Salt forms, crystalline forms of complement factor B inhibitors, and methods of making and using same

Abstract

Pharmaceutically acceptable salt forms, crystalline forms, and methods for their preparation and use of the compound of formula I are provided below. [Formula 1] JPEG2025501178000036.jpg54169

Description

[Technical field]

[0001] The present invention claims priority to a prior application, filed on January 26, 2022 with the National Intellectual Property Office of the People's Republic of China under the application number 202210096073.X and entitled "Salt forms, crystalline forms, and preparation and use thereof of complement factor B inhibitors," and a prior application, filed on September 9, 2022 with the National Intellectual Property Office of the People's Republic of China under the application number 202211104894.X and entitled "Salt forms, crystalline forms, and preparation and use thereof of complement factor B inhibitors," the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the pharmaceutical field, specifically to the salt forms and crystalline forms of complement factor B inhibitors, as well as the preparation and use thereof. [Background technology]

[0003] Complement is a type of soluble pattern recognition molecule in the immune system, which can perform multiple effector functions. Under natural conditions, complement components exist in the form of inactive zymogens, which are degraded by multiple specific and nonspecific immunological mechanisms to form active large and small fragments. Among them, the large fragments usually remain on the surface of pathogens or cells and cause the latter to pyrolyze or accelerate their clearance, while the small fragments detach from the surface of cells and mediate multiple inflammatory responses. Complement activation is composed of two processes that are closely connected, thereby forming a cascade reaction of complement activation. Currently known complement activation pathways mainly include the classical pathway, the lectin pathway, and the alternative pathway. The three complement activation pathways have different initiation mechanisms and activation sequences, but share a common terminal pathway. Among them, the activation of the alternative pathway does not depend on the antigen-antibody complex. Usually, C3b deposited on the surface of cells binds to factor B, which makes it susceptible to degradation by factor D in serum. In this process, factor B is degraded to Ba and Bb, and then C3b and Bb form a complex to become C3 invertase 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. Here, C3b is not only the product that appears after C3 invertase degrades C3, but also a component of the alternative pathway C3 invertase, thereby forming a feedback amplification mechanism in which the classical pathway and the alternative pathway mutually influence each other. Current research has found that multiple types of diseases, such as hematological, autoimmune, inflammatory and neurodegenerative diseases, lead to dysfunction of the complement system.

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic persistent hemolytic disease. Its etiology is a non-malignant clonal disease caused by acquired somatic PIG-A gene mutation in one or more hematopoietic stem cells, and it belongs to ultra-rare blood diseases (Medicine (Baltimore) 1997, 76(2): 63-93). The course of the disease is manifested by various degrees of worsening hemolysis (paroxysmal), chronic or recurrent acute intravascular hemolysis or subsequent formation of venous / arterial thrombus, which eventually leads to progressive end-organ damage and death. Most patients often have atypical, insidious onset, long disease course, and variable disease severity.

[0005] There are over 10 types of proteins on the surface of red blood cells that inhibit the activation of the complement pathway; all of these are anchored to the cell membrane by glycosylphosphatidylinositol (GPI) and are collectively known as GPI-anchored proteins (APs). The current mechanism of PNH is thought to be as follows: first, a hematopoietic stem cell undergoes a mutation under certain conditions, producing a PNH clone that is deficient in glycosylphosphatidylinositol (GPI); then, some factor (currently thought to be an immune factor) damages or weakens hematopoietic function, and the PNH clone acquires a proliferation advantage over normal clones. Multiple antigens connected to GPI also cause complexity in the interpretation of the biological behavior of PNH cells, among which the most important proteins that inhibit the activation of the complement pathway, C3 invertase decay accelerating factor CD55 and membrane attack complex (MAC) inhibitor CD59, are closely related to PNH in terms of pathogenesis, clinical findings, diagnosis and treatment (Frontiers in Immunology 2019, 10, 1157). CD59 can block the formation of membrane attack units by blocking the entry of C9 into the C5b-8 complex, thereby inhibiting the complement terminal attack response. Currently, intravascular hemolysis and thrombosis, which are typical findings of PNH, are thought to be caused by CD59 deficiency. It has been reported that patients with congenital CD59 deficiency exhibit many typical symptoms of PNH, such as intravascular hemolysis, hemoglobinuria and venous thrombosis. In PNH patients, CD59 cannot bind to the cell membrane of red blood cells due to GPI synthesis deficiency, and the function of inhibiting the activation of the complement pathway is lost, which causes abnormal activation of the complement pathway and attacks red blood cells, resulting in multiple clinical symptoms such as intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. At present, there is no effective treatment for PNH other than the restoration of normal hemopoietic function by hematopoietic stem cell transplantation. Since hematopoietic stem cell transplantation has certain risks and PNH is a benign clonal disease, controlling the onset of hemolysis remains the main measure in the clinical treatment of this disease. Currently, only eculizumab is approved as a treatment for PNH.However, many patients still suffer from anemia even after treatment with eculizumab, and many patients still require continuous blood transfusions. In addition, eculizumab must be administered intravenously. Therefore, the development of novel complement pathway inhibitors for PNH is of great importance.

[0006] IgAN is the most common primary glomerulonephritis, and the disease is characterized by IgA deposition in the mesangial compartment as demonstrated by immunofluorescence. The clinical manifestations of the disease are diverse, and the usual finding is recurrent episodes of microscopic or gross hematuria. According to existing data, the occurrence of IgAN is associated with congenital or acquired immune dysregulation. Irritation of the airway or digestive tract by viruses, bacteria, food proteins, etc. increases mucosal IgA1 synthesis or deposits immune complexes containing IgA1 in the mesangial compartment, and activates the alternative pathway, causing glomerular damage. Human IgA molecules are divided into two isoforms, IgA1 and IgA2, of which IgA1 is the main form in the blood circulation of healthy individuals (accounting for about 85%) and is also the main component deposited in the glomerular mesangial compartment of IgAN patients. IgA molecules can exist in two forms: monomeric and polymeric. IgA1 molecules have a special heavy chain hinge region between the first and second constant regions, which can be a domain of binding sites for O-linked glycan groups. Recent studies have found that the IgA molecules in the serum and deposited in the glomerular mesangial compartment of IgAN patients are mainly glycosylation-deficient IgA1 (gd-IgA1). It is currently believed that the initiation part of the pathogenesis of IgAN is the increase in abnormalities occurring in gd-IgA1.

[0007] More than 90% of IgAN patients have complement C3 deposition in the glomerular mesangial compartment. 75%-100% of IgAN patients have codeposits of properdin, IgA, and C3 in renal tissue, and 30%-90% of IgAN patients have codeposits of complement factors H, IgA, and C3 in renal tissue. In addition to deposition in renal tissue, some studies have also found that the levels of alternative pathway markers in the plasma of IgAN patients are associated with IgAN activity (J Nephrol 2013, 26(4): 708-715). Studies have confirmed that renal and urinary C3a and C3a receptors in renal tissue are significantly associated with the activity and severity of renal injury (J clin Immunol 2014, 34(2): 224-232). Another study confirmed that IgA can activate the alternative pathway under in vitro conditions. In this process, the abnormality of the IgA hinge region does not play a critical role, and the formation of IgA polymers is an essential part (Eur J Immunol 1987, 17(3): 321-326). At present, the deposition of complement C3 in the glomerular mesangial region has already become one of the auxiliary diagnostic markers of IgAN. A study of C3c and C3d immunofluorescence detection in renal tissues of 163 IgAN patients showed that IgAN patients with a higher C3c deposition intensity than that of C3d deposition intensity had a lower glomerular filtration rate, a higher incidence of glomerular endocapillary proliferation, and more severe hematuria, suggesting that the deposition of glomerular C3c is associated with the active lesions of IgAN (Am J Nephrol. 2000, 20(2):122-128). Currently, there is no specific drug for treating IgAN, and the drugs available are mainly generic renin-angiotensin inhibitors (ACEI or ARB), glucocorticoids, and various immunosuppressants. In addition, the safety of these drugs is also an issue that cannot be ignored. For example, glucocorticoids have the effect of reducing proteinuria, but the STOP-IgAN and TESTING-I trials have clearly confirmed the potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0008] Arthritis is a common chronic disease, an inflammatory disease caused by inflammation, infection, degeneration, wounds or other factors. Its clinical manifestations are joint redness, swelling, heat, pain, functional impairment and joint deformation, which often cause people to suffer from severe pain, limited movement and body deformation, and in severe cases, cause permanent disability and affect the quality of life of patients. Research has found that K / BxN mouse serum cannot induce arthritis in mice lacking complement factor B, but wild-type mice can develop arthritis disease when induced by K / BxN mouse serum (Immunity, 2002, 16, 157-168). This indicates that the complement system plays an important pathogenic role in the K / BxN mouse serum-induced arthritis model, and that complement factor B is a potential target for treating arthritis.

[0009] Other diseases associated with the complement cascade further 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), hepatic inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases.

[0010] At present, there are no small molecule drugs for complement factor B inhibitors for clinical treatment, and the only known and currently under investigation projects are oligonucleotide drugs developed by IONIS Pharmaceuticals Inc. that treat, prevent or alleviate diseases associated with complement alternative pathway disorders as specific inhibitors of complement factor B (CFB) (WO2015038939). Small molecule complement factor B inhibitors developed by Novartis AG are used to treat diseases such as age-related macular degeneration (AMD) (WO2013164802, WO2013192345, WO2014143638, WO2015009616, WO2015066241), or to treat diseases such as C3G and IgAN (WO2019043609A1). Small molecule complement factor B inhibitors developed by Achillion Pharmaceuticals Inc. are used to treat diseases such as age-related macular degeneration (AMD) (WO2018005552).

[0011] Inflammation and immune-related diseases are characterized by diversity and intractability. The only drug available for PNH disease is eculizumab, but it is expensive and places a great burden on patients. Many patients still suffer from anemia even after being treated with eculizumab, and many patients still require continuous blood transfusions. Furthermore, eculizumab must be administered intravenously. Meanwhile, some diseases, such as IgAN, do not have specific therapeutic drugs to date. There are unmet clinical needs in these areas, and the development of new small molecule drugs for medical treatment is required.

[0012] Therefore, there is currently a need to develop highly efficient, low-toxicity, and / or long-acting pharma- ceutically acceptable active ingredients to ameliorate the above technical problems. Summary of the Invention

[0013] In order to remedy the above technical problems, the present invention provides a pharma- ceutically acceptable salt of a compound of formula I,

[0014] [ka]

[0015] The above-mentioned pharma- ceutically acceptable salt is a salt formed between the compound of formula I and an acid or a base, and is preferably selected from the salts formed between the compound of formula I and an acid.

