Salts of piperidinyl indole compounds and methods for producing the same

Abstract

This invention relates to a salt of a piperidinyl indole compound, a method for producing the same, and its pharmaceutical uses. Specifically, it relates to a salt of the compound shown in general formula (I), its crystalline form, a method for producing it, a pharmaceutical composition containing a therapeutically effective amount of the crystalline form, and its pharmaceutical uses for treating diseases or disorders. TIFF2026522775000047.tif54170

Description

[Technical Field]

[0001] This invention belongs to the field of biopharmaceuticals and specifically relates to the crystalline form of piperidinyl indole compounds, their production methods, and applications. [Background technology]

[0002] The complement system is part of innate immune surveillance and plays a crucial role in eliminating pathogens and maintaining tissue homeostasis. The complement cascade can be activated by three distinct pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). CP and LP are initiated on target surfaces by the binding of immune complexes, mannan-binding lectins, or ficolins to specific microbial sugar moiety patterns, respectively. AP, however, does not require a specific initiation. The AP cascade is triggered by the spontaneous hydrolysis (tick-over) of C3 and the subsequent deposition of C3b on the activated surface. The three complement activation pathways are concentrated in two main events: C3 fission and C5 fission. C3 convertases split C3 into C3a and C3b. C3b forms additional AP C3 convertases (amplified) and C5 convertases. C5 convertases split C5 into C5a and C5b. The resulting C5b initiates the formation of the C5b-9 membrane invasion complex (MAC) with C6-C9, inducing bacterial and cell division by inserting into the membrane. The division products C3a and C5a act as allergic toxins, promoting pro-inflammatory responses through leukocyte activation and chemotaxis. C3b also promotes phagocytosis through conditioning, playing a crucial role in the removal of bacteria and cellular waste, such as immune complexes and apoptotic cells. (Front Immunol.2015 Jun 2;6:262.doi:10.3389 / fimmu.2015.00262.eCollection 2015.Complement System Part I-Molecular Mechanisms of Activation and Regulation.Nicolas S Merle,Sarah Elizabeth Church,Veronique Fremeaux-Bacchi,Lubka T Roumenina). AP maintains basal complement activity through "body tick-over". Furthermore, even when initiated by other CPs or LPs, APs contribute to the activation of over 80% of terminal cleavage pathways (MAC formation) via the amplification loop.(Harboe, M., Garred, P., Karlstro M, E., Lindstad, JK, Stahl, GL, Molnes, TE, 2009). The downstream effects of mannan-induced lectin complement pathway activation are quantitatively dependent on the amplification of alternative pathways (Mol.Immunol. 47, 373-380. https: / / doi.org / 10.1016 / j.molimm.2009.09.005). Spontaneously activated C3 forms C3 convertase by binding with factor B (FB). After factor D cleaves FB to Bb, C3b and Bb produce AP C3 convertase (C3bBb). The newly formed C3bBb cleaves more C3, producing more AP-C3 convertase and causing amplification of the complement cascade. Because AP can exert all complement activity within seconds, if not properly controlled, it can damage healthy tissue. (J Clin Invest. 2020 May 1;130(5):2152-2163.doi:10.1172 / JCI136094. Complementopathies and precision medicine. Eleni Gavriilaki, Robert A Brodsky). Imbalances in complement activation have already been shown to be associated with diseases of various organs, including paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, rheumatoid arthritis, hemolytic uremic syndrome, myasthenia gravis, and C3 glomerulonephritis. (J Clin Invest. 2020 May 1;130(5):2152-2163,doi:10.1172 / JCI136094). Therefore, controlling AP by FB inhibition may be a promising strategy to limit excessive activation of the complement pathway.

[0003] Currently, no small molecules for modulating the complement pathway have been approved. Examples of factor B inhibitors are described in the following publications: Advanced Vision Therapies Inc, W02008 / 106644, titled "Treatment of Inflammatory Diseases"; Wellstat Immunotherapy Patent Publication WO2012 / 151468, titled "Complement Factor B Analogue and Uses"; William Marsh Rice University, WO2014 / 035876, titled "Thermo-Inactivated Complement Factor B Composition and Method"; Muse Research and Development Foundation, PCT / US1999 / 023485, titled "Blocking Factor B for Treatment of Complement-Mediated Immune Diseases"; and Novartis patents WO2013 / 192345 and US2015 / 126492, titled "Complement Pathway Modulators and Uses". Other complement factor B inhibitors are described in Novartis patents WO2015 / 06241, US2016 / 311779, W0215 / 009166, US2016 / 152605, WO2014 / 14638, and US2016 / 024079. Another example of a complement factor B inhibitor is IONIS Pharmaceuticals' WO2015 / 038939, titled “Complement Factor B Modulator.” Examples of licensed patents relating to complement factor B inhibitors include US9452990, US9676728, US9682968, and US9475806.

[0004] Due to the numerous diseases caused by excessive activity of the complement pathway, there is a high but unmet need among patients with complement disorders. The present invention aims to provide compounds that regulate factor B and treat diseases associated with complement pathway imbalance.

[0005] PCT / CN2022 / 127975 discloses the structures of a series of piperidinyl indole compounds. In order to find suitable crystals that facilitate handling, filtration, and drying of the product in subsequent studies, are easily storable, and have excellent long-term product stability, the present invention has comprehensively studied the crystalline forms of the above compounds. [Overview of the Initiative]

[0006] All the content related to Patent PCT / CN2022 / 127975 is incorporated herein by reference into the present invention.

[0007] In one aspect, it is an acidic salt of a compound represented by general formula (I), and the structure of the compound is as shown below:

Chemical formula

Chemical formula

[0008] In some embodiments of the present invention, R1 is selected from C1-C3 alkyl groups, R2 is selected from C1-C3 alkoxy groups or cyclopropyl groups, R3 is selected from -COOH, R4 is selected from hydrogen, C1-C3 alkyl groups or C1-C3 haloalkyl groups, R5 and R6 are each independently selected from hydrogen or halogen.

[0009] In some embodiments of the present invention, the general formula (I) is [ka] Selected from the following compounds, Here, the acid is an inorganic acid or an organic acid, where the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, and the organic acid is selected from 1,5-naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, isethionic acid, acetic acid, maleic acid, fumaric acid, oxalic acid, malonic acid, tartaric acid, malic acid, adipic acid, hippuric acid, succinic acid or camphanic acid, preferably, where the acid is selected from p-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid, and more preferably, where the acid is selected from hydrochloric acid.

[0010] In some embodiments of the present invention, the compound is (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid, where the acid is an inorganic acid or an organic acid, where the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, and the organic acid is selected from 1,5-naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, isethionic acid, acetic acid, maleic acid, fumaric acid, oxalic acid, malonic acid, tartaric acid, malic acid, adipic acid, hippuric acid, succinic acid or camphanic acid, preferably where the acid is selected from p-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid, and more preferably where the acid is selected from hydrochloric acid.

[0011] In some embodiments of the present invention, the number of acids is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3, and even more preferably 1.

[0012] In some embodiments of the present invention, the acidic salt is a hydrate or an anhydrous, preferably an anhydrous, and when the acidic salt is a hydrate, the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3.

[0013] In a preferred embodiment of the present invention, a compound of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid (compound 3) or its stereoisomers and salts are provided, the structure of which is: [ka] That is the case.

[0014] In some embodiments of the present invention, the acidic salt of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid is in crystalline form.

[0015] In a preferred embodiment of the present invention, the salt crystal form of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid is selected from hydrobromide crystal form A, hydrochloride crystal form A, methanesulfonate crystal form A, hippurate crystal form A, malonate crystal form A, oxalate crystal form A, adipinate crystal form A, succinate crystal form A, phosphate crystal form A, and fumarate crystal form A.

[0016] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, 31.0, and 35.5, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected.

[0017] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide crystalline form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 8.8, 15.3, 17.5, and 22.8, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 22.0 and 26.4, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 25.4 and 31.0, and more preferably further including a characteristic peak at position where 2θ(±0.2°) is 35.5.

[0018] For example, the characteristic peak 2θ (±0.2°) is, 8.8, 17.5, 15.3, 22.8, 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, The values ​​are 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, 31.0, and 35.5.

[0019] Table 1 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and the interplanar spacing d value, obtained using Cu-Kα irradiation.

[0020] [Table 1]

[0021] The hydrobromide crystalline form A of compound 3 described in the present invention has an X-ray powder diffraction pattern substantially as shown in Figure 1, and its DSC pattern substantially as shown in Figure 2.

[0022] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.2, 15.7, 11.4, 16.8, 20.0, 13.7, 19.6, 20.3, and 21.7, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 9.2, 11.4, 15.7, and 20.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 13.7 and 16.8, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 19.6 and 20.3, and more preferably further including characteristic peaks at positions where 2θ(±0.2°) is 16.5 and 21.7.

[0023] For example, the characteristic peak 2θ (±0.2°) is, 15.7, 20.0, 9.2, 15.7, 20.0, 9.2, 15.7, 11.4, 16.8, 9.2, 15.7, 11.4, 20.0, 9.2, 15.7, 16.8, 20.0, 9.2, 15.7, 11.4, 16.8, 20.0, 19.6, 9.2, 15.7, 11.4, 16.8, 19.6, 13.7, 9.2, 21.7, 11.4, 16.8, 20.0, 13.7, 9.2, 15.7, 11.4, 21.7, 20.0, 13.7, 19.6, 15.7, 16.5, 16.8, 21.7, 13.7, 9.2, 15.7, 16.5, 16.8, 19.6, 13.7, 9.2, 15.7, 11.4, 16.8, 20.0, 13.7, 16.5, 20.3, 9.2, 15.7, 11.4, 16.8, 21.7, 13.7, 19.6, 20.3, 9.2, 15.7, 11.4, 16.8, 20.0, 16.5, 19.6, 20.3, 21.7, 15.7, 11.4, 16.5, 20.0, 13.7, 19.6, 20.3, 9.2, 21.7, 11.4, 16.8, 20.0, 13.7, 19.6, 16.5, 9.2, 15.7, 21.7, 16.8, 20.0, 13.7, 19.6, 20.3, The values ​​were 9.2, 15.7, 11.4, 16.8, 20.0, 13.7, 19.6, 20.3, and 21.7. Table 2 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0024] [Table 2]

[0025] For the hydrochloride salt crystal form A of compound 3 described in the present invention, its X-ray powder diffraction pattern is substantially as shown in Figure 3, its DSC pattern is substantially as shown in Figure 4, and its TGA pattern is substantially as shown in Figure 5.

[0026] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form B includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, 17.7, and 21.5, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form B has one or more characteristic peaks at positions where 2θ(±0.2°) is 7.2, 7.8, 14.0, and 15.9, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.5 and 20.0, and even more preferably including one or more characteristic peaks at positions where 2θ(±0.2°) is 17.7 and 21.5.

[0027] For example, the characteristic peak 2θ (±0.2°) is, 7.2, 15.9, 7.8, 14.0, 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, The values ​​are 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, 17.7, and 21.5.

