Salt form, crystalline form, and method of producing and using complement factor B inhibitors

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] This invention claims priority to the following prior applications, filed with the China National Intellectual Property Administration on January 26, 2022, with patent application number 202210096073.X and title "Salt form, crystalline form, method of manufacturing and use thereof for complement factor B inhibitors," and filed with the China National Intellectual Property Administration on September 9, 2022, with patent application number 202211104894.X and title "Salt form, crystalline form, method of manufacturing and use thereof for complement factor B inhibitors." The entire text of these prior applications is incorporated herein by reference.

[0002] This invention belongs to the pharmaceutical field and specifically relates to the salt form, crystalline form, and method of producing and using complement factor B inhibitors. [Background technology]

[0003] Complement is a type of soluble pattern recognition molecule in the immune system that can perform multiple effector functions. Under natural conditions, complement components exist in the form of inactive zymogens, which are broken down by multiple specific and nonspecific immunological mechanisms to form active large and small fragments. Of these, the large fragments usually remain on the surface of pathogens or cells, causing the latter to be thermally decomposed or accelerating their clearance, while the small fragments detach from the cell surface and mediate multiple inflammatory responses. Complement activation consists of two closely linked processes, thereby forming a cascade of complement activation. Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the second pathway. The three complement activation pathways differ in their initiation mechanisms and activation sequence, but share a common terminal pathway. Of these, the activation of the second pathway is independent of antigen-antibody complexes. Normally, C3b deposited on the cell surface binds to factor B, making it more susceptible to degradation by factor D in the serum. In this process, factor B is broken down into Ba and Bb, and then C3b and Bb form a complex, becoming the C3 invertase C3bBb in the second pathway. In this process, complement factor B plays an initial and central role in the activation of the second pathway of the complement cascade. Here, C3b is not only a product that appears after C3 invertase degrades C3, but is also a component of the second pathway C3 invertase, thereby forming a feedback amplification mechanism in which the classical pathway and the second pathway mutually influence each other. Current research has found that multiple types of diseases, including hematological, autoimmune, inflammatory, and neurodegenerative diseases, lead to dysfunction of the complement system.

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a persistent hemolytic chronic disease, a non-malignant clonal disorder caused by the mutation of one or more hematopoietic stem cells in acquired somatic cell PIG-A, and is classified as an extremely rare hematological disorder (Medicine (Baltimore) 1997, 76(2): 63-93). The course of the disease manifests as varying degrees of hemolytic exacerbation (paroxysmal), chronic or recurrent acute intravascular hemolysis or subsequent venous / arterial thrombosis, ultimately leading to progressive peripheral organ damage and death. Most patients are often atypical, the disease has an insidious onset, a long course, and varying degrees of severity.

[0005] The surface of red blood cells contains more than a dozen proteins that inhibit the activation of the complement pathway, all of which are anchored to the cell membrane by glycosylphosphatidylinositol (GPI) and are collectively called GPI-anchored proteins (APs). Currently, the pathogenesis of PNH is thought to be as follows: first, hematopoietic stem cells undergo mutation under certain conditions, producing PNH clones that are deficient in glycosylphosphatidylinositol (GPI); and then, hematopoietic function is damaged or weakened due to some factor (currently thought to be an immune factor), and the PNH clones gain a proliferative advantage over normal clones. Multiple antigens linked to the GPI also contribute to the complexity of interpreting the biological behavior of PNH cells. Among these, the most important proteins that inhibit complement pathway activation, C3 invertase breakdown promoter 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 inhibit the formation of membrane attack units and suppress the complement terminal attack response by blocking C9 entry into the C5b-8 complex. Currently, intravascular hemolysis and thrombosis, typical findings of PNH, are thought to be caused by CD59 deficiency. Patients with congenital CD59 deficiency have been reported to exhibit many typical symptoms of PNH, such as intravascular hemolysis, hemoglobinuria, and venous thrombosis. In PNH patients, a deficiency in GPI synthesis prevents CD59 from binding to the cell membrane of red blood cells, resulting in a loss of the function that inhibits the activation of the complement pathway. This leads to abnormal activation of the complement pathway, which attacks red blood cells, causing multiple clinical manifestations such as intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. Currently, there is no effective treatment for PNH other than restoring normal hematopoietic function through hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation carries certain risks, and since PNH is a benign clonal disease, controlling the onset of hemolysis remains the main strategy for the clinical treatment of this disease. Currently, eculizumab is the only drug approved for the treatment of PNH.However, many patients still experience anemia even after treatment with eculizumab, and many still require continuous blood transfusions. Furthermore, 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 form of primary glomerulonephritis, characterized by the presence of IgA deposits in the mesangial region, as indicated by immunofluorescence. The clinical manifestations of the disease vary, with the usual finding being recurrent episodes of microscopic or macroscopic hematuria. According to existing data, the development of IgAN is associated with congenital or acquired immunomodulatory disorders. Irritation of the respiratory or gastrointestinal tract by viruses, bacteria, and dietary proteins increases mucosal IgA1 synthesis, or leads to the accumulation of IgA1-containing immune complexes in the mesangial region, and activates the complement II pathway, resulting in glomerular damage. Human IgA molecules are divided into two isoforms, IgA1 and IgA2. Of these, IgA1 is the primary form in the blood circulation of healthy individuals (accounting for approximately 85%) and is also the main component deposited in the glomerular mesangial region of IgAN patients. IgA molecules can exist in two forms: monomers and polymers. The IgA1 molecule has a special heavy chain hinge region between its first and second constant regions, which can serve as a domain for the binding site of O-linked glycan groups. Recent studies have found that IgA molecules deposited in the serum and glomerular mesangial region of IgAN patients are mainly glycosylation-deficient IgA1 (gd-IgA1). Currently, it is believed that the initiation of the pathogenesis of IgAN is an increase in abnormalities occurring in gd-IgA1.

[0007] Over 90% of IgAN patients have complement C3 deposits in the glomerular mesangial region. 75%–100% of IgAN patients have co-deposits of propardin, IgA, and C3 in their renal tissue, and 30%–90% of IgAN patients have co-deposits of complement factor H, IgA, and C3 in their renal tissue. In addition to deposits in renal tissue, several studies have also found that marker levels of complement pathway II in the plasma of IgAN patients are associated with IgAN activity (J Nephrol 2013, 26(4): 708-715). Studies have confirmed that C3a in renal tissue and urine, 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, under in vitro conditions, IgA can activate the complement II pathway. In this process, abnormalities in the IgA hinge region do not play a decisive role, and the formation of IgA multimers is a crucial part of it (Eur J Immunol 1987, 17(3): 321-326). Currently, the accumulation of complement C3 in the glomerular mesangial region is already one of the auxiliary diagnostic markers for IgAN. A study in which C3c and C3d immunofluorescence detection was performed on the renal tissue of 163 IgAN patients showed that IgAN patients with higher C3c accumulation intensity than C3d accumulation intensity had lower glomerular filtration rates, a higher incidence of glomerular intracapillary proliferation, and more severe hematuria, suggesting that glomerular C3c accumulation is associated with active lesions in IgAN (Am J Nephrol. 2000, 20(2):122-128). Currently, there is no specific drug for the clinical treatment of IgAN, and treatment mainly involves generic drugs such as renin-angiotensin inhibitors (ACEIs or ARBs), glucocorticoids, and various immunosuppressants. Furthermore, the safety of these drugs is a significant concern. For example, while glucocorticoids reduce proteinuria, the STOP-IgAN and TESTING-I trials clearly demonstrated the potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0008] Arthritis is a common chronic disease, an inflammatory disorder caused by inflammation, infection, degeneration, wound, or other factors. Clinical findings include redness, swelling, heat, pain, dysfunction, and joint deformity, often causing severe pain, limited movement, and physical deformation. In severe cases, it can lead to permanent disability and affect the patient's quality of life. Studies have shown that K / BxN mouse serum cannot induce arthritis in mice deficient in complement factor B, but wild-type mice develop arthritis when induced by K / BxN mouse serum (Immunity, 2002, 16, 157-168). This suggests that the complement system plays a crucial 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 include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographical atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neurospinal inflammation (NMO), hepatic inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases, and cardiovascular diseases.