[0016] According to an embodiment of the present invention, 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, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic 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, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid. , 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid. Illustratively, the acid is one selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid and benzenesulfonic acid.

[0017] According to an embodiment of the present invention, the base may be selected from inorganic bases, such as alkali metal hydroxides or alkaline earth metal hydroxides, preferably sodium hydroxide or potassium hydroxide.

[0018] According to a preferred embodiment of the present invention, the pharma- ceutically acceptable salt of the compound of formula I is one selected from its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate and oxalate salts.

[0019] According to a more preferred embodiment of the present invention, the pharma- ceutically acceptable salt of the compound of formula I is a salt formed between the compound of formula I and hydrochloric acid, i.e., the hydrochloride salt of the compound of formula I, preferably the monohydrochloride salt of the compound of formula I.

[0020] According to an embodiment of the present invention, in the pharma- ceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid or base may be independently selected from 1:1, 2:1, or 3:1, provided that the ionic charge of the ion of the compound of formula I in the salt is balanced with the ionic charge of the acid or base. For example, when the number of ionizable hydrogen atoms in the acid (such as hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) is 1, the molar ratio of the compound of formula I to the acid may be 1:1 or 2:1 when the number of ionizable hydrogen atoms in the acid (such as sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, etc.) is 2, and when the number of ionizable hydrogen atoms in the acid (such as phosphoric acid) is 3, the molar ratio of the compound of formula I to the acid is 1:1, 2:1, or 3:1.

[0021] The present invention further provides a process for preparing a pharma- ceutically acceptable salt of a compound of formula I, said process comprising reacting a compound of formula I with an acid or base as defined above to obtain a pharma- ceutically acceptable salt of a compound of formula I.

[0022] According to an embodiment of the present invention, the process comprises reacting a compound of formula I with an acid or base as described above in a solvent to obtain a pharma- ceutically acceptable salt of the compound of formula I.

[0023] According to an embodiment of the present invention, said acids or bases, independently of each other, have the above definitions.

[0024] According to an embodiment of the present invention, the solvent may be selected from alcohols, ketones, esters, ethers, a combination of two or more of the above solvents, or a mixture of each of the above solvents or combinations with water.

[0025] According to an embodiment of the present invention, the alcohol may be selected from alcohols having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination of two or more thereof; the ketone may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination of two or more thereof; the ester may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more thereof; and the ether may be a linear or branched alkyl ether or cyclic ether compound, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more thereof.

[0026] According to an embodiment of the present invention, 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, and more preferably 1:1.0 to 1:1.1.

[0027] According to an embodiment of the present invention, in the above production method, the reaction temperature can be selected from a relatively wide range, for example, from 20°C to 80°C, preferably from 30°C to 60°C.

[0028] According to an embodiment of the present invention, the above preparation method further comprises performing a filtration and / or drying step after the reaction is completed to obtain a pharma- ceutically acceptable salt of the compound of formula I.

[0029] According to an embodiment of the present invention, in the above-mentioned production method, the drying temperature can be selected from a relatively wide range and may be, for example, from 20°C to 80°C, preferably from 30°C to 60°C.

[0030] According to an embodiment of the present invention, in the above-mentioned production method, the drying pressure may be 0 to 20 kPa, preferably 0 to 10 kPa, and more preferably 5 to 10 kPa.

[0031] The present invention further provides a crystal, preferably a single crystal, of the monohydrochloride salt of the compound of formula I, wherein the unit cell parameters of said single crystal are as follows:

[0032] Orthorhombic system, space group P212121, a = 9.4704 (18) Å, b = 15.324 (4) Å, c = 17.437 (4) Å, V = 2530.5 (10) Å 3 , Z = 4.

[0033] The present invention further provides a crystal of the monohydrochloride salt of the compound of formula I above, and in particular provides a method for preparing a single crystal thereof, which comprises dissolving the monohydrochloride salt of the compound of formula I in solvent A and then diffusing it in an atmosphere of solvent B.

[0034] The above solvent A may be an alcohol solvent, for example, a combination of two or more of methanol, ethanol, and the like.

[0035] The solvent B may be an ester solvent, an ether solvent, or a combination of two or more of these. The ester solvent may be selected from organic carboxylates such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more of these, and the ether solvent may be a linear or branched alkyl ether, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more of these, a cyclic ether compound, or a combination of two or more of these.

[0036] The present invention further provides a crystalline form of the monohydrochloride salt of the compound of formula I selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E as described below.

[0037] The X-ray powder diffraction, expressed as 2θ angles using Cu-Kα radiation, is of crystalline form A of the monohydrochloride salt of the compound of formula I, with characteristic peaks at 9.66±0.20°, 16.08±0.20° and 23.46±0.20°.

[0038] Preferably, the crystalline form A has characteristic peaks at 9.66±0.20°, 16.08±0.20°, 18.10±0.20°, 21.30±0.20°, and 21.68±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0039] Preferably, the crystalline form A has characteristic peaks at 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°, and 25.42±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0040] Preferably, the crystalline form A has characteristic peaks at 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°, and 25.42±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0041] Preferably, the crystalline form A has characteristic peaks as shown in Table 1 in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, and the error range of the 2θ angles is ±0.20°.

[0042] [Table 1]

[0043] Preferably, said crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG.

[0044] According to an embodiment of the present invention, said crystalline form A is an anhydrous form of the monohydrochloride salt of the compound of formula I.

[0045] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form A shows that upon heating to a peak temperature of about 192.73°C, a first endothermic peak appears and a first exothermic peak appears at a peak temperature of about 201.78°C.

[0046] Preferably, said crystalline form A has a DSC pattern essentially as shown in FIG.

[0047] According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the crystalline form A shows a weight loss of about 1.41% in the range of 90°C to 180°C.

[0048] Preferably, said crystalline form A has a TGA pattern essentially as shown in FIG.

[0049] According to an embodiment of the present invention, the crystalline form A is an irregular morphology crystal. Preferably, the crystalline form A has a particle size of 20 μm or less.

[0050] Preferably, said crystalline form A has a PLM pattern essentially as shown in FIG.

[0051] The X-ray powder diffraction, expressed as 2θ angles using Cu-Kα radiation, is of crystalline form B of the monohydrochloride salt of the compound of formula I, with characteristic peaks at 18.10±0.20°, 19.80±0.20° and 22.10±0.20°.

[0052] Preferably, the crystalline form B has characteristic peaks at 9.48±0.20°, 15.44±0.20°, 18.10±0.20°, 19.80±0.20°, 22.10±0.20°, and 30.92±0.20° in X-ray powder diffraction using Cu-Kα radiation and 2θ angles.

[0053] Preferably, the crystalline form B has characteristic peaks at 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°, and 30.92±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0054] Preferably, the X-ray powder diffraction of the crystalline form B using Cu-Kα radiation and expressed as 2θ angles has characteristic peaks as shown in Table 2, wherein the error range of the 2θ angles is ±0.20°.

[0055] [Table 2]

[0056] Preferably, said crystalline form B has an X-ray powder diffraction pattern essentially as shown in FIG.

[0057] According to an embodiment of the present invention, said crystalline form B is a hydrate of the monohydrochloride salt of the compound of formula I, such as a monohydrate of the monohydrochloride salt of the compound of formula I.

[0058] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of said crystalline form B shows that upon heating to a peak temperature of about 85.87°C, a first endothermic peak appears, a second endothermic peak appears at a peak temperature of about 197.54°C, and a first exothermic peak appears at a peak temperature of about 205.68°C.

[0059] Preferably, said crystalline form B has a DSC pattern essentially as shown in FIG.

[0060] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form B shows that it has a weight loss of about 3.42% from 21.49°C to 120°C and a weight loss of about 0.49% from 179.88°C to 207.94°C.

[0061] Preferably, said crystalline form B has a TGA pattern essentially as shown in FIG.

[0062] According to an embodiment of the present invention, the crystalline form B is an irregular morphology crystal. Preferably, the particle size of the crystalline form B is 20 μm or less.

[0063] Preferably, said crystalline form B has a PLM pattern essentially as shown in FIG.

[0064] According to an embodiment of the present invention, the crystalline form A is subjected to high humidity conditions to obtain the crystalline form B. The high humidity conditions are preferably at 40° C. and a relative humidity of 75% to 95%.

[0065] According to an embodiment of the present invention, the crystalline form B is dried to obtain the crystalline form A. The drying conditions are preferably vacuum drying at 40°C.

[0066] The X-ray powder diffraction, expressed as 2θ angles using Cu-Kα radiation, is of crystalline form C of the monohydrochloride salt of the compound of formula I, with characteristic peaks at 14.74±0.20°, 17.80±0.20°, 20.08±0.20° and 21.98±0.20°.

[0067] Preferably, the crystalline form C has characteristic peaks at 14.74±0.20°, 17.80±0.20°, 19.58±0.20°, 20.08±0.20°, 21.98±0.20°, 22.94±0.20°, and 25.92±0.20° in X-ray powder diffraction using Cu-Kα radiation and 2θ angles.

[0068] Preferably, the crystalline form C has characteristic peaks at 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°, and 33.48±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0069] Preferably, the crystalline form C has characteristic peaks as shown in Table 3 in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, the error range of the 2θ angles being ±0.20°.

[0070] [Table 3]

[0071] Preferably, said crystalline form C has an X-ray powder diffraction pattern essentially as shown in FIG.

[0072] According to an embodiment of the present invention, said crystalline form C is an anhydrous form of the monohydrochloride salt of the compound of formula I.

[0073] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form C shows that upon heating to a peak temperature of about 209.93°C, a first endothermic peak appears and a first exothermic peak appears at a peak temperature of about 215.80°C.

[0074] Preferably, said crystalline form C has a DSC pattern essentially as shown in FIG.

[0075] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the crystalline form C shows that it has 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.

[0076] Preferably, said crystalline form C has a TGA pattern essentially as shown in FIG.

[0077] According to an embodiment of the present invention, the crystalline form C is an irregular morphology crystal. Preferably, the grain size of the crystalline form C is 20 μm or less.

[0078] Preferably, said crystalline form C has a PLM pattern essentially as shown in FIG.

[0079] The X-ray powder diffraction, expressed as 2θ angles using Cu-Kα radiation, is of crystalline form D of the monohydrochloride salt of the compound of formula I, with characteristic peaks at 15.74±0.20°, 16.58±0.20°, 21.98±0.20° and 23.82±0.20°.

[0080] Preferably, the crystalline form D has characteristic peaks at 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°, and 23.82±0.20° in X-ray powder diffraction using Cu-Kα radiation and 2θ angles.

[0081] Preferably, the crystalline form D has characteristic peaks at 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°, and 27.50±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0082] Preferably, the crystalline form D has characteristic peaks as shown in Table 4 in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, wherein the error range of the 2θ angles is ±0.20°.

