盐中的一种；
    更优选地，所述式Ⅰ化合物药学上可接受的盐是式Ⅰ化合物与盐酸形成的盐；更优选地，所述式Ⅰ化合物药学上可接受的盐是式Ⅰ化合物与盐酸形成的单盐酸盐。
  2. 权利要求1所述式Ⅰ化合物药学上可接受的盐的制备方法，其特征在于，所述制备方法包括将式Ⅰ化合物与所述酸或碱反应，制备得到式Ⅰ化合物药学上可接受的盐；
    优选地，所述制备方法包括将式Ⅰ化合物与所述酸或碱在溶剂中反应，制备得到式I化合物药学上可接受的盐；
    优选地，所述溶剂选自醇类、酮类、酯类、醚类，所述溶剂中两种以上的组合，或上述溶剂或组合分别与水的混合物；
    优选地，所述醇类选自具有1-8个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其中两种以上的组合；所述酮类可以选自具有3-10个碳原子的酮，例如丙酮、丁酮、戊酮、甲基乙基酮、4-甲基-2-戊酮或其中两种以上的组合；所述酯类可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸乙丙酯或其中两种以上的组合；所述醚类可以为直链或支链烷基醚或环醚类化合物，例如甲基叔丁基醚、四氢呋喃、2-甲基-四氢呋喃或其中两种以上的组合；
    优选地，所述式Ⅰ化合物与所述酸或碱的摩尔比为1:0.8～1:1.5；
    所述酸或碱彼此独立地具有权利要求1所述的定义。
  3. 根据权利要求1所述式Ⅰ化合物的单盐酸盐的单晶，其特征在于，所述单晶的晶胞参数如下：
    正交晶系，空间群P212121；




    Z＝4。
  4. 权利要求1所述式Ⅰ化合物的单盐酸盐的晶型A，其特征在于，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、16.08±0.20°、23.46±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、16.08±0.20°、18.10±0.20°、21.30±0.20°、21.68±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、11.62±0.20°、16.08±0.20°、18.10±0.20°、21.30±0.20°、21.68±0.20°、23.40±0.20°、25.42±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.66±0.20°、11.62±0.20°、16.08±0.20°、16.84±0.20°、18.10±0.20°、19.64±0.20°、21.30±0.20°、21.68±0.20°、23.40±0.20°、24.96±0.20°、25.42±0.20°处具有特征峰；
    优选地，所述晶型A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如下特征峰， 其中所述2θ角度的误差范围为±0.20°：
    优选地，所述晶型A具有基本如图1所示的粉末X射线衍射图；
    优选地，所述晶型A为式Ⅰ化合物单盐酸盐的无水物；
    优选地，所述晶型A具有基本如图2所示的DSC图；
    优选地，所述晶型A具有基本如图3所示的TGA图；
    优选地，所述晶型A为不规则形貌晶体；优选地，所述晶型A的粒径不超过20μm；
    优选地，所述晶型A具有基本如图4所示的PLM图谱。
  5. 权利要求1所述式Ⅰ化合物的单盐酸盐的晶型B，其特征在于，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.10±0.20°、19.80±0.20°、22.10±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.48±0.20°、15.44±0.20°、18.10±0.20°、19.80±0.20°、22.10±0.20°、30.92±0.20°处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.48±0.20°、10.78±0.20°、15.44±0.20°、18.10±0.20°、19.18±0.20°、19.80±0.20°、22.10±0.20°、30.92±0.20°、处具有特征峰；
    优选地，所述晶型B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如下特征峰， 其中所述2θ角度的误差范围为±0.20°：