[0010] Currently, there are no small molecule complement factor B inhibitors available for clinical treatment. Known and ongoing projects include oligonucleotide drugs developed by IONIS Pharmaceuticals Inc., which treat, prevent, or alleviate diseases associated with complement pathway II dysfunction 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 conditions such as age-related macular degeneration (AMD) (WO2018005552).

[0011] Inflammatory and immune-related diseases are characterized by their diversity and difficulty in treatment. Currently, eculizumab is the only commercially available drug for PNH (progressive neuropathy), but its high price places a significant burden on patients. Furthermore, many patients still experience anemia after treatment with eculizumab, and many still require continuous blood transfusions. In addition, eculizumab must be administered intravenously. Meanwhile, several diseases, such as IgAN (irradiated anemia neuropathy), have not yet found effective treatments. In these areas, there are unmet clinical needs, and the development of new small molecule drugs is necessary for medical treatment.

[0012] Therefore, there is currently a need to develop pharmaceutically acceptable active ingredients that are highly efficient, low in toxicity, and / or long-acting, in order to improve the technical problems described above. [Overview of the project]

[0013] To improve the above technical problems, the present invention provides a pharmaceutically acceptable salt of the compound of formula I,

[0014] [ka]

[0015] The above-mentioned pharmaceutically acceptable salts are salts formed with the compound of formula I and an acid or a base, and are preferably selected from salts formed with the compound of formula I and an acid.

[0016] According to embodiments of the present invention, the above acid may be selected from inorganic acids or organic acids, for example, 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, and pivalic acid. These include 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfate, 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, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid, or thiocyanic acid. As an example, the above 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 embodiments of the present invention, the base may be selected from inorganic bases, for example, alkali metal hydroxides or alkaline earth metal hydroxides, and is preferably selected from sodium hydroxide or potassium hydroxide.

[0018] According to a preferred embodiment of the present invention, a pharmaceutically 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.

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

[0020] According to embodiments of the present invention, in a pharmaceutically 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 charges of the ions of the compound of formula I and the acid or base in the salt are in equilibrium. For example, if the number of ionizable hydrogen atoms in the acid (such as hydrochloric acid, methanesulfonic acid, or p-toluenesulfonic acid) is 1, the molar ratio of the compound of formula I to the acid is 1:1; if the number of ionizable hydrogen atoms in the acid (such as sulfuric acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, or oxalic acid) is 2, the molar ratio of the compound of formula I to the acid may be 1:1 or 2:1; and if 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 method for producing a pharmaceutically acceptable salt of a compound of formula I, the method comprising reacting a compound of formula I with an acid or base to obtain a pharmaceutically acceptable salt of a compound of formula I.

[0022] According to embodiments of the present invention, the above-mentioned production method includes reacting a compound of formula I with the acid or base in a solvent to obtain a pharmaceutically acceptable salt of the compound of formula I.

[0023] According to embodiments of the present invention, the above-mentioned acid or base has the above-mentioned definition independently of each other.

[0024] According to an embodiment of the present invention, the solvent may be selected from an alcohol-based, a ketone-based, an ester-based, an ether-based, 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-based 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-based 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-based 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-based may be a linear or branched alkyl ether or a 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, 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, it is 20°C to 80°C, preferably 30°C to 60°C.

[0028] According to an embodiment of the present invention, the above production method further includes performing filtration and / or drying steps after the reaction is completed to obtain a pharmaceutically acceptable salt of the compound of formula I.

[0029] According to embodiments of the present invention, in the above manufacturing method, the drying temperature can be selected from a relatively wide range, for example, 20°C to 80°C, preferably 30°C to 60°C.

[0030] According to embodiments of the present invention, in the above manufacturing 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 crystals, preferably single crystals, of the monohydrochloride salt of the compound of formula I. The unit cell parameters of the above 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 crystals of a monohydrochloride salt of the compound of formula I, and more particularly provides a method for producing a single crystal thereof, comprising dissolving the monohydrochloride salt of the compound of formula I in solvent A and then diffusing it into an atmosphere of solvent B.

[0034] The solvent A mentioned above may be a combination of two or more alcohol-based solvents, such as methanol and ethanol.

[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 carboxylic acid esters such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more of these. The ether solvent may be a linear or branched alkyl ether, cyclic ether compound, or a combination of two or more of these, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more of these.

[0036] The present invention further provides crystalline forms of monohydrochloride salts of compounds of formula I, selected from crystalline forms A, B, C, D, or E described below.

[0037] X-ray powder diffraction using Cu-Kα rays, expressed at a 2θ angle, shows characteristic peaks at 9.66±0.20°, 16.08±0.20°, and 23.46±0.20°, indicating that this is crystalline form A of the monohydrochloride salt of compound I.

[0038] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0039] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0040] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0041] Preferably, the above crystal form A has characteristic peaks as shown in Table 1 when the X-ray powder diffraction is expressed using Cu-Kα rays at a 2θ angle, and the error range of the 2θ angle is ±0.20°.

[0042] [Table 1]

[0043] Preferably, the above crystal form A basically has the X-ray powder diffraction pattern shown in Figure 1.

[0044] According to embodiments of the present invention, the above-mentioned crystalline form A is the 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 above crystal form A shows that when heated to a peak temperature of around 192.73°C, a first endothermic peak appears, and a first exothermic peak appears at a peak temperature of around 201.78°C.

[0046] Preferably, the above crystal form A basically has the DSC pattern shown in Figure 2.

[0047] According to embodiments of the present invention, thermogravimetric analysis (TGA) of the above crystal form A shows a weight loss of approximately 1.41% in the range of 90°C to 180°C.

[0048] Preferably, the above crystal form A basically has the TGA pattern shown in Figure 3.

[0049] According to embodiments of the present invention, the crystal form A is a crystal with an irregular shape. Preferably, the grain size of the crystal form A is 20 μm or less.

[0050] Preferably, the above crystal form A basically has the PLM pattern shown in Figure 4.

[0051] X-ray powder diffraction using Cu-Kα rays, expressed at a 2θ angle, shows characteristic peaks at 18.10±0.20°, 19.80±0.20°, and 22.10±0.20°, indicating that this is crystalline form B of the monohydrochloride salt of compound I.

[0052] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed as a 2θ angle.

[0053] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0054] Preferably, the above crystal form B has characteristic peaks as shown in Table 2 when the X-ray powder diffraction is expressed using Cu-Kα rays at a 2θ angle, and the error range of the 2θ angle is ±0.20°.

[0055] [Table 2]

[0056] Preferably, the above crystal form B basically has the X-ray powder diffraction pattern shown in Figure 5.

[0057] According to embodiments of the present invention, the above-mentioned crystalline form B is a hydrate of a monohydrochloride salt of a compound of formula I, such as a monohydrate of a monohydrochloride salt of a compound of formula I.

[0058] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the above crystal form B shows that when heated to a peak temperature of around 85.87°C, a first endothermic peak appears, a second endothermic peak appears at a peak temperature of around 197.54°C, and a first exothermic peak appears at a peak temperature of around 205.68°C.

[0059] Preferably, the above crystal form B basically has the DSC pattern shown in Figure 6.

[0060] According to embodiments of the present invention, thermogravimetric analysis (TGA) of the above crystal form B shows that it has a weight loss of approximately 3.42% between 21.49°C and 120°C, and a weight loss of approximately 0.49% between 179.88°C and 207.94°C.

[0061] Preferably, the above crystal form B basically has the TGA pattern shown in Figure 7.

[0062] According to embodiments of the present invention, the crystal form B is a crystal with an irregular shape. Preferably, the grain size of the crystal form B is 20 μm or less.

[0063] Preferably, the above crystal form B basically has the PLM pattern shown in Figure 8.

[0064] According to embodiments of the present invention, crystal form A is converted to crystal form B under high humidity conditions. The high humidity conditions are preferably 40°C and a relative humidity of 75% to 95%.

[0065] According to embodiments of the present invention, crystal form B is obtained by drying under drying conditions. The drying conditions are preferably vacuum drying at 40°C.

[0066] X-ray powder diffraction using Cu-Kα rays, expressed in 2θ angles, shows characteristic peaks at 14.74±0.20°, 17.80±0.20°, 20.08±0.20°, and 21.98±0.20°, indicating that crystalline form C is the monohydrochloride salt of compound I.