[0083] [Table 4]

[0084] Preferably, said crystalline form D has an X-ray powder diffraction pattern essentially as shown in FIG.

[0085] According to an embodiment of the present invention, said crystalline form D is a solvate of the monohydrochloride salt of the compound of formula I, such as a dichloromethane solvate of the monohydrochloride salt of the compound of formula I, a monodichloromethane solvate of the monohydrochloride salt of the compound of formula I (also referred to as monodichloromethane solvate).

[0086] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the crystalline form D shows that a first exothermic peak appears upon heating to around a peak temperature of 196.53°C.

[0087] Preferably, said crystalline form D has a DSC pattern essentially as shown in FIG.

[0088] According to an embodiment of the present invention, the 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.

[0089] Preferably, said crystalline form D has a TGA pattern essentially as shown in FIG.

[0090] According to an embodiment of the present invention, the crystalline form D is an irregular morphology crystal. Preferably, the crystalline form C has a particle size of 10 μm or less.

[0091] Preferably, said crystalline form D has a PLM pattern essentially as shown in FIG.

[0092] The X-ray powder diffraction, expressed as 2θ angles using Cu-Kα radiation, is of crystalline form E of the monohydrochloride salt of the compound of formula I, with characteristic peaks at 9.36±0.20°, 15.22±0.20°, 16.88±0.20° and 22.10±0.20°.

[0093] Preferably, the crystalline form E has characteristic peaks at 7.20±0.20°, 9.36±0.20°, 15.22±0.20°, 16.88±0.20°, 21.10±0.20°, 22.10±0.20°, and 23.68±0.20° in X-ray powder diffraction using Cu-Kα radiation and 2θ angles.

[0094] Preferably, the crystalline form E has characteristic peaks at 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°, and 27.86±0.20° in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles.

[0095] Preferably, the crystalline form E has characteristic peaks as shown in Table 5 in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, and the error range of the 2θ angles is ±0.20°.

[0096] [Table 5]

[0097] Preferably, said crystalline form E has an X-ray powder diffraction pattern essentially as shown in FIG.

[0098] According to an embodiment of the present invention, said crystalline form E is a solvate of the monohydrochloride salt of the compound of formula I, such as a mono-isopropanol solvate of the monohydrochloride salt of the compound of formula I.

[0099] The present invention further provides a process for the preparation of the above-mentioned crystalline form of the monohydrochloride salt of the compound of formula I.

[0100] The first method for preparing the crystalline form A includes dissolving the compound of formula I in an alcoholic solvent, adding a solution of HCl in the alcoholic solvent to form a salt, and then adding a normal alkane to crystallize the salt to obtain the crystalline form A.

[0101] The alcohol solvent is selected from ethanol and / or isopropanol, preferably isopropanol.

[0102] The normal alkane is selected from n-hexane and / or n-heptane, preferably n-heptane.

[0103] The mass to volume ratio of the compound of the above formula I, the alcohol solvent, and the normal alkane is 1 g:(10-30) mL:(10-30) mL, preferably 1 g:(15-25) mL:(15-25) mL.

[0104] The concentration of the solution of HCl in the alcohol solvent is 1 to 3 mol / L, for example, 2 mol / L.

[0105] The heating temperature is 45 to 75°C, preferably 48 to 60°C.

[0106] The second method for preparing the crystalline form A includes heating and stirring the monohydrochloride of the compound of formula I in an alcoholic solvent and a normal alkane, dissolving and clarifying the monohydrochloride, and then crystallizing the monohydrochloride to obtain the crystalline form A.

[0107] The alcohol solvent is selected from ethanol and / or isopropanol, preferably isopropanol.

[0108] The normal alkane is selected from n-hexane and / or n-heptane, preferably n-heptane.

[0109] The mass to volume ratio of the monohydrochloride salt of the compound of the above formula I, the alcoholic solvent, and the normal alkane is 1 g:(10-30) mL:(10-30) mL, preferably 1 g:(15-25) mL:(15-25) mL, for example, 1 g:20 mL:20 mL.

[0110] The heating temperature is 45 to 75°C, preferably 48 to 60°C.

[0111] According to an embodiment of the present invention, the first or second method for preparing crystalline form A further comprises the steps of cooling, filtering and drying.

[0112] According to a preferred embodiment of the present invention, the method for preparing said crystalline form A includes dissolving the compound of formula I in isopropanol, adding a solution of HCl in isopropanol, mixing and dissolving, adding n-heptane, stirring, filtering and drying to obtain said crystalline form A.

[0113] According to a preferred embodiment of the present invention, the method for preparing said crystalline form A includes adding monohydrochloride of compound of formula I to a mixed solvent of isopropanol and n-heptane, heating and stirring, cooling to room temperature, filtering, and drying in vacuum to obtain said crystalline form A.

[0114] The mass to volume ratio of the monohydrochloride salt of the compound of formula I, isopropanol and n-heptane is 1 g:(10-30) mL:(10-30) mL, for example, 1 g:20 mL:20 mL.

[0115] The method for producing crystalline form B includes subjecting said crystalline form A to high humidity conditions to obtain crystalline form B.

[0116] According to an embodiment of the present invention, the high humidity conditions are a temperature of 30 to 50° C. and a humidity of 60% to 98%.

[0117] The high humidity conditions are preferably 40° C. and a humidity of 75% to 95%.

[0118] The method for preparing crystalline form C includes dissolving the compound of formula I in an alcoholic solvent, then adding a solution of HCl in the alcoholic solvent to form a salt, and then adding an ether or ester solvent to crystallize to obtain crystalline form C.

[0119] According to an embodiment of the present invention, a method for preparing crystalline form C includes dissolving compound of formula I in an alcoholic solvent, adding a solution of HCl in the alcoholic solvent, stirring, filtering, adding an ether or ester solvent dropwise to the filtrate, stirring, filtering, and drying to obtain crystalline form C.

[0120] The alcohol solvent is selected from methanol, ethanol, or isopropanol, and is preferably methanol.

[0121] The ether solvent is selected from methyl ether, ethyl ether, propyl ether, or methyl tert-butyl ether, and is preferably methyl tert-butyl ether.

[0122] The ester solvent is selected from ethyl acetate or isopropyl acetate.

[0123] The mass to volume ratio of the compound of the above formula I, the alcohol solvent, and the ether solvent is 1 g:(2-8) mL:(20-40) mL, preferably 1 g:(3-6) mL:(20-30) mL, for example, 1 g:4 mL:25 mL.

[0124] The concentration of the solution of HCl in the alcohol-based solvent is 1 to 3 mol / L, for example, 1.5 to 2.5 mol / L, illustratively 1.8 mol / L, and the mass ratio of the compound of formula I to the solution of HCl in the alcohol-based solvent is 1 g:(0.5 to 1.5) g, for example, 1 g:(0.8 to 1.2) g.

[0125] According to a preferred embodiment of the present invention, the method for preparing said crystalline form C includes dissolving the compound of formula I in methanol, adding a solution of HCl in methanol, stirring, filtering, adding methyl tert-butyl ether to the filtrate, filtering, and drying to obtain crystalline form C.

[0126] The method for preparing crystalline form D comprises suspending and stirring the monohydrochloride salt of the compound of formula I in a halogenated alkane at room temperature to form crystals to obtain crystalline form D.

[0127] According to an embodiment of the present invention, a method for preparing crystalline form D comprises adding the monohydrochloride salt of compound of formula I to a halogenated alkane, stirring, separating the resulting suspension, and drying the separated solid, and identifying the resulting solid as crystalline form D.

[0128] The halogenated alkane is selected from dichloromethane, chloroform or carbon tetrachloride, preferably dichloromethane.

[0129] The mass to volume ratio of the monohydrochloride salt of the compound of the above formula I to the halogenated alkane is 1 g:(15-35) mL, preferably 1 g:(18-25) mL, for example, 1 g:20 mL.

[0130] The above separation can be carried out by a known separation method, but is preferably carried out by a centrifugation method.

[0131] The drying is carried out by vacuum drying under heating conditions, and vacuum drying at reduced pressure at 40°C is preferred.

[0132] According to a preferred embodiment of the present invention, the method for preparing said crystalline form D comprises adding monohydrochloride salt of compound of formula I to dichloromethane, stirring at room temperature, and then isolating the solid to obtain crystalline form D.

[0133] The method for preparing crystalline form E includes suspending and stirring the monohydrochloride salt of the compound of formula I in an alcoholic solvent at room temperature to form crystals, thereby obtaining crystalline form E.

[0134] According to an embodiment of the present invention, the monohydrochloride salt of compound of formula I is added to an alcoholic solvent and stirred, the resulting suspension is separated, and the separated solid is dried, and the resulting solid is identified as crystalline form E.

[0135] The alcohol solvent is selected from methanol, ethanol, or isopropanol, and is preferably isopropanol.

[0136] The mass to volume ratio of the monohydrochloride salt of the compound of the above formula I to the alcoholic solvent is 1 g:(15-35) mL, preferably 1 g:(18-25) mL, for example, 1 g:20 mL.

[0137] The above separation can be carried out by a known separation method, but is preferably carried out by a centrifugation method.

[0138] The drying is carried out by vacuum drying under heating conditions, and vacuum drying under reduced pressure at 40°C is preferred.

[0139] According to a preferred embodiment of the present invention, the method for preparing the crystalline form E comprises adding the monohydrochloride salt of the compound of formula I to isopropanol, stirring at room temperature, and then isolating the solid to obtain the crystalline form E.

[0140] The present invention further provides a pharmaceutical composition comprising at least one of the pharma- ceutically acceptable salts of the compound of formula I (e.g., the hydrochloride salt, e.g., crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E of the hydrochloride salt), and optionally a pharma- ceutically acceptable auxiliary.Preferably, the pharmaceutical composition is in the form of a formulation.

[0141] The present invention further provides a formulation comprising a pharma- ceutically acceptable salt of the compound of formula I above, at least one of crystalline form A, crystalline form B, crystalline form C, crystalline form D, and crystalline form E, and optionally a pharma- ceutically acceptable adjuvant.

[0142] The present invention further provides the use of at least one pharma- ceutically acceptable salt of the compound of formula I (e.g. the hydrochloride salt, e.g. crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E of the hydrochloride salt), or a pharmaceutical composition as described above, in the manufacture of a medicament for the prophylaxis and / or treatment of a complement factor B mediated disease or condition.

[0143] According to an embodiment of the present invention, the complement factor B-mediated disease or condition is at least one selected from 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 inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory disease, and cardiovascular diseases.

[0144] The present invention further provides a method for preventing and / or treating a disease associated with a complement factor B inhibitor, comprising administering to a subject in need thereof a therapeutically effective amount of at least one of a pharma- ceutically acceptable salt of the compound of formula I (e.g., the hydrochloride salt, e.g., crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E of the hydrochloride salt), or a pharmaceutical composition.