[0028] Table 3 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0029] [Table 3]

[0030] The X-ray powder diffraction pattern of the hydrochloride salt crystal form B of compound 3 described in the present invention is substantially as shown in Figure 6, and its DSC pattern is substantially as shown in Figure 7.

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form C includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.2, 16.0, 14.8, 15.2, 8.8, and 18.4, and preferably includes characteristic peaks at two, four, or six of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form C has one or more characteristic peaks at positions where 2θ(±0.2°) is 9.2, 14.8, 15.2, and 16.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 8.8 and 18.4.

[0032] For example, the characteristic peak 2θ (±0.2°) is, 9.2, 16.0, 14.8, 15.2, The values ​​are 9.2, 16.0, 14.8, 15.2, 8.8, and 18.4.

[0033] Table 4 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0034] [Table 4]

[0035] The X-ray powder diffraction pattern of the hydrochloride salt crystal form C of compound 3 described in the present invention is substantially as shown in Figure 8, and its DSC pattern is substantially as shown in Figure 9.

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form D includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 23.3, 16.1, 13.1, 8.2, 15.9, 24.7, and 27.1, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form D has one or more characteristic peaks at positions where 2θ(±0.2°) is 8.2, 13.1, 23.3, and 16.1, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 15.9 and 24.7, and even more preferably including a characteristic peak at position 2θ(±0.2°) is 27.1.

[0037] For example, the characteristic peak 2θ (±0.2°) is, 23.3, 16.1, 13.1, 8.2, 23.3, 16.1, 13.1, 8.2, 15.9, 24.7, The values ​​are 23.3, 16.1, 13.1, 8.2, 15.9, 24.7, and 27.1. Table 5 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0038] [Table 5]

[0039] The X-ray powder diffraction pattern of the hydrochloride salt crystal form D of compound 3 described in the present invention is substantially as shown in Figure 10, and its DSC pattern is substantially as shown in Figure 11.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form E includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 23.0, 15.3, 9.8, 11.2, 12.7, 17.4, 20.6, and 25.0, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form E has one or more characteristic peaks at positions where 2θ(±0.2°) is 9.8, 11.2, 23.0, and 15.3, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 12.7 and 17.4, and even more preferably including one or more characteristic peaks at positions where 2θ(±0.2°) is 20.6 and 25.0.

[0041] For example, the characteristic peak 2θ (±0.2°) is, 23.0, 15.3, 9.8, 11.2, 23.0, 15.3, 9.8, 11.2, 12.7, 17.4, The values ​​were 23.0, 15.3, 9.8, 11.2, 12.7, 17.4, 20.6, and 25.0. Table 6 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0042] [Table 6]

[0043] The X-ray powder diffraction pattern of the hydrochloride salt crystal form E of compound 3 described in the present invention is substantially as shown in Figure 12, and its DSC pattern is substantially as shown in Figure 13.

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form F includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.3, 19.4, 8.4, 10.3, 13.2, 17.5, and 18.9, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form F has one or more characteristic peaks at positions where 2θ(±0.2°) is 8.4, 9.3, 10.3, and 19.4, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 13.2 and 17.5, and even more preferably including one or more characteristic peaks at position 2θ(±0.2°) is 18.9.

[0045] For example, the characteristic peak 2θ (±0.2°) is, 9.3, 19.4, 8.4, 10.3, 9.3, 19.4, 8.4, 10.3, 13.2, 17.5, The values ​​were 9.3, 19.4, 8.4, 10.3, 13.2, 17.5, and 18.9. Table 7 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0046] [Table 7]

[0047] The X-ray powder diffraction pattern of the hydrochloride salt crystal form F of compound 3 described in the present invention is substantially as shown in Figure 14, and its DSC pattern is substantially as shown in Figure 15.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form G includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.0, 9.9, 13.0, 13.9, 16.0, 16.6, and 22.9, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form G has one or more characteristic peaks at positions where 2θ(±0.2°) is 8.0 and 9.9, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 13.0 and 13.9, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 16.0 and 16.6, and more preferably further including a characteristic peak at position where 2θ(±0.2°) is 22.9.

[0049] For example, the characteristic peak 2θ (±0.2°) is, 8.0, 9.9, 13.0, 13.9, 8.0, 9.9, 13.0, 13.9, 16.0, 16.6, The values ​​are 8.0, 9.9, 13.0, 13.9, 16.0, 16.6, and 22.9. Table 8 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0050] [Table 8]

[0051] The X-ray powder diffraction pattern of the hydrochloride salt crystal form G of compound 3 described in the present invention is substantially as shown in Figure 16.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form H includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 6.8, 10.0, 11.4, 13.6, 20.0, 21.5, 26.0, and 31.9, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form H has one or more characteristic peaks at positions where 2θ(±0.2°) is 6.8, 10.0, 11.4, and 13.6, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 20.0 and 21.5, and even more preferably including one or more characteristic peaks at positions where 2θ(±0.2°) is 26.0 and 31.9.

[0053] For example, the characteristic peak 2θ (±0.2°) is, 6.8, 10.0, 11.4, 13.6, 6.8, 10.0, 11.4, 13.6, 20.0, 21.5, The values ​​were 6.8, 10.0, 11.4, 13.6, 20.0, 21.5, 26.0, and 31.9. Table 9 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0054] [Table 9]

[0055] The X-ray powder diffraction pattern of the hydrochloride salt crystal form H of compound 3 described in the present invention is substantially as shown in Figure 17, and its DSC pattern is substantially as shown in Figure 18.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form I includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.5, 19.6, 13.8, 23.0, 24.2, 16.8, 18.0, and 21.2, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form I has one or more characteristic peaks at positions where 2θ(±0.2°) is 9.5, 13.8, 19.6, and 23.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.4 and 24.2, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 16.8 and 18.0, and more preferably further including characteristic peaks at positions where 2θ(±0.2°) is 8.8 and 21.2. For example, the characteristic peak 2θ (±0.2°) is, 9.5, 19.6, 9.5, 19.6, 13.8, 9.5, 19.6, 13.8, 23.0, 9.5, 19.6, 10.4, 23.0, 9.5, 10.4, 13.8, 23.0, 10.4, 19.6, 13.8, 24.2, 9.5, 10.4, 19.6, 13.8, 23.0, 24.2, 9.5, 10.4, 19.6, 13.8, 23.0, 16.8, 9.5, 10.4, 19.6, 13.8, 16.8, 24.2, 9.5, 10.4, 19.6, 18.0, 23.0, 24.2, 16.8, 10.4, 18.0, 13.8, 23.0, 24.2, 9.5, 16.8, 18.0, 13.8, 23.0, 24.2, 9.5, 19.6, 13.8, 23.0, 24.2, 10.4, 16.8, 18.0, 8.8, 19.6, 13.8, 23.0, 24.2, 10.4, 16.8, 21.2, 9.5, 19.6, 13.8, 23.0, 24.2, 10.4, 8.8, 18.0, 9.5, 19.6, 13.8, 23.0, 24.2, 8.8, 21.2, 18.0, 9.5, 8.8, 13.8, 23.0, 21.2, 10.4, 16.8, 18.0, The values ​​were 9.5, 19.6, 8.8, 21.2, 24.2, 10.4, 16.8, and 18.0. Table 10 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0057] [Table 10]

[0058] The hydrochloride salt crystal form I of compound 3 described in the present invention has a substantially X-ray powder diffraction pattern as shown in Figure 19, and a substantially DSC pattern as shown in Figure 20. The hydrochloride salt crystal form I is a hydrate crystal form. The hydrochloride salt crystal form I of the present invention has good reproducibility and stability, and is suitable for industrial production.

[0059] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form J includes diffraction peaks at one or more locations among those where 2θ(±0.2°) is 9.5, 19.6, 13.8, 23.0, 21.2, 21.7, 26.5, 7.5, 8.8, 9.5, 18.0, and 18.1, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystalline form J has one or more characteristic peaks at positions where 2θ(±0.2°) is 9.5, 13.8, 19.6, and 23.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 21.2 and 21.7, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 7.5 and 26.5, and more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 8.8, 9.5, 18.0, and 18.1.

[0060] For example, the characteristic peak 2θ (±0.2°) is, 9.5, 19.6, 13.8, 23.0, 9.5, 19.6, 13.8, 23.0, 21.2, 21.7, 26.5, The values ​​were 9.5, 19.6, 13.8, 23.0, 21.2, 21.7, 26.5, 7.5, 8.8, 9.5, and 18.1. Table 11 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0061] [Table 11]

[0062] The X-ray powder diffraction pattern of the hydrochloride salt crystal form J of compound 3 described in the present invention is substantially as shown in Figure 21, and its DSC pattern is substantially as shown in Figure 22.

[0063] In some embodiments of the present invention, for methanesulfonate crystal form A, the X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.4, 20.0, 13.7, 14.5, 23.6, 20.5, and 23.8, and preferably includes characteristic peaks at two, four, or six of these locations, which are selected from among them. In some embodiments of the present invention, for methanesulfonate crystal form A, the X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ(±0.2°) is 8.4 and 20.0, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 13.7 and 14.5, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 20.5 and 23.6, and more preferably further including a characteristic peak at position where 2θ(±0.2°) is 23.8.

[0064] For example, the characteristic peak 2θ (±0.2°) is, 8.4, 20.0, 13.7, 14.5, 8.4, 20.0, 13.7, 14.5, 23.6, The values ​​were 8.4, 20.0, 13.7, 14.5, 23.6, 20.5, and 23.8. Table 12 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0065] [Table 12]

[0066] The X-ray powder diffraction pattern of the methanesulfonate crystalline form A of compound 3 described in the invention is substantially as shown in Figure 23, and its DSC pattern is substantially as shown in Figure 24.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, 19.5, and 23.3, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 7.2, 8.6, 10.9, and 12.8, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 16.4 and 17.7, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.6 and 13.4, and more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 14.0, 18.2, 19.5, and 23.3.

[0068] For example, the characteristic peak 2θ (±0.2°) is, 7.2, 12.8, 8.6, 10.9, 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, The values ​​were 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, 19.5, and 23.3. Table 13 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0069] [Table 13]

[0070] The X-ray powder diffraction pattern of p-toluenesulfonate crystalline form A of compound 3 described in the invention is substantially as shown in Figure 25, and its DSC pattern is substantially as shown in Figure 26.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the hippurate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 8.1, 14.2, 21.6, 10.5, 20.5, and 25.8, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the hippurate crystal form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 7.4, 8.1, 10.0, and 14.2, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.5 and 21.6, and even more preferably including one or more characteristic peaks at positions where 2θ(±0.2°) is 20.5 and 25.8.

[0072] For example, the characteristic peak 2θ (±0.2°) is, 7.4, 10.0, 8.1, 14.2, 7.4, 10.0, 8.1, 14.2, 21.6, 10.5, 20.5, The values ​​are 7.4, 10.0, 8.1, 14.2, 21.6, 10.5, 20.5, and 25.8.

[0073] Table 14 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0074] [Table 14]

[0075] The X-ray powder diffraction pattern of the hippurate crystalline form A of compound 3 described in the invention is substantially as shown in Figure 27.