[0067] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed as a 2θ angle.

[0068] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0069] Preferably, the above crystal form C has characteristic peaks as shown in Table 3 when the X-ray powder diffraction is expressed using Cu-Kα rays at a 2θ angle, and the error range of the 2θ angle is ±0.20°.

[0070] [Table 3]

[0071] Preferably, the above crystal form C basically has the X-ray powder diffraction pattern shown in Figure 9.

[0072] According to embodiments of the present invention, the above-mentioned crystalline form C is the 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 above-mentioned crystal form C shows that when heated to a peak temperature of approximately 209.93°C, a first endothermic peak appears, and when heated to a peak temperature of approximately 215.80°C, a first exothermic peak appears.

[0074] Preferably, the above crystal form C basically has the DSC pattern shown in Figure 10.

[0075] According to embodiments of the present invention, thermogravimetric analysis (TGA) of the above crystalline form C shows that it has a weight loss of approximately 0.29% in the range of 21.62°C to 120°C and a weight loss of approximately 0.52% in the range of 173.94°C to 216.60°C.

[0076] Preferably, the above crystal form C basically has the TGA pattern shown in Figure 11.

[0077] According to embodiments of the present invention, the crystal form C is a crystal with an irregular shape. Preferably, the grain size of the crystal form C is 20 μm or less.

[0078] Preferably, the above crystal form C basically has the PLM pattern shown in Figure 12.

[0079] X-ray powder diffraction using Cu-Kα rays, expressed in 2θ angles, shows characteristic peaks at 15.74±0.20°, 16.58±0.20°, 21.98±0.20°, and 23.82±0.20°, indicating that this is crystalline form D of the monohydrochloride salt of compound I.

[0080] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0081] Preferably, the above crystal 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° when the X-ray powder diffraction is measured using Cu-Kα rays at a 2θ angle.

[0082] Preferably, the above crystal form D has characteristic peaks as shown in Table 4 when the X-ray powder diffraction is expressed using Cu-Kα rays at a 2θ angle, and the error range of the 2θ angle is ±0.20°.

[0083] [Table 4]

[0084] Preferably, the above crystal form D basically has the X-ray powder diffraction pattern shown in Figure 13.

[0085] According to embodiments of the present invention, the 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, or a monodichloromethane solvate of the monohydrochloride salt of the compound of formula I (or referred to as monodichloromethane solvate).

[0086] According to embodiments of the present invention, differential scanning calorimetry (DSC) analysis of the above crystal form D shows that when heated to a peak temperature of approximately 196.53°C, a first exothermic peak appears.

[0087] Preferably, the above crystal form D basically has the DSC pattern shown in Figure 14.

[0088] According to embodiments of the present invention, thermogravimetric analysis (TGA) of the above crystal form D shows a weight loss of approximately 6.31% in the range of 22.07°C to 120°C.

[0089] Preferably, the crystal form D has basically the TGA pattern shown in Figure 15.

[0090] According to embodiments of the present invention, the crystal form D is a crystal with an irregular shape. Preferably, the grain size of the crystal form C is 10 μm or less.

[0091] Preferably, the crystal form D has basically the PLM pattern shown in Figure 16.

[0092] X-ray powder diffraction using Cu-Kα rays, expressed at a 2θ angle, shows characteristic peaks at 9.36±0.20°, 15.22±0.20°, 16.88±0.20°, and 22.10±0.20°, indicating that the monohydrochloride salt of compound I is crystalline form E.

[0093] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0094] Preferably, the above crystal 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° when measured using Cu-Kα rays and expressed at a 2θ angle.

[0095] Preferably, the above crystal form E has characteristic peaks as shown in Table 5 when the X-ray powder diffraction is expressed using Cu-Kα rays at a 2θ angle, and the error range of the 2θ angle is ±0.20°.

[0096] [Table 5]

[0097] Preferably, the above crystal form E basically has the X-ray powder diffraction pattern shown in Figure 17.

[0098] According to embodiments of the present invention, the above-mentioned crystalline form E is a solvate of the monohydrochloride salt of the compound of formula I, such as the monoisopropanol solvate of the monohydrochloride salt of the compound of formula I.

[0099] The present invention further provides a method for producing the above crystalline form of the monohydrochloride salt of the compound of formula I.

[0100] A method for producing crystalline form A includes dissolving the compound of formula I in an alcohol-based solvent, adding a solution containing HCl in the alcohol-based solvent to form a salt, then adding a n-alkane to crystallize and obtain the crystalline form A.

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

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

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

[0104] The concentration of the above solution in which HCl is in an alcoholic 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] Method two for producing crystalline form A includes heating and stirring the monohydrochloride salt of the compound of formula I in an alcoholic solvent and a n-alkane to dissolve and clarify it, and then crystallizing it to obtain the crystalline form A.

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

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

[0109] The mass-to-volume ratio of the monohydrochloride salt of the compound of formula I, the alcoholic solvent, and the n-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 embodiments of the present invention, one or two methods for producing crystalline form A further include the steps of cooling, filtering, and drying.

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

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

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

[0115] The method for producing crystal form B includes obtaining crystal form B by placing crystal form A under high humidity conditions.

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

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

[0118] A method for producing crystalline form C includes dissolving the compound of formula I in an alcohol-based solvent, then adding a solution containing HCl in the alcohol-based solvent to form a salt, and then adding an ether-based solvent or an ester-based solvent to crystallize and obtain crystalline form C.

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

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

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

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

[0123] The mass-to-volume ratio of the compound of formula I, the alcohol-based solvent, and the ether-based 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 above solution in which HCl is in an alcohol-based solvent is 1 to 3 mol / L, for example 1.5 to 2.5 mol / L, and specifically 1.8 mol / L. The mass ratio of the compound of formula I to the solution in which HCl is in an 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 producing the above-mentioned crystalline form C includes dissolving the compound of formula I in methanol, adding a methanol solution of HCl, stirring, filtering, adding methyl tert-butyl ether to the filtrate, filtering, drying, and obtaining the crystalline form C.

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

[0127] According to embodiments of the present invention, a method for producing crystalline form D includes adding a monohydrochloride salt of a compound of formula I to a halogenated alkane, stirring, separating the resulting suspension, drying the separated solid, and obtaining the resulting solid as crystalline form D.

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

[0129] 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, preferably 1 g:(18-25) mL, for example, 1 g:20 mL.

[0130] The above separation is performed using a known separation method, but separation by centrifugal separation is preferred.

[0131] The above drying method involves vacuum drying under reduced pressure while heating, and it is preferable to perform vacuum drying under reduced pressure at 40°C.

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

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

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

[0135] The above alcohol-based 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 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 is performed using a known separation method, but separation by centrifugal separation is preferred.

[0138] The above drying method involves vacuum drying under reduced pressure while heating, and it is preferable to perform vacuum drying under reduced pressure at 40°C.

[0139] According to a preferred embodiment of the present invention, the method for producing the above-mentioned crystalline form E includes adding a monohydrochloride salt of the compound of formula I to isopropanol, stirring at room temperature, and then separating the solid to obtain the crystalline form E.

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

[0141] The present invention further provides a formulation comprising a pharmaceutically acceptable salt of the compound of formula I, at least one of crystal forms A, B, C, D, and E, and an optionally pharmaceutically acceptable adjuvant.

[0142] The present invention further provides the use of at least one of the above-mentioned pharmaceutically acceptable salts of the compound of formula I (e.g., the hydrochloride salt, e.g., crystalline forms A, B, C, D, and E of the hydrochloride salt) or the above-mentioned pharmaceutical composition in the manufacture of a drug for the prevention and / or treatment of complement factor B-mediated diseases or conditions.

[0143] According to embodiments of the present invention, the complement factor B-mediated disease or condition is at least one selected from diseases such as paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographical atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neurospinal inflammation (NMO), arthritis, rheumatoid arthritis, hepatic inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases, and cardiovascular diseases.

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

[0145] According to embodiments of the present invention, the disease or condition associated with the complement factor B inhibitor is at least one selected from the following diseases: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographical atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neurospinal inflammation (NMO), arthritis, rheumatoid arthritis, hepatic inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases, and cardiovascular diseases.