[0145] According to an embodiment of the present invention, the disease or condition associated with the complement factor B inhibitor is at least one selected from 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 inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory disease, and cardiovascular disease.

[0146] The treatment method of the present invention may include administering a pharma- ceutically acceptable salt of the compound of formula I of the present invention (e.g., the hydrochloride salt, e.g., crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E of the hydrochloride salt) or the pharmaceutical composition alone, and administering one, two or more of the pharma- ceutical compositions of the compound of formula I of the present invention (e.g., the hydrochloride salt, e.g., crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E of the hydrochloride salt) in combination with one, two or more other chemotherapeutic agents. The administration of multiple drugs may be performed simultaneously or sequentially.

[0147] In the context of this specification, "more than," "less than," and "within" should be understood to be inclusive. As an illustration, "at least one" should be understood as "one, two, or more." As another example, "two or more" should be understood as "two or more," e.g., "two, three, four, or more."

[0148] Beneficial effects The salts of the compound of formula I of the present invention (especially the hydrochloride, phosphate, and maleate) have high stability and high water solubility, significantly enhancing the absorption ability when orally administered and improving the bioavailability. And the crystalline form of the hydrochloride of the compound of formula I of the present invention has high stability, good solubility, low hygroscopicity, and good prospects for drug discovery. Furthermore, the method for preparing the salts and crystalline forms of the compound of formula I of the present invention is simple to operate, easy to control, good reproducibility, mild reaction conditions, high product yield, and favorable for industrial production. [Brief description of the drawings]

[0149] [Figure 1] 1 is an XRPD pattern of the monohydrochloride salt crystalline form A of the compound of formula I. [Diagram 2] 1 is a DSC pattern of the monohydrochloride salt crystalline form A of the compound of formula I. [Diagram 3] 1 is a TGA pattern of the monohydrochloride salt crystalline form A of the compound of formula I. [Figure 4] 1 is a PLM pattern of the monohydrochloride salt crystalline form A of the compound of formula I. [Diagram 5] 1 is an XRPD pattern of the monohydrochloride salt crystalline form B of the compound of formula I. [Figure 6] 1 is a DSC pattern of the monohydrochloride salt crystalline form B of the compound of formula I. [Figure 7] 1 is a TGA pattern of the monohydrochloride salt crystalline form B of the compound of formula I. [Figure 8] 1 is a PLM pattern of the monohydrochloride salt crystalline form B of the compound of formula I. [Figure 9] 1 is an XRPD pattern of the monohydrochloride salt crystalline form C of the compound of formula I. [Figure 10] 1 is a DSC pattern of the monohydrochloride salt crystalline form C of the compound of formula I. [Figure 11] 1 is a TGA pattern of the monohydrochloride salt crystalline form C of the compound of formula I. [Figure 12] 1 is a PLM pattern of the monohydrochloride salt crystalline form C of the compound of formula I. [Figure 13] 1 is an XRPD pattern of the monohydrochloride salt crystalline form D of the compound of formula I. [Figure 14]1 is a DSC pattern of the monohydrochloride salt crystalline form D of the compound of formula I. [Figure 15] 1 is a TGA pattern of the monohydrochloride salt crystalline form D of the compound of formula I. [Figure 16] 1 is a PLM pattern of the monohydrochloride salt crystalline form D of the compound of formula I. [Figure 17] 1 is an XRPD pattern of the monohydrochloride salt crystalline form E of the compound of formula I. [Figure 18] The monohydrochloride salt crystalline form C of the compound of formula I is the XRPD result pattern after being subjected to accelerated, high temperature conditions for one month. [Figure 19] The monohydrochloride salt crystalline form C of the compound of formula I is the XRPD result pattern after exposure to high temperature and humidity for 1 day. [Figure 20] The monohydrochloride salt crystalline form C of the compound of formula I is the XRPD result pattern after exposure to high temperature and humidity for 3 days. [Figure 21] 1 shows experimental data (ng / mL) of blood drug concentration curves in cynomolgus monkeys in a biological example. [Figure 22] 1 shows experimental data (% relative to 0 h) of serum AP activity curves in cynomolgus monkeys in a biological example. [Diagram 23] 1 shows experimental data of streptococcus-induced rheumatoid arthritis in rats in biological examples. [Figure 24] FIG. 2 is a single crystal representation of the monohydrochloride salt of the compound of formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0150] The technical solution of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included in the scope of the claims of the present invention.

[0151] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0152] Experimental equipment parameters X-ray powder diffraction (XRPD) The instrument was a Shimadzu XRD-6000 and the samples were scanned with the following parameters:

[0153] The radiation source was a CuKα target (1.54056 Å).

[0154] The minimum operating voltage and current of the light tube are 40 kV and 30 mA, respectively. The 2-Theta value of the sample scan range is 2 o ~50 o The scan speed was set to 5 deg / min.

[0155] Thermogravimetric analysis (TGA) Approximately 5 mg of the sample was weighed into a crucible and heated from 30°C to 300°C under nitrogen gas protection at a heating rate of 20°C / min and held at 300°C for 1 min.

[0156] Differential Scanning Calorimetry (DSC) Approximately 1-5 mg of powder sample was weighed and placed in a sealed aluminum crucible, and a pinhole was drilled in the lid of the crucible. Under nitrogen gas protection, the sample was heated from 30°C to 300°C, and differential calorimetric scanning was performed, and the sample was held at 300°C for 1 min. The heating rate was 20°C / min.

[0157] Polarized Light Microscope (PLM) The samples were dispersed in a medium (silicone oil) and observed using a 10X eyepiece, a 10X objective lens, and images were recorded with a camera computer system.

[0158] Dynamic Water Sorption (DVS) Approximately 10 mg of sample was weighed out and subjected to a moisture absorption / desorption characteristic test at 25°C under a 0%~95%~0% relative humidity (RH) cycle using the following parameters.

[0159] [Table 6]

[0160] Single crystal testing equipment and conditions Device model number: D8 Venture Equipment parameters: Light source: Mo target X-ray: Mo-Kα (=0.71073 Å) Detector: CMOS area detector Resolution: 0.80 Å Current voltage: 50 kV, 1.4 mA Exposure time: 10 s Distance from surface detector to sample: 40 mm Test temperature: 170(2)K Explanation of Abbreviations 40℃ / 75% RH means conditions of 40℃ and 75% humidity.

[0161] 40℃ / 75% RH-closed means that the product was left sealed under conditions of 40℃ and 75% humidity.

[0162] 40℃ / 75% RH-open means that the product was left open under conditions of 40℃ and 75% humidity.

[0163] 60℃-closed means that the product was left sealed at 60℃.

[0164] 40℃ / 75% RH-closed-2 wks means that the product was left sealed for 2 weeks at 40℃ and 75% humidity.

[0165] 40℃ / 75% RH-open-2 wks means that the product was left open for 2 weeks under conditions of 40℃ and 75% humidity.

[0166] 60℃-Closed-2 wks means that the container was left sealed at 60℃ for 2 weeks.

[0167] "Initial" means the initial state.

[0168] SGF stands for simulated gastric fluid.

[0169] FaSSIF stands for simulating fasted intestinal fluid.

[0170] FeSSIF stands for simulated fed state intestinal fluid.

[0171] 1 d means 1 day and 3 d means 3 days.

[0172] Preparation 1: Preparation of compounds of formula I Reaction scheme for the synthesis of compounds of formula I and intermediate b

[0173] [ka]

[0174] Preparation of intermediate b In a 250 mL single-neck flask, dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), Boc anhydride (5.68 g), 4-dimethylaminopyridine (227 mg) and triethylamine (2.26 g) were added in this order and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated ammonium chloride solution (5 mL), extracted three times with dichloromethane (20 mL), the combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain intermediate a (4.6 g, yield: 94%). MS m / z (ESI): 262.0[M+1].

[0175] In a 250 mL single-neck flask, dichloromethane (80 mL), N-methylformanilide (3.8 g) and oxalyl chloride (3.6 g) were added in that order and reacted at room temperature with stirring for 3 hours. The reaction was then cooled to -14°C, intermediate a (2.5 g) was added, the reaction system was allowed to naturally warm to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted three times with dichloromethane (100 mL), the combined extract phase was washed twice with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain intermediate b (1.3 g, yield: 47%).

[0176] MS m / z (ESI): 290.0[M+1]. 1 H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 7.49 (d, J = 3.4 Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

[0177] Preparation of Compounds of Formula I Step 1: In a 3 L three-neck flask, tetrahydrofuran (150 mL) and 4-bromobenzonitrile (50 g) were added in that order, and isopropyl magnesium chloride lithium chloride complex (1.3 M, 210 mL) was gradually added to the reaction system under nitrogen gas protection, and the reaction was allowed to proceed at room temperature for 2 hours. Next, the reaction system was diluted with anhydrous tetrahydrofuran (500 mL), cooled to -5°C, 4-methoxypyridine (25 mL) was added, and benzyl chloroformate (35 mL) was gradually added dropwise (the system temperature was maintained below 0°C). After the addition was completed, the reaction was allowed to proceed with stirring at 0°C for 2 hours, and then the temperature was raised to room temperature and the reaction continued at room temperature for 16 hours. After the reaction was completed, 6 M hydrochloric acid (150 mL) was added and stirred for 30 min, then water (1000 mL) was added to dilute the mixture, and the mixture was extracted twice with ethyl acetate (500 mL). The combined extracts were washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product obtained was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain compound 1 (23 g, yield: 23%).

[0178] MS m / z (ESI): 333.0[M+1].

[0179] Step 2: Compound 1 (28 g) was taken from 46 g produced in two batches in step 1, zinc powder (55 g) and acetic acid (200 mL) were added in sequence to a 500 mL single-neck flask, the reaction was heated to 100 ° C and stirred at that temperature for 16 hours. After the reaction was completed, it was filtered, the filtrate was diluted with water (500 mL), extracted with ethyl acetate (500 mL), the extracted phase was washed twice with saturated aqueous sodium bicarbonate solution (500 mL), washed once with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2 (26 g, yield: 73%).

[0180] MS m / z (ESI): 334.8[M+1].

[0181] Step 3: In a 500 mL single-neck flask, tetrahydrofuran (100 mL), ethanol (100 mL) and compound 2 (26 g) were added in this order, then sodium borohydride (2 g) was added in several portions, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the system was cooled to 0°C, and saturated aqueous ammonium chloride solution (30 mL) was added until the temperature no longer rose, and water (500 mL) was added for dilution, followed by extraction twice with ethyl acetate (200 mL). The combined extract phase was washed with saturated saline (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3 (25 g, yield: 76%).

[0182] MS m / z (ESI): 336.9[M+1].