[0076] In some embodiments of the present invention, the X-ray powder diffraction pattern of the malonate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 11.7, 14.3, 18.1, and 20.4, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the malonate crystal form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 4.8, 7.4, 9.5, and 19.1, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 12.3 and 23.1, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 11.7 and 14.3, and more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 18.1 and 20.4.

[0077] For example, the characteristic peak 2θ (±0.2°) is, 4.8, 19.1, 7.4, 9.5, 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 11.7, 14.3, The values ​​are 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 11.7, 14.3, 18.1, and 20.4.

[0078] Table 15 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0079] [Table 15]

[0080] The X-ray powder diffraction pattern of malonate crystalline form A of compound 3 described in the invention is substantially as shown in Figure 28.

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the oxalate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 4.8, 9.6, 10.1, 14.4, 19.2, 18.6, 22.1, 22.8, and 24.1, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the oxalate crystal form A has an X-ray powder diffraction pattern with one or more characteristic peaks at positions where 2θ(±0.2°) is 4.8, 9.6, 10.1, and 14.4, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 18.6 and 19.2, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 22.1 and 22.8, and more preferably further including a characteristic peak at position where 2θ(±0.2°) is 24.1.

[0082] For example, the characteristic peak 2θ (±0.2°) is, 4.8, 9.6, 10.1, 14.4, 4.8, 9.6, 10.1, 14.4, 19.2, 18.6, The values ​​are 4.8, 9.6, 10.1, 14.4, 19.2, 18.6, 22.1, 22.8, and 24.1.

[0083] Table 16 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0084] [Table 16]

[0085] The oxalate crystal form A of compound 3 described in the invention has a substantially X-ray powder diffraction pattern as shown in Figure 29, and its DSC pattern is substantially as shown in Figure 30.

[0086] In some embodiments of the present invention, the X-ray powder diffraction pattern of the adipinate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, 14.2, 14.9, 20.5, 21.2, 21.5, and 23.2, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the adipinate crystal form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 7.4, 7.7, 10.0, and 12.3, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 19.5 and 21.7, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 1.8 and 25.8, and more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 14.2, 14.9, 20.5, 21.2, 21.5, and 23.2.

[0087] For example, the characteristic peak 2θ (±0.2°) is, 7.4, 10.0, 7.7, 12.3, 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, The values ​​were 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, 14.2, 14.9, 20.5, 21.2, 21.5, and 23.2. Table 17 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0088] [Table 17]

[0089] The X-ray powder diffraction pattern of the adipinate crystalline form A of compound 3 described in the invention is substantially as shown in Figure 31, and its DSC pattern is substantially as shown in Figure 32.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of succinate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 8.1, 11.8, 18.2, and 25.9, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the succinate crystal form A has an X-ray powder diffraction pattern with one or more characteristic peaks at positions where 2θ(±0.2°) is 7.4, 7.8, 9.5, and 10.0, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 19.1 and 20.5, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 8.1 and 11.8, and more preferably further including characteristic peaks at positions where 2θ(±0.2°) is 18.2 and 25.9.

[0091] For example, the characteristic peak 2θ (±0.2°) is, 7.4, 10.0, 7.8, 9.5, 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 8.1, 11.8, The scores were 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 8.1, 11.8, 18.2, and 25.9. Table 18 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0092] [Table 18]

[0093] The X-ray powder diffraction pattern of succinate crystal form A of compound 3 described in the invention is substantially as shown in Figure 33.

[0094] In some embodiments of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 5.5, 8.6, 7.5, 12.9, 18.3, 10.6, 12.4, 17.3, and 25.3, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the phosphate crystal form A has an X-ray powder diffraction pattern with one or more characteristic peaks at positions where 2θ(±0.2°) is 5.5, 8.6, 7.5, and 12.9, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.6 and 18.3, more preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 12.4 and 17.3, and more preferably further including a characteristic peak at position where 2θ(±0.2°) is 25.3.

[0095] For example, the characteristic peak 2θ (±0.2°) is, 5.5, 8.6, 7.5, 12.9, 5.5, 8.6, 7.5, 12.9, 18.3, 10.6, The values ​​were 5.5, 8.6, 7.5, 12.9, 18.3, 10.6, 12.4, 17.3, and 25.3. Table 19 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0096] [Table 19]

[0097] The phosphate crystal form A of compound 3 described in the invention has a substantially X-ray powder diffraction pattern as shown in Figure 34, and a substantially DSC pattern as shown in Figure 35.

[0098] In some embodiments of the present invention, the X-ray powder diffraction pattern of the fumarate crystal form A includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.5, 10.7, 7.9, 14.4, 15.0, 8.3, 10.0, and 20.5, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected from among them. In some embodiments of the present invention, the X-ray powder diffraction pattern of the fumarate crystal form A has one or more characteristic peaks at positions where 2θ(±0.2°) is 7.5, 10.7, 7.9, and 14.4, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ(±0.2°) is 8.3 and 15.0, and even more preferably including one or more characteristic peaks at positions where 2θ(±0.2°) is 10.0 and 20.5.

[0099] For example, the characteristic peak 2θ (±0.2°) is, 7.5, 10.7, 7.9, 14.4, 7.5, 10.7, 7.9, 14.4, 15.0, 8.3, The values ​​are 7.5, 10.7, 7.9, 14.4, 15.0, 8.3, 10.0, and 20.5.

[0100] Table 20 shows the characteristic X-ray diffraction peaks, expressed by the 2θ angle and lattice plane spacing d, obtained using Cu-Kα radiation.

[0101] [Table 20]

[0102] The X-ray powder diffraction pattern of the fumarate crystal form A of compound 3 described in the invention is substantially as shown in Figure 36.

[0103] In a more preferred embodiment of the present invention, the crystalline form described above is a crystalline form containing a solvent, where the solvent is selected from water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, n-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, or isopropyl ether.

[0104] In a more preferred embodiment of the present invention, the number of solvents is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 0.5, 1, 2, or 3.

[0105] The present invention further provides a method for producing compounds of a compound represented by general formula (I), or its stereoisomers and salt crystal forms, specifically, Step 1) involves weighing an appropriate amount of free base and dissolving it in a good solvent, Step 2) involves weighing an appropriate amount of counterionic acid and dissolving it in an organic solvent, wherein the amount of counterionic acid is preferably 1 equivalent. Step 3) involves combining the two solutions mentioned above and stirring to precipitate them, or adding a poor solvent dropwise and then stirring to precipitate them. Step 4) involves rapidly centrifuging or letting it stand and blow-drying to obtain the desired product, Here, The good solvent is selected from methanol, dichloromethane, 1,4-dioxane, acetone, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, N,N-dimethylacetamide, or N-methylpyrrolidone, and is preferably methanol or ethyl acetate. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide, preferably methanol, acetone, or ethyl acetate. The good solvent and the organic solution must be miscible at the time of use. The poor solvent is selected from heptane, water, and cyclohexane, and is preferably water or n-heptane. The present invention further provides a method for producing compounds of a compound represented by general formula (I), or its stereoisomers and salt crystal forms, specifically, Step 1) involves weighing an appropriate amount of free base and suspending it in a poor solvent, Step 2) involves weighing an appropriate amount of counterionic acid and dissolving it in an organic solvent, wherein the amount of counterionic acid is preferably 1 equivalent. Step 3) involves combining the two solutions mentioned above, stirring to dissolve them, and then continuing to stir to precipitate them, or adding a poor solvent dropwise and then stirring to precipitate them. Step 4) involves rapidly centrifuging or letting it stand and blow-drying to obtain the desired product, The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide, and is preferably methanol. The poor solvent is selected from heptane, acetonitrile, ethanol, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, or toluene, preferably methyl tert-butyl ether, and the poor solvent and the organic solution must be miscible at the time of use. The aforementioned counterionic acids include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, and ethanesulfonic acid. The acid is selected from formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid, preferably methanesulfonic acid, p-toluenesulfonic acid, or hydrochloric acid, most preferably hydrochloric acid.

[0106] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of an acidic salt of the compound described above, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0107] The present invention further relates to a method for treating a disease or disorder related to the activation of a complement alternative pathway by modulating complement factor B in a subject requiring such treatment, comprising administering to the subject an effective amount of an acidic salt of the compound described above, or a pharmaceutical composition described above.

[0108] Furthermore, the aforementioned diseases or disorders include age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal chorioretinopathy, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot chorioretinopathy, sympathetic ophthalmitis, ocular pemphigoid, pemphigus ophthalmosum, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induction toxicity during IL-2 treatment, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in extracorporeal circulation or renal bypass, and atherosclerotic dysplasia. Pulmonary sclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex disease and autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative glomerulonephritis, hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibroblastic dust disease, pulmonary fibrosis, asthma, allergy The following conditions are selected: bronchoconstriction, hypersensitivity pneumonitis, parasitic infections, Goodpasture syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, primary glomerulonephritis (IgAN) and obesity, C3 glomerulonephritis (C3G), lupus nephritis (LN), immunoglobulin A (IgA) nephropathy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), early to mid-age-related macular degeneration (e / i AMD), idiopathic membranous nephropathy, and immune complex membrane proliferative glomerulonephritis (IC-MPGN). [Brief explanation of the drawing]

[0109] [Figure 1] This is the XRPD pattern of hydrobromide crystalline form A. [Figure 2] This is the DSC pattern of hydrobromide crystalline form A. [Figure 3] This is the XRPD pattern of hydrochloride crystalline form A. [Figure 4] This is the DSC pattern of hydrochloride crystalline form A. [Figure 5] This is the TGA pattern of hydrochloride crystalline form A. [Figure 6] This is the XRPD pattern of hydrochloride crystalline form B. [Figure 7] This is the DSC pattern of hydrochloride crystalline form B. [Figure 8] This is the XRPD pattern of hydrochloride crystalline form C. [Figure 9] This is the DSC pattern of hydrochloride crystalline form C. [Figure 10] This is the XRPD pattern of hydrochloride crystalline form D. [Figure 11] This is the DSC pattern of hydrochloride crystalline form D. [Figure 12] This is the XRPD pattern of hydrochloride crystal form E. [Figure 13] This is the DSC pattern of hydrochloride crystalline form E. [Figure 14] This is the XRPD pattern of hydrochloride crystalline form F. [Figure 15] This is the DSC pattern of hydrochloride crystalline form F. [Figure 16] This is the XRPD pattern of hydrochloride crystalline form G. [Figure 17] This is the XRPD pattern of the hydrochloride crystalline form H. [Figure 18] This is the DSC pattern of the hydrochloride crystalline form H. [Figure 19] This is the XRPD pattern of hydrochloride crystalline form I. [Figure 20] This is the DSC pattern of hydrochloride crystalline form I. [Figure 21] This is the XRPD pattern of hydrochloride crystalline form J. [Figure 22] This is the DSC pattern of hydrochloride crystalline form J. [Figure 23] This is the XRPD pattern of methanesulfonate crystal form A. [Figure 24] This is the DSC pattern of methanesulfonate crystal form A. [Figure 25] This is the XRPD pattern of p-toluenesulfonate crystal form A. [Figure 26]This is the DSC pattern of p-toluenesulfonate crystal form A. [Figure 27] This is the XRPD pattern of hippurate crystal form A. [Figure 28] This is the XRPD pattern of malonate crystal form A. [Figure 29] This is the XRPD pattern of oxalate crystal form A. [Figure 30] This is the DSC pattern of oxalate crystal form A. [Figure 31] This is the XRPD pattern of adipinate crystal form A. [Figure 32] This is the DSC pattern of adipinate crystal form A. [Figure 33] This is the XRPD pattern of succinate crystal form A. [Figure 34] This is the XRPD pattern of phosphate crystal form A. [Figure 35] This is the DSC pattern of phosphate crystal form A. [Figure 36] This is the XRPD pattern of fumarate crystal form A. [Figure 37] This figure shows the in vitro evaluation of the inhibitory effect on mouse plasma PD. [Figure 38] This is the TGA pattern of hydrochloride crystalline form I. [Figure 39] This is the DVS pattern of hydrochloride crystalline form I. [Figure 40] These are the XRPD patterns of hydrochloride crystal form I after polishing for 1 minute and 3 minutes. [Modes for carrying out the invention]

[0110] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0111] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, and 5-methylhexyl group. Examples include 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.