[0146] The therapeutic method of the present invention may include administering a pharmaceutically acceptable salt of the compound of formula I of the present invention (e.g., the hydrochloride salt, e.g., crystalline forms A, B, C, D, E of the hydrochloride salt) or the pharmaceutical composition alone, or administering one, two, or more of the pharmaceutically acceptable salts of the compound of formula I of the present invention (e.g., the hydrochloride salt, e.g., crystalline forms A, B, C, D, E of the hydrochloride salt) or the pharmaceutical composition in combination with one, two, or more other chemotherapeutic agents. The administration of multiple drugs may be carried out simultaneously or sequentially.

[0147] In the context of this specification, "greater than or equal to," "less than or equal to," and "within" should be understood to include the number of items. For example, "at least one type" should be understood as "one type, two types, or more." For another example, "two or more types" should be understood as "two types or more," for example, "two types, three types, four types, or more."

[0148] Beneficial effects The salts (particularly hydrochloride, phosphate, and maleate) of the compound of formula I of the present invention exhibit high stability, high water solubility, significantly enhance absorption capacity during oral administration, and improve bioavailability. Furthermore, the crystalline form of the hydrochloride of the compound of formula I of the present invention exhibits high stability, good solubility, low hygroscopicity, and good prospects for drug discovery. Moreover, the method for producing the salts and crystalline forms of the compound of formula I of the present invention is simple to operate, easy to control, highly reproducible, requires mild reaction conditions, yields high product yields, and is advantageous for industrial production. [Brief explanation of the drawing]

[0149] [Figure 1] This is the XRPD pattern of the monohydrochloride salt crystal form A of the compound of formula I. [Figure 2] This is the DSC pattern of the monohydrochloride salt crystal form A of the compound of formula I. [Figure 3] This is the TGA pattern of the monohydrochloride salt crystal form A of the compound of formula I. [Figure 4] This is the PLM pattern of the monohydrochloride salt crystal form A of the compound of formula I. [Figure 5] This is the XRPD pattern of the monohydrochloride salt crystal form B of compound I. [Figure 6] This is the DSC pattern of the monohydrochloride salt crystal form B of compound I. [Figure 7] This is the TGA pattern of the monohydrochloride salt crystal form B of the compound of formula I. [Figure 8] This is the PLM pattern of the monohydrochloride salt crystal form B of the compound of formula I. [Figure 9] This is the XRPD pattern of the monohydrochloride salt crystal form C of the compound of formula I. [Figure 10] This is the DSC pattern of the monohydrochloride salt crystal form C of the compound of formula I. [Figure 11] This is the TGA pattern of the monohydrochloride salt crystal form C of the compound of formula I. [Figure 12] This is the PLM pattern of the monohydrochloride salt crystal form C of the compound of formula I. [Figure 13] This is the XRPD pattern of the monohydrochloride salt crystal form D of the compound of formula I. [Figure 14]This is the DSC pattern of the monohydrochloride salt crystal form D of compound I. [Figure 15] This is the TGA pattern of the monohydrochloride salt crystal form D of the compound of formula I. [Figure 16] This is the PLM pattern of the monohydrochloride salt crystal form D of the compound of formula I. [Figure 17] This is the XRPD pattern of the monohydrochloride salt crystal form E of the compound of formula I. [Figure 18] The monohydrochloride crystalline form C of the compound of formula I is the XRPD result pattern after being placed under accelerated, high-temperature conditions for one month. [Figure 19] The monohydrochloride crystalline form C of the compound of formula I is the XRPD result pattern after exposure to high temperature and high humidity for one day. [Figure 20] The monohydrochloride crystalline form C of the compound of formula I is the XRPD result pattern after exposure to high temperature and high humidity for 3 days. [Figure 21] This is experimental data (ng / mL) of the blood drug concentration curve in cynomolgus monkeys in a biological example. [Figure 22] This shows experimental data (percentage relative to 0 h) of the serum AP activity curve in cynomolgus monkeys in biological examples. [Figure 23] These are experimental data from a biological example of Streptococcus-induced rheumatoid arthritis in rats. [Figure 24] This is a single crystal diagram of the monohydrochloride salt of the compound of formula I. [Modes for carrying out the invention]

[0150] The technical aspects of the present invention will be described in more detail below, in accordance with specific embodiments. The embodiments described below are merely illustrative and interpretable to illustrate the present invention, and should not be interpreted as limiting the scope of the claims. Any technology realized based on the above-described aspects of the present invention falls within the scope of the claims according to the present invention.

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

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

[0153] The radiation source was a Cu~Kα target (1.54056 Å).

[0154] The minimum operating voltage and current of the phototube are 40 kV and 30 mA, respectively. The 2-Theta value of the sample scanning 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 minute.

[0156] Differential scanning calorimeter (DSC) Approximately 1-5 mg of the powder sample was weighed and placed in a sealed aluminum crucible, with a pinhole made in the crucible lid. Under nitrogen gas protection, the temperature was increased from 30°C to 300°C, and differential calorimetry was performed, holding the temperature at 300°C for 1 minute. The heating rate was 20°C / min.

[0157] Polarizing microscope (PLM) The sample was dispersed in a medium (silicone oil), observed using a 10X eyepiece and a 10X objective lens, and the image was recorded using a camera computer system.

[0158] Dynamic moisture adsorption (DVS) Approximately 10 mg of sample was weighed under a 0%~95%~0% relative humidity (RH) cycle, and moisture absorption / desorption characteristics tests were performed at 25°C using the following parameters.

[0159] [Table 6]

[0160] Single crystal testing apparatus and conditions Equipment model number: D8 Venture Instrument parameters: Light source: Mo target X-ray: Mo-Kα (=0.71073 Å) Detector: CMOS surface 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°K Explanation of abbreviations 40℃ / 75% RH means the conditions are 40℃ and 75% humidity.

[0161] "40℃ / 75% RH-closed" means that the product was left in a sealed container at 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 kept sealed and stored at 60℃.

[0164] "40℃ / 75% RH-closed-2 wks" means that the product was left in a sealed container for two weeks under conditions of 40℃ and 75% humidity.

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

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

[0167] "Initial" refers to the initial state.

[0168] SGF stands for SGF, which means simulating gastric juice.

[0169] FaSSIF means simulating the intestinal fluid of a fasted state.

[0170] FeSSIF means simulating intestinal fluid during feeding.

[0171] 1d means one day, and 3d means three days.

[0172] Manufacturing Example 1: Preparation of the compound of formula I Reaction equation for the synthesis of compound I and intermediate b

[0173] [ka]