[0183] Step 4: Dichloromethane (200 mL) was added to a 500 mL single-neck flask, followed by compound 3 (25 g), imidazole (6.6 g) and tert-butyldiphenylchlorosilane (25 g) in that order, and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was washed with water (500 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound 4 (5.7 g, yield: 13%, Rf=0.55, trans isomer Rf=0.50).

[0184] MS m / z (ESI): 597.0[M+23].

[0185] Step 5: In a 250 mL single-neck flask, compound 4 (5 g) and a tetrabutylammonium fluorotetrahydrofuran solution (1 M, 30 mL) were added in this order and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (100 mL), extracted three times with ethyl acetate (50 mL), and the combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1 to 0: 1) to obtain a racemate, which was then chirally separated by SFC (Apparatus: SFC Thar prep 80, Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm, Modifier: 35% methanol (0.2% ammonia water), column temperature: 40 ° C., column pressure: 60 bar, wavelength: 214 / 254 nm, flow rate: 40 g / min, Rt = 4.78 min) to obtain compound 5 (1.2 g, yield: 41%).

[0186] MS m / z (ESI): 358.8[M+23].

[0187] Step 6: Imidazole (486 mg) and tert-butyldimethylchlorosilane (593 mg) were added to a solution of compound 5 (1200 mg) in N,N-dimethylformamide (10 mL), and the mixture was allowed to react with stirring at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The extracted phase was washed once with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain compound 6 (600 mg, yield: 90%).

[0188] MS m / z (ESI): 472.8[M+23].

[0189] Step 7: Compound 6 (700 mg) was taken out from 1.2 g of compound 6 in two batches of step 6 at room temperature, and added to dichloromethane (10 mL). Under the condition of nitrogen gas protection and -78 ° C, cyclopropanecarboxaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction solution, and the reaction system was maintained at -78 ° C and stirred for 1 hour, then triethylsilane (180 mg) was added, and the reaction was allowed to naturally warm to room temperature and continued to stir at that temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), the organic phase was washed once with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 7 (400 mg, yield: 46%).

[0190] MS m / z (ESI): 390.9[M+1].

[0191] Step 8: Compound 7 (400 mg), isopropanol (2 mL), water (3 mL) and sodium hydroxide (400 mg) were added in this order to a 50 mL single-neck flask, and the reaction mixture was heated to 100° C. and stirred at that temperature for 16 hours. After the reaction was completed, the reaction mixture was adjusted to pH 5-6 by adding dilute hydrochloric acid (1 M) in an ice bath, diluted with water (5 mL), extracted with ethyl acetate (5 mL), and the organic phase was washed once with saturated saline (5 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated at 45° C. to obtain compound 8 (200 mg, yield: 33%).

[0192] MS m / z (ESI): 431.8[M+23].

[0193] Step 9: Potassium carbonate (135 mg) and iodomethane (140 mg) were added to a solution of compound 8 (200 mg) in acetonitrile (5 mL), and the reaction solution was heated to 50° C. and stirred at that temperature for 16 hours. After completion of the reaction, the reaction solution was directly concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 9 (180 mg, yield: 40%).

[0194] MS m / z (ESI): 445.8[M+23].

[0195] Step 10: Palladium / carbon (50 mg) was added to a solution of compound 9 (180 mg) in tetrahydrofuran (3 mL), and the reaction solution was subjected to catalytic hydrogenation reaction at room temperature under a hydrogen gas atmosphere for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was directly concentrated to obtain compound 10 (120 mg, yield: 54%).

[0196] MS m / z (ESI): 290.0[M+1].

[0197] Step 11: Compound 10 (120 mg) was added to a solution of intermediate b (119 mg) in 1,2-dichloroethane (5 mL), and the reaction was stirred at room temperature for 8 hours, followed by the addition of sodium borohydride acetate (261 mg) and continued stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol=20:1) to give compound 11 (200 mg, yield: 26%).

[0198] MS m / z (ESI): 562.8[M+1].

[0199] Step 12 In a 50 mL single-neck flask, methanol (2 mL), water (2 mL), compound 11 (200 mg) and sodium hydroxide (150 mg) were added in this order, and the reaction mixture was heated to 75° C. and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath, and then directly concentrated and purified by Prep-HPLC (column: Gemini-C18, 150×21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 20-40%) to obtain the compound of formula I (30.6 mg, yield: 18%, containing 0.5 equivalents of formic acid).

[0200] MS m / z (ESI): 448.9[M+1].

[0201] 1 H NMR (400 MHz, CD3OD): δ8.18 (d, J = 7.7 Hz, 2H), 7.69 (d, J = 7.7 Hz, 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 = 7.2 Hz, 2H), 0.28 (d, J = 3.8 Hz, 2H).

[0202] Any compound of formula I described below is a compound of formula I prepared by the above process or by repeating the above process, unless otherwise specified.

[0203] Example 1: Preparation of the monohydrochloride salt of the compound of formula I

[0204] [ka]

[0205] After preparing the compound of formula I in multiple batches, 400 mg of the compound of formula I was taken, added with 8 mL of isopropanol, and dissolved by heating at 50°C. Then, 460 μL of hydrogen chloride isopropanol solution (concentration: 2 mol / L) was slowly added dropwise, stirred for 30 min, and then 8 mL of n-heptane was added and stirred for 2 hours. After filtration, the filter cake was dried under reduced pressure at 50°C to obtain 390 mg of the monohydrochloride salt I-1 of the compound of formula I with a yield of 90%.

[0206] 50 mg of the monohydrochloride salt I-1 of the compound of formula I was taken into a 4 mL sample bottle, and 0.5 mL of methanol was added to dissolve the compound. The sample opening was then placed into a 40 mL sample vial containing 5 mL of ethyl acetate, and the 40 mL sample vial was kept sealed. The single crystal was obtained by allowing the two solvents to slowly diffuse and the single crystal structure diagram is shown in Figure 24. The single crystal was tested, and the single crystal data of the monohydrochloride salt I-1 of the compound of formula I was obtained as follows:

[0207] [Table 7]

[0208] Example 2. Method for preparing the phosphate salt of the compound of formula I Compound of formula I was prepared in multiple batches. 440 mg of compound of formula I was taken, 5 mL of acetone was added, and the mixture was heated to 40°C and dissolved by ultrasonication. Then, 460 μL of 2 mol / L phosphoric acid in methanol was slowly added dropwise. Viscous solid was found, and another 5 mL of acetone was added and stirred at room temperature for 4 hours. After filtering and washing, the filter cake was dried under reduced pressure at 50°C to obtain 462 mg of phosphate salt of compound of formula I with a yield of 87%.

[0209] Example 3: Method for preparing the maleate salt of the compound of formula I Compound of formula I was prepared in multiple batches. 400 mg of compound of formula I was taken, 15 mL of ethyl acetate was added, and the mixture was heated to 50°C to dissolve the compound. Then, 109 mg of maleic acid powder was added and stirred at room temperature for 2-3 hours. After filtration, the filter cake was dried under reduced pressure at 50°C to obtain 470 mg of the maleate salt of compound of formula I in a yield of 91%.

[0210] Example 4 Stability Test of the Monohydrochloride, Phosphate, and Maleate Salts of the Compound of Formula I Stability studies were performed on the compound of formula I, the monohydrochloride salt of the compound of formula I in Example 1, the phosphate salt of the compound of formula I in Example 2, and the maleate salt of the compound of formula I in Example 3. Stability consideration conditions: 40℃ / 75% RH-closed, 40℃ / 75% RH-open, 60℃-closed. Stability consideration contents: Status of related substances and crystal form changes.

[0211] Detection of related substances: Approximately 6-7 mg of sample was weighed into each 10 mL volumetric flask, dissolved by adding 50% acetonitrile aqueous solution, diluted to the mark, and 10 μL of sample was injected. The chromatographic conditions are shown in Table 6.

[0212] The experimental results of the stability study of the compound of formula I and its hydrochloride, phosphate and maleate salts are shown in Table 7.

[0213] [Table 8]

[0214] [Table 9]

[0215] The results in Table 7 show that the compound of formula I and its monohydrochloride, phosphate and maleate are all stable, with the monohydrochloride of the compound of formula I being particularly stable.

[0216] Example 5 Solubility Test of the Compound of Formula I and Its Hydrochloride and Phosphate Salts The solubilities of the compound of formula I, the monohydrochloride salt of the compound of formula I, and the phosphate salt of the compound of formula I in water, SGF, FaSSIF, and FeSSIF at 37° C. were examined. Experimental method: 30 mg (in water) or 15 mg of sample was weighed into a 4 mL vial, 3 mL of the medium to be measured (water, SGF, FaSSIF, FeSSIF) was added, and stirring was continued at 37°C. 0.5 mL was sampled at 1 h and 24 h, and centrifuged at 12000 rpm for 10 min. The supernatant was diluted with 50% acetonitrile aqueous solution at an appropriate multiple, and the concentration was measured. The chromatography conditions for the solubility test are shown in Table 8.

[0217] Control and linear: 10 mg of compound of formula I was weighed into a 50 mL measuring flask, dissolved in 50% acetonitrile aqueous solution, and diluted to the mark, and two were prepared in parallel. A control of compound of formula I was taken and diluted to 100 μg / mL, 50 μg / mL, and 10 μg / mL with 50% acetonitrile aqueous solution, and 5 μL of the sample was injected to draw a standard curve.

[0218] The results of the solubility test of the compound of formula I and its hydrochloride and phosphate salts are shown in Table 9.

[0219] [Table 10]

[0220] [Table 11]

[0221] As can be seen from Table 9, the compound of formula I has improved solubility in water after forming a salt.

[0222] Control Compound

[0223] [ka]

[0224] Methanol (3 mL), water (1 mL), intermediate 1 (160 mg), and sodium hydroxide (230 mg) were added to a 50 mL single-neck flask. The reaction was allowed to proceed at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (10 mL), and the pH was adjusted to 7-8 with dilute hydrochloric acid solution (1 M). The solvent was removed under reduced pressure (water bath: 45°C). The residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 15-30%) to obtain the reference compound (29 mg, yield: 24%). MS m / z (ESI): 423.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 2.8 Hz, 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 = 6.8 Hz, 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 = 6.8 Hz, 3H). Biological Example 1 1. Optical Surface Plasmon Resonance (SPR) Binding Force Detection SPR experiments were 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 a Biacore 8K from GE Healthcare. 400 mM EDC and 100 mM NHS were used to activate a CM7 chip (GE Healthcare) for 420 s at a flow rate of 30 μL / min. Complement factor B was covalently immobilized on the detection chip by diluting it to 50 μg / mL with 10 mM sodium acetate (pH 4.0) and then coupling for 1200 s at a flow rate of 10 μL / min (protein immobilization level is 25000 RU), and then the detection chip was sealed with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 s. The concentration of the compound to be measured was 500 μM, the binding time was 120 s, and the separation time was 300 s. Data analysis was performed using a 1:1 binding model (Biacore Insight Evaluation Software, Version 2.0.15.12933).