    优选地，所述晶型B具有基本如图5所示的粉末X射线衍射图；
    优选地，所述晶型B为式Ⅰ化合物单盐酸盐的水合物，如式Ⅰ化合物单盐酸盐的一水合物；
    优选地，所述晶型B具有基本如图6所示的DSC图；
    优选地，所述晶型B具有基本如图7所示的TGA图；
    优选地，所述晶型B为不规则形貌晶体；优选地，所述晶型B的粒径不超过20μm；
    优选地，所述晶型B具有基本如图8所示的PLM图谱。
  6. 权利要求1所述式Ⅰ化合物的单盐酸盐的晶型C，其特征在于，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、20.08±0.20°、21.98±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、19.58±0.20°、20.08±0.20°、21.98±0.20°、22.94±0.20°、25.92±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.74±0.20°、17.80±0.20°、19.58±0.20°、20.08±0.20°、21.98±0.20°、22.94±0.20°、25.92±0.20°、33.48±0.20°处具有特征峰；
    优选地，所述晶型C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如下特征峰，其中所述2θ角度的误差范围为±0.20°：
    优选地，所述晶型C具有基本如图9所示的粉末X射线衍射图；
    优选地，所述晶型C为式Ⅰ化合物单盐酸盐的无水物；
    优选地，所述晶型C具有基本如图10所示的DSC图；
    优选地，所述晶型C具有基本如图11所示的TGA图；
    优选地，所述晶型C为不规则形貌晶体；优选地，所述晶型C的粒径不超过20μm；
    优选地，所述晶型C具有基本如图12所示的PLM图谱。
  7. 权利要求1所述式Ⅰ化合物的单盐酸盐的晶型D，其特征在于，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.74±0.20°、16.58±0.20°、21.98±0.20°、23.82±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.16±0.20°、11.90±0.20°、15.74±0.20°、16.58±0.20°、19.22±0.20°、20.24±0.20°、21.98±0.20°、23.82±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在10.16±0.20°、11.90±0.20°、12.60±0.20°、15.74±0.20°、16.58±0.20°、19.22±0.20°、19.80±0.20°、21.98±0.20°、22.66±0.20°、23.18±0.20°、23.82±0.20°、24.94±0.20°、26.24±0.20°、26.80±0.20°、27.50±0.20°处具有特征峰；
    优选地，所述晶型D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如下特征峰，其中所述2θ角度的误差范围为±0.20°：
    优选地，所述晶型D具有基本如图13所示的粉末X射线衍射图；
    优选地，所述晶型D为式Ⅰ化合物单盐酸盐的溶剂化物，如式Ⅰ化合物单盐酸盐的二氯甲烷溶剂化物，如式Ⅰ化合物单盐酸盐的单二氯甲烷溶剂化物。
    优选地，所述晶型D具有基本如图14所示的DSC图；
    优选地，所述晶型D具有基本如图15所示的TGA图；
    优选地，所述晶型D为不规则形貌晶体；优选地，所述晶型C的粒径不超过10μm；
    优选地，所述晶型D具有基本如图16所示的PLM图谱。
  8. 权利要求1所述式Ⅰ化合物的单盐酸盐的晶型E，其特征在于，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在9.36±0.20°、15.22±0.20°、16.88±0.20°、22.10±0.20°处具有特征峰；
    优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.20±0.20°、9.36±0.20°、15.22±0.20°、16.88±0.20°、21.10±0.20°、22.10±0.20°、23.68±0.20°处具有特征峰；