[0174] Production of intermediate b In a 250 mL single-necked 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 sequence and reacted at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to the reaction mixture to quench it, and the mixture was extracted three times with dichloromethane (20 mL). The combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. 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-necked flask, dichloromethane (80 mL), N-methylformanilide (3.8 g), and oxalyl chloride (3.6 g) were added in sequence, and the reaction was carried out at room temperature with stirring for 3 hours. Next, the reaction was cooled to -14°C, intermediate a (2.5 g) was added, and the reaction system was allowed to rise naturally to room temperature and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture 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 the compound of formula I Step 1: In a 3 L three-necked flask, tetrahydrofuran (150 mL) and 4-bromobenzonitrile (50 g) were added sequentially. Under nitrogen gas protection, isopropyl magnesium chloride lithium chloride complex (1.3 M, 210 mL) was gradually added to the reaction system, and the mixture was reacted at room temperature for 2 hours. Next, anhydrous tetrahydrofuran (500 mL) was added to the reaction system to dilute it, and the temperature was lowered 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 complete, the mixture was reacted at 0°C for 2 hours with stirring, and then the temperature was raised to room temperature and the mixture was continued to react at room temperature for 16 hours. After the reaction was complete, 150 mL of 6 M hydrochloric acid was added and the mixture was stirred for 30 minutes. The mixture was then diluted with 1000 mL of water, extracted twice with 500 mL of ethyl acetate, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product 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: 46 g of compound 1 prepared in two batches in Step 1 (28 g) was taken out, and zinc powder (55 g) and acetic acid (200 mL) were added sequentially to a 500 mL single-necked flask. The reaction was heated to 100°C and stirred at that temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water (500 mL), extracted with ethyl acetate (500 mL), the extracted phase was washed twice with saturated sodium bicarbonate aqueous solution (500 mL), washed once with saturated brine (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-necked flask, tetrahydrofuran (100 mL), ethanol (100 mL), and compound 2 (26 g) were added in sequence, followed by the addition of sodium borohydride (2 g) in several batches. The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the system was cooled to 0°C, and saturated ammonium chloride aqueous solution (30 mL) was added until the temperature no longer rose. The mixture was then diluted with water (500 mL), extracted twice with ethyl acetate (200 mL), washed with saturated brine (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-necked flask, then compound 3 (25 g), imidazole (6.6 g), and tert-butyldiphenylchlorosilane (25 g) were added in sequence, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed with water (500 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 = 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-necked flask, compound 4 (5 g) and a tetrabutylammonium fluorotetrahydrofuran solution (1 M, 30 mL) were added sequentially, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted three times with ethyl acetate (50 mL), washed with saturated brine (100 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 = 3:1~0:1) to obtain a racemic mixture. This racemic mixture was then chiral-separated by SFC (Apparatus: SFC Thar prep 80, Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm, Modifier: 35% methanol (0.2% aqueous ammonia), 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: To a solution of compound 5 (1200 mg) in N,N-dimethylformamide (10 mL), imidazole (486 mg) and tert-butyldimethylchlorosilane (593 mg) were added and the mixture was reacted at room temperature with stirring for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL), the extracted phase was washed once with saturated saline solution (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: At room temperature, compound 6 (700 mg) was removed from 1.2 g of compound 6 in two batches of step 6 and added to dichloromethane (10 mL). Under the protection of nitrogen gas and under conditions of -78°C, cyclopropanecarboxyaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction mixture, and the reaction system was stirred for 1 hour while maintaining the temperature at -78°C. Then triethylsilane (180 mg) was added, and the reaction was allowed to proceed by allowing the temperature to rise naturally to room temperature, and the mixture was stirred at that temperature for 16 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture to quench it, water (10 mL) was added to dilute it, and the mixture was 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 sequentially to a 50 mL single-necked flask. The reaction mixture was heated to 100°C and stirred at that temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture under an ice bath to adjust the pH to 5-6. Water (5 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (5 mL). The organic phase was washed once with saturated brine (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and 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 mixture was heated to 50°C and stirred at that temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, 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: To a solution of compound 9 (180 mg) in tetrahydrofuran (3 mL), palladium / carbon (50 mg) was added, and the reaction mixture was subjected to a catalytic hydrogenation reaction under a hydrogen gas atmosphere at room temperature for 2 hours. After the reaction was complete, the reaction mixture 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. Then sodium borohydride acetate (261 mg) was added and the mixture was stirred at room temperature for another 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 11 (200 mg, yield: 26%).

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

[0199] Step 12 In a 50 mL single-necked flask, methanol (2 mL), water (2 mL), compound 11 (200 mg), and sodium hydroxide (150 mg) were added in sequence. The reaction mixture was heated to 75°C and stirred at that temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture under an ice bath to adjust the pH to 7. The mixture was then concentrated directly and purified by Prep-HPLC (column: Gemini-C18, 150 × 21.2 mm, 5 μm, liquid 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] Unless otherwise specified, all compounds of formula I described below are compounds of formula I produced by the method described above or by repeating the method described above.

[0203] Example 1: Method for producing the monohydrochloride salt of compound I

[0204] [ka]

[0205] After preparing the compound of formula I in multiple batches, 400 mg of the compound of formula I was taken, 8 mL of isopropanol was added, and the mixture was heated and dissolved at 50°C. Then, 460 μL of isopropanol hydrogen chloride solution (concentration 2 mol / L) was slowly added dropwise, and the mixture was stirred for 30 minutes. A further 8 mL of n-heptane was added, and the mixture was stirred for 2 hours. The mixture was filtered, and the filtered cake was vacuum-dried under reduced pressure at 50°C to obtain 390 mg of the monohydrochloride salt I-1 of the compound of formula I in 90% yield.

[0206] 50 mg of the monohydrochloride salt I-1 of the compound of formula I was taken out into a 4 mL sample vial, and 0.5 mL of methanol was added to dissolve the compound. Then, the sample opening was placed into a 40 mL sample vial containing 5 mL of ethyl acetate, and the 40 mL sample vial was kept sealed. After standing, the two solvents were gradually diffused to obtain a single crystal, and the single crystal structure diagram is shown in Figure 24. The above single crystal was tested, and the single crystal data for the monohydrochloride salt I-1 of the compound of formula I was obtained as follows.

[0207] [Table 7]

[0208] Example 2: Method for producing the compound phosphate of formula I The compound of formula I was prepared in multiple batches. 440 mg of the compound of formula I was taken, 5 mL of acetone was added, and the mixture was heated to 40°C and dissolved by sonication. Then, 460 μL of 2 mol / L methanol phosphate solution was slowly added dropwise. A viscous solid was found, and another 5 mL of acetone was added. The mixture was stirred at room temperature for 4 hours. The mixture was filtered, washed, and the filtered cake was vacuum-dried under reduced pressure at 50°C to obtain 462 mg of the phosphate of the compound of formula I in 87% yield.

[0209] Example 3: Method for producing the maleate of compound I The compound of formula I was prepared in multiple batches. 400 mg of the compound of formula I was taken, 15 mL of ethyl acetate was added, and the compound was dissolved by heating to 50°C. Then, 109 mg of maleic acid powder was added, and the mixture was stirred at room temperature for 2-3 hours. The mixture was filtered, and the filtered cake was vacuum-dried under reduced pressure at 50°C to obtain 470 mg of the maleate of the compound of formula I in 91% yield.

[0210] Example 4: Stability test of monohydrochloride, phosphate, and maleate salts of compound I The stability of the compound of formula I, the monohydrochloride salt of the compound of formula I from Example 1, the phosphate salt of the compound of formula I from Example 2, and the maleate salt salt of the compound of formula I from Example 3 were investigated. Stability assessment conditions: 40°C / 75% RH-closed, 40°C / 75% RH-open, 60°C-closed. Stability assessment content: Related substances and changes in crystal form.

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

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

[0213] [Table 8]

[0214] [Table 9]

[0215] The results in Table 7 show that the compound of formula I, as well as its monohydrochloride, phosphate, and maleate salts, are all stable, and the monohydrochloride salt of the compound of formula I is particularly stable.

[0216] Example 5 Solubility test of compound I and its hydrochloride and phosphate salts The solubility of the compound of formula I, its monohydrochloride salt, and its phosphate salt in water, SGF, FaSSIF, and FeSSIF at 37°C was investigated. Experimental method: 30 mg (in water) or 15 mg of the sample was weighed into a 4 mL vial, 3 mL of a test medium (water, SGF, FaSSIF, FeSSIF) was added, and stirring was continued at 37°C. 0.5 mL samples were taken at 1 h and 24 h, and the mixture was centrifuged at 12000 rpm for 10 min. The supernatant was diluted with 50% acetonitrile aqueous solution in appropriate proportions, and the concentration was measured. The chromatographic conditions for the solubility test are shown in Table 8.

[0217] Control and Linear Analysis: 10 mg of compound I was weighed into a 50 mL volumetric flask, dissolved in 50% acetonitrile aqueous solution, and diluted to the marked level. Two samples were prepared in parallel. The control sample of compound I was diluted with 50% acetonitrile aqueous solution to 100 μg / mL, 50 μg / mL, and 10 μg / mL. 5 μL of each sample was injected, and a standard curve was drawn.

[0218] Table 9 shows the results of solubility tests for the compound of formula I and its hydrochloride and phosphate salts.

[0219] [Table 10]

[0220] [Table 11]

[0221] As is clear from Table 9, the compound of formula I exhibits 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-necked flask. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the solution 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), and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 × 21.2 mm, 5 μm, liquid phase: acetonitrile-water (0.1% formic acid), gradient: 15-30%) to obtain the control 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. Detection of optical surface plasmon resonance (SPR) coupling forces The SPR experiment was performed at 25°C using PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO as the electrophoresis buffer. The analytical instrument used was a GE Healthcare Biacore 8K. 400 mM EDC and 100 mM NHS activated the CM7 chip (GE Healthcare) for 420 s at a flow rate of 30 μL / min. Complement factor B was diluted to 50 μg / mL with 10 mM sodium acetate (pH 4.0), and then covalently immobilized on the detection chip by coupling at a flow rate of 10 μL / min for 1200 s (protein immobilization level: 25000 RU). The detection chip was then sealed by reacting it with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 s. The concentration of the compound awaiting measurement 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] Experimental results: The experimental results are shown in Table 10. At a concentration of 500 μM, the compound of formula I exhibited a more pronounced binding ability to the target protein, significantly superior to the control compound, indicating that the compound of formula I has a relatively good binding ability to the target protein.