[0225] Test Results: The experimental results are shown in Table 10. At a concentration of 500 μM, the compound of formula I has a more significant binding ability with the target protein, which is significantly superior to the control compound, indicating that the compound of formula I has a relatively good binding ability with the target protein.

[0226] [Table 12]

[0227] 2. Detection of TR-FRET binding strength The compounds were screened for their inhibitory activity against human complement factor B by competitive binding experiments using a Cy5 fluorescently labeled small molecule inhibitor as a probe. TM Sulfo-NHS-LC-LC-Biotin was incubated on ice for 1 hour at a ratio of 1:2, and the reaction was terminated by adding 1 M Tris (pH 7.5). TMBiotin-labeled complement factor B was obtained by purifying twice with a desalt spin column (EZ-LinkTM Sulfo-NHS-LC-Biotin manual). In the experiment, biotin-labeled complement factor B with a final concentration of 10 nM and various concentrations of compounds were pre-incubated in buffer at room temperature for 1 hour. Cy5 fluorescently labeled probe and europium chelate labeled streptavidin (petroleum ether rkin Elmer, #AD0060) with final concentrations of 75 nM and 5 nM, respectively, were added to start the reaction. Kinetic readings were performed with a microplate reader (excitation at 337 nm, emission at 665 nm, time-gated for 70 μs) to read the time-dependent fluorescence energy transfer (TR-FRET) data and the IC 50 It was decided.

[0228] 3. Detection of C3 hydrolysis activity by the complement system The test compound was diluted 3-fold starting from 10 μM, with seven concentration points, and detected per well. In a 96-well plate, the test compound was diluted with DMSO to a solution with a final concentration of 1000 times, and further diluted with Diluent (WIESLAB® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) to a solution with a final concentration of 5 times. 30 μL was transferred to a 96-well plate, 120 μL of spare serum was added, and incubated at room temperature for 15 min. 30 μL of 5‰ DMSO and 120 μL of spare serum were added to the positive control well, and 30 μL of 5‰ DMSO and 120 μL of Diluent were added to the negative control well. (3) 100 μL was added to the reaction plate, and incubated at 37°C for 60 min. The liquid in the wells was discarded, and each well was washed three times with 300 μL of washing solution. 100 μL of conjugate (WIESLAB® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) was added to each well and incubated at room temperature for 30 min. The liquid in the well was discarded, and each well was washed three times with 300 μL of washing solution. Next, 100 μL of substrate was added to each well and incubated at room temperature for 30 min. Detection was performed using a microplate reader (Perkin Elmer, EnSight), and the OD405 value was read. 4. Detection of complement hemolytic activity The hemolysis experiment was performed as described in Xuan Yuan et al., Haematologica (2017) 102: 466-475. Prior to the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% thermal decomposition of rabbit red blood cells (RE) was obtained by titration testing. In the experiment, NHS was diluted in GVB0 buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement technology) containing 10 mM Mg-EGTA, and incubated with various concentration gradients of test compounds at 37°C for 15 min. RE (taken from healthy Japanese white rabbits) freshly suspended in GVB0 buffer containing 10 mM Mg-EGTA was diluted with 1×10 8 to reach a final concentration of cells / mL and incubated at 37°C for 30 min. The positive control (100% thermolysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA with NHS and RE but without test compound, and the negative control (0% thermolysis) consisted of GVB0 buffer containing inactivated NHS (heated at 56°C for 30 min or heated at 65°C for 5 min) and RE but without test compound containing 10 mM Mg-EGTA. The samples were centrifuged at 2000g for 5 min, after which the supernatant was collected. The absorbance at 415 nm (A415) was detected by a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 Values ​​were calculated from the percentage hemolysis as a function of test compound concentration by non-linear regression.

[0229] Test Results: The experimental results are shown in Table 11, which shows that the compound of formula I has significantly better inhibitory activity against complement factor B in human serum than the control compound, and the compounds of the present invention can relatively effectively inhibit complement factor B activity in human serum and prevent hemolysis caused by attack on rabbit red blood cells.

[0230] [Table 13]

[0231] 5. Liver microsome stability experiments (1) Preparation of buffer solutions A 0.1 M distilled aqueous solution of dipotassium dihydrogen phosphate (containing 1 mM ethylenediaminetetraacetic acid) was taken, and then the pH was adjusted to 7.4 with a 0.1 M distilled aqueous solution of potassium dihydrogen phosphate (containing 1 mM ethylenediaminetetraacetic acid).

[0232] (2) Preparation of microsome source and working solution Microsomal Source: Rat: SD Rat Liver Microsomes, Cat. No.: LM-DS-02M, RILD Research on Liver Disease (Shanghai) Co., Ltd.

[0233] Monkey: Cynomolgus Monkey Liver Microsomes, Cat. No.: LM-SXH-02M, RILD Ruide Liver Disease Research (Shanghai) Co., Ltd.

[0234] Human: Pooled Human Liver Microsomes (Mongolian), Cat. No.: LM-R-02M, RILD Research Institute of Liver Diseases (Shanghai) Co., Ltd.

[0235] Preparation of working fluid The control compound and the test compound were each prepared into a 10 mM solution in DMSO, and then 10 μL was taken and added to 190 μL of acetonitrile to prepare a 0.5 mM mother solution. 1.5 μL of the 0.5 mM compound mother solution was taken and added to 18.75 μM liver microsomes 20 mg / mL and 479.75 μL of buffer solution. (The actual preparation amount can be adjusted according to the usage situation.)

[0236] (3) Experimental process Reduced coenzyme II (NADPH) was prepared at 10 mg / mL in buffer. A 96-well plate was placed on ice, and the corresponding wells for each compound at different time points (0, 10, 30, 60, 90 min, Non-NADPH) were placed, and 30 μL of working solution was added to each well. 155 μL of ice acetonitrile solution (internal standard concentration is 1 μM) was first added to the 0 min well, and 15 μL of NADPH (10 mg / mL) was added after uniform mixing with a pipette. Before the reaction started, the 96-well plate was pre-incubated for 5 min in a thermostatic microwell plate shaker (37 °C), and then 15 μL of NADPH (10 mg / mL) was added to each well to start the metabolic reaction. After the reaction for 10, 30, 60, and 90 min, 155 μL of ice acetonitrile solution (internal standard concentration is 1 μM) was added to the corresponding wells to stop the reaction. After 90 min in the non-NADPH system, 155 μL of ice acetonitrile solution (internal standard concentration is 1 μM) was added to stop the reaction. After the reaction was completed, the 96-well plate was shaken for 10 min on a microwell plate shaker (600 rpm), then centrifuged for 15 min at 4°C and 4000 g, 50 μL of the supernatant was taken and added to one new 2 mL 96-well plate, and 300 μL of deionized water was added, and the mixture was analyzed by AB SCIEX ExionLC-Triple Quad 5500 high-performance liquid chromatography mass spectrometer, and the software used was Analyst 1.6.3. The results are shown in Table 12.

[0237] [Table 14]

[0238] Experimental Results: Data indicate that compounds of formula I have remarkable liver microsomal stability.

[0239] 6.PK study of single intragastric administration in rats Testing Method: 6-9 week old Wistar Han male rats (Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.) were used, fasted overnight, and 3 rats per group were intragastrically administered with 3 mg / kg of the control compound and the compound of formula I, respectively, with a dosing volume of 10 mL / kg. Blood was collected from the jugular vein, 0.2 mL at each time point, and anticoagulated with EDTA-K2, then immediately centrifuged at 4000 rpm*5 min, 4°C, and the supernatant was taken and stored in a refrigerator at -80°C until detection. Blood collection time points: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h. After administration, the condition of the animals was observed at any time, and the animals were euthanized after blood collection was completed at all time points. Plasma samples were measured by LC-MS / MS, and the data was used to calculate kinetic parameters (Tmax, Cmax, T1 / 2, AUC) using WinNonlin software.

[0240] Test Results: The test results are shown in Table 13.

[0241] [Table 15]

[0242] 7. PK / PD study of single intragastric administration in cynomolgus monkeys Testing Method: Cynomolgus monkeys were used, and 3 animals per group were administered 3 mpk of control compound, 30 mpk of control compound, 3 mpk of compound of formula I, and 30 mpk of compound of formula I by intragastric administration. Blood was collected at different time points for drug concentration analysis and complement activity detection. Plasma compound concentration was measured by LC-MS / MS, and serum complement activity was detected by wieslab assay (Svar Life Science AB, COMPL AP330 RUO) kit, among which Normal Human Serum (Complement Technology, NHS).

[0243] Test Results: Within the concentration and time range of detection, under the same dose, the average value of the blood drug concentration of the compound of formula I is obviously higher than that of the control compound.The blood drug concentration curve of cynomolgus monkey is shown in Figure 21, and the inhibition of serum AP activity of cynomolgus monkey is shown in Figure 22. Figure 22 shows that the compound of formula I can effectively inhibit serum AP activity of cynomolgus monkey.

[0244] 8. Streptococcus pyogenes-induced rheumatoid arthritis (RA) model in rats Testing Method: In the experiment, 6-9 week old female Lewis rats (Beijing Weitong Lihua) were used, 6 rats per group, and on D1, streptococcus and some other bacteria cell wall peptidoglycan complex (2-3 mg per rat) was administered by intraperitoneal injection, and the control compound (15 mpk) and the compound of formula I (15 mpk) were administered intragastrically every day for 25 consecutive days, and the rats were scored for arthritis at different times. The scoring criteria are as follows: The lesions were scored on a scale of 0-4 points according to their respective degrees (redness and swelling), with the maximum score of each individual limb being 4 points, and the maximum score of all four limbs of each individual animal being 16 points. The scoring criteria are as follows: A score of 0 is no redness or swelling, 1 is redness or swelling of 1-2 interphalangeal joints, 2 is redness or swelling of 3-4 interphalangeal joints, 3 is redness or swelling of 4 or more interphalangeal joints, and 4 is severe redness or swelling from the toes or fingers to the ankle or wrist joints.

[0245] Test Results: The experimental results are shown in Figure 23. The data show that the compound of formula I can improve the score for arthritis, and the effect is significantly superior to that of the control compound, proving that the compound of formula I can more effectively improve streptococcus-induced rheumatoid arthritis in rats.