[0112] The alkyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available bonding site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups, and in the present invention, preferably methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, haloalkyl groups, deuterated alkyl groups, alkyl groups substituted with alkoxy groups, and alkyl groups substituted with hydroxyl groups, and the alkyl group substituted with a hydroxyl group may be a 2-hydroxyisopropyl group or a 1-hydroxyethyl group.

[0113] In the present invention, the alkoxy group refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of alkyl group is as described above, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most even more preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. The alkoxy group may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups. Non-limiting examples of alkoxy groups include propane-2-oxy groups, among others.

[0114] In the present invention, a haloalkyl group refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above. Non-limiting examples of haloalkyl groups include trifluoromethyl groups and trifluoroethyl groups. Non-limiting examples of haloalkyl groups include difluoromethyl groups, 1,1,2,2-tetrafluoroethyl groups, perfluoroethyl groups, and the like.

[0115] In the present invention, a haloalkoxy group refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above. The haloalkoxy group may be perhalogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., and the halogen is preferably F, Cl, Br, or I, and may be, for example, a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a perfluoroethoxy group, etc.

[0116] In the present invention, a cycloalkyl group refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may be optionally substituted with one or more substituents. In specific embodiments, the ring of the cycloalkyl group is 3-20(C 3-20 ), 3~12(C 3-12 ), 3~8(C 3-8 ) or 3-6 (C 3-6 ) containing carbon atoms, in one embodiment, the cycloalkyl ring is 6-14(C 6-14 ) or 7-10 (C 7-10It contains ) carbon atoms, which may contain one or more double bonds but do not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, or cyclooctyl groups, and in one embodiment, polycyclic cycloalkyl groups include spirocycloalkyl groups, condensed cycloalkyl groups, and crosslinked cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group as described elsewhere in this specification, or a cycloalkyl group optionally condensed with a heterocyclyl, aryl, or heteroaryl group, and non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl groups.

[0117] "Hydroxy group" refers to the -OH group.

[0118] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0119] The term "amino group" refers to -NH2.

[0120] The "cyano group" refers to -CN.

[0121] The "nitro group" refers to -NO2.

[0122] "THF" refers to tetrahydrofuran.

[0123] ",''" refers to ethyl acetate.

[0124] "DMSO" refers to dimethyl sulfoxide.

[0125] "IPA" refers to isopropanol.

[0126] "MeOH" refers to methanol.

[0127] "EtOH" refers to ethanol.

[0128] Various phrases such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all express the same meaning, indicating that X can be one or more of A, B, or C.

[0129] "Optional" or "optionally" means that the events or environments described later may occur, but are not required to occur, and the description includes cases where the events or environments have occurred or not.

[0130] "Substituting" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are substituted independently of each other by a corresponding number of substituents. Needless to say, substituents exist only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable if bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

[0131] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0132] As used herein, the names of compounds are intended to encompass all possible isomeric forms, including stereoisomers of the compound (e.g., enantiomers, diastereomers, racemates or racemic mixtures and any mixture thereof).

[0133] Any of the hydrogen atoms described in the present invention may be substituted with its isotope deuterium, and any of the hydrogen atoms in the compounds of the examples according to the present invention may also be substituted with a deuterium atom.

[0134] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0135] A powder X-ray diffraction pattern (XRPD) refers to the diffraction pattern observed experimentally or the parameters derived therefrom, characterized by the peak position (horizontal coordinate) and peak intensity (vertical coordinate). As those skilled in the art will understand, the experimental error within it depends on the instrument conditions, sample preparation, and sample purity. In particular, as is well known to those skilled in the art, the X-ray diffraction pattern usually varies depending on the instrument conditions, and as those skilled in the art should understand, appropriate error tolerances for the XRPD may be 2θ±0.5°, 2θ±0.4°, 2θ±0.3°, and 2θ±0.2°. It should be especially noted that the relative intensity of the X-ray diffraction pattern may also vary depending on the experimental conditions, so the order of peak intensities is not the sole or decisive factor. Furthermore, due to the influence of experimental factors such as sample height, an overall shift in the peak angles occurs, and a certain degree of shift is usually acceptable. Therefore, as those skilled in the art will understand, any crystal form having characteristic peaks that are the same as or similar to the characteristic peaks of the pattern of the present invention falls within the scope of the present invention.

[0136] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0137] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0138] "HPLC" refers to a high-performance liquid chromatography (HPLC) experiment.

[0139] "PK" refers to pharmacokinetic (PK) experiments.

[0140] The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention. Manufacturing of compounds

[0141] The following examples are for interpreting the present invention, but should not be considered as limiting the scope of the invention. Where specific experimental conditions are not specifically described in the examples of the present invention, the usual or recommended conditions of the raw materials and product manufacturers are generally followed. Reagents whose specific source is not specified are commonly available commercially.

[0142] The structure of each compound is identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR chemical displacement (δ) is 10 -6 The values ​​are given in ppm. NMR is measured using a Varian Mercury 300 MHz instrument and a Bruker Avance III 400 MHz instrument. The solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD).

[0143] High-performance liquid chromatography (HPLC) is measured using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6mm chromatography column). Liquid chromatography (LCMS) is measured using an Agilent 1200 high-pressure liquid chromatograph & mass spectrometer (Sunfire C18 4.6*50mm 3.5um chromatography column) and an Agilent 19091S-433 HP-5 high-pressure liquid chromatograph & mass spectrometer (XBridge C18 4.6*50mm 3.5um chromatography column).

[0144] Chiral high-performance liquid chromatography (HPLC) is measured using SFC Thar 80, 150, and 200 (waters).

[0145] Victor Nivo multimodal reader (PerkinElmer, USA) measured mean ATPase inhibition rate and IC50. 50 Measure the value.

[0146] The thin-layer silica gel plates used in thin-layer chromatography are Yantai Xinnuo silica gel plates. The plate size used in TLC is 0.15 mm to 0.2 mm, while the plate size used in thin-layer chromatography for product purification is 0.4 mm to 0.5 mm.

[0147] Column chromatography typically uses 200-300 mesh silica gel as a support.

[0148] The known raw materials of the present invention can be produced by conventional synthesis methods or purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, or Dari Chemical Company.

[0149] MS stands for Mass Spectrometry, where (+) usually indicates a positive pattern that gives M+1 (or M+H) absorption, and M = molecular weight. Example 1 [ka] Step 1: Synthesis of Intermediate 1-1

[0150] To a solution of 4-bromo-3-formylmethyl benzoate (10.2 g, 42.2 mmol) in dichloroethane (153 ml, 15V), DAST (33.99 g, 210.9 mmol) was added, and the mixture was heated to room temperature at -80°C under an N2 atmosphere and maintained for 4 hours. The reaction mixture was quenched with NH4Cl solution and concentrated under vacuum to obtain a yellow oily product 1-1 (7.70 g, yield 69%). LCMS (m / z): [M+H]+ Calculated value for C9H8BrF2O2, 265.0; measured value, 265.0. Step 2: Synthesis of Intermediate 1-2

[0151] At room temperature, under a N2 atmosphere, B2Pin2 (10.3 g, 40.7 mmol), Pd(dppf)Cl2·CH2Cl2 (2.38 g, 2.91 mmol) and KOAc (8.28 g, 84.4 mmol) were added to a solution of 1-1 (7.70 g, 29.1 mmol) in dioxane (116 mL, 15 V). The mixture was heated at 90 °C for 4 h and then filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether = 10 / 1) to afford the yellow oil product 1-2 (5.10 g, yield 56%). LCMS (m / z): [M+H] + C 15 H 20 Calculated value for CBF2O4, 313.1; measured value, 313.0. Step 3: Synthesis of Intermediate 1-3

[0152] At room temperature, in a glove box, purified water (5 mL, 2 V), Rh(Acac)(C2H4)2 (84 mg, 0.32 mmol) and (R,R)-Ph-PBE (164 mg, 0.324 mmol) were added to a solution of 43-2 (5.06 g, 16.2 mmol, 1.5 equiv) and benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.50 g, 10.8 mmol, 1.0 equiv) in tert-pentanol (50 mL, 20 V). The mixture was stirred at 50 °C for 12 h and then filtered. The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether = 4 / 1) to afford the yellow oil product 1-3 (2.08 g, yield 46%, 100% ee). LCMS (m / z): [M+H] + C 22 H 22 Calculated value for C25H28F2NO5, 418.15; measured value, 418.19.