[0226] [Table 12]

[0227] 2. Detection of TR-FRET binding force The inhibitory activity of compounds against human complement factor B was screened by competitive binding experiments using small molecule inhibitors labeled with Cy5 fluorescence as probes. TM Sulfo-NHS-LC-LC-Biotin was incubated on ice for 1 hour in a 1:2 ratio, then 1 M Tris (pH 7.5) was added to terminate the reaction. Subsequently, 2 mL of Zeba TMPurified twice using a desalt spin column to obtain complement factor B labeled with biotin (EZ-LinkTM Sulfo-NHS-LC-Biotin instruction manual). When conducting the experiment, complement factor B labeled with biotin at a final concentration of 10 nM and compounds at various concentrations were taken and pre-incubated in buffer at room temperature for 1 hour. Probes labeled with Cy5 fluorescence at final concentrations of 75 nM and 5 nM respectively and streptavidin labeled with a europium chelate compound (Perkin Elmer, #AD0060) were added to initiate the reaction. Dynamic readings were performed using a microplate reader (exciting light at 337 nm, emitting light at 665 nm, 70 μs time-gated), and data on time-dependent fluorescence energy transfer (TR-FRET) were read to determine IC 50 .

[0228] 3. Detection of C3 hydrolysis activity by the complement system The test compound was initially concentrated at 10 μM, then diluted 3-fold to 7 concentration points, and detected in each well. In a 96-well plate, the test compound was diluted with DMSO to a final concentration of 1000-fold, and then further diluted with Diluent (WIESLAB® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) to a final concentration of 5-fold. 30 μL was transferred to a 96-well plate, 120 μL of reserve serum was added, and the plate was incubated at room temperature for 15 minutes. 30 μL of 5‰ DMSO and 120 μL of reserve 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 minutes. 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 minutes. The liquid in the wells 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 minutes. The OD405 values ​​were read using a microplate reader (Perkin Elmer, EnSight). 4. Detection of complement hemolytic activity The hemolysis experiment was performed referring to the description 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 erythrocytes (RE) was obtained by titration. In this experiment, NHS was diluted in GVB0 buffer containing 10 mM Mg-EGTA (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement technology) and incubated with test compounds of various concentration gradients at 37°C for 15 min. Freshly suspended RE (taken from healthy Japanese white rabbits) in GVB0 buffer containing 10 mM Mg-EGTA was subjected to 1 × 10⁶ of titration. 8 The solution was added until the final cell / mL concentration was reached, and incubated at 37°C for 30 minutes. The positive control group (100% pyrolysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA, which included NHS and RE but did not contain the test compound. The negative control group (0% pyrolysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA, which included inactivated NHS (heated at 56°C for 30 minutes or at 65°C for 5 minutes) and RE but did not contain the test compound. After centrifugation of the samples at 2000 g for 5 minutes, the supernatant was collected. Absorbance at 415 nm (A415) was detected by a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 The values ​​were calculated from the hemolysis percentage, which is a function of the test compound concentration, using nonlinear regression.

[0229] Experimental results: The experimental results are shown in Table 11. Among these, the compound of formula I showed significantly superior inhibitory activity against complement factor B in human serum compared to the control compound. This indicates that the compound 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 experiment (1) Preparation of buffer solution Take a 0.1 M aqueous solution of dipotassium hydrogen phosphate distilled water (containing 1 mM of ethylenediaminetetraacetic acid), and then adjust the pH to 7.4 with a 0.1 M aqueous solution of potassium dihydrogen phosphate distilled water (containing 1 mM of ethylenediaminetetraacetic acid).

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

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

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

[0235] Preparation of working solution Prepare 10 mM solutions of the control compound and the test compound in DMSO respectively, then take 10 μL and add it to 190 μL of acetonitrile to prepare a 0.5 mM stock solution. Take 1.5 μL of the 0.5 mM compound stock solution and add 20 mg / mL of 18.75 μM liver microsomes and 479.75 μL of buffer solution. (The actual preparation amount can be adjusted according to the usage situation).

[0236] (3) Experimental procedure Reduced coenzyme II (NADPH) at 10 mg / mL was prepared with buffer. One 96-well plate was placed on ice, and corresponding wells (0, 10, 30, 60, 90 min, Non-NADPH) at different time points were set up for each compound, and 30 μL of the working solution was added to each well. First, 155 μL of ice-cold acetonitrile solution (internal standard concentration was 1 μM) was added to the 0-min well, and after mixing uniformly with a pipette, 15 μL of NADPH (10 mg / mL) was added. Before the start of the reaction, the 96-well plate was pre-incubated for 5 min in a thermostatic microplate shaker (37 °C), and then 15 μL of NADPH (10 mg / mL) was added to each well to initiate the metabolic reaction. After reacting for 10, 30, 60, 90 min, 155 μL of ice-cold acetonitrile solution (internal standard concentration was 1 μM) was added to the corresponding wells to stop the reaction. After 90 min in the Non-NADPH system, 155 μL of ice-cold acetonitrile solution (internal standard concentration was 1 μM) was added to stop the reaction. After the reaction was completed, the 96-well plate was shaken in a microplate shaker (600 rpm) for 10 min, then centrifuged at 4 °C and 4000 g for 15 min, 50 μL of the supernatant was taken and added to one new 2-mL 96-well plate, and 300 μL of deionized water was further added, and it was analyzed with an 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: According to the data, the compounds of formula I are shown to have significant liver microsomal stability.

[0239] 6. PK experiment of single oral administration in rats Experimental method: 6-9 week old male Wistar han rats (Shanghai Wistar-Bikai Laboratory Animal Co., Ltd.) were used. After fasting overnight, 3 rats per group were administered intragastricly with 3 mg / kg each of the control compound and compound I, with a total volume of 10 mL / kg. Blood was collected from the jugular vein at each time point (0.2 mL). After anticoagulation with EDTA-K2, the samples were immediately centrifuged at 4000 rpm for 5 min at 4°C, and the supernatant was collected. The samples were stored in a refrigerator at -80°C until detection. Blood collection times: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. After administration, the animals' condition was observed continuously, and they were euthanized after blood collection was completed at all time points. Plasma samples were measured by LC-MS / MS, and kinetic parameters (Tmax, Cmax, T1 / 2, AUC) were calculated using WinNonlin software.

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

[0241] [Table 15]

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

[0243] Experimental results: Within the detectable concentration and time range, the mean blood drug concentration of the compound of formula I is significantly higher than that of the control compound at the same dose. The blood drug concentration curves in cynomolgus monkeys are shown in Figure 21, and the inhibition of serum AP activity in cynomolgus monkeys is shown in Figure 22. Figure 22 shows that the compound of formula I can effectively inhibit serum AP activity in cynomolgus monkeys.

[0244] 8. Streptococcal-induced rat rheumatoid arthritis (RA) model Experimental method: In the experiment, 6-9 week old female Lewis rats (Beijing Weitong Lihua) were used, with 6 rats per group. On day 1, a cell wall peptidoglycan complex of streptococci and several other bacteria (2-3 mg per rat) was administered by intraperitoneal injection. A control compound (15 mpk) and compound I (15 mpk) were administered intragastricly daily for 25 consecutive days, and arthritis was scored in the rats at different times. The scoring criteria were as follows: Each lesion was scored on a scale of 0-4 points depending on its severity (redness and swelling), with a maximum score of 4 points for an individual limb and a maximum score of 16 points for all four limbs of an individual animal. The scoring criteria were as follows: A score of 0 indicates no redness or swelling, 1 indicates redness and swelling of 1-2 interphalangeal joints, 2 indicates redness and swelling of 3-4 interphalangeal joints, 3 indicates redness and swelling of 4 or more interphalangeal joints, and 4 indicates severe redness and swelling extending from the toes and fingers to the ankle and wrist joints.