[0246] Example 6: Preparation of Crystalline Form A of the Monohydrochloride Salt of the Compound of Formula I 400 mg of the compound of formula I was taken, 8 mL of isopropanol was added, and the mixture was heated to 50° C. to dissolve. Then, 460 μL of hydrogen chloride isopropanol solution (concentration: 2 mol / L) was slowly added dropwise, and the mixture was stirred for 30 min. Then, 8 mL of n-heptane was added, and the mixture was stirred for 2 hours. After filtration, the filter cake was dried under reduced pressure at 50° C. to obtain 390 mg of crystalline form A of the monohydrochloride salt of the compound of formula I in a yield of 90%.

[0247] Crystalline form A was characterized by XRPD, DSC, TGA and PLM.

[0248] The crystalline form A was anhydrous. The positions and intensities of the XRPD characteristic peaks are shown in Table 1, and the XRPD pattern is shown in Figure 1.

[0249] DSC showed that upon heating to a peak temperature of about 192.73° C., the first endothermic peak appeared, and at a peak temperature of about 201.78° C., the first exothermic peak appeared, as shown in FIG.

[0250] TGA showed a weight loss of about 1.41% in the range of 90 °C to 180 °C, as shown in Figure 3.

[0251] The PLM pattern, which shows that the sample is crystalline with irregular morphology of ∼20 μm, is shown in Figure 4 .

[0252] The XRPD pattern of crystalline form A is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ angles and relative intensities of the diffraction peaks are shown in Table A, wherein the error range of the 2θ angles is ±0.20°.

[0253] [Table 16]

[0254] Example 7: Preparation of Crystalline Form B of the Monohydrochloride Salt of Compound of Formula I Form A was stored open at accelerated conditions (40° C. / 75% RH) for 72 h and converted to form B, which is the monohydrate of the monohydrochloride salt of compound of formula I.

[0255] Crystalline form B was characterized by XRPD, DSC, TGA and PLM.

[0256] The positions and intensities of the XRPD characteristic peaks are given in Table 2, and the XRPD pattern is shown in FIG.

[0257] DSC showed that upon heating to a peak temperature of about 85.87°C, a first endothermic peak appeared, a second endothermic peak appeared at a peak temperature of about 197.54°C, and a first exothermic peak appeared at a peak temperature of about 205.68°C, as shown in Figure 6.

[0258] TGA showed that there was a weight loss of about 3.42% in the interval from 21.49° C. to 120° C., and a weight loss of about 0.49% in the interval from 179.88° C. to 207.94° C., as shown in FIG.

[0259] The PLM pattern, in which the sample is ∼20 μm in size and has irregular morphology crystals, is shown in Figure 8 .

[0260] The XRPD pattern of crystalline form B is an X-ray powder diffraction pattern expressed in 2θ angles, and the 2θ angles and relative intensities of the diffraction peaks are shown in Table B, wherein the error range of the 2θ angles is ±0.20°.

[0261] [Table 17]

[0262] Example 8: Method for preparing crystalline form C of the monohydrochloride salt of the compound of formula I The compound of formula I (3.15 g) was added to a three-neck flask, and methanol (12.6 mL) was added and stirred to completely dissolve. A 1.8N HCl solution in methanol (3.05 g) was added dropwise at room temperature, and the mixture was stirred for 10 min and then filtered. The filtrate was placed in a three-neck flask, and methyl tert-butyl ether (78.75 mL) was added dropwise at room temperature, and the mixture was stirred for 2 hours, filtered, and the filter cake was dried to obtain crystalline form C (3.06 g), with a yield of 90%.

[0263] Crystalline form C is anhydrous and was characterized by XRPD, DSC, TGA and PLM.

[0264] The positions and intensities of the XRPD characteristic peaks are given in Table 3, and the XRPD pattern is shown in FIG.

[0265] DSC showed that upon heating to a peak temperature of about 209.93° C., the first endothermic peak appeared, and at a peak temperature of about 215.80° C., the first exothermic peak appeared, as shown in FIG.

[0266] TGA showed that there was a weight loss of about 0.29% in the interval from 21.62° C. to 120° C., and a weight loss of about 0.52% in the interval from 173.94° C. to 216.60° C., as shown in FIG.

[0267] The PLM pattern, in which the sample is crystalline with irregular morphology of ∼20 μm, is shown in Figure 12 .

[0268] The XRPD pattern of crystalline form C is an X-ray powder diffraction pattern expressed in terms of 2θ angles, and the 2θ angles and relative intensities of the diffraction peaks are shown in Table C.

[0269] [Table 18]

[0270] Example 9: Method for preparing crystalline form D of the monohydrochloride salt of the compound of formula I 400 mg of the monohydrochloride salt of the compound of formula I was taken, 8 mL of dichloromethane was added, and the mixture was stirred at room temperature for 24 hours. The resulting suspension was separated by centrifugation, and the solid was dried under reduced pressure at 40°C. The solid was found to be crystalline form D.

[0271] The above crystalline form D was a mono-dichloromethane solvate (or referred to as mono-dichloromethane solvate) of the monohydrochloride salt of the compound of formula I.

[0272] Crystalline form D was characterized by XRPD, DSC, TGA and PLM.

[0273] The positions and intensities of the XRPD characteristic peaks are given in Table 4, and the XRPD pattern is shown in FIG.

[0274] DSC showed that the first exothermic peak appeared around the peak temperature of 196.53° C., and is shown in FIG.

[0275] TGA showed a weight loss of about 6.31% in the range of 22.07 °C to 120 °C, as shown in Figure 15.

[0276] The PLM pattern, in which the sample is crystalline with irregular morphology of 10 μm or less, is shown in Figure 16 .

[0277] The XRPD pattern of crystalline form D is an X-ray powder diffraction pattern expressed in terms of 2θ angles, and the 2θ angles and relative intensities of the diffraction peaks are shown in Table D.

[0278] [Table 19]

[0279] Example 10: Preparation of Crystalline Form E of the Monohydrochloride Salt of the Compound of Formula I 400 mg of the monohydrochloride salt of the compound of formula I was taken, and 8 mL of isopropanol was added, followed by stirring at room temperature for 72 hours. The resulting suspension was separated by centrifugation, and the solid was dried under reduced pressure at 40°C, and the solid was found to be crystalline form E.

[0280] The above crystalline form E is a mono-isopropanol solvate of the monohydrochloride salt of the compound of formula I.

[0281] Crystalline form E was characterized by XRPD and the XRPD pattern is shown in FIG.

[0282] The XRPD pattern of crystalline form E is an X-ray powder diffraction pattern expressed in terms of 2θ angles, and the 2θ angles and relative intensities of the diffraction peaks are shown in Table E.

[0283] [Table 20]

[0284] Example 11. Stability Study of Crystalline Form C of the Monohydrochloride Salt of the Compound of Formula I Crystal form C of the monohydrochloride salt of the compound of formula I was stored under the conditions of 40°C / 75% RH-closed, 40°C / 75% RH-open, and 60°C-open, and was removed after one month to examine the stability of the crystal form.

[0285] The chromatographic conditions tested are shown in Table 14.

[0286] Method for measuring related substances in stability samples: Approximately 6 mg of sample was weighed into a 40 mL clean glass bottle, 10 mL of 50% acetonitrile aqueous solution was added, and the sample was completely dissolved by ultrasonication, and 10 μL of the sample was injected to test for related substances, as shown in Table 15. The XRPD pattern is shown in Figure 18, of which HCl-salt Form3-initial (hereinafter referred to as initial) represents the XRPD pattern of crystalline form C prepared in Example 8.

[0287] [Table 21]

[0288] [Table 22]

[0289] From the above data, it can be seen that the crystalline form C of the monohydrochloride salt of the compound of formula I has good chemical stability after being left at 40°C / 75% RH and 60°C for one month. Also, from Figure 18, it can be seen that the crystalline form of the crystalline form C of the monohydrochloride salt of the compound of formula I does not change.

[0290] Example 12 Effect of high temperature and high humidity on crystalline form C Crystalline form C of the monohydrochloride salt of compound of formula I was exposed to open conditions at 60° C., 80% RH, and 92.5% RH to assess whether the crystal form changed significantly. The XRPD was examined after 1 d and 3 d, respectively. The XRPDs are shown in Figures 19 and 20.

[0291] 19 and 20 show that the crystalline form C of the monohydrochloride salt of compound of formula I remained unchanged even after exposure to high temperature and high humidity conditions for 1 and 3 days.

[0292] Example 13 Solubility test of the compound of formula I, a mixture of crystalline forms A and B, and crystalline form C An appropriate amount of test sample was weighed into a vial, 3 mL of medium (water, SGF, FaSSIF, FeSSIF, etc.) was added, and the mixture was stirred at 37°C. An appropriate amount of sample was taken at 1 h and 24 h, and centrifuged at 12000 rpm for 10 min. The supernatant was diluted with 50% acetonitrile aqueous solution to an appropriate number of times, and the concentration was measured. The chromatography conditions for the solubility test are shown in Table 16.

[0293] Control and linear: 10 mg of the compound of formula I was weighed into a 50 mL measuring flask, dissolved in 50% acetonitrile aqueous solution, and diluted to the mark, and two were prepared in parallel. A control was taken and diluted to 100 μg / mL, 50 μg / mL, and 10 μg / mL with 50% acetonitrile aqueous solution, and 5 μL of the sample was injected to draw the standard curve.

[0294] The test results are shown in Table 17.

[0295] [Table 23]

[0296] [Table 24]

[0297] From the above experimental results, it is clear that crystalline form C has a lower solubility in water than the mixture of crystalline forms A and B.

[0298] The exemplary embodiments of the present invention have been described above. However, the scope of the claims of the present application should not be limited to the above exemplary embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the scope of the spirit and principles of the present invention should be included within the scope of the claims of the present application.

Claims

1. A pharma- ceutically acceptable salt of a compound of formula I, 【Chemistry 1】 The pharma- ceutically acceptable salts are salts formed with a compound of formula I and an acid or base, The acid may be hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic 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, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid, preferably one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, lauric acid, benzoic acid, and benzenesulfonic acid, the base is selected from alkali metal hydroxides or alkaline earth metal hydroxides, preferably sodium hydroxide or potassium hydroxide; Preferably, the pharma- ceutically acceptable salt of the compound of formula I is one selected from its hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, fumarate, maleate, citrate, L-tartrate and oxalate salts; More preferably, the pharma- ceutically acceptable salt of the compound of formula I is a salt formed with the compound of formula I and hydrochloric acid, and even more preferably, the pharma- ceutically acceptable salt of the compound of formula I is a monohydrochloride salt formed with the compound of formula I and hydrochloric acid. A pharma- ceutically acceptable salt of a compound of formula I.