    优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.20±0.20°、9.36±0.20°、15.22±0.20°、16.88±0.20°、18.78±0.20°、21.10±0.20°、22.10±0.20°、23.68±0.20°、26.04±0.20°、27.86±0.20°处具有特征峰；
    优选地，所述晶型E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如下特征峰，其中所述2θ角度的误差范围为±0.20°：
    优选地，所述晶型E具有基本如图17所示的粉末X射线衍射图；
    优选地，所述晶型E为式Ⅰ化合物单盐酸盐的溶剂化物，如式Ⅰ化合物单盐酸盐的一异丙醇溶剂化物。
  9. 权利要求4-8任一项所述晶型A、晶型B、晶型C、晶型D或晶型E的制备方法，其特征在于：
    所述晶型A的制备方法包括选自下列方法中的一种：
    方法一，包括：将式Ⅰ化合物溶于醇类溶剂，加入HCl在醇类溶剂中的溶液成盐，再加入正烷烃结晶，得到所述晶型A；
    优选地，所述醇类溶剂选自乙醇和/或异丙醇；
    优选地，所述正烷烃选自正己烷和/或正庚烷；
    优选地，所述式Ⅰ化合物、醇类溶剂和正烷烃的质量体积比为1g：(10-30)mL：(10-30)mL；
    优选地，所述HCl在醇类溶剂中的溶液的浓度为1-3mol/L；
    方法二，包括：将式Ⅰ化合物单盐酸盐在醇类溶剂和正烷烃下加热搅拌至溶清后结晶，得到所述晶型A；
    优选地，所述醇类溶剂选自乙醇和/或异丙醇；
    优选地，所述正烷烃选自正己烷和/或正庚烷；
    优选地，所述式Ⅰ化合物单盐酸盐、醇类溶剂和正烷烃的质量体积比为1g：(10-30)mL：(10-30)mL；
    优选地，所述加热的温度为45-75℃；
    所述晶型B的制备方法包括：将权利要求4所述晶型A置于高湿条件下得到晶型B；
    优选地，所述高湿条件的温度为30-50℃，湿度为60％-98％；
    优选地，所述高湿条件的温度为40℃，湿度75％～95％；
    所述晶型C的制备方法包括：将式Ⅰ化合物溶于醇类溶剂，再加入HCl在醇类溶剂中的溶液成盐，再加入醚类溶剂或酯类溶剂结晶，得到晶型C；
    优选地，所述醇类溶剂选自甲醇、乙醇或异丙醇；
    优选地，所述醚类溶剂选自甲醚、乙醚、丙醚或甲基叔丁基醚；
    优选地，所述酯类溶剂选自乙酸乙酯或乙酸异丙酯；
    优选地，所述式Ⅰ化合物、醇类溶剂和醚类溶剂的质量体积比为1g：(2-8)mL：(20-40)mL；
    优选地，所述HCl在醇类溶剂中的溶液的浓度为1-3mol/L；所述式Ⅰ化合物和HCl在醇类溶剂中的溶液的质量比为1g：(0.5-1.5)g；
    所述晶型D的制备方法包括：将式Ⅰ化合物单盐酸盐在卤代烷烃中室温悬浮搅拌结晶，得到晶型D；
    优选地，所述卤代烷烃选自二氯甲烷、三氯甲烷或四氯化碳；
    优选地，所述式Ⅰ化合物单盐酸盐与卤代烷烃的质量体积比为1g:(15-35)mL；
    所述晶型E的制备方法包括：将式Ⅰ化合物单盐酸盐在醇类溶剂中室温悬浮搅拌结晶，得到晶型E；
    优选地，所述醇类溶剂选自甲醇、乙醇或异丙醇；
    优选地，所述式Ⅰ化合物单盐酸盐与醇类溶剂的质量体积比为1g:(15-35)mL。
  10. 一种药物组合物，包含权利要求1-8任一项所述式I化合物药学上可接受的盐、晶型A、晶型B、晶型C、晶型D、晶型E中的至少一种，以及任选存在的药学上可接受的辅料；
    优选地，所述药物组合物为制剂形式。
  11. 权利要求1-8任一项所述式Ⅰ化合物药学上可接受的盐、晶型A、晶型B、晶型C、晶型D、晶型E或权利要求10所述药物组合物中的至少一种在制备用于预防和/或治疗补体因子B介导的疾病或病症的药物中的用途；
    优选地，所述补体因子B介导的疾病或病症选自下列中的至少一种：阵发性睡眠性血红蛋白尿症(PNH)、原发性肾小球肾炎(IgAN)、膜性肾病(MN)、C3肾小球肾炎(C3G)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、非典型溶血尿毒症综合征(aHUS)、溶血尿毒症综合征(HUS)、糖尿病性视网膜病变(DR)、血液透析并发症、溶血性贫血或血液透析、神经脊髓炎(NMO)、关节炎、类风湿性关节炎、肝脏类炎症、皮肌炎和肌萎缩性侧索硬化、重症肌无力(MG)、呼吸系统疾病和心血管等疾病。
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