[0245] Experimental results: The experimental results are shown in Figure 23. The data indicates that the compound of formula I can improve the score for arthritis, and its effect is significantly superior to that of the control compound. This proves that the compound of formula I can more effectively improve streptococcal-induced rat rheumatoid arthritis.

[0246] Example 6: Method for producing crystalline form A of the monohydrochloride salt of compound I. 400 mg of the compound of formula I was taken, 8 mL of isopropanol was added, and it was heated and dissolved at 50 °C. Then, 460 μL of hydrogen chloride isopropanol solution (concentration 2 mol / L) was slowly added dropwise, stirred for 30 min, and further 8 mL of n-heptane was added, and stirring was continued for 2 h. It was filtered, and the filter cake was dried under reduced pressure and vacuum at 50 °C to obtain 390 mg of crystalline form A of the monohydrochloride of the compound of formula I with a yield of 90%.

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

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

[0249] DSC showed that when heated near a peak temperature of 192.73 °C, a first endothermic peak appeared, and a first exothermic peak appeared near a peak temperature of 201.78 °C, as shown in Figure 2.

[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 showed that the sample was crystals in an irregular form of 20 μm or less, as shown in Figure 4.

[0252] The XRPD pattern of crystalline form A shows the 2θ angles and relative intensities of the diffraction peaks in the X-ray powder diffraction pattern represented by the 2θ angle, among which the error range of the above 2θ angle is ±0.20°.

[0253]

Table 16

[0254] Example 7 Method for producing crystalline form B of the monohydrochloride of the compound of formula I Crystalline form A was left standing in an open state for 72 h under accelerated conditions (40 °C / 75% RH) and was converted to crystalline form B. The crystalline form B is a monohydrate of the monohydrochloride of the compound of formula I.

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

[0256] Table 2 shows the location and intensity of the characteristic XRPD peaks, and Figure 5 shows the XRPD pattern.

[0257] The DSC shows that when heated to a peak temperature of around 85.87°C, a first endothermic peak appears, a second endothermic peak appears at a peak temperature of around 197.54°C, and a first exothermic peak appears at a peak temperature of around 205.68°C, as shown in Figure 6.

[0258] The TGA showed a weight loss of approximately 3.42% in the range of 21.49°C to 120°C and a weight loss of approximately 0.49% in the range of 179.88°C to 207.94°C, as shown in Figure 7.

[0259] The PLM pattern is a crystal with an irregular morphology of 20 μm or less in size, as shown in Figure 8.

[0260] The XRPD pattern of crystal form B is an X-ray powder diffraction pattern represented by a 2θ angle. The 2θ angle and relative intensity of the diffraction peak are shown in Table B, and the error range of the 2θ angle is ±0.20°.

[0261] [Table 17]

[0262] Example 8: Method for producing crystalline form C of compound monohydrochloride of formula I 3.15 g of compound I was added to a three-necked flask, and methanol (12.6 mL) was added and stirred until completely dissolved. 3.05 g of methanol solution in 1.8 N HCl was added dropwise at room temperature, and the mixture was stirred for 10 minutes before filtering. The filtrate was placed in a three-necked flask, and 78.75 mL of methyl tert-butyl ether was added dropwise at room temperature. 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] Crystal form C is an anhydrous form, and was characterized by XRPD, DSC, TGA, and PLM.

[0264] Table 3 shows the location and intensity of the characteristic XRPD peaks, and Figure 9 shows the XRPD pattern.

[0265] The DSC shows that when heated to a peak temperature of around 209.93°C, a first endothermic peak appears, and when heated to a peak temperature of around 215.80°C, a first exothermic peak appears, as shown in Figure 10.

[0266] The TGA showed a weight loss of approximately 0.29% in the range of 21.62°C to 120°C and a weight loss of approximately 0.52% in the range of 173.94°C to 216.60°C, as shown in Figure 11.

[0267] The PLM pattern is a crystal with an irregular morphology of 20 μm or less in size, as shown in Figure 12.

[0268] The XRPD pattern of crystal form C is an X-ray powder diffraction pattern represented by a 2θ angle, and the 2θ angle and relative intensity of the diffraction peaks are shown in Table C.

[0269] [Table 18]

[0270] Example 9 Method for producing crystalline form D of compound monohydrochloride of formula I 400 mg of the monohydrochloride salt of compound 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 vacuum-dried under reduced pressure at 40°C. The solid was found to be crystalline form D.

[0271] The above-mentioned crystalline form D was the monodichloromethane solvate (or monodichloromethane solvate) of the monohydrochloride salt of the compound of formula I.

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

[0273] Table 4 shows the location and intensity of the characteristic XRPD peaks, and Figure 13 shows the XRPD pattern.

[0274] The DSC shows that the first exothermic peak appears around a peak temperature of 196.53°C, as shown in Figure 14.

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

[0276] The PLM pattern is a crystal with an irregular morphology of 10 μm or less in size, as shown in Figure 16.

[0277] The XRPD pattern of crystal form D is an X-ray powder diffraction pattern represented by a 2θ angle, and the 2θ angle and relative intensity of the diffraction peaks are shown in Table D.

[0278] [Table 19]

[0279] Example 10: Method for producing crystalline form E of compound monohydrochloride of formula I 400 mg of the monohydrochloride salt of compound I was taken, 8 mL of isopropanol was added, and the mixture was stirred at room temperature for 72 hours. The resulting suspension was separated by centrifugation, and the solid was vacuum-dried under reduced pressure at 40°C. The solid was found to be crystalline form E.

[0280] The above crystal form E is the monoisopropanol solvate of the monohydrochloride salt of the compound of formula I.

[0281] Crystal form E was characterized by XRPD, and the XRPD pattern is shown in Figure 17.

[0282] The XRPD pattern of crystal form E is an X-ray powder diffraction pattern represented by a 2θ angle, and the 2θ angle and relative intensity of the diffraction peaks are shown in Table E.

[0283] [Table 20]

[0284] Example 11: Consideration of the stability of crystalline form C of the monohydrochloride salt of compound I. The monohydrochloride salt of compound I was subjected to three crystalline forms C under the conditions of 40°C / 75% RH-closed, 40°C / 75% RH-open, and 60°C-open. After one month, the samples were removed, and the stability of the crystalline forms was investigated.

[0285] Table 14 shows the results of the chromatography conditions tests.

[0286] Method for measuring stability-related substances in the sample: Approximately 6 mg of the sample was weighed into a 40 mL clean glass vial, 10 mL of 50% acetonitrile aqueous solution was added, and the sample was completely dissolved by sonication. 10 μL of the sample was then injected to test for related substances, and the results are shown in Table 15. The XRPD patterns are shown in Figure 18, where HCl-salt Form3-initial (hereinafter referred to as initial) represents the XRPD pattern of crystalline form C produced 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 compound I exhibits good chemical stability after being left at 40°C / 75% RH and 60°C for one month. Furthermore, Figure 18 shows that the crystalline form of crystalline form C of the monohydrochloride salt of compound I has not changed.

[0290] Example 12: Effect of high temperature and high humidity on the crystal form C The monohydrochloride salt of compound I, in crystalline form C, was placed in an open state under conditions of 60°C, 80% RH, and 92.5% RH, and its crystalline form was evaluated for significant changes. The XRPD was sampled and tested at 1 d and 3 d, respectively. The XRPDs are shown in Figures 19 and 20.

[0291] Figures 19 and 20 show that the crystalline form C of the compound monohydrochloride of formula I did not change even after exposure to high temperature and high humidity conditions for 1 day and 3 days.

[0292] Example 13 Solubility test of compound I, 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 a medium (water, SGF, FaSSIF, FeSSIF, etc.) was added, and the mixture was stirred at 37°C. Appropriate amounts of the sample were taken at 1 h and 24 h, and the mixture was centrifuged at 12000 rpm for 10 min. The supernatant was diluted to an appropriate ratio with 50% acetonitrile aqueous solution, and its concentration was measured. The chromatographic conditions for the solubility test are shown in Table 16.