2. A method for preparing a pharma- ceutically acceptable salt of a compound of formula I according to claim 1, said method comprising reacting a compound of formula I with an acid or base to obtain a pharma- ceutically acceptable salt of a compound of formula I, Preferably, the process comprises reacting a compound of formula I with an acid or base as described above in a solvent to obtain a pharma- ceutically acceptable salt of the compound of formula I; Preferably, the solvent is selected from the group consisting of alcohols, ketones, esters, ethers, combinations of two or more of the above solvents, or mixtures of each of the above solvents or combinations with water; Preferably, the alcohol is selected from alcohols having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination of two or more thereof; the ketone may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination of two or more thereof; the ester may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more thereof; the ether may be a linear or branched alkyl ether or cyclic ether compound, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more thereof; Preferably, the molar ratio of the compound of formula I to said acid or base is from 1:0.8 to 1:1.5; The acid or base, independently of one another, have the definition according to claim 1. A manufacturing method comprising the steps of:

3. A single crystal of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the unit cell parameters of the single crystal are as follows: Orthorhombic system, space group P2 1 2 1 2 1 , a = 9.4704 (18) Å, b = 15.324 (4) Å, c = 17.437 (4) Å, V = 2530.5 (10) Å 3 、 Z = 4、 A single crystal characterized by:

4. The crystalline form A of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline form A has characteristic peaks at 9.66±0.20°, 16.08±0.20° and 23.46±0.20° in X-ray powder diffraction at 2θ angles using Cu-Kα radiation; Preferably, the crystalline form A has characteristic peaks at 9.66±0.20°, 16.08±0.20°, 18.10±0.20°, 21.30±0.20°, and 21.68±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form A has characteristic peaks at 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°, and 25.42±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form A has characteristic peaks at 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°, and 25.42±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form A has the following characteristic peaks in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, wherein the error range of the 2θ angles is ±0.20°: 【Table 1】 Preferably, said crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG. Preferably, said crystalline form A is an anhydrous form of the monohydrochloride salt of the compound of formula I, Preferably, the crystalline form A has a DSC pattern essentially as shown in FIG. Preferably, the crystalline form A has a TGA pattern essentially as shown in FIG. Preferably, said crystalline form A is an irregular morphology crystal, and preferably, said crystalline form A has a particle size of 20 μm or less; Preferably, the crystalline form A has a PLM pattern essentially as shown in FIG. Crystal form A is characterized by the above.

5. The crystalline form B of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline form B has characteristic peaks at 18.10±0.20°, 19.80±0.20° and 22.10±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form B has characteristic peaks at 9.48±0.20°, 15.44±0.20°, 18.10±0.20°, 19.80±0.20°, 22.10±0.20°, and 30.92±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form B has characteristic peaks at 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°, and 30.92±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form B has the following characteristic peaks in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, wherein the error range of the 2θ angles is ±0.20°: 【Table 2】 Preferably, said crystalline form B has an X-ray powder diffraction pattern essentially as shown in FIG. Preferably, said crystalline form B is a hydrate of the monohydrochloride salt of the compound of formula I, such as a monohydrate of the monohydrochloride salt of the compound of formula I; Preferably, the crystalline form B has a DSC pattern essentially as shown in FIG. Preferably, the crystalline form B has a TGA pattern essentially as shown in FIG. Preferably, said crystalline form B is an irregular morphology crystal, and preferably, said crystalline form B has a particle size of 20 μm or less; Preferably, the crystalline form B has a PLM pattern essentially as shown in FIG. Crystal form B, characterized by:

6. The crystalline form C of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline form C has characteristic peaks at 14.74±0.20°, 17.80±0.20°, 20.08±0.20° and 21.98±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form C has characteristic peaks at 14.74±0.20°, 17.80±0.20°, 19.58±0.20°, 20.08±0.20°, 21.98±0.20°, 22.94±0.20°, and 25.92±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form C has characteristic peaks at 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°, and 33.48±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form C has the following characteristic peaks in X-ray powder diffraction at 2θ angles using Cu-Kα radiation, the error range of the 2θ angles being ±0.20°: 【Table 3】 Preferably, the crystalline form C has an X-ray powder diffraction pattern essentially as shown in Figure 9; Preferably, said crystalline form C is an anhydrous form of the monohydrochloride salt of the compound of formula I, Preferably, the crystalline form C has a DSC pattern essentially as shown in FIG. Preferably, the crystalline form C has a TGA pattern essentially as shown in FIG. Preferably, said crystalline form C is an irregular morphology crystal, and preferably, said crystalline form C has a particle size of 20 μm or less; Preferably, the crystalline form C has a PLM pattern essentially as shown in FIG. Crystal form C, characterized by:

7. The crystalline form D of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline form D has characteristic peaks at 15.74±0.20°, 16.58±0.20°, 21.98±0.20° and 23.82±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form D has characteristic peaks at 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°, and 23.82±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form D has characteristic peaks at 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°, and 27.50±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form D has the following characteristic peaks in the X-ray powder diffraction pattern at 2θ angles using Cu-Kα radiation, wherein the error range of the 2θ angles is ±0.20°: 【Table 4】 Preferably, the crystalline form D has an X-ray powder diffraction pattern essentially as shown in Figure 13; Preferably, said crystalline form D is a solvate of the monohydrochloride salt of the compound of formula I, such as a dichloromethane solvate of the monohydrochloride salt of the compound of formula I, a monodichloromethane solvate of the monohydrochloride salt of the compound of formula I, Preferably, the crystalline form D has a DSC pattern essentially as shown in FIG. Preferably, the crystalline form D has a TGA pattern essentially as shown in FIG. Preferably, the crystalline form D is an irregular morphology crystal, and preferably, the particle size of the crystalline form D is 10 μm or less; Preferably, the crystalline form D has a PLM pattern essentially as shown in FIG. The crystalline form D is characterized by the fact that

8. The crystalline form E of the monohydrochloride salt of the compound of formula I according to claim 1, wherein the crystalline form E has characteristic peaks at 9.36±0.20°, 15.22±0.20°, 16.88±0.20° and 22.10±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form E has characteristic peaks at 7.20±0.20°, 9.36±0.20°, 15.22±0.20°, 16.88±0.20°, 21.10±0.20°, 22.10±0.20°, and 23.68±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form E has characteristic peaks at 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°, and 27.86±0.20° in X-ray powder diffraction using Cu-Kα radiation at 2θ angles; Preferably, the crystalline form E has the following characteristic peaks in X-ray powder diffraction using Cu-Kα radiation and expressed as 2θ angles, wherein the error range of the 2θ angles is ±0.20°: 【Table 5】 Preferably, the crystalline form E has an X-ray powder diffraction pattern essentially as shown in Figure 17; Preferably, said crystalline form E is a solvate of the monohydrochloride salt of the compound of formula I, such as a monoisopropanol solvate of the monohydrochloride salt of the compound of formula I. Crystal form E, characterized by

9. A method for producing the crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E according to any one of claims 4 to 8, comprising the steps of: The method for producing the crystalline form A includes one selected from the following methods: The first preparation method includes dissolving the compound of formula I in an alcoholic solvent, adding a solution of HCl in the alcoholic solvent to form a salt, and then adding a normal alkane to crystallize the salt to obtain the crystalline form A; Preferably, the alcoholic solvent is selected from ethanol and / or isopropanol; Preferably, the normal alkane is selected from n-hexane and / or n-heptane; Preferably, the mass to volume ratio of the compound of formula I, the alcoholic solvent, and the normal alkane is 1 g:(10-30) mL:(10-30) mL; Preferably, the concentration of the solution of HCl in the alcoholic solvent is 1-3 mol / L; The second preparation method includes heating and stirring the monohydrochloride of the compound of formula I in an alcoholic solvent and a normal alkane, dissolving and clarifying the monohydrochloride, and then crystallizing the monohydrochloride to obtain the crystalline form A; Preferably, the alcoholic solvent is selected from ethanol and / or isopropanol; Preferably, the normal alkane is selected from n-hexane and / or n-heptane; Preferably, the mass to volume ratio of the monohydrochloride salt of the compound of formula I, the alcoholic solvent, and the normal alkane is 1 g:(10-30) mL:(10-30) mL; Preferably, the heating temperature is between 45 and 75° C. The method for producing the crystalline form B includes subjecting the crystalline form A according to claim 4 to a high humidity condition to obtain the crystalline form B, Preferably, the high humidity conditions are a temperature of 30 to 50° C. and a humidity of 60% to 98%; Preferably, the high humidity conditions are a temperature of 40° C. and a humidity of 75% to 95%; The method for preparing the crystalline form C includes dissolving the compound of formula I in an alcoholic solvent, then adding a solution of HCl in the alcoholic solvent to form a salt, and then adding an ether or ester solvent to crystallize to obtain the crystalline form C; Preferably, the alcoholic solvent is selected from methanol, ethanol or isopropanol; Preferably, the ether solvent is selected from methyl ether, ethyl ether, propyl ether or methyl tert-butyl ether; Preferably, the ester solvent is selected from ethyl acetate or isopropyl acetate; Preferably, the mass to volume ratio of the compound of formula I, the alcohol solvent, and the ether solvent or the ester solvent is 1 g:(2-8) mL:(20-40) mL; Preferably, the concentration of the solution of HCl in the alcoholic solvent is 1-3 mol / L, and the mass ratio of the compound of formula I to the solution of HCl in the alcoholic solvent is 1 g:(0.5-1.5) g; The method for preparing the crystalline form D includes suspending and stirring the monohydrochloride salt of the compound of formula I in a halogenated alkane at room temperature to form crystals, thereby obtaining the crystalline form D; Preferably, the halogenated alkane is selected from dichloromethane, chloroform or carbon tetrachloride; Preferably, the mass to volume ratio of the monohydrochloride salt of the compound of formula I to the halogenated alkane is 1 g:(15-35) mL; The method for preparing the crystalline form E includes suspending and stirring the monohydrochloride of the compound of formula I in an alcoholic solvent at room temperature to form crystals, thereby obtaining the crystalline form E; Preferably, the alcoholic solvent is selected from methanol, ethanol or isopropanol; Preferably, the mass to volume ratio of the monohydrochloride salt of the compound of formula I to the alcoholic solvent is 1 g:(15-35) mL. A manufacturing method comprising the steps of:

10. A pharmaceutical composition comprising a pharma- ceutically acceptable salt of a compound of formula I according to any one of claims 1 to 8, at least one of crystalline forms A, B, C, D and E, and optionally a pharma- ceutically acceptable auxiliary, Preferably, the pharmaceutical composition is in the form of a formulation. Pharmaceutical compositions.

11. Use of at least one pharma- ceutically acceptable salt of the compound of formula I according to any one of claims 1 to 8, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E or the pharmaceutical composition according to claim 10 in the manufacture of a medicament for the prevention and / or treatment of a complement factor B mediated disease or condition, comprising Preferably, the complement factor B-mediated disease or condition is at least one selected from 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 inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory disease, and cardiovascular disease; use.

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