[0153] Test method: Column for chromatography: CHIRALPAK IA 4.6*250 mm, 5 μm Mobile phase: 60% hexane, 40% ethanol, 0.1% methanesulfonic acid Flow rate: 1.0mL / min Column temperature: 30℃ Holding time=7.9min Step 4: Synthesis of Intermediates 1-4

[0154] At room temperature, under an N2 atmosphere, NaOtBu (684 mg, 7.12 mmol, 1.43 equiv) was added to a solution of PPh3CH3Br (2.668 g, 7.47 mmol, 1.5 equiv) in toluene (21.6 mL, 20 V) using a balloon. The mixture was stirred at room temperature for 2 hours. At room temperature, the above mixture was added to a solution of 1-3 (0.080 g, 4.94 mmol, 1.0 equiv) in toluene (10.8 mL, 10 V) and stirred for 1 hour. The reaction mixture was quenched with 108 mL (50 V) saturated NH4Cl solution, extracted with ethyl acetate (156 mL x 2,75 V), washed with saline solution (52 mL, 25 V), dried over Na2SO4, concentrated under vacuum, and purified by high-performance column chromatography (ethyl acetate:petroleum ether = 1 / 16~1 / 8) on silica gel to obtain a colorless oily substance 1-4 (1.16 g, yield 56%). LCMS(m / z):[M+H] + C 23 H 24 F2NO4 calculated value: 416.2; measured value: 416.3. Step 5: Synthesis of Intermediates 1-5

[0155] Under nitrogen gas atmosphere and at a temperature of 20°C, trichloroacetyl chloride (4.4g, 24 mmol, 10 equiv) was added to a dioxane (70 mL, 70 V) suspension of Cu-Zn (3.5 g, 3% Cu) and 1-4 (1.0 g, 2.4 mmol, 1.0 equiv) within 30 minutes. The mixture was heated at 35°C for 3 hours. The reaction mixture was quenched with NH4Cl solution. The solid was filtered off, and the filtrate was extracted with ethyl acetate (30 mL x 3, 30 V) and washed with saline solution (40 mL, 40 V). The combined filtrate was dried over Na2SO4 and concentrated under vacuum to obtain the oily crude product 1-5 (1.17 g), which was used in the next step without purification. LCMS (m / z): [M+H] + C 25 H 23 Calculated value of Cl2F2NO5: 526.1; measured value: 526.3. Step 6: Synthesis of Intermediates 1-6

[0156] At room temperature, NH4Cl (2.6 g, 48 mmol) and zinc (1.6 g, 24 mmol) were added to a solution of 1-5 (1.17 g, crude) in MeOH (50 mL). The reaction mixture was stirred at 60 °C for 2 hours and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by high-performance column chromatography (ethyl acetate:petroleum ether = 4 / 1) on silica gel to obtain the oily product 1-6 (830 mg, 2-step yield 75%). LCMS (m / z): [M+H] + C 25 H 26 F2NO5 calculated value: 458.2; measured value: 458.3. Step 7: Synthesis of Intermediates 1-7

[0157] 1-6 (830 mg, 1.82 mmol) was dissolved in BAST (1.5 mL) at 0°C. The reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was cooled to room temperature and 15 mL of ethyl acetate was added. The reaction mixture was carefully poured onto ice (10 g). The residue was extracted with ethyl acetate (30 mL x 3), washed with saline solution (30 mL), and dried over Na2SO4. The filtrate was concentrated under vacuum and purified by high-performance column chromatography (ethyl acetate:petroleum ether = 4 / 1) on silica gel to obtain the oily product 1-7 (569 mg, yield 65%). LCMS (m / z): [M+H] + C 25 H 26 F4NO4 calculated value: 480.2; measured value: 480.1. Step 8: Synthesis of Intermediates 1-8

[0158] Activated carbon (569 mg) was added to a solution of 1-7 (569 mg, 1.19 mmol) in MeOH (17 mL). The reaction was heated under reflux for 0.5 hours. The activated carbon was filtered, and Pd / C (57 mg, Pd 10%) was added to the filtrate. The reaction mixture was stirred at room temperature using an H2 balloon for 2 hours. Pd / C was removed, and the filtrate was filtered under vacuum to obtain the oily product 1-8 (328 mg, yield 80%). LCMS (m / z): [M+H] + C 17 H 20 F4NO2 calculated value: 346.1; measured value: 346.2. Step 9: Synthesis of Intermediates 1-9

[0159] Aldehyde (316 mg, 1.09 mmol) and NaBH(OAc)3 (632 mg, 2.98 mmol) were added to a 1.5 mL solution of 1-8 (330 mg, 0.95 mmol) in DCE. The mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with 1.0 mL of water, the solvent was removed by distillation, and the mixture was concentrated to obtain the crude product. The crude product was purified by high-performance column chromatography (ethyl acetate:petroleum ether = 10 / 1) on silica gel to obtain the white solid product 1-9 (270 mg, yield 46%). LCMS (m / z): [M+H] + C 33 H 39Calculated value of F4N2O5, 619.3; Measured value, 619.2. Step 10: Synthesis of Example 1

[0160] 30% KOH solution (0.8 mL) was added to a solution of 1-9 (270 mg, 0.44 mmol) in EtOH (8 mL), and the mixture was stirred at 80 °C for 4 h. The reaction mixture was adjusted to pH = 6 and concentrated under vacuum to obtain a 120 mL solution. The solution was purified by preparative HPLC. The preparative solution was concentrated to remove CH3CN, extracted with ethyl acetate (20 mL × 5), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain a white solid, Example 1 (32 mg, yield 15%). LCMS (m / z): [M+H] + C 27 H 29 Calculated value of F4N2O3, 505.21; Measured value, 505.29; 1H NMR (400 MHz, CD3OD): δ 8.34 (d, J = 7.8 Hz, 1H), 8.26 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.17 (br, 1H), 7.04 (br, 1H), 6.77 (s, 1H), 6.46 (d, J = 3.2 Hz, 1H), 4.56 (s, 1H), 4.19 (d, J = 12.0 Hz, 1H), 4.05 - 3.87 (m, 1H), 3.79 (s, 3H), 3.50 - 3.39 (m, 1H), 3.27 - 3.05 (m, 1H), 2.80 - 2.55 (m, 2H), 2.52 (s, 3H), 2.42 (t, J = 12.4 Hz, 2H), 2.25 - 1.95 (m, 3H), 1.92 - 1.80 (m, 1H). Example 2

Chemical formula

[0161] Example 2 was prepared by referring to the method of Example 1, LCMS: m / z = 465.1 (M+1, ESI+); 11H NMR (400 MHz, MeOD) δ 8.31 (brs, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 3.1 Hz, 1H), 6.59 (s, 1H), 6.40 (brs, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.15 - 4.03 (m, 2H), 3.33 - 3.27 (m, 1H), 3.04 - 2.91 (m, 1H), 2.72 - 2.53 (m, 2H), 2.43 - 2.33 (m, 4H), 2.27 - 2.17 (m, 1H), 2.08 - 1.66 (m, 5H), 0.78 - 0.72 (m, 2H), 0.25 (brs, 1H), -0.00 (brs, 1H). Example 3

Chemical Structure

[0162] Example 3 was prepared by referring to the method of Example 1, LCMS: m / z = 469.30 (M + 1, ESI+); 1 1H NMR (400 MHz, CD3OD): δ 8.05 (d, J = 6.9 Hz, 1H), 7.94 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 6.78 (s, 1H), 6.40 (d, J = 3.1 Hz, 1H), 4.55 (d, J = 11.3 Hz, 1H), 4.30 (d, J = 12.4 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.79 (s, 3H), 3.54 - 3.42 (m, 1H), 3.32 - 3.24 (m, 1H), 2.80 - 2.65 (m, 2H), 2.56 (s, 3H), 2.52 (s, 3H), 2.50 - 2.40 (m, 2H), 2.26 - 2.12 (m, 1H), 2.11 - 2.00 (m, 2H), 1.96 - 1.85 (m, 1H). Biological Test Evaluation

[0163] Hereinafter, the present invention will be further described in conjunction with test examples, but these examples do not mean to limit the scope of the present invention.

[0164] Biological Experiment 1: TR-FRET Factor B Binding Assay Materials and related reagents 1. Recombinant human factor B catalyst polyamine (aa470-764, C-terminal his labeling, in-house produced) 2.5X Kinase Buffer A (Thermo Fisher, CAT#PV3189) 3.LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer, CAT#AD0401) 4. Probe (TRFRET_tool 2, described in WO2015 / 00916) [ka] 5. Dimethyl sulfoxide (Thermo Fisher Scientific) 6. Compound-DMSO 10 mM reserve 7. Victor Nivo Multimodal Reader (PerkinElmer) 8. OptiPlate-384, white opaque 384-well microplate (PerkinElmer, CAT#6007290) Experimental method:

[0165] The factor B binding affinity of each test compound was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. 10 nM recombinant his-labeled factor B catalytic domain, different concentrations of inhibitors, 4 nM LANCE Eu-W1024 anti-6xHis antibody, and 100 nM TR-FRET_tool2 tracer were incubated in 1X kinase buffer A for 1 hour. 5 μL of the test compound was measured in a 15 μL reaction volume, and 5 μL of the factor B / antibody mixture and 5 μL of the tracer were added to a white opaque 384-well plate. TR-FRET signals were read using a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. The TR-FRET signals of different concentrations of the compound were measured, and the relationship between the relative fluorescence emission ratio (665 nm / 615 nm) and the inhibitor was plotted. ICs were calculated based on the compound and emission ratio using a 4-parameter dose-response inhibition curve of a variable gradient model in GraphPad Prism. 50By estimating this, the binding affinity of each compound was determined.

[0166] The above assay was used to measure the binding affinity of the compound of the present invention to the recombinant factor B catalyst domain, and IC 50 The values ​​(nM) are shown in Table 1 below.

[0167] [Table 21]

[0168] Biological example 2: Target residence time of factor B inhibitors measured by surface plasmon resonance (SPR) Materials and related reagents 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal his labeling, in-house produced) 2.PBS-P+Buffer 10X (Cytiva, CAT number 28995084) 3. S-series sensor chip NTA (Cytiva, CAT#BR100532) 4. Amine coupling kit (Cytiva, CAT#BR100050) 5. Dimethyl sulfoxide (Millipore Sigma, CAT#34869-1L) 6. Greiner 96-well plate, polyacrylic (Sigma Aldrich, CAT#M7310-100EA) 7. Microplate foil, 96 orifice (Cytiva, CAT#28975816) 8. Biacore 8k (Cytiva) Experimental method:

[0169] Before docking to the Cytiva NTA chip, the Biacore 8k instrument was pretreated using 1X PBS-P+ buffer. Recombinant human factor B catalytic domain was immobilized on the NTA chip using 1X PBS-P+ buffer [20 mM phosphate buffer, 2.7 mM KCl, 137 mM NaCl, and 0.05% (v / v) Tween-20], reaching a level of approximately 5000 resonance units (RU). The protein ligand was further cross-linked to the sensor chip surface using an amine coupling kit. Immobilization and binding experiments were performed at room temperature.

[0170] After exchanging the buffer to 1X PBS-P+ buffer containing 2% (v / v) dimethyl sulfoxide, a pre-run was performed at a flow rate of 30 μl / min for at least 30 minutes to obtain a stable surface. The kinetic constants of the compound were determined by a single-cycle kinetics of 6 consecutive injections (or multi-cycle kinetics of 8 consecutive injections), and depending on the effectiveness, the concentration of the compound was increased within the range of 0.8 - 200 nM, 12.5 - 400 nM, 4.1 - 1000 nM, or 41 - 10000 nM. The single-cycle kinetic experiment was performed with an association time of 60 s and a dissociation time of 300 s for each concentration (or a dissociation time of 120 s for the multi-cycle kinetic experiment). The flow rate was 30 μl / min. A blank test was performed under the same conditions before injecting the compound.

[0171] The SPR sensorgram was analyzed by the double-reference method using Biacore Insight Evaluation software. The obtained curve was fitted using a 1:1 binding model. The compound that binds based on the induced fitting model was fitted with a two-state reaction model. The repeated kinetic constants (k on , k off , K D ) were averaged. The binding half-life (t1 / 2) of the 1:1 binding model and the two-state reaction model was calculated from the dissociation constant koff, and the formula is t 1 / 2 = ln2 / k off . The target residence time (t 1 / 2 ) and the residence time (1 / k off ) are shown in Table 2 below.

[0172] [Table 22] Conclusion: The compounds of the embodiments of the present invention possess remarkable binding affinity.

[0173] Biological example 3: Pharmacokinetic studies of rat eyes Three-month-old brown Norwegian rats were orally administered the compound of the example, in a suspension of 2 equivalents in 1N HCl + 30% PEG300 + 50% (20% Cremophor EL aqueous solution). Ocular tissue and plasma were collected from both eyes of the rats at 0.25, 0.5, 1, 6, and 24 hours post-administration. The collected ocular tissue consisted of the retina and posterior ocular cup (RPE / choroid and posterior sclera). The tissue was diluted with phosphate-buffered saline containing 10% acetonitrile, homogenated, and centrifuged before analysis. At each time point, the concentrations of the test substance in plasma and ocular homogenate supernatant in four separate retinal, four separate posterior ocular cup, and two separate plasma samples were measured by HPLC-MS / MS. Chromatography was performed using a Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds-Ford, PA), with a gradient elution method using water containing 0.025% formic acid-1M NH4OAc and acetonitrile. Mass spectrometry in positive electrospray ionization was performed to quantify the mass transition with [M+H]+ as a precursor using an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA). Relevant pharmacokinetic parameters were estimated using the non-atrioventricular method with WinNonlin (Enterprise, version 8.2). The results of the rat PK studies are shown in Table 3 below.

[0174] [Table 23] Conclusion: The compounds of the present invention exhibited better exposure in the retina.

[0175] Biological example 4: In vivo evaluation of mouse AP complement function activity Twenty hours before the end of the study, female C57BL / 6 mice were force-administered the compound formulation from Example 3 (20 mg / kg, 0.5% (w / v) methylcellulose, 0.5% (v / v) Zween 80). To activate the complement pathway, lipopolysaccharide (LPS) (2.5 mg / kg) from Salmonella typhi (Sigma) was intraperitoneally injected 7.5 hours before the end of the study. Control mice were intraperitoneally injected with physiological saline and administered excipients by force-administering. Plasma samples were collected from the mice at the end of the study. AP complement activation was evaluated by measuring plasma C3 cleavage products C3b / iC3b / C3c using an ELISA method with rat anti-mouse C3b / iC3b / C3c monoclonal antibody (clone 2 / 11, Hycult Biotechnology, 0.1 ug / well) and goat anti-rat IgG (total molecule)-peroxidase (Sigma) (TBS / 0.05% Tween20) diluted in TBST. Plasma C3b / iC3b / C3c levels are shown in Table 4.

[0176] [Table 24] Conclusion: The results showed that the compound in Example 3 exhibited sustained inhibitory activity in mouse in vivo PD measurement at 20 hours (*: p<0.05, **: p<0.01, ***: p<0.001, ns: no significant difference).

[0177] Biological example 5: In vitro evaluation of rat plasma PD inhibition Male Sprague-Dawley rats (n=3) were orally administered a carrier (0.5% (w / v) methylcellulose, 0.5% (v / v) Zween 80), compound Iptacopan, or a formulation of the example compound (in 0.5% (w / v) methylcellulose, 0.5% (v / v) Zween 80) at a dose of 2 mg / kg. Rat serum samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration and stored at -80°C. 96-well microtiter plates (Black Maxisorp, Invitrogen) coated with 3 μg / ml LPS from Salmonella enteritis strains were used for overnight substituted complement pathway (AP) ELISA (TLRGRADE, Enzo Life Sciences, in PBS / 10 mM MgCl2) at 4°C. The coated plates were washed with GVB buffer containing 5 mM MgCl2 and 10 mM EGTA (complement technology) (blocking the classical and lectin pathways). The collected serum samples were diluted by adding an equal volume of GVB buffer containing 10 mM MgCl2 and 20 mM EGTA. For the negative control, serum was diluted with GVB buffer containing 40 mM EDTA (blocking all complement pathways). Aliquots (50 μL) of 50% serum samples were placed in LPS-coated wells. The reaction plates were left at 37°C for 20 minutes (rat serum). The plates were inverted into the wells and blocking buffer (50 μL, SuperBlock® T20 (TBS) blocking buffer, Thermo#37536) was added. To detect rat MAC deposition on LPS, mAb 2A1 (HM3033-IA, Hycult Biotech, 0.1 ug / well) and goat anti-mouse IgG (Fc-specific)-peroxidase (Sigma, #A2554) were detected using an anti-rat C5b-9 neoepitope. Inhibition percentages for each well were generated using baseline (EDTA-treated serum) and maximum signal (EGTA-treated serum from carrier-treated rats).

[0178] Rats (3 rats / group) were orally administered either compound Iptacopan or Example 3 (2 mg / kg), and the AP deposition inhibitory activity in 50% compound serum was evaluated at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Each data point in Figure 37 represents the mean value of AP activity in rat serum. The data results showed that the compound of Example 3 exhibited a sustained inhibitory effect in rat ex vivo PD measurement at 24 hours.

[0179] [Table 25] Research on salts and crystalline forms 1.1 Experimental Instruments 1.1.1 Parameters of Physicochemical Detectors

[0180] [Table 26] 1.2 Instruments and Liquid-Phase Analysis Conditions 1.2.1 Instruments and Equipment

[0181] [Table 27]

[0182] [Table 28] 1.2.2 Chromatography Conditions Chromatography column: Aglient Bonus, 3.5 μm, 4.6 x 150 mm Flow rate: 1mL / min Column temperature: 40 o C Detection wavelength: 254nm Sample input volume: 5.0 μL Execution time: 15 min Diluent: Methanol-water (50:50, v:v) Mobile phase: A: Water (0.1% phosphate); B: Acetonitrile

[0183] [Table 29] 2. Screening for compound salt-type crystal forms 2.1 Experimental Objectives Different counterions were selected, and compound salts were formed using appropriate crystallization methods. 2.2. Experimental Steps 2.2.1 Instruments and Equipment

[0184] [Table 30] 2.2.2 Operating Procedure and Results 1) Natural evaporation method using methanol, tetrahydrofuran, acetone, ethyl acetate, or toluene

[0185] Salt type screening experiments were conducted using the solvent evaporation method. Approximately 10 mg of the free base from Example 3 was weighed and placed in a 2 mL glass bottle. 100 μL of organic solvent was added to each bottle to dissolve the base. A methanol solution of the counterionic acid was then added dropwise in a 1:1 molar ratio to each bottle, and the resulting clear solution was evaporated under room temperature conditions. The obtained solids were first evaluated by PLM. If no birefringence occurred, the solvent was added and the mixture was beaten. If birefringence occurred, evaluation was performed by XRPD. Compounds with high crystallinity were selected and evaluated by DSC and TGA. The phenomena observed during the evaporation process and the evaluation results are shown in the table below.

[0186] [Table 31] 2) Salt formation by reaction crystallization method

[0187] Approximately 10 mg of the free base compound from Example 3 was weighed and placed in a 2 mL glass bottle. 100 μL of organic solvent was added to each bottle to dissolve the compound. 22 μL of ethyl acetate solution was then slowly added dropwise in a 1:1 molar ratio to each bottle, and the mixture was stirred. The resulting clear solution was stirred at room temperature for approximately 24 hours. The resulting solid was vacuum-dried at 40°C, and evaluated by XRPD, DSC, and TGA. The phenomena observed and evaluation results during this process are shown in the table below.

[0188] [Table 32]

[0189] Salt type screening was performed using evaporation and reaction crystallization methods, yielding a total of nine types of salts: crystalline hydrobromide, hydrochloride, methanesulfonate, p-toluenesulfonate, fumarate, adipine, oxalate, hippurate, and malonate. 3) Production of phosphate crystalline form A

[0190] Approximately 10 mg of the free base compound from Example 3 was weighed, 200 μL of ethyl acetate was added, and a 1:1 methanol solution of phosphoric acid was slowly added dropwise. An off-white solid gradually precipitated, and after stirring at room temperature for 1 day, it was collected by centrifugation and vacuum-dried at 40°C to obtain phosphate crystal form A. 4) Screening of hydrochloride-stabilized crystalline forms

[0191] Approximately 20 mg of the hydrochloride crystalline form A of the free base compound from Example 3 was weighed, 100 μL of solvent was added, and the sample was beaten at room temperature for two weeks. The sample was then centrifuged, and the resulting solid was vacuum-dried overnight at 40°C. XRPD evaluation was performed, and if the crystalline form changed, DSC and TGA evaluation were performed. The phenomena and evaluation results are as follows.

[0192] [Table 33]

[0193] In a screening experiment for the stabilized crystalline form of hydrochloride, hydrochloride crystalline form C, hydrochloride crystalline form D, hydrochloride crystalline form E, hydrochloride crystalline form F, and hydrochloride crystalline form G were produced. 5) Production of hydrochloride crystalline form H

[0194] 52.06 mg of Example 3 was weighed and placed in a 4 mL glass bottle. 400 μL of 2-Me-THF was added, and the mixture was magnetically stirred until completely dissolved. H2O-HCl system (6M) was slowly added dropwise at a salt formation ratio of 1:1.3, and an off-white solid precipitated, yielding the hydrochloride crystalline form H. 6) Preparation of hydrochloride crystalline form I

[0195] Approximately 20 mg of Example 3 was weighed, dissolved in 137 μL of ethyl acetate, then 40 μL of acetone-water (88:12;v:v) was added to obtain a clear solution. The solution was magnetically stirred at room temperature, and a 1 M EA-HCl solution was slowly added dropwise in a 1:1 salt formation ratio. An off-white solid gradually precipitated, and after stirring for 3 hours, the solid was collected by centrifugation. The obtained solid was vacuum-dried under conditions of 40°C, and XRPD evaluation was performed to obtain hydrochloride crystalline form I. 7) Production of hydrochloride crystalline form J

[0196] Approximately 20 mg of Example 3 was weighed, dissolved in 137 μL of ethyl acetate, then 40 μL of water was added to obtain a clear solution, which was magnetically stirred at room temperature. A 1 M EA-HCl solution was slowly added dropwise in a 1:1 salt formation ratio, and an off-white solid gradually precipitated. After stirring for 3 hours, the solid was collected by centrifugation, and the obtained solid was vacuum-dried under conditions of 40°C. XRPD evaluation was performed to obtain the hydrochloride crystalline form J. 3. Hygroscopic experiment 3.1 Experimental Objectives

[0197] This study investigates the hygroscopicity of different salts of compounds under different relative humidity conditions, providing a basis for screening and preserving compound salts. 3.2 Experimental Plan

[0198] Compound salts were placed in saturated water vapor at different relative humidity levels, and the compounds and water vapor were dynamically equilibrated. The percentage of weight increase due to moisture absorption of the compounds after equilibration was then calculated. 3.3 Experimental Results 3.3.1 Hygroscopicity of the hydrochloride crystalline form of the compound of Example 3

[0199] Hygroscopicity of hydrochloride crystalline form A: Under dynamic hygroscopic conditions, hydrochloride crystalline form A of the compound in Example 3 exhibited slight hygroscopicity, and its crystalline form did not change after the hygroscopicity measurement. 4. Solid Stability Experiment (Screening) 4.1 Polishing Experiment

[0200] Crystalline form I of the hydrochloride salt was polished in a mortar for 1 minute and 3 minutes, and the crystalline form did not change, indicating that crystalline form I has good stability under polishing conditions. The XRPD evaluation of crystalline form I after polishing is shown in Figure 40. 5. Stability experiment

[0201] When hydrochloride crystal form I samples were left for 30 days under high temperatures of 60°C and 40°C, high humidity of 92.5% and 75%, and light irradiation conditions, there was no change in crystal form and no increase in related substances. This demonstrated that crystal form I has good stability and is suitable for pharmaceutical development.

[0202] [Table 34]

Claims

1. The acidic salt of the compound shown in general formula (I), the structure of the compound is as follows: 【Chemistry 1】 Here, R １ C １ -C ３ Alkyl alkyl group or C ３ -C ６ Selected from cycloalkyl groups, R ２ is selected from a C １ -C ３ alkyl group, a C １ -C ３ alkoxy group or a C ３ -C ６ cycloalkyl group, R ３ is -COOH, -C(O)NHSO ２ CH ３ or -S(O)NHCH ３ Selected from, R ４ is hydrogen, halogen, C １ -C ３ Alkyl alkyl group or C １ -C ３ Selected from haloalkyl groups, R ５ and R ６ Each is independently selected from halogens. As a condition, the compound shown in general formula (I) is 【Chemistry 2】 Instead, The acid is either an inorganic acid or an organic acid, the inorganic acid being selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid, and the organic acid being 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, di Acidic salts of compounds selected from benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid.

2. R １ C １ -C ３ Selected from alkyl groups, R ２ C １ -C ３ Selected from an alkoxy group or a cyclopropyl group, R ３ It is selected from -COOH, R ４ is hydrogen, C １ -C ３ Alkyl alkyl group or C １ -C ３ Selected from haloalkyl groups, R ５ and R ６ The acidic salt of the compound according to claim 1, characterized in that each of the elements is independently selected from hydrogen or halogen.

3. The above general formula (I) is, 【Transformation 3】 Selected from the following compounds, Herein, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, and the organic acid is selected from 1,5-naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, isethionic acid, acetic acid, maleic acid, fumaric acid, oxalic acid, malonic acid, tartaric acid, malic acid, adipic acid, hippuric acid, succinic acid, or camphanic acid, preferably the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, or hydrochloric acid, and more preferably the acid is hydrochloric acid, characterized in that the acidic salt of the compound according to claim 1.

4. The acidic salt of the compound according to claim 2, wherein the compound is (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-3-methylbenzoic acid, where the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, and the organic acid is selected from 1,5-naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, isethionic acid, acetic acid, maleic acid, fumaric acid, oxalic acid, malonic acid, tartaric acid, malic acid, adipic acid, hippuric acid, succinic acid or camphanic acid, preferably the acid is selected from p-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid, and more preferably the acid is hydrochloric acid.

5. The acidic salt of the compound according to any one of claims 1 to 4, characterized in that the number of acids is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

6. The acidic salt of the compound according to any one of claims 1 to 5 is characterized in that the acidic salt is a hydrate or an anhydrous, and when the acidic salt is a hydrate, the number of water molecules is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

7. The acidic salt of the compound according to claim 4 is characterized in that the acidic salt of (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)-7-azaspiro[3.5]nonane-6-yl)-3-methylbenzoic acid is in crystalline form.

8. The acidic salt crystal form is selected from hydrobromide crystal form A, hydrochloride crystal form A-J, methanesulfonate crystal form A, p-toluenesulfonate crystal form A, hippurate crystal form A, malonate crystal form A, oxalate crystal form A, adipine crystal form A, succinate crystal form A, phosphate crystal form A, or fumarate crystal form A. For hydrobromide crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, 31.0, and 35.5, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For hydrochloride crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.2, 15.7, 11.4, 16.8, 20.0, 13.7, 19.6, 20.3, and 21.7, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For hydrochloride crystal form B, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, 17.7, and 21.5, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For hydrochloride crystal form C, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.2, 16.0, 14.8, 15.2, 8.8, and 18.4, and preferably includes characteristic peaks at two, four, or six of these locations, which are arbitrarily selected. For hydrochloride crystal form D, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 23.3, 16.1, 13.1, 8.2, 15.9, 24.7, and 27.1, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For hydrochloride crystal form E, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 23.0, 15.3, 9.8, 11.2, 12.7, 17.4, 20.6, and 25.0, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For hydrochloride crystal form F, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.3, 19.4, 8.4, 10.3, 13.2, 17.5, and 18.9, preferably including characteristic peaks at two, four, or six of these locations, which are arbitrarily selected. For hydrochloride crystal form G, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.0, 9.9, 13.0, 13.9, 16.0, 16.6, and 22.9, and preferably includes characteristic peaks at two or four arbitrarily selected locations among them. For hydrochloride crystalline form H, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 6.8, 10.0, 11.4, 13.6, 20.0, 21.5, 26.0, and 31.9, preferably including characteristic peaks at two, four, or six of these locations, which are arbitrarily selected. For hydrochloride crystal form I, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 9.5, 19.6, 13.8, 23.0, 24.2, 16.8, 18.0, and 21.2, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For hydrochloride crystal form J, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.5, 8.8, 9.5, 13.8, 19.6, 21.2, 23.0, and 26.5, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For methanesulfonate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 8.4, 20.0, 13.7, 14.5, 23.6, 20.5, and 23.8, preferably including characteristic peaks at two, four, or six of these locations, which are selected arbitrarily. For p-toluenesulfonate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, 19.5, and 23.3, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For hippurate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 8.1, 14.2, 21.6, 10.5, 20.5, and 25.8, preferably including characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For malonate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 11.7, 14.3, 18.1, and 20.4, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For oxalate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 4.8, 9.6, 10.1, 14.4, 19.2, 18.6, 22.1, 22.8, and 24.1, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For adipinate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, 14.2, 14.9, 20.5, 21.2, 21.5, and 23.2, and preferably includes characteristic peaks at two, four, six, or eight of these locations, which are arbitrarily selected. For succinate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 8.1, 11.8, 18.2, and 25.9, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. For phosphate crystal form A, its X-ray powder diffraction pattern includes diffraction peaks at one or more locations among those where 2θ (±0.2°) is 5.5, 8.6, 7.5, 12.9, 18.3, 10.6, 12.4, 17.3, and 25.3, preferably including characteristic peaks at two, four, six, or eight of these locations, which are selected arbitrarily. The acidic salt of the compound according to claim 7, wherein the X-ray powder diffraction pattern of the fumarate crystal form A includes diffraction peaks at one or more positions among those where 2θ (±0.2°) is 7.5, 10.7, 7.9, 14.4, 15.0, 8.3, 10.0, and 20.5, and preferably includes characteristic peaks at two, four, six, or eight of these positions, which are arbitrarily selected.

9. For hydrobromide crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 8.8, 15.3, 17.5, and 22.8, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 22.0 and 26.4, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 25.4 and 31.0, more preferably including a characteristic peak at position 2θ (±0.2°) is 35.5, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 1, its DSC pattern is substantially as shown in Figure 2, and even more preferably, the X-ray powder diffraction pattern of hydrobromide crystal form A is 2θ (±0.2°) ８．８、１７．５、１５．３、２２．８、 Alternatively, 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, Alternatively, diffraction peaks are located at 8.8, 17.5, 15.3, 22.8, 26.4, 22.0, 25.4, 31.0, and 35.

5. For hydrochloride crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 9.2, 11.4, 15.7, and 20.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 13.7 and 16.8, and even more preferably including 2θ (±0.2°) at 19.6 and 2 The X-ray powder diffraction pattern further includes one or more characteristic peaks at the position 0.3, more preferably further includes characteristic peaks at the positions where 2θ (±0.2°) is 16.5 and 21.7, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 3, the DSC pattern is substantially as shown in Figure 4, the TGA pattern is substantially as shown in Figure 5, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form A is 2θ (±0.2°) ９．２、１５．７、１１．４、１６．８、２０．０、１３．７、１６．５、２０．３、 Alternatively, 9.2, 15.7, 11.4, 16.8, 21.7, 13.7, 19.6, 20.3, Alternatively, 21.7, 15.7, 11.4, 16.5, 20.0, 13.7, 19.6, 20.3, Alternatively, 9.2, 15.7, 21.7, 16.8, 20.0, 13.7, 19.6, 20.3, Alternatively, diffraction peaks are located at 9.2, 15.7, 11.4, 16.8, 20.0, 13.7, 19.6, 20.3, and 21.

7. For hydrochloride crystal form B, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.2, 7.8, 14.0, and 15.9, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 10.5 and 20.0, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 17.7 and 21.5, most preferably the X-ray powder diffraction pattern is substantially as shown in 6, its DSC pattern is substantially as shown in Figure 7, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form B is 2θ (±0.2°) ７．２、１５．９、７．８、１４．０、 Alternatively, 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, Alternatively, diffraction peaks are located at 7.2, 15.9, 7.8, 14.0, 20.0, 10.5, 17.7, and 21.

5. For hydrochloride crystal form C, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 9.2, 14.8, 15.2, and 16.0, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 8.8 and 18.4, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 8, its DSC pattern is substantially as shown in Figure 9, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form C is 2θ (±0.2°) ９．２、１６．０、１４．８、１５．２、 Alternatively, diffraction peaks are located at 9.2, 16.0, 14.8, 15.2, 8.8, and 18.

4. For hydrochloride crystal form D, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 8.2, 13.1, 23.3, and 16.1, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 15.9 and 24.7, and even more preferably including 2θ (±0.2°) It further includes a characteristic peak at a position where is 27.1, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 10, its DSC pattern is substantially as shown in Figure 11, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form D is 2θ (±0.2°) ８．２、１３．１、１５．９、１６．１、２３．３、２４．７、 Alternatively, diffraction peaks are located at 23.3, 16.1, 13.1, 8.2, 15.9, 24.7, and 27.

1. For hydrochloride crystal form E, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 9.8, 11.2, 23.0, and 15.3, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 12.7 and 17.4, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 20.6 and 25.0, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 12, its DSC pattern is substantially as shown in Figure 13, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form E is 2θ (±0.2°) ２３．０、１５．３、９．８、１１．２、１２．７、１７．４、 Alternatively, diffraction peaks are located at 23.0, 15.3, 9.8, 11.2, 12.7, 17.4, 20.6, and 25.

0. For hydrochloride crystalline form F, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 8.4, 9.3, 10.3, and 19.4, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 13.2 and 17.5, even more preferably including one or more characteristic peaks at position where 2θ (±0.2°) is 18.9, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 14, its DSC pattern is substantially as shown in Figure 15, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystalline form F is 2θ (±0.2°) ９．３、１９．４、８．４、１０．３、１３．２、１７．５、 Alternatively, diffraction peaks are located at 9.3, 19.4, 8.4, 10.3, 13.2, 17.5, and 18.

9. For hydrochloride crystalline form G, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 8.0 and 9.9, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 13.0 and 13.9, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 16.0 and 16.6, even more preferably including a characteristic peak at position where 2θ (±0.2°) is 22.9, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 16, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystalline form G is 2θ (±0.2°) ８．０、９．９、１３．０、１３．９、１６．０、１６．６、 Alternatively, diffraction peaks are located at 8.0, 9.9, 13.0, 13.9, 16.0, 16.6, and 22.

9. For hydrochloride crystal form H, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 6.8, 10.0, 11.4, and 13.6, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 20.0 and 21.5, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 26.0 and 31.9, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 17, its DSC pattern is substantially as shown in Figure 18, and even more preferably, the X-ray powder diffraction pattern of hydrochloride crystal form G is 2θ (±0.2°) ６．８、１０．０、１１．４、１３．６、２０．０、２１．５、 Alternatively, diffraction peaks are located at 6.8, 10.0, 11.4, 13.6, 20.0, 21.5, 26.0, and 31.

9. For hydrochloride crystal form I, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 9.5, 13.8, 19.6, and 23.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 10.4 and 24.2, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 16.8 and 18.0, more preferably further including characteristic peaks at positions where 2θ (±0.2°) is 8.8 and 21.2, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form I has 2θ (±0.2°) ９．５、８．８、１３．８、２１．２、１０．４、１６．８、１８．０、 Alternatively, 9.5, 19.6, 13.8, 23.0, 24.2, 10.4, 16.8, 18.0, Alternatively, 8.8, 19.6, 13.8, 23.0, 24.2, 10.4, 16.8, 21.2, Alternatively, diffraction peaks are located at 9.5, 8.8, 21.2, 24.2, 10.4, 16.8, and 18.

0. Most preferably, the X-ray powder diffraction pattern is substantially as shown in Figure 19, the DSC pattern is substantially as shown in Figure 20, and the TGA pattern is substantially as shown in Figure 38. For hydrochloride crystal form J, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 9.5, 13.8, 19.6, and 23.0, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and further preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 21.2 and 21.7, and even more preferably including 2θ (±0.2°) at 7.5 and further includes one or more characteristic peaks at the position 26.5, more preferably further includes one or more characteristic peaks at the positions 2θ (±0.2°) 8.8, 9.5, 18.0 and 18.1, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 21, the DSC pattern is substantially as shown in Figure 22, and even more preferably the X-ray powder diffraction pattern of hydrochloride crystal form J is 2θ (±0.2°) ９．５、１９．６、１３．８、２３．０、２１．２、２１．７、２６．５、 Alternatively, diffraction peaks are located at 9.5, 19.6, 13.8, 23.0, 21.2, 21.7, 26.5, 7.5, 8.8, 9.5, and 18.

1. For methanesulfonate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 8.4 and 20.0, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 13.7 and 14.5, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 20.5 and 23.6, even more preferably including a characteristic peak at position where 2θ (±0.2°) is 23.8, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 23, its DSC pattern is substantially as shown in Figure 24, and even more preferably the X-ray powder diffraction pattern of methanesulfonate crystal form A is 2θ (±0.2°) ８．４、２０．０、１３．７、１４．５、２３．６、 Alternatively, diffraction peaks are located at 8.4, 20.0, 13.7, 14.5, 23.6, 20.5, and 23.

8. For p-toluenesulfonate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.2, 8.6, 10.9, and 12.8, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 16.4 and 17.7, and even more preferably including 2θ (±0.2°) at 10.6 and The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A further includes one or more characteristic peaks at the position where θ (±0.2°) is 14.0, 18.2, 19.5 and 23.3, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 25, the DSC pattern is substantially as shown in Figure 26, and even more preferably the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A is 2θ (±0.2°) ７．２、１２．８、８．６、１０．９、１６．４、１７．７、 Alternatively, 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, Alternatively, diffraction peaks are located at 7.2, 12.8, 8.6, 10.9, 16.4, 17.7, 10.6, 13.4, 14.0, 18.2, 19.5, and 23.

3. For hippurate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.4, 8.1, 10.0, and 14.2, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 10.5 and 21.6, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 20.5 and 25.8, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 27, and even more preferably the X-ray powder diffraction pattern of hippurate crystal form A is 2θ (±0.2°) ７．４、１０．０、８．１、１４．２、２１．６、１０．５、２０．５、 Alternatively, diffraction peaks are located at 7.4, 10.0, 8.1, 14.2, 21.6, 10.5, 20.5, and 25.

8. For malonate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 4.8, 7.4, 9.5, and 19.1, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 12.3 and 23.1, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 11.7 and 14.3, more preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 18.1 and 20.4, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 28, and even more preferably the X-ray powder diffraction pattern of malonate crystal form A is 2θ (±0.2°) ４．８、１９．１、７．４、９．５、１２．３、２３．１、１１．７、１４．３、 Alternatively, diffraction peaks are located at 4.8, 19.1, 7.4, 9.5, 12.3, 23.1, 11.7, 14.3, 18.1, and 20.

4. For oxalate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 4.8, 9.6, 10.1, and 14.4, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 18.6 and 19.2, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 22.1 and 22.8, more preferably including a characteristic peak at position where 2θ (±0.2°) is 24.1, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 29, its DSC pattern is substantially as shown in Figure 30, and even more preferably the X-ray powder diffraction pattern of oxalate crystal form A is 2θ (±0.2°) ４．８、９．６、１０．１、１４．４、１９．２、１８．６、 Alternatively, diffraction peaks are located at 4.8, 9.6, 10.1, 14.4, 19.2, 18.6, 22.1, 22.8, and 24.

1. For adipinate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.4, 7.7, 10.0, and 12.3, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, and preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 19.5 and 21.7, and even more preferably including 2θ (±0.2°) at 1.8 and 25. It further includes one or more characteristic peaks at position 8, more preferably one or more characteristic peaks at positions where 2θ (±0.2°) is 14.2, 14.9, 20.5, 21.2, 21.5 and 23.2, most preferably its X-ray powder diffraction pattern is substantially as shown in Figure 31, its DSC pattern is substantially as shown in Figure 32, and even more preferably the X-ray powder diffraction pattern of adipinate crystal form A is such that 2θ (±0.2°) ７．４、１０．０、７．７、１２．３、１９．５、２１．７、 Alternatively, 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, Alternatively, diffraction peaks are located at 7.4, 10.0, 7.7, 12.3, 19.5, 21.7, 25.8, 1.8, 14.2, 14.9, 20.5, 21.2, 21.5, and 23.

2. For succinate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.4, 7.8, 9.5, and 10.0, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 19.1 and 20.5, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 8.1 and 11.8, more preferably including characteristic peaks at positions where 2θ (±0.2°) is 18.2 and 25.9, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 33, and even more preferably the X-ray powder diffraction pattern of succinate crystal form A is 2θ (±0.2°) ７．４、１０．０、７．８、９．５、１９．１、２０．５、８．１、１１．８、 Alternatively, diffraction peaks are located at 7.4, 10.0, 7.8, 9.5, 19.1, 20.5, 8.1, 11.8, 18.2, and 25.

9. For phosphate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 5.5, 8.6, 7.5, and 12.9, preferably including 2 to 4 of these positions, more preferably including 3 to 4 positions, most preferably including 4 positions, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 10.6 and 18.3, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 12.4 and 17.3, more preferably including a characteristic peak at position where 2θ (±0.2°) is 25.3, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 34, its DSC pattern is substantially as shown in Figure 35, and even more preferably the X-ray powder diffraction pattern of phosphate crystal form A is 2θ (±0.2°) ５．５、８．６、７．５、１２．９、１８．３、１０．６、 Alternatively, diffraction peaks are located at 5.5, 8.6, 7.5, 12.9, 18.3, 10.6, 12.4, 17.3, and 25.

3. For fumarate crystal form A, its X-ray powder diffraction pattern has one or more characteristic peaks at positions where 2θ (±0.2°) is 7.5, 10.7, 7.9, and 14.4, preferably including 2 to 4 of these, more preferably including 3 to 4, most preferably including 4, preferably further including one or more characteristic peaks at positions where 2θ (±0.2°) is 8.3 and 15.0, even more preferably including one or more characteristic peaks at positions where 2θ (±0.2°) is 10.0 and 20.5, most preferably the X-ray powder diffraction pattern is substantially as shown in Figure 36, and even more preferably the X-ray powder diffraction pattern of fumarate crystal form A is 2θ (±0.2°) ７．５、１０．７、７．９、１４．４、１５．０、８．３、 Alternatively, the acidic salt of the compound according to claim 8, characterized in that it has diffraction peaks at positions of 7.5, 10.7, 7.9, 14.4, 15.0, 8.3, 10.0, and 20.

5.

10. A method for producing an acidic salt of a compound according to any one of claims 1 to 9, more specifically, Step 1) involves weighing an appropriate amount of free base and dissolving it in a good solvent, Step 2) involves weighing an appropriate amount of counterionic acid and dissolving it in an organic solvent, wherein the amount of counterionic acid is preferably 1 equivalent. Step 3) involves combining the two solutions mentioned above and stirring to precipitate them, or adding a poor solvent dropwise and then stirring to precipitate them. Step 4) involves rapidly centrifuging or letting it stand and blowing dry to obtain the target product, Here, The good solvent is selected from methanol, dichloromethane, 1,4-dioxane, acetone, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, N,N-dimethylacetamide, or N-methylpyrrolidone, and is preferably methanol or ethyl acetate. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide, preferably methanol, acetone, or ethyl acetate. The good solvent and the organic solution must be miscible at the time of use. The poor solvent is selected from heptane, water, and cyclohexane, and is preferably water or n-heptane. Or, Step 1) involves weighing an appropriate amount of free base and suspending it in a poor solvent, Step 2) involves weighing an appropriate amount of counterionic acid and dissolving it in an organic solvent, wherein the amount of counterionic acid is preferably 1 equivalent. Step 3) involves combining the two solutions mentioned above, stirring to dissolve them, and then continuing to stir to precipitate them, or adding a poor solvent dropwise and then stirring to precipitate them. Step 4) involves rapidly centrifuging or letting it stand and blowing dry to obtain the target product, The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide, preferably, the organic solvent is selected from methanol. The poor solvent is selected from heptane, acetonitrile, ethanol, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, or toluene, preferably methyl tert-butyl ether, and the poor solvent and the organic solution must be miscible at the time of use. The aforementioned counterionic acids include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, decanoic acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphanic acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, and galacid. A method comprising: a counterionic acid selected from tonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphanic acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid, preferably the counterionic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, or hydrochloric acid, and more preferably the counterionic acid is hydrochloric acid.

11. A pharmaceutical composition comprising a therapeutically effective amount of an acidic salt of a compound according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. Uses of an acidic salt of a compound according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 11, for producing a drug for treating a disease or disorder related to the activation of a complement alternative pathway.

13. The use according to claim 12, characterized in that the disease or disorder is a disease or disorder related to the activation of a complement alternative pathway, which is treated by regulating complement factor B.

14. The aforementioned disease or disorder is Age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal chorioretinitis, Vogt-Koyangi-Hara syndrome, mid-stage uveitis, birdshot chorioretinopathy, sympathetic ophthalmitis, ocular pemphigoid, pemphigus ophthalmos, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorder, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induction toxicity during IL-2 treatment, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia reperfusion conditions, myocardial infarction, balloon angioplasty, body Uses according to claim 12 or 13, selected from post-pump syndrome in external circulation or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative glomerulonephritis, hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibroblastic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity.

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