[0293] Control and Linear Analysis: 10 mg of the compound of formula I was weighed into a 50 mL volumetric flask, dissolved in 50% acetonitrile aqueous solution, and diluted to the marked level. Both samples were prepared in parallel. The control sample was taken and diluted with 50% acetonitrile aqueous solution to 100 μg / mL, 50 μg / mL, and 10 μg / mL. 5 μL of each sample was injected, and a standard curve was drawn.

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

[0295] [Table 23]

[0296] [Table 24]

[0297] From the above experimental results, it can be seen that crystalline form C has lower solubility in water compared to a mixture of crystalline forms A and B.

[0298] Exemplary embodiments of the present invention have been described above. However, the claims of this application are not limited to the above-described exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art, without departing from the spirit and principles of the present invention, should all be included within the scope of the claims of this application.

Claims

1. A pharmaceutically acceptable salt of the compound of formula I, 【Chemistry 1】 A pharmaceutically 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. A pharmaceutically acceptable salt of the compound of formula I.

2. The pharmaceutically acceptable salt of the compound of formula I is the monohydrochloride salt of the compound of formula I. A pharmaceutically acceptable salt of the compound of formula I as described in claim 1.

3. A method for producing a pharmaceutically acceptable salt of a compound of formula I, the method comprising reacting a compound of formula I with an acid to obtain a pharmaceutically acceptable salt of a compound of formula I, 【Chemistry 2】 The acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, citric acid, L-tartaric acid, and oxalic acid, and the molar ratio of the compound of formula I to the acid is 1:0.8 to 1:1.

5. A manufacturing method characterized by the following features.

4. The above-mentioned manufacturing method includes reacting a compound of formula I with the above-mentioned acid in a solvent to obtain a pharmaceutically acceptable salt of the compound of formula I, The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination of two or more of these; acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination of two or more of these; methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more of these; methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more of these. The manufacturing method according to claim 3.

5. A single crystal of the monohydrochloride salt of the compound of formula I, 【Transformation 3】 The unit cell parameters of the aforementioned single crystal are as follows: Orthorhombic crystal 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 the following features.

6. Crystal form A of the monohydrochloride salt of compound I, 【Chemistry 4】 The aforementioned crystal form A exhibits characteristic peaks at 9.66±0.20°, 16.08±0.20°, and 23.46±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form A characterized by the above.

7. The aforementioned crystal form A exhibits characteristic peaks at 9.66±0.20°, 16.08±0.20°, 18.10±0.20°, 21.30±0.20°, 21.68±0.20°, and 23.46±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form A as described in feature 6.

8. The aforementioned crystal form A exhibits characteristic peaks in its X-ray powder diffraction, expressed using Cu-Kα rays at a 2θ angle, with an error range of ±0.20° for the 2θ angle. Table 1 and / or, the crystalline form A is the anhydrous form of the monohydrochloride salt of the compound of formula I, and / or, the crystal form A is a crystal with an irregular shape, and the particle size of the crystal form A is 20 μm or less. Crystal form A as described in feature 6.

9. Crystalline form B of the monohydrochloride salt of compound I, 【Transformation 5】 The aforementioned crystal form B exhibits characteristic peaks at 18.10±0.20°, 19.80±0.20°, and 22.10±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form B characterized by this feature.

10. The aforementioned crystal form B exhibits 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° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form B according to feature 9.

11. The aforementioned crystal form B exhibits characteristic peaks in its X-ray powder diffraction, expressed using Cu-Kα rays at a 2θ angle, with an error range of ±0.20° for the 2θ angle. Table 2 and / or, the crystalline form B is the monohydrate of the monohydrochloride salt of the compound of formula I, and / or, the crystal form B is a crystal with an irregular shape, and the particle size of the crystal form B is 20 μm or less. Crystal form B according to feature 9.

12. The crystalline form C of the compound monohydrochloride salt of formula I, 【Transformation 6】 The aforementioned crystal form C exhibits characteristic peaks at 14.74±0.20°, 17.80±0.20°, 20.08±0.20°, and 21.98±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. A crystal form C characterized by the above.

13. The aforementioned crystalline form C exhibits 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° when measured using Cu-Kα rays and expressed at a 2θ angle. The crystal form C according to feature 12.

14. The aforementioned crystal form C exhibits characteristic peaks in its X-ray powder diffraction, expressed using Cu-Kα rays at a 2θ angle, with an error range of ±0.20°. Table 3 and / or, the crystalline form C is the anhydrous monohydrochloride salt of the compound of formula I, and / or, the crystal form C is a crystal with an irregular shape, and the particle size of the crystal form C is 20 μm or less. The crystal form C according to feature 12.

15. The crystalline form D of the compound monohydrochloride salt of formula I, 【Transformation 7】 The aforementioned crystal form D exhibits characteristic peaks at 15.74±0.20°, 16.58±0.20°, 21.98±0.20°, and 23.82±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form D characterized by this feature.

16. Crystal form E of the monohydrochloride salt of compound I, 【Transformation 8】 The aforementioned crystal form E exhibits characteristic peaks at 9.36±0.20°, 15.22±0.20°, 16.88±0.20°, and 22.10±0.20° when measured using Cu-Kα rays and expressed at a 2θ angle. Crystal form E characterized by the above.

17. A method for producing crystalline form A according to any one of claims 6 to 8, The process involves dissolving the compound of formula I in an alcoholic solvent, adding a solution containing HCl in the alcoholic solvent to form a salt, then adding a n-alkane to crystallize it and obtain the crystalline form A. The concentration of the solution in which the HCl is in an alcohol-based solvent is 1 to 3 mol / L, or The process involves heating and stirring the monohydrochloride salt of the compound of formula I in an alcoholic solvent and a n-alkane, dissolving and clarifying it, and then crystallizing it to obtain the crystalline form A. The heating temperature is 45 to 75°C. The aforementioned alcohol-based solvent is selected from ethanol and / or isopropanol. The n-alkane is selected from n-hexane and / or n-heptane. The mass-to-volume ratio of the compound of formula I or the monohydrochloride salt of the compound of formula I:alcoholic solvent:n-alkane is 1 g:(10-30) mL:(10-30) mL. A method for producing crystal form A, characterized by the above.

18. A method for producing crystalline form B according to any one of claims 9 to 11, This includes obtaining crystal form B by placing crystal form A described in any one of claims 6 to 8 under high humidity conditions, The aforementioned high humidity conditions are a temperature of 30 to 50°C and a humidity of 60% to 98%. A method for producing crystalline form B, characterized by the above.

19. A method for producing crystalline form C according to any one of claims 12 to 14, The process involves dissolving the compound of formula I in an alcohol-based solvent, then adding a solution containing HCl in the alcohol-based solvent to form a salt, and then adding an ether-based solvent or an ester-based solvent to crystallize and obtain crystalline form C. The aforementioned alcohol-based solvent is selected from methanol, ethanol, or isopropanol. The ether-based solvent is selected from methyl ether, ethyl ether, propyl ether, or methyl tert-butyl ether. The ester solvent is selected from ethyl acetate or isopropyl acetate. The mass-to-volume ratio of the compound of formula I, the alcohol-based solvent, and the ether-based solvent or ester-based solvent is 1 g: (2-8) mL: (20-40) mL. The concentration of the solution in which HCl is in an alcohol-based solvent is 1 to 3 mol / L, and the mass ratio of the compound of formula I to the solution in which HCl is in an alcohol-based solvent is 1 g : (0.5 to 1.5) g. A method for producing crystalline form C, characterized by the above.

20. A pharmaceutical composition comprising a pharmaceutically acceptable salt, single crystal, or at least one of the compounds of formula I described in any one of claims 1 to 2 and 5 to 16, crystalline form A, crystalline form B, crystalline form C, crystalline form D, and crystalline form E, and optionally pharmaceutically acceptable adjuvants. Pharmaceutical composition.

21. Use of at least one of the pharmaceutically acceptable salts, single crystals, crystal form A, crystal form B, crystal form C, crystal form D, and crystal form E of the compound of formula I described in any one of claims 1 to 2 and 5 to 16 in the manufacture of a drug for the prevention and / or treatment of complement factor B-mediated diseases or conditions.

22. The aforementioned complement factor B-mediated diseases or conditions are at least one selected from paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographical atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neurospinal inflammation (NMO), arthritis, rheumatoid arthritis, hepatic inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases, and cardiovascular diseases. The use described in claim 21